Table

1.4

A Developmental History of the New Morbidities in Child Health*

THE NEW
THE NEW MORBIDITIES THE “NEW” NEW MORBIDITIES (2010 to
MORBIDITIES (1982–
REVISITED (2001) Present)
1993)
Behavioral disorders/mental School problems Adverse childhood experiences (ACEs)
health
Family crisis Mood and anxiety disorders Toxic stress
Abuse & neglect Adolescent suicide/homicide Allostatic load
Long term disease Firearms in home Chronic illnesses of lifestyle (e.g., obesity, type-
2 diabetes, hypertension)
Substance abuse School violence Behavioral conditions (autism, ADHD,
depression, anxiety)
School difficulties Drug and alcohol abuse Food insecurity
HIV infection Oral health
Effects of media Witnessing community/interpersonal violence
Poverty Peer victimization/bullying
Homelessness Discrimination
Single-parent families
Effects of divorce
Struggle of working parents
Childcare quality & policy

Table 1.5

Classification of Adverse Childhood Experiences (ACEs)

CATEGORY ITEMS
Abuse & neglect Physical abuse*
Physical neglect*
Emotional abuse*
Emotional neglect*
Sexual abuse*
Family dysfunction Intimate partner violence*
Substance use in household*
Mental illness in household*
Parental separation or divorce*
Family member incarcerated*
Parental discord
Community-level adversity Witnessing community violence
Neighborhood safety
Lack of neighborhood connectedness/trust
Experiencing discrimination
Others Being bullied/peer victimization
Living in foster care
Social isolation
Low socioeconomic status/poverty

FIG. 1.3 New proposed biologic pathways that mediate effects of selected stressful or
adversarial poverty-associated risks to neurocognitive outcomes in children. Complex
interactions among key poverty-related risk factors, focusing on primary biologic
pathways related to malnutrition, infection and inflammation, and neuroendocrine
responses to stress. (From Jensen SKG, Berens AE, Nelson CA: Effects of poverty on
interacting biological systems underlying child development, Lancet 1:225–238, 2017,
Fig 1, p 228.)
Table 1.6
H e a t h C o n d i t i o n s i n C h i l d re n Wi t h S p e c i a l H e a l t h
C a r e N e e d s ( C S H C N )*

Attention-deficit/hyperactivity disorder
Depression

Anxiety
problems

Behavioral or conduct problems
Autism,
pervasive
developmental disorder,
autism spectrum disorder

Developmental delay
Intellectual
disability

Communication
disorder

Asthma

Diabetes

Epilepsy
or seizure disorder
Migraines
or frequent
headaches
Headinjury,traumatic
brain injury
Heartproblems,including
congenital
heart disease
Bloodproblems,including
anemia
or sickle cell
disease
Cystic fibrosis
Cerebral palsy
Muscular
dystrophy

Down syndrome
Arthritis
or joint problems
Allergies

Functional
Difficulties
in Children
With
Special H
e a l t h C a r e N e e d s ( C S H C N )*
Experiencing Difficulty With …

Breathing, or respiratory problem


Swallowing, digesting food, or metabolism
Blood circulation

Repeated or chronic
physical pain, including

headaches

Seeing, even
when
wearing glasses or contact
lenses
Hearing, even when using a hearing aid or other
devise
Taking care of self, such as eating, dressing, or bathing

Coordination or moving around
Using his/her hands
Learning, understanding, or paying attention
Speaking, communicating,
or being understood

Feeling anxious or depressed
Behavior problems
as acting out, fighting, bullying, or arguing
such
Making and keeping friends

Table 2.1
Child Health Disparities

FAMILY
HEALTH INDICATOR RACE/ETHNICITY RESIDENCE
INCOME
Child health status fair or poor Black & Hispanic > White & Asian Poor >
Not Poor
Children with special health care needs Black > White > Hispanic Poor >
(CSHCN) Not Poor
One or more chronic health conditions Black > White > Hispanic > Asian Poor >
Not Poor
Asthma Mainland Puerto Rican > Black > White & Poor > Urban > Rural
Mexican American Not Poor
Obesity Hispanic & Black > White and Asian Poor > Rural > Urban
Not Poor
Infant mortality Black > Hispanic > White Poor >
Not Poor
Low birthweight (<2,500 g.) Black > White, Hispanic, American Poor >
 Indian/Native Alaskan, Asian/Pacific Not Poor
Islander
Mainland Puerto Rican > Mexican
American
Preterm birth (<37 wk) Black > American Indian/Native Poor >
Alaskan, Hispanic, White, Not Poor
Asian/Pacific Islander
Mainland Puerto Rican > Mexican
American
Seizure disorder, epilepsy Black > White, Hispanic Poor >
Not Poor
Bone, joint, or muscle problem White > Black, Hispanic Poor >
Not Poor
Ever breastfed White, Hispanic, Asian > Black Not Poor Urban > Rural
> Poor
No physical activity in the past week Hispanic > Black, Asian > White Poor >
Poor > Not Poor Not Poor
Hearing problem Poor >
Not Poor
Vision problem Poor >
Not Poor
Oral health problems (including caries Hispanic > Black > White, Asian Poor > Rural > Urban
and untreated caries) Not Poor
Attention-deficit/hyperactivity disorder White, Black > Hispanic Poor > Rural > Urban
(ADHD) Not Poor
Have ADHD but not taking medication Hispanic, Black > White
Anxiety problems White > Black, Hispanic Poor >
Not Poor
Depression Poor > Rural > Urban
Not Poor
Behavior or conduct problem (ODD, Black > White, Hispanic Poor >
conduct disorder) Not Poor
Autism Spectrum Disorder White > Black > Hispanic Poor >
Not Poor
Learning disability Black > White, Hispanic Poor > Rural > Urban
Not Poor
Developmental delay Black > White > Hispanic, Asian Poor >
Not Poor
Risk of developmental delay, by Hispanic > Black & White Poor >
parental concern Not Poor
Speech or language problems Poor >
Not Poor
Adolescent suicide attempts (consider, Girls: Hispanic > Black & White
attempt, needed medical attention for an Boys:Hispanic & Black > White
attempt)
Adolescent suicide rate Girls: American Indian > White,
Asian/Pacific Islander, Hispanic, Black
Boys: American Indian & White >
Hispanic, Black, Asian/Pacific Islander
Child maltreatment (reported) Black, American Indian/Alaskan Native, Poor >
Multiracial > White, Hispanic, Asian, Not Poor
Pacific islander

AIDS (adolescents) Black > Hispanic > White

AIDS, Acquired immunodeficiency syndrome; ODD, oppositional defiant disorder.

Table 2.2
Child Healthcare Disparities

FAMILY
HEALTHCARE INDICATOR RACE/ETHNICITY RESIDENCE
INCOME
Did not receive any type of medical care in past 12 mo Hispanic, Black, Asian Poor > Not Rural > Urban
> White Poor
No well-child checkup or preventive visit in past 12 mo Hispanic > White & Poor > Not Rural > Urban
Black Poor
Delay in medical care Hispanic > Black > Poor > Not
White Poor
Unmet need in healthcare due to cost Black > Hispanic > Poor > Not
White > Asian Poor
No coordinated, comprehensive, or ongoing care in a Hispanic > Black & Poor > Not Rural > Urban
medical home Asian > White Poor
Problem accessing specialist care when needed Hispanic & Black > Poor > Not
White Poor
No preventative dental care visit in past 12 mo Hispanic & Asian > Poor > Not Rural > Urban
Black > White Poor
No vision screening in past 2 yr Hispanic & Asian > Poor > Not
Black & White Poor
Did not receive needed mental health treatment or Black & Hispanic > Poor > Not
counseling in past 12 mo White Poor
Not receiving a physician recommendation for HPV Black & Hispanic >
vaccination among 13-17-yr- old girls White
Immunization rates: adolescent HPV vaccine Girls: White >
Black & Hispanic
Boys: Black &
Hispanic > White
HPV, Human papillomavirus.

Table 2.3
New Social and Health Inequities in the United States

BLACK NATIVE
WHITE HISPANIC NON- AMERICAN
TOTAL NON- ASIAN* OR HISPANIC OR
HISPANIC LATINO † ALASKA
NATIVE
Wealth: median household assets $68,828 $110,500 $89,339 $7,683 $6,314 NR
(2011)
Poverty: proportion living below 14.8%; 10.1%; 12.0%; 23.6%; 26.2%; 28.3%;
poverty level, all ages (2014); 21.0% 12.0% 12.0% 32.0% 38.0% 35.0%
children <18 yr (2014)
Unemployment rate (2014) 6.2% 5.3% 5.0% 7.4% 11.3% 11.3%
Incarceration: male inmates per 982 610 185 836 3,611 1,573
100,000 (2008)
Proportion with no health insurance, 13.3% 13.3% 10.8% 25.5% 13.7% 28.3%
age <65 yr (2014)
Infant mortality per 1000 live births 6.0 5.1 4.1 5.0 10.8 7.6
(2013)
Self-assessed health status (age- 8.9% 8.3% 7.3% 12.2% 13.6% 14.1%
adjusted): proportion with fair or
poor health (2014)
Potential life lost: person-years per 6621.1 6659.4 2954.4 4676.8 9490.6 6954.0
100,000 before age 75 yr (2014)
Proportion reporting serious 3.4% 3.4% 3.5% 1.9% 4.5% 5.4%
psychological distress ‡ in past 30
days, age ≥18 yr, age-adjusted
(2013–14)
Life expectancy at birth (2014), yr 78.8 79.0 NR 81.8 75.6 NR
Diabetes-related mortality: age- 20.9 19.3 15.0 25.1 37.3 31.3
adjusted mortality per 100,000
(2014)
Mortality related to heart disease: 167.0 165.9 86.1 116.0 206.3 119.1
age-adjusted mortality per 100,000
(2014)

 HEALTH AND MULTISECTOR ACTIONS
• Ensuring food security for the family (or mother and child)
• Maternal education
• Safe drinking water and sanitation
• Handwashing with soap
• Reduced household air pollution
• Health education in schools
AGE-SPECIFIC ACTIONS
Prevention Treatment
ADOLESCENCE AND PRE-PREGNANCY
• Family planning
• Preconception care
PREGNANCY
• Appropriate care for normal and high-risk • Antenatal steroids for premature births
pregnancies (maternal tetanus vaccination) • Intermittent preventive treatment for malaria
CHILDBIRTH
• Maternal intrapartum care and monitoring
• Skilled delivery • Newborn resuscitation (e.g., Healthy Babies Breathe)
• Thermal care for all newborns • Premature: surfactant administration, continuous positive
• Clean cord and skin care airway pressure (CPAP), treatment of jaundice
• Early initiation and exclusive breastfeeding • Feeding support for small/preterm infants
within 1st hr
PRENATAL PERIOD
• Appropriate postnatal visits • Extra care for small and sick babies (kangaroo mother
care, treatment of infection, support for feeding,
management of respiratory complications)
• Antibiotics for newborns at risk and for treatment of
bacterial infections (PROM, sepsis, meningitis,
pneumonia)
INFANCY AND CHILDHOOD
• Exclusive breastfeeding for 6 mo and continued
breastfeeding up to at least 2 yr with appropriate
complementary feeding from 6 mo
• Monitoring and care for child growth and • Case management of severe acute malnutrition
development
• Routine immunization childhood diseases
• Micronutrient supplementation, including vitamin A
from 6 mo
• Prevention of childhood diseases • Management of childhood diseases
• Malaria (insecticide-treated bed nets) • Malaria (antimalarials)
• Pneumonia • Pneumonia (case management, antibiotics)
• Diarrhea (rotavirus immunization) • Diarrhea (ORS, zinc supplement, continued feeding)
• Meningitis (meningococcal/Hib/pneumococcal • Meningitis (case management, antibiotics)
vaccination) • Measles (vitamin A suppl)
• Measles (vaccination) • Comprehensive care of children exposed to or infected
• Prevention of mother-to-child HIV transmission with HIV (HAART)
HAART, Highly active antiretroviral therapy; ORS, oral rehydration solution (salts).
Adapted from Were W, Daelmans B, Bhutta ZA, et al. Children's health priorities and
interventions, BMJ 351:h4300, 2015.

Addressing the SDGs to improve health of mothers, children, and adolescents

takes a life course approach. Fig. 3.8 displays estimates of coverage for essential
interventions across the continuum of care, indicating the wide range of
coverage rates within countries that will need to be addressed if SDGs are to be
attained.

FIG. 3.8 Coverage of interventions across the continuum of care based on the most
recent data since 2012 in Countdown countries. Bars show median national coverage of
interventions; dots show country-specific data. (From Countdown to 2030
Collaboration: Tracking progress towards universal coverage for reproductive,
maternal, newborn, and child health, Lancet 391:1538-1548, 2018. Fig 1.)

Vaccine-Preventable Diseases
In 2002 an estimated 1.5 million under-5 deaths were caused by vaccine-
preventable diseases. Top contributors were pneumococcus and rotavirus,
followed by Haemophilus influenzae B (Hib), measles, pertussis, and tetanus.
The World Health Organization (WHO) Expanded Program on Immunization
(EPI) has resulted in a dramatic reduction in deaths, illness, and disability from
many of these diseases, as well as the near-elimination of poliomyelitis.
Recommendations for routine immunizations have continued to grow with the
development of new vaccines that have demonstrated significant lifesaving
potential in industrialized countries (Table 3.2 ).

Table 3.2
Routine Immunizations Recommended by the World Health
Organization (2017)

INTERVAL BETWEEN
DOSES IN DOSES
VACCINE AGE AT 1st BOOSTER
PRIMARY ADOLESCENT CONSIDERATIO
(ANTIGEN) DOSE 3rd DOSE
SERIES 2nd to
1st to 2nd to
3rd
4th
BCG (bacille Birth 1
Calmette-Guérin)

Hepatitis B Birth 3 (or 4) 4 wk w/ 4 wk w/ (or 3 doses for high-

DTP2 DTP3 4 risk groups if not
wk) previously
immunized

OPV (oral polio bOPV + 4 4 wk 4 wk 4-8

vaccine) IPV 1-2 w/ w/ wk
IPV/bOPV IPV/2 DTP2 DTP3
IPV bOPV 4-8 4-8
3 wk wk
4-8 4-8
wk wk

DTP (diphtheria, 6 wk 3 4-8 wk 4-8 wk 3 boosters: 1 booster: 9-15

tetanus, and 12-23 mo; yr (Td)
pertussis) 4-7 yr (Td);
and 9-15 yr
Td)

Hib 6 wk-59 mo 3 4 wk 4 wk At least 6

(Haemophilus 2-3 w/ w/ mo after
 influenzae B) DTP2 DTP3 last dose
8 wk 4 wk
if if 3
only doses
2
doses
4 wk
if 3
doses
Pneumococcus 6 wk 3 4 wk 4 wk Yes, if
(PCV10 or 13) 6 wk 2-3 8 wk not
given
at 10
wk
9-15
mo
Rotavirus 6 wk w/ Rotarix: 4 wk 4 wk Not recommended
DTP1 6 wk w/ w/ w/ mo old
6 wk w/ DTP1 DTP2 DTP3
DTP1 Rota 4-10
Teq: 6 wk
wk w/ w/
DTP1 DTP2
Measles 9 or 12 mo 2 4 wk

Rubella 9 or 12 mo (w/ 1 1 dose

measles- (adolescent girls
containing and/or
vaccines) childbearing-age
women, if not
previously
vaccinated)

HPV 9 yr (female) 2 6 mo 2 doses (female)

CRS, Congenital rubella syndrome; IPV, inactivated polio vaccine; TB, tuberculosis.
Adapted from WHO Routine Guidelines for Immunization.
http://www.who.int/immunization/policy/Immunization_routine_table2.pdf?ua=1 .

promotion activities (Fig. 3.9 ).

FIG. 3.9 Health services delivery systems.

 FIG. 3.10 Integrated Management of Childhood Illness (IMCI). (Adapted from WHO
2014. Revised WHO classification and treatment of pneumonia in children at health
facilities: evidence summaries; and WHO 2008. Integrated Management of Childhood


FIG. 3.11 Country categorization based on adolescent burden of disease.
Categorization into 3 groups according to adolescent burden of disease and reflecting
passage through epidemiologic transition. DALYs, Disability-adjusted life-years; HIV,
human immunodeficiency virus; NCD, noncommunicable diseases. (From Patton GC,
Sawyer SM, Santelli JS, et al: Our future: a Lancet commission on adolescent health
and wellbeing, Lancet 387:2423–2478, 2016, Fig 7.)
Valuable information can be obtained from PDSA cycles that are successful, and
those that are not, to help plan the next iteration of the PDSA cycle. The PDSA
cycle specifically requires that improvements be data driven. Many clinicians
attempt to make changes for improvement in their practice based on clinical
intuition rather than on interpretation of empirical data.

FIG. 4.1 A, The plan-do-study-act (PDSA) cycle. B, Use of PDSA cycles: a
ramp. (From Langley GJ: The improvement guide: a practical guide to
enhancing organizational performance, San Francisco, 1996, Jossey-Bass.
© 1996 by Gerald J. Langley, Kevin M. Nolan, Thomas W. Nolan, L.
Norman, and Lloyd P. Provost.)

FIG. 4.2 Improving quality by reducing variation.

FIG. 4.3 A and B, Lean methodology—waste reduction.

 FIG. 4.4 Management sciences—discrete event stimulation. PICU, Pediatric intensive
care unit.

FIG. 4.5 Management sciences—cognitive mapping.

FIG. 4.6 Key driver diagram: theory of how to achieve an aim.

FIG. 4.7 Failure modes and effects analysis (FMEA).


FIG. 4.8 Pareto chart.

Table 4.1

Properties of Robust Quality Measures

ATTRIBUTE RELEVANCE
Validity Indicator accurately captures the concept being measured.
Reliability Measure is reproducible.
Feasibility Data can be collected using paper or electronic records.
Usability Measure is useful in clinical practice.

 FIG. 4.9 Development of a rigorous quality measure.

Table 4.2
Examples of National Pediatric Quality Measures

NQF NQF-ENDORSED
NQF-ENDORSED
PEDIATRIC INPATIENT NQF-ENDORSED INPATIENT
OUTPATIENT PEDIATRIC
QUALITY MEASURES PEDIATRIC CARE MEASURES
CARE MEASURES
INDICATORS AMONG PICUs
Neonatal PICU CAC-1 relievers for inpatient Appropriate testing for
bloodstream standardized asthma children with pharyngitis
infection rate mortality ratio CAC-2 systemic corticosteroids CAHPS clinician/group
Transfusion PICU severity- for inpatient asthma surveys (adult primary
reaction adjusted length Admit decision time to ED care, pediatric care, and
Gastroenteritis of stay departure time for admitted specialist care surveys)
admission rate PICU patients Child and adolescent
unplanned Follow-up after hospitalization for major depressive
readmission mental illness (FUH) disorder: diagnostic
rate NHSN Catheter-Associated evaluation
Urinary Tract Infection (CAUTI) Child and adolescent
outcome measure major depressive
NHSN Central Line-Associated disorder: suicide risk
Bloodstream Infection (CLABSI) assessment
outcome measure Follow-up after
Percent of residents or patients hospitalization for mental
assessed and appropriately given illness (FUH)
the pneumococcal vaccine (short Median time from ED
stay) arrival to ED departure
Restraint prevalence (vest and for discharged ED
limb) patients
 Validated family-centered survey Pediatric symptom
questionnaire for parents' and checklist (PSC)
patients' experiences during
inpatient pediatric hospital stay
Nursing hours per patient day
Preventive care and screening:
screening for clinical depression
and follow-up plan
Skill mix (RN, LVN/LPN, UAP,
and contract)


FIG. 4.10 Success ingredients for large-scale quality improvement.

Table 4.3

National Organizations Involved in Pediatric Quality Improvement (QI)

ORGANIZATION ROLE ACTIVITIES
American Academy Represents more than 60,000 pediatricians Resources for QI to improve health for all
of Pediatrics (AAP) and pediatric subspecialists worldwide children, best practices, advocacy, policy,
research and practice, and medical home
American Board of Certifying board for pediatrics and pediatric Certification policies and resources for
Pediatrics (ABP) subspecialties activities such as Maintenance of
Certification (MOC)
American Medical Physician member association Physician Consortium for Performance
Association (AMA) Improvement (PCPI)—physician-led
initiative
Children's Hospital Formerly the National Association of Databases, QI collaboratives, and policy
Association (CHA) Children's Hospitals and Related Institutions;
and the Child Health Corporation of America

Institute for QI organization for adult and pediatric care QI collaboratives, QI educational workshops
Healthcare and materials
Improvement (IHI)
National Initiative QI organization for pediatric care QI training, improvement networks
for Child Health
Quality (NICHQ)
The Joint Hospital accreditation organization Unannounced surveys to evaluate quality of
Commission care in hospitals
National QI organization Healthcare Effectiveness Data and
Committee for Information Set (HEDIS) and quality
Quality Assurance measures for improvement
(NCQA)
National Quality Multidisciplinary group including healthcare Endorsing national quality measures,
Forum (NQF) providers, purchases, consumers, and convening expert groups, and setting
accrediting bodies national priorities
improvements in process measures and outcomes measure in a hypothetical
CLA-BSI project. In this case, after improvement interventions targeted 2
process measures known to be important in CLA-BSI risk—the line insertion
and the line maintenance bundles—the QI team saw improvement in both
measures and coincident reduction in CLA-BSIs.

Table 5.1
Common Healthcare-Associated Conditions (HACs)
Targeted in Quality Improvement Efforts with Interventions

COST
POTENTIALLY EFFECTIVE
HAC DEFINITION PER
INTERVENTIONS
EVENT
Central line– Laboratory-confirmed bloodstream $55,646 Line insurance bundle (e.g.,
associated infection with central line in place at time handwashing, chlorhexidine scrub),
bloodstream of or 48 hr before onset of event (details at maintenance bundle (catheter care,
infections https://www.cdc.gov/nhsn ) change dressing, discuss daily if
catheter is needed)
Catheter- Urinary tract infection where an indwelling $7,200 Protocols for reviewing and removing
associated urinary urinary catheter was in place >2 days on catheters daily, clear indications for
tract infections day of event (details at inserting catheters, physician
https://www.cdc.gov/nhsn ) champions, audit and feedback of data
Adverse drug Harm associated with any dose of a drug $3,659 Pharmacist review of medication
events (details at http://www.nccmerp.org/types- order, computerized physician order
medication-errors ) entry, co-ordering of laxatives in
patients on opiates
Peripheral IV Moderate or serious harm (e.g., diminished — Hourly reviews of IV status,
infiltrates pulses, >30% swelling) associated with a limitations on use of desiccants
peripheral IV infiltrate (details at through peripheral IVs, remove IVs
http://www.solutionsforpatientsafety.org ) when no longer needed
Pressure injuries Localized damage to skin and/or underlying — Screening of high-risk patients (e.g.,
soft tissue usually over a bony prominence Braden Q Scale), regular turning of
or related to a device (details at low-mobility patients, regular
http://www.solutionsforpatientsafety.org ) inspection and skin care; specialized
device padding
Surgical site Infection of incision or deep tissue space — Surgical checklist, antimicrobial
infections after operative procedure (details at prophylaxis within 60 min before
https://www.cdc.gov/nhsn ) incision, preoperative baths,
postoperative antibiotic redosing
Venous Blood clot in deep vein, stratified as central $27,686 Screening for high-risk patients,
thromboembolism line–associated vs not (details at removal of central line catheters when
https://www.cdc.gov/nhsn ) no longer needed, targeted prophylaxis
IV, Intravenous line.
FIG. 5.2 Quality improvement interventions targeted process improvement
in the A, line insertion bundle, where performance improved from 46% to
95%), and B, line maintenance bundle, where performance improved from
13% to 66%. Coincident with the improved bundle performance, the rate of
processes, and easy access to lifts for larger children with limited mobility.
Violence and patient interaction injuries, often from children with psychiatric
disease or developmental disabilities, are a growing source of harm to clinicians.

Emerging Areas of Safety Research and

Improvement
Diagnostic error is recognized as an increasingly common and impactful event.
There are 2 systems of clinical decision-making. System 1 is fast, instinctual,
and largely unconscious. System 2 is slow, effortful, and calculating. System 1
and its heuristics or biases allows for quick—almost automatic—decision-
making, often by associating new information with existing patterns or beliefs
(e.g., that red object on right side of road is a stop sign; I should stop). However,
system 1 thinking can be dangerous in diagnostic thinking, particularly when
new data are unconsciously made to fit the preconceived pattern, and are not
seen as disconfirming. Many current efforts aim to better understand how well-
described cognitive biases (e.g., premature closure, availability bias) play out in
clinical care, and what system-based strategies can mitigate their effects (Tables
5.2 to 5.4 ). Diagnostic error is often an error of omission, making it difficult to
measure or to produce valid epidemiologic estimates of its incidence. Despite
this, many health systems are pursuing research and improvement to move
clinicians from system 1 to system 2 thinking, such as being explicit on
uncertainty (e.g., patients admitted from ED as “diagnosis unknown”) or using
decision aids to prompt revisiting provisional diagnoses (Table 5.5 ).

Table 5.2

Cognitive Biases Related to Heuristic Failure

BIASES DEFINITION
Anchoring Locking into a diagnosis based on initial presenting features, failing to adjust diagnostic
impressions when new information becomes available.
Confirmation Looking for and accepting only evidence that confirms a diagnostic impression, rejecting or not
bias seeking contradictory evidence.
Diagnostic Perpetuating a diagnostic label over time, usually by multiple providers both within and across
momentum healthcare systems, despite the label being incomplete or inaccurate.
Expertise Believing that a patient who has already undergone an extensive evaluation will have nothing
bias/yin-yang more to gain from further investigations, despite the possibility that the disease process or
out diagnostic techniques may have evolved so as to allow for appropriate diagnosis.
Overconfidence Believing one knows more than one does, acting on incomplete information or hunches, and
 bias prioritizing opinion or authority, as opposed to evidence.
Premature Accepting the first plausible diagnosis before obtaining confirmatory evidence or considering all
closure available evidence. “When the diagnosis is made, thinking stops.”
Unpacking Failing to explore primary evidence or data in its entirety and subsequently failing to uncover
principle important facts or findings, such as accepting a biopsy report or imaging study report without
reviewing the actual specimen or image; especially important in undiagnosed and rare diseases.
From Bordini BJ, Stephany A, Kliegman R: Overcoming diagnostic errors in medical practice, J
Pediatr 185:19–25, 2017 (Table I, p 20).

Table 5.3

Cognitive Biases Related to Errors of Attribution

BIASES DEFINITION
Affective bias Allowing emotions to interfere with a diagnosis, either positively or negatively; dislikes of
patient types (“frequent flyers”).
Appeal to authority Deferring to authoritative recommendations from senior, supervising, or “expert” clinicians,
independent of the evidentiary support for such recommendations.
Ascertainment bias Maintaining preconceived expectations based on patient or disease stereotypes.
Attribution error Placing undue importance on the perceived internal characteristics or motivations of others,
whether they are the patient, the patient's family, or other members of the evaluation team.
Countertransference Being influenced by positive or negative subjective feelings toward a specific patient.
Outcome bias Minimizing or overemphasizing the significance of a finding or result, often based on
subjective feelings about a patient, a desired outcome, or personal confidence in one's own
clinical skills. The use of “slightly” to describe abnormal results.
Psych-out bias Maintaining biases about people with presumed mental illness.
From Bordini BJ, Stephany A, Kliegman R: Overcoming diagnostic errors in medical practice, J
Pediatr 185:19–25, 2017 (Table II, p 21).

Table 5.4

Cognitive Biases Related to Errors of Context

BIASES DEFINITION
Availability Basing decisions on the most recent patient with similar symptoms, preferentially recalling recent
bias and more common diseases.
Base-rate Prioritizing specific information (e.g., a lab value) pertaining to a case while ignoring general
neglect base rate information about the prevalence of disease in populations (pre-test probability).
Framing effect Being influenced by how or by whom a problem is described or by the context in which the
evaluation takes place.
Frequency Believing that common things happen commonly and usually are benign in general practice.
bias
Hindsight bias Reinforcing diagnostic errors once a diagnosis is discovered despite these errors. May lead to a
clinician overestimating the efficacy of his or her clinical reasoning and may reinforce ineffective
techniques.
Posterior Considering the likelihood of a particular diagnosis in light of a patient's chronic illness. New
probability headaches in a patient with a history of migraines may in fact be a tumor.
error
Representative Basing decisions on an expected typical presentation. Not effective for atypical presentations.
 bias Overemphasis on disease-diagnostic criteria or “classic” presentations. “Looks like a duck,
quacks like a duck.”
Sutton's slip Ignoring alternate explanations for “obvious” diagnoses (Sutton's law is that one should first
consider the obvious).
Thinking in Restricting diagnostic considerations to a particular specialty or organ system. Each discipline has
silo a set of diseases within its comfort zone, which reduces diagnostic flexibility or team-based
communication.
Zebra retreat Lacking conviction to pursue rare disorders even when suggested by evidence.
From Bordini BJ, Stephany A, Kliegman R: Overcoming diagnostic errors in medical practice, J
Pediatr 185:19–25, 2017 (Table III, p 21).

Table 5.5
Solutions to Avoid Diagnostic Errors

1. Enhancing foundational knowledge in medical education

• Teach symptoms and their differential pathophysiology, not just
diseases.
• Emphasize red flags and must-not-miss diagnoses.
2. Minimizing errors related to heuristic failure
• Build understanding of system 1 and system 2 thought processes
and the risks of heuristic failure.
• Actively model and encourage counterfactual reasoning and
hypothesis generation to enhance system 2 skills.
3. Mitigating errors of attribution
• Increase awareness of biases toward specific patients by promoting
self-reflection.
• Use a team-based approach and diagnostic strategies that actively
dispel biases.
4. Avoiding errors of context
• Solicit input across a variety of specialties when appropriate.
• Consciously acknowledge the risk of thinking in silo and actively
seek explanations outside one's specialty.
5. Optimizing data gathering, analysis, and hypothesis generation
• Develop differential diagnoses based on pathophysiology; consider
alternatives and competing options.
• Realize that diagnostic criteria for certain diseases do not account
for atypical disease manifestations.
• Rely on objective individual data, not just disease prevalence rates,
when considering the pretest likelihood of a particular diagnosis.
CHAPTER 7

Pediatric Palliative Care

Christina Ullrich, Janet Duncan, Marsha Joselow, Joanne Wolfe

According to the World Health Organization (WHO), “Palliative care for

children is the active total care of the child's body, mind and spirit and also
involves giving support to the family. Optimally, this care begins when a life-
threatening illness or condition is diagnosed and continues regardless of whether
or not a child receives treatment directed at the underlying illness.” Provision of
palliative care applies to children with a wide variety of diagnoses, including
cancer, cystic fibrosis, complex or severe cardiac disease, neurodegenerative
disorders, severe malformations, and trauma with life-threatening sequelae
(Table 7.1 ). Medical and technologic advances have resulted in children living
longer, often with significant dependence on expensive technologies. These
children have complex chronic conditions across the spectrum of congenital and
acquired life-threatening disorders. Children with complex chronic conditions
benefit from integration of palliative care strategies. These children, who often
survive near-death crises followed by the renewed need for rehabilitative and
life-prolonging treatments, are best served by a system that is flexible and
responsive to changing needs and blended goals of care.
Table 7.1
Conditions Appropriate for Pediatric
Palliative Care
Conditions for Which Curative Treatment Is Possible but May Not Succeed

Advanced or progressive cancer or cancer with a poor prognosis

Complex and severe congenital or acquired heart disease
Conditions for Which There Is Intensive Long-Term Treatment Aimed at
Prolonging Life and Maintaining Quality of Life, but Premature Death Is
Still Possible

Cystic fibrosis
Severe immunodeficiency
High-risk solid-organ transplant candidates and/or recipients (e.g., lung,
multivisceral)
Chronic or severe respiratory failure
Muscular dystrophy
Complex multiple congenital malformation syndromes
Primary pulmonary hypertension
Severe chromosomal disorders (aneuploidy, deletions, duplications)

Progressive Conditions for Which There Is No Curative Option and in

Which Treatment Is Almost Exclusively Palliative After Diagnosis

Progressive metabolic disorders (Tay-Sachs disease)

Batten disease
Severe forms of osteogenesis imperfecta

Conditions Involving Severe, Nonprogressive Disability, Causing Extreme

Vulnerability to Health Complications

Severe cerebral palsy with recurrent infection or difficult-to-control

symptoms
Severe neurologic sequelae of infectious disease
Hypoxic or anoxic brain injury
Brain malformations (e.g., holoprosencephaly, lissencephaly)

Adapted from The Together for Short Lives [formerly the Association for
Children's Palliative Care (ACT)] Life-limiting/Life-threatening Condition
Categories.
http://www.togetherforshortlives.org.uk/professionals/childrens_palliative_care_essentials/app
.
 Although often mistakenly understood as equivalent to end-of-life care , the
scope and potential benefits of palliative care are applicable throughout the
illness trajectory . Palliative care emphasizes optimization of quality of life,
communication, and symptom control, goals that may be congruent with
maximal treatment aimed at sustaining or prolonging life.
The mandate of the pediatrician and other pediatric clinicians to attend to
children's physical, mental, and emotional health and development includes the
provision of palliative care for those who live with a significant possibility of
death before adulthood (Fig. 7.1 ). Such comprehensive physical, psychological,
social, and spiritual care requires an interdisciplinary approach.

FIG. 7.1 Typical illness trajectories for children with life-threatening illness. (From Field
M, Behrman R, editors: When children die: improving palliative and end-of-life care for
children and their families, Washington, DC, 2003, National Academies Press, p 74.)

In the United States the healthcare and reimbursement structure, combined

with frequent use of medical technology (e.g., home ventilatory support) or
continuous home nursing, historically precluded formal enrollment of children
on the hospice benefit when they were otherwise eligible (i.e., had estimated
prognosis of ≤6 mo). Section 2302 of the Patient Protection and Affordable Care
Act (ACA), the Concurrent Care for Children Requirement (CCCR) ,
eliminated the requirement that Medicaid patients <21 yr old forgo curative or
developmentally appropriate fashion (Table 7.2 ) to a child's questions about
death (e.g., “What's happening to me?” or “Am I dying?”) requires a careful
exploration of what is already known by the child, what is really being asked
(the question behind the question ), and why the question is being asked at this
particular time and in this setting. It may signal a need to be with someone who
is comfortable listening to such unanswerable questions. Many children find
nonverbal expression much easier than talking; art, play therapy, and storytelling
may be more helpful than direct conversation.

Table 7.2
Developmental Questions, Thoughts, and Concepts of
Dying, With Responsive Strategies
TYPICAL
QUESTIONS
AND THOUGHTS THAT DEVELOPMENTAL STRATEGIES AND
STATEMENTS GUIDE BEHAVIOR UNDERSTANDING OF DEATH RESPONSES
ABOUT
DYING
MONTHS TO 3 YR OF AGE
“Mommy, Child has limited Child may have “sense” that Optimize comfort, and
don't cry.” understanding of events, something is wrong. Death is often consistency; familiar
“Daddy, future and past, and of the viewed as continuous with life persons, objects,
will you difference between living (analogous to being awake and being routines. Use soothing
still tickle and nonliving. asleep). songs, words, and
me when touch.
I'm dead?” “I will always love
you.”
“I will always take
care of you.”
“I will tickle you
forever.”
AGE 3-5 YR
“I did Concepts are simple and Child may see death as Assure child that
something reversible. Variations temporary and reversible and not illness not her fault.
bad and so I between reality and universal. Provide consistent
will die.” fantasy. Child may feel responsible for caregivers.
“Can I eat illness. Promote honest simple
anything I Death may be perceived as an language.
want in external force that can get you. Use books to explain
heaven?” the life cycle and
promote questions and
answers.
“You did not do
anything to cause
this.”
“You are so special to
us, and we will always
 love you.”
“We know (God,
Jesus, Grandma,
Grandpa) are waiting
to see you.”
AGE 5-10 YR
“How will I Child begins to Child begins to understand death as Be honest and provide
die?” demonstrate organized, real and permanent. Death means that specific details if they
“Will it logical thought. Thinking your heart stops, your blood does not are requested. Help
hurt?” becomes less esoteric. circulate, and you do not breathe. It and support the child's
“Is dying Child begins to problem- may be viewed as a violent event. need for control.
scary?” solve concretely, reason Child may not accept death could Permit and encourage
logically, and organize happen to himself or to anyone he the child's
thoughts coherently. knows but starts to realize that people participation in
However, child has limited that he knows will die. decision making.
abstract reasoning. “We will work
together to help you
feel comfortable. It is
very important that
you let us know how
you are feeling and
what you need. We
will always be with
you, so you do not
need to be afraid.”
AGE 10-18 YR
“I'm afraid Abstract thoughts and Understand death as irreversible, Reinforce
if I die my logic possible. inevitable and universal. child/adolescent's self-
mom will Body image is Child needs reassurance of esteem, sense of
just break important. continued care and love. worth, and self-
down.” Child needs peer Search for meaning and purpose respect. Allow need
“I'm too relationships for of life. for privacy,
young to support and for independence, access
die. I want validation. to friends and peers.
to get Child expresses Tolerate expression of
married and altruistic values, such strong emotions and
have as staying alive for permit participation in
children.” family (parents, decision-making.
“Why is siblings) and donating “I can't imagine how
God letting organs/tissue. you must be feeling.
this Disbelief that she is Despite it all, you are
happen?” dying. doing an incredible
job. I wonder how I
can help?”
“What's most
important to you
now?”
“What are your hopes
… your worries?”
“You have taught me
so much; I will always
remember you.”

Adapted from Hurwitz C, Duncan J, Wolfe J: Caring for the child with cancer at the close of life,
JAMA 292:2141–2149, 2003.
overwhelmed to provide this at crucial times.

The Staff
Inadequate support for the staff providing palliative care can result in depression,
emotional withdrawal, and other symptoms. Offering educational opportunities
and emotional support for staff at various stages of caring for a child with life-
threatening illness can be helpful in bettering patient/family care and preventing
staff from experiencing compassion fatigue, burnout, and long-term
repercussions, including leaving the field.

Goals of Care and Decision-Making

In the course of a child's life-limiting illness, a series of important decisions may
arise in relation to location of care, medications with risks and benefits, not
starting or discontinuing life-prolonging treatments, experimental treatments in
research protocols, and use of integrative therapies (see Chapter 78 ). Such
family decisions are greatly facilitated by opportunities for in-depth and guided
discussions around goals of care for the child. This is often accomplished by
eliciting parent (and child) understanding of the child's condition and asking
open-ended questions that explore the parent's and child's hopes, worries, and
family values. Goals-of-care conversations include what is most important for
them as a family, considerations of their child's clinical condition, and their
values and beliefs, including cultural, religious, and spiritual considerations.
Table 7.3 presents specific questions that can effectively guide these discussions.
The conversation should also include a review of previous discussions, active
listening to concerns and issues as they are raised, opportunities to repeat back
elements of the discussion to ensure clarity, and provision of honest, factual
answers even in areas of uncertainty.

Table 7.3

Five Basic Questions to Guide “Goals of Care” Conversation

PHRASING FOR ADULT OR OLDER
PHRASING FOR CHILD
ADOLESCENT
Tell us about your child as a person. Tell me about yourself before you got sick.
What does your child enjoy?
What is your understanding of your child's Why are you in the hospital?
illness/condition? What do you understand about your illness?
 In light of your understanding, what is most important to What do you want others to know or do for you when
you regarding your child's care? taking care of you?
What are you hoping for? I wonder if there is anything that is worrying you
What are your worries? or that is keeping you up at night.
Is there anything you wish you could talk about?
What gives you strength in the face of your child's What helps you get through the day?
illness/condition? What helps you feel good?

Decision-making should be focused on the goals of care, as opposed to

limitations of care ; “This is what we can offer,” instead of, “There is nothing
more we can do.” Rather than meeting specifically to discuss withdrawing
support or a do-not-resuscitate (DNR) order, a more general discussion centered
on the goals of care will naturally lead to considering which interventions are in
the child's best interests and can present an opportunity for the clinicians to make
recommendations based on these goals. By offering medical recommendations
based on family goals and the clinical reality, the team can decrease the burden
of responsibility for decision-making that parents carry.

Resuscitation Status
Many parents do not understand the legal mandate requiring attempted
resuscitation for cardiorespiratory arrest unless a written DNR order is in place.
In broaching this topic, rather than asking parents if they want to forgo
cardiopulmonary resuscitation (CPR) for their child (and placing the full burden
of decision-making on them), it is preferable to discuss whether or not
resuscitative interventions are likely to benefit the child. It is important to make
recommendations based on overall goals of care and medical knowledge of
potential benefit and/or harm of these interventions. Once the goals of therapy
are agreed on, the physician is required to write a formal order. Out-of-hospital
DNR verification forms are available in many states, which if completed on
behalf of the child, affirm that rather than initiating resuscitative efforts,
emergency response teams are obligated to provide appropriate symptom
management with comfort and relief of suffering with appropriate interventions
when called to the scene.
Almost half of all states have implemented the physician orders for life
treatment (POLST) system . A POLST order is completed for children with
life-threatening illness, translating the expressed parent's and/or child's wishes
for interventions to do or not do into actionable orders (www.polst.org ). It is
usually helpful to frame discussions about POLST as ways for parents to
maintain some control, by communicating their goals and care preferences, so
that they may be honored, irrespective of the setting. It may also be beneficial to
write a letter that delineates decisions regarding resuscitation interventions and
supportive care measures to be undertaken for the child, particularly if POLST
are not available. The letter should be as detailed as possible, including
recommendations for comfort medications and contact information for
caregivers best known to the patient. Such a letter, given to the parents, with
copies to involved caregivers and institutions, can be a useful communication
aid, especially in times of crisis. In any case, if a child may die in the home
setting, and the parents opt to use on out-of-hospital DNR verification form or
POLST, plans to pronounce the child and provide support for the family must be
in place. If the child has been referred to hospice, the hospice usually fulfills
those responsibilities.
Conflicts in decision-making can occur within families, within healthcare
teams, between the child and family, and between the family and professional
caregivers (see Chapter 6 ). For children who are developmentally unable to
provide guidance in decision-making (neonates, very young children, or children
with cognitive impairment), parents and healthcare professionals may come to
different conclusions as to what is in the child's best interests. Decision-making
around the care of adolescents presents specific challenges, given the shifting
boundary that separates childhood from adulthood. In some families and
cultures, truth-telling and autonomy are secondary to maintaining the integrity of
the family (see Chapter 11 ). Although frequently encountered, differences in
opinion are often manageable for all involved when lines of communication are
kept open, team and family meetings are held, and the goals of care are clear.

Symptom Management
Intensive symptom management is another cornerstone of pediatric palliative
care. Alleviation of symptoms reduces suffering of the child and family and
allows them to focus on other concerns and participate in meaningful
experiences. Despite increasing attention to symptoms, and pharmacologic and
technical advances in medicine, children often suffer from multiple symptoms.
Table 7.4 provides key elements and general approaches to managing symptoms.
Table 7.4
Key Elements of Effective Symptom
Management
Setting the Stage

• Establish and periodically revisit goals of care and ensure that goals are
communicated to entire care team.
• Plan for symptoms (including unanticipated ones) before they occur.

Assessment

• Assess the child for symptoms regularly, using consistent and

developmentally appropriate assessment tools.
• Utilize self-report, if the child is able to reliably report symptoms.
• Evaluate all aspects of the symptom, including quality, frequency, duration,
and intensity.
• Consider the holistic nature of symptoms.
• Explore the meaning that symptoms may have for families in their social,
cultural, and religious context.
• Assess distress caused by the symptom.
• Evaluate the degree of functional impairment from the symptom.

Treatment

• Understand the pathophysiology of the symptom, and establish a complete

differential diagnosis.
• Treat the underlying cause if possible, weighing benefits and risks, in the
context of goals of care.
• Choose the least invasive route for medications—by mouth whenever
possible.
• Prescribe regular medications for constant symptoms, and consider prn
doses for breakthrough or uncontrolled symptoms.
• Consider all approaches (i.e., pharmacologic/nonpharmacologic and
local/systemic).
• Partner with families to identify and address any barriers to optimal control
of symptoms.
• Address spiritual, emotional, and existential suffering in addition to physical
 suffering since these are often interrelated.

Ongoing Care

• Reassess the symptom and response to interventions regularly.

• For refractory symptoms, revisit the differential diagnosis and review
potentially contributing factors.
• Effective interventions relieve the symptom and reduce distress and
functional impairment.

Pain is a complex sensation triggered by actual or potential tissue damage and

influenced by cognitive, behavioral, emotional, social, and cultural factors.
Effective pain relief is essential to prevent central sensitization , a central
hyperexcitation response that may lead to hypersensitivity and escalating pain,
and to diminish a stress response that may have a variety of physiologic effects.
Assessment tools include self-report tools for children who are able to
communicate their pain verbally, as well as tools based on behavioral cues for
children who are unable to do so because of their medical condition or a
neurodevelopmental disorder. Tables 7.5 to 7.7 address management of pain (see
also Chapter 76 ).
Table 7.5
Guidelines for Pain Management
• Use nonopioid analgesics as monotherapy for mild pain, and together with
opioids for more severe pain.
Nonopioid analgesics include acetaminophen, nonsteroidal
antiinflammatory drugs (NSAIDs), salicylates, and selective
cyclooxygenase (COX-2) inhibitors.
• For moderate or severe pain, start with a short-acting opioid at regular
intervals.
When dose requirements have stabilized, consider converting opioid
to a long-acting formulation with doses available for
breakthrough or uncontrolled pain, as needed.
• For uncontrolled pain, increase opioid dose by 30–50%; for
severe pain, increase by 50–100%.
 • Avoid codeine and opioids with mixed-agonist activity (e.g.,
butorphanol, pentazocine).
• Administer medications by the simplest, most effective, and least distressing
route.
• Dispel the myth that strong medications should be saved for extreme
situations or the very end of life.
Opioids do not have a “ceiling effect,” and escalating symptoms can
usually be treated with an increase in dose. If further titration
does not provide adequate analgesia, the opioid may be rotated to
another (see below).
• Clarify for families the differences among tolerance, physical dependence,
and addiction.
• Anticipate and treat/prevent common analgesic side effects (gastritis with
NSAIDs; constipation, pruritus, nausea, and sedation with opioids).
Always initiate a bowel regimen to prevent constipation when
starting opioids.
Consider a stimulant for opioid-induced somnolence.
Pruritus rarely indicates a true allergy. If not responsive to an
antihistamine, consider low-dose naloxone or switching opioids.
Consider switching to a different opioid for intolerable side effects
or neurotoxicity (e.g., myoclonus).
Use an equianalgesic conversion table when switching opioids, and
account for incomplete cross-tolerance with dose reduction.
• Consider the use of adjuvant drugs for specific pain syndromes, and for their
opioid-sparing effect:
Antidepressants (e.g., amitriptyline, nortriptyline) and
anticonvulsants (e.g., gabapentin, carbamazepine, topiramate) for
neuropathic pain
Steroids or NSAIDs for bone pain
Sedatives and hypnotics for anxiety and muscle spasm
To enhance analgesia from opioids, consider clonidine or ketamine.
• Use topical local anesthetics (lidocaine, prilocaine,
bupivacaine) when possible
• Consider anesthetic blocks for regional pain.
• Consider palliative radiation therapy.
• Consider psychological approaches (e.g., cognitive or
 behavioral therapy) and integrative therapies (e.g.,
acupuncture, massage).

Table 7.6
Pharmacologic Approach to Symptoms Commonly
Experienced by Children With Life-Threatening Illness

SYMPTOM MEDICATION STARTING DOSE COMMENTS

Pain—mild Acetaminophen 15 mg/kg PO q4h, max 4 g/day Available PO (including liquid), PR,
or IV
Ibuprofen 10 mg/kg PO q6h PO (including liquid) only; avoid if
risk of bleeding; use only in infants ≥6
mo. Use with caution in congestive
heart failure. Chewable tablets contain
phenylalanine.
Choline 10-20 mg/kg PO tid (max 500- Trilisate may have less antiplatelet
magnesium 1000 mg/dose) activity and therefore pose less risk for
trisalicylate bleeding than other salicylates.
Salicylates, however, have been
associated with Reye syndrome in
children <2 yr.
Celecoxib 1-2 mg/kg (max 100 mg) PO Selective cyclooxygenase (COX-2)
q12-24h inhibitor has low risk of gastritis and
low antiplatelet activity.
Pain— Morphine 0.3 mg/kg PO q4h if <50 Also available in IV/SQ formulation. ‡
moderate/severe immediate kg §
release (i.e., 5-10 mg PO q4h if >50
MSIR) kg* †
Oxycodone 0.1 mg/kg PO q4h if <50 No injectable formulation. ‡ §
kg
5-10 mg PO q4h if >50
kg* †
Hydromorphone 0.05 mg/kg PO q4h if <50 Also available in IV/SQ formulation.
kg Injectable form very concentrated,
1-2 mg PO q4h if >50 kg* facilitating subcutaneous delivery. ‡ §
†
Fentanyl 0.5-1.5 µg/kg IV/SQ q30min* † Rapid infusion may cause chest wall
rigidity. ‡ §
Methadone Starting dose 0.1-0.2 mg/kg Only opioid with immediate and
PO bid. May give tid if needed. prolonged effect available as a liquid;
Recommend consultation with do not adjust dose more often than
experienced clinician for every 72 hr because prolonged
equivalence dosing from other biologic half-life > therapeutic half-
opioids.* † life. Knowledge of methadone
pharmacokinetics is needed for
converting to and from doses of other
opioids. Also available IV/SQ. May
cause QT interval prolongation
(consider ECG), especially in adults
 on >200 mg/day or in those at risk for
QT prolongation. Interacts with
several antiretroviral agents. §
Pain—sustained MS Contin Total daily dose of MSIR Do not crush MS Contin. For those
release Kadian divided bid-tid unable to swallow pills, Kadian and
(contains Avinza capsules may be opened and
sustained contents mixed with food but cannot
release be chewed . Kadian contents may be
pellets) mixed in 10 mL water and given via
Avinza 16-French G-tube. Avoid alcohol with
(contains Avinza. Larger-dose formulation may
immediate not be suitable for small children. §
and extended
release
beads)
Oramorph
Oxycontin Total daily dose of oxycodone Do not crush. §
divided bid-tid
Transdermal Divide 24 hr PO morphine Smallest patch size may be too high
fentanyl patch dose by 2 to determine starting for small children. For children >2 yr.
dose of transdermal fentanyl. Apply to upper back in young
No data exist on the children. Patch may not be cut.
equianalgesic conversion from Typically for patients taking at least 60
transdermal fentanyl to any mg morphine/day or its equivalent.
oral opioid. Not appropriate when dosage changes
are frequent or for opioid-naïve
patients. Fever >40°C results in higher
serum concentrations. §
Pain—neuropathic Nortriptyline 0.5 mg/kg PO at bedtime (max Fewer anticholinergic side effects than
150 mg/day) amitriptyline. May cause constipation,
sedation, postural hypotension, and
dry mouth. May cause QT interval
prolongation (consider ECG). At
higher doses, monitor ECG and
plasma levels.
Gabapentin Start at 5 mg/kg/day at bedtime May cause neuropsychiatric events in
and gradually increase to 10-15 children (aggression, emotional
mg/kg/day divided tid; titrate lability, hyperkinesia), usually mild
up by 5 mg/kg/day q 3-4 days but may require discontinuation of
as needed but not to exceed 50- gabapentin. May cause dizziness,
75 mg/kg/day (3600 mg/day) drowsiness, tremor, nystagmus, ataxia,
and swelling.
Pregabalin Start at 1 mg/kg/dose PO at
bedtime for 3 days, then
increase to 1 mg/kg/dose bid.
Increase every 3 days to 3
mg/kg/dose PO bid (max 6
mg/kg/dose).

Methadone See previous listing See previous listing.

Dyspnea Morphine, 0.1 mg/kg PO q4h prn* † All opioids may relieve dyspnea. For
immediate dyspnea, the starting dose is 30% of
release (i.e., the dose that would be administered
MSIR) for pain. §
Lorazepam 0.025-0.05 mg/kg IV/PO q6h, See previous listing
 up to 2 mg/dose
Respiratory Scopolamine 1.5 mg patch, change q72h (for Excessive drying of secretions can
secretions patch children >8-12 yr old) cause mucus plugging of airways.
Good for motion-induced nausea and
vomiting. Handling patch and
contacting eye may cause anisocoria
and blurry vision. May fold patches,
but do not cut them. Anticholinergic
side effects possible.
Glycopyrrolate 0.04-0.1 mg/kg PO q4-8h Powerful antisialagogue. Excessive
drying of secretions can cause mucus
plugging of airways. Anticholinergic
side effects possible. Quaternary
ammonium structure limits its ability
to cross lipid membranes, such as the
blood-brain barrier (in contrast to
atropine, scopolamine, and
hyoscyamine sulfate), so may exert
fewer central anticholinergic effects.
Hyoscyamine 4 gtt PO q4h prn if <2 yr Anticholinergic side effects possible,
sulfate 8 gtt PO q4h prn if 2-12 yr including sedation. May be given
Do not exceed 24 gtt/24 sublingually.
hr.
Atropine 1-2 gtt SL q4-6h prn Give 0.5% ophthalmic drops
sublingually.
Nausea Metoclopramide 0.1-0.2 mg/kg/dose q6h, up to Helpful when dysmotility is an
10 mg/dose (prokinetic and issue; may cause extrapyramidal
mild nausea dosing). For reactions, particularly in children
chemotherapy-associated following IV administration of
nausea, 0.5-1 mg/kg q6h prn high doses. Contraindicated in
PO/IV/SC; give with complete bowel obstruction or
diphenhydramine and continue pheochromocytoma.
diphenhydramine for 24 hr Avoid concomitant use with
after last dose of high-dose olanzapine.
metoclopramide to prevent
extrapyramidal reaction.
Ondansetron 0.15 mg/kg dose IV/PO q8h Significant experience in pediatrics.
prn. No single IV dose should Good empirical therapy for nausea in
exceed 16 mg due to risk of palliative care population. Oral
QT prolongation. dissolving tablet contains
phenylalanine. Higher doses used with
chemotherapy although single 32 mg
IV dose is no longer available (risk for
QT prolongation). Consider ECG
monitoring in patients with electrolyte
abnormalities, congestive heart failure,
bradyarrhythmias, or in patients taking
other medications with potential to
cause QT prolongation.
Dexamethasone 0.1 mg/kg/dose tid PO/IV; max Also helpful with hepatic capsular
dose 10 mg/day distension, bowel wall edema,
anorexia, increased ICP. May cause
mood swings or psychosis.
Lorazepam See previous listing. See previous listing
Dronabinol 2.5-5 mg/m2 /dose q3-4h Available in 2.5 and 5 mg capsules.
 May remove liquid contents from
capsules for children who cannot
swallow capsules. Avoid in patients
with sesame oil hypersensitivity or
history of schizophrenia. May cause
euphoria, dysphoria, or other mood
changes. Tolerance to CNS side effects
usually develops in 1-3 days of
continuous use. Avoid in patients with
depression or mania.
Scopolamine See previous listing. See previous listing
patch
Olanzapine 4-6 yr: 1.25 mg PO daily Little evidence to guide antiemetic
6-12 yr: 2.5 mg PO daily dosing. Ranges largely derived from
≥12 yr: 5 mg daily olanzapine dosing for other purposes.
Avoid concomitant use with
metoclopramide.
Anxiety Lorazepam See previous listing. See previous listing.
Agitation Haloperidol 0.01 mg/kg PO tid prn for May cause extrapyramidal reactions,
acute onset: 0.025-0.050 mg/kg which can be reversed with
PO, may repeat 0.025 mg/kg in diphenhydramine or Cogentin. Safety
1 hr prn not established in children <3 yr.
Sleep Lorazepam See previous listing. See previous listing.
disturbance/insomnia Trazodone Children 6-18 yr: 0.75-1 Potentially arrhythmogenic
mg/kg/dose, given bid-tid
if needed
If >18 yr, start at 25-50
mg/dose, given bid-tid if
needed
Fatigue Methylphenidate 0.3 mg/kg/dose titrated as Rapid antidepressant effect; also
needed, up to 60 mg/day improves cognition. Administer before
meals to avoid appetite suppression.
Use with caution in children at risk for
cardiac arrhythmia. Available as liquid
and chewable tablet.
Pruritus Diphenhydramine 0.5-1 mg/kg q6h IV/PO (100 May reverse phenothiazine-induced
mg max per day) dystonic reactions. Topical
formulation on large areas of the skin
or open area may cause toxic
reactions. May cause paradoxical
reaction in young children.
Hydroxyzine 0.5-1 mg/kg q6h IV/PO (600
mg max per day)

Constipation Docusate 40-150 mg/day PO in 1-4 Stool softener available as liquid or

divided doses capsule
Miralax Tasteless powder may be mixed in
<5 yr: scoop (8.5 g) in
beverage of choice. Now available
4 oz water daily
over the counter.
>5 yr: 1 scoop (17 g) in 8
oz water daily

Lactulose 5-10 mL PO up to q2h until Bowel stimulant; dosing q2h may

bowel movement cause cramping.
Senna 2.5 mL PO daily (for children Bowel stimulant; available as granules
>27 kg)
 Dulcolax 3-12 yr: 5-10 mg PO daily Available in oral or rectal formulation
>12 yr 5-15 mg PO daily
Pediatric Fleets 2.5 oz pediatric enema for May repeat ×1 if needed. Do not use in
Enema children 2-11 yr; adult enema neutropenic patients.
for children ≥12 yr
Methylnaltrexone 10-20 kg: 2 mg SC Peripherally acting opioid antagonist
21-33 kg: 4 mg SC for opioid-induced constipation.
34-46 kg: 6 mg SC Usually works within 30-60 min of
47.62 kg: 8 mg SC administration.
63-114 kg: 12 mg SC
≥155 kg: 0.15 mg/kg SC
Administer 1 dose every
other day as needed; max
1 dose/24 hr
Muscle spasm Diazepam 0.5 mg/kg/dose IV/PO q6h May be irritating if given by
prn peripheral IV line.
Initial dose for children <5
yr: 5 mg dose; for children
≥5 yr: 10 mg/dose
Baclofen 5 mg PO tid, increase by 5 Helpful with neuropathic pain and
mg/dose as needed. spasticity; abrupt withdrawal may
result in hallucinations and seizures;
not for children <10 yr
Seizures Lorazepam 0.1 mg/kg IV/PO/SL/PR;
repeat q10min ×2
Diazepam 0.1 mg/kg q6h (max 5 mg/dose May be given PR as Diastat (0.2
if <5 yr; max 10 mg/dose if >5 mg/kg/dose q15min ×3 doses)
yr)
Neuroirritability Gabapentin See previous listing.
Clonidine Starting dose: 0.05 mg/day. Transdermal patch may contain
May increase every 3-5 days metal (e.g., aluminum) that may
by 0.05 mg/day to 3-5 cause burns if worn during MRI
µg/kg/day given in divided scan. Remove patch prior to MRI.
doses 3-4 times/day; max dose
Patch may be cut into or
0.3 mg/day. May switch from
fractions based on dose needed.
oral to transdermal route once
optimal oral dose is
established. Transdermal dose
is equivalent to the total oral
daily dose (e.g., if total oral
dose is 0.1 mg/day, apply 1
patch (delivers 0.1 mg/day).
Change patch every 7 days.
Clonazepam <10 yr or <30 kg: initial
dose 0.01-0.03 mg/kg/day
divided tid
≥10 yr (≥30 kg): initial
dose up to 0.25 mg PO tid;
may increase by 0.5-1
mg/day every 3 days
Maintenance dose: 0.05-
0.2 mg/kg/day up to 20
mg/day
Anorexia Megestrol acetate 10 mg/kg/day in 1-4 divided For children >10 yr. Acute adrenal
doses, may titrate up to 15 insufficiency may occur with abrupt
 mg/kg/day or 800 mg/day withdrawal after long-term use. Use
with caution in patients with diabetes
mellitus or history of
thromboembolism. May cause
photosensitivity.
Dronabinol See previous listing. See previous listing.
Cyproheptadine Children ≥2 yr and Potent antihistamine and serotonin
adolescents: 0.08 mg/kg antagonist
PO q8h; if no benefit in 5
days, increase dose by
0.04-0.08 mg/kg/dose
Max daily dose: ≤6 yr: 12
mg/day; 7-14 yr: 16
mg/day; ≥15 yr: 32
mg/day
* Infants <6 mo should receive 25–30% of the usual opioid starting dose.

† Although the usual opioid starting dose is presented, dose may be titrated as needed. There is
no ceiling/maximum dose for opioids.
‡ Breakthrough dose is 10% of 24 hr dose. See Chapter 76 for information regarding titration of

opioids.
§ Side effects from opioids include constipation, respiratory depression, pruritus, nausea, urinary

retention, physical dependence.

Note: Some medications or dosing may not apply to infants (≤12 mo). Verify suitability and
dosing of all medications before administering to neonates.
IV, Intravenous(ly); PO, by mouth; PR, rectally; prn, as needed; gtt, drops; SC, subcutaneously;
bid, twice daily; tid, 3 times daily; q4h, every 4 hours; q30min, every 30 minutes; CNS, central
nervous system; ECG, electrocardiogram; ICP, intracranial pressure.
Adapted from Ullrich C, Wolfe J: Pediatric pain and symptom control. In Walsh TD, Caraceni AT,
Fainsinger R, et al: Palliative medicine , Philadelphia, 2008, Saunders).

Table 7.7
Nonpharmacologic Approach to Symptoms Commonly
Experienced by Children With Life-Threatening Illness

SYMPTOM APPROACH TO MANAGEMENT

Pain Prevent pain when possible by limiting unnecessary painful procedures, providing
sedation, and giving preemptive analgesia before a procedure (e.g., including sucrose for
procedures in neonates).
Address coincident depression, anxiety, sense of fear or lack of control.
Consider guided imagery, relaxation, hypnosis, art/pet/play therapy,
acupuncture/acupressure, biofeedback, massage, heat/cold, yoga, transcutaneous electric
nerve stimulation, distraction.

Dyspnea or air Suction oral secretions if present; positioning, comfortable loose clothing, fan to provide
hunger cool, blowing air.
Limit volume of intravenous fluids; consider diuretics if fluid overload/pulmonary edema
 present.
Behavioral strategies, including breathing exercises, guided imagery, relaxation, music,
distraction.
Fatigue Sleep hygiene (establish a routine, promote habits for restorative sleep).
Regular, gentle exercise; prioritize or modify activities.
Address potentially contributing factors (e.g., anemia, depression, side effects of
medications).
Aromatherapy* : peppermint, rosemary, basil.
Nausea/vomiting Consider dietary modifications (bland, soft, adjust timing/volume of foods or feeds).
Aromatherapy* : ginger, peppermint, lavender, acupuncture/acupressure.
Constipation Increase fiber in diet, encourage fluids, ambulation (if possible).
Oral Oral hygiene and appropriate liquid, solid and oral medication formulation (texture, taste,
lesions/dysphagia fluidity). Treat infections, complications (mucositis, pharyngitis, dental abscess, esophagitis).
Oropharyngeal motility study and speech (feeding team) consultation.
Anorexia/cachexia Manage treatable lesions causing oral pain, dysphagia, or anorexia. Support caloric intake
during phase of illness when anorexia is reversible. Acknowledge that anorexia/cachexia
is intrinsic to the dying process and may not be reversible.
Prevent/treat coexisting constipation.
Pruritus Moisturize skin.
Trim child's nails to prevent excoriation.
Try specialized anti-itch lotions.
Apply cold packs.
Counterstimulation, distraction, relaxation.
Diarrhea Evaluate/treat if obstipation.
Assess and treat infection.
Dietary modification.
Depression Psychotherapy, behavioral techniques, setting attainable daily goals.
Aromatherapy* : bergamot, lavender.
Anxiety Psychotherapy (individual and family), behavioral techniques.
Aromatherapy* : clary sage, angelica, mandarin, lavender.
Agitation/terminal Evaluate for organic or drug causes.
restlessness Educate family.
Orient and reassure child; provide calm, nonstimulating environment, use familiar music,
verse, voice, touch.
Aromatherapy* : frankincense, ylang ylang.
* Best if aromatherapy is administered by a practitioner trained in aromatherapy use and safety
and if child has choice of essential oil aroma that stimulates positive response.
From Sourkes B, Frankel L, Brown M, et al: Food, toys, and love: pediatric palliative care, Curr
Probl Pediatr Adolesc Health Care 35:345–392, 2005.

Many children with life-threatening illness experience pain that requires

opioids for adequate relief at some point in their illness trajectory. The WHO
pain guidelines recommend the first step for mild pain and the second step for
moderate to severe pain. Although it was previously recommended, prescribing
codeine should generally be avoided because of its side effect profile and lack of
superiority over nonopioid analgesics. Furthermore, relatively common genetic
polymorphisms in the CYP2D6 gene lead to wide variation in codeine
metabolism. Specifically, 10–40% of individuals carry polymorphisms causing
them to be poor metabolizers who cannot convert codeine to its active form,
chronic medical problems that are not always immediately evident, including
malnutrition, growth deficiencies; stool pathogens, anemia, elevated blood lead,
dental decay, strabismus, birth defects, developmental delay, feeding and sensory
difficulty, and social-emotional concerns. All children who are adopted from
other countries undergo comprehensive screening for infectious diseases and
disorders of growth, development, vision, and hearing (Tables 8.1 and 8.2 ).
Regardless of test results before arrival, all children should be screened for
tuberculosis with either a tuberculin skin test (TST) or interferon-γ release
assays (IGRA). If the child's purified protein derivative (PPD) skin test is
negative, it should be repeated in 4-6 mo; children may have false-negative tests
because of poor nutrition. Additional tests (e.g., malaria) should be ordered
depending on the prevalence of disease in the child's country of origin (see
Chapter 10 ). Immunization records should be carefully reviewed.
Internationally adopted children frequently have incomplete records or have
been vaccinated using alternative schedules. Pediatricians may choose to check
titers to determine which vaccines need to be given, or they can choose to
reimmunize the child. The unique medical and developmental needs of
internationally adopted children have led to the creation of specialty clinics
throughout the United States, which may be a valuable resource for adoptive
families at all stages in the adoption process and throughout the adopted child's
life.
Table 8.1
Recommended Screening Tests for
International Adoptees on U.S. Arrival
Screening Tests

Complete blood cell count

Blood lead level
Newborn screening (young infants)
Vision and hearing screening
Dental screening
Developmental testing

Other Screening Tests to Consider Based on Clinical Findings and

Age of Child
 Stool cultures for bacterial pathogens
Glucose-6-phosphate dehydrogenase deficiency screening
Sickle cell test
Urine pregnancy test

INFECTIOUS DISEASE SCREENING (see Table 8.2 )

Table 8.2
Screening Tests for Infectious Diseases in
International Adoptees
Recommended Tests

Hepatitis A total Ig (with reflex testing for IgM if total Ig is positive)

Hepatitis B virus serologic testing*
• Hepatitis B surface antigen (HBsAg)
• Antibody to hepatitis B surface antigen (anti-HBs)
• Antibody to hepatitis B core antigen (anti-HBc)
Hepatitis C virus serologic testing* †
Syphilis serologic testing
• Nontreponemal test (RPR, VDRL, or ART)
• Treponemal test (MHA-TP or FTA-ABS)
HIV-1 and HIV-2 testing (ELISA if >18 mo, PCR if <18 mo)*
Complete blood cell count with red blood cell indices and differential (if
eosinophilia, see Chapter 10 )
Stool examination for ova and parasites (optimal: 3 specimens) with
specific requests for Giardia lamblia and Cryptosporidium spp. testing
Tuberculin skin test (with CXR if >5 mm induration) or interferon-γ
release assay* †

Optional Tests (for Special Populations or Circumstances)

GC/Chlamydia
Strongyloides spp.
Schistosoma spp.
Trypanosoma cruzi
 ART, Automated reagin test; CXR, chest radiograph; ELISA, enzyme-linked
immunosorbent assay; FTA-ABS, fluorescent treponemal antibody absorption;
GC, gonococcus; HIV, human immunodeficiency virus; MHA-TP,
microhemagglutination test for Treponema pallidum ; PCR, polymerase chain
reaction; RPR, rapid plasma reagin; VDRL, Venereal Disease Research
Laboratories.

* Repeat 3-6 mo after arrival.

† See Chapter 10 .

Growth Delays
Physical growth delays are common in internationally adopted children and may
represent the combined result of many factors, such as unknown/untreated
medical conditions, malnutrition, and psychological deprivation. It is more
important to monitor growth over time, including preplacement measurements,
since trend data may provide a more objective assessment of the child's
nutritional and medical status. Children who present with low height-for-age
(growth stunting ) may have a history of inadequate nutrition as well as chronic
adversity. Although most children experience a significant catch-up in physical
growth following adoption, many remain shorter than their U.S. peers.

Developmental Delays
Many children adopted internationally exhibit delays in at least 1 area of
development, but most exhibit significant gains within the 1st 12 mo after
adoption. Children adopted at older ages are likely to have more variable
outcomes. In the immediate post-adoption period, it may be impossible to
determine with any certainty whether developmental delays will be transient or
long-lasting. Careful monitoring of development within the first years of
adoption can identify a developmental trend over time that may be more
predictive of long-term functioning than assessment at any specific point in time.
When in doubt, it is better to refer early for developmental intervention, rather
than wait to see if the children will catch up.

Language Development
inadequate health services before placement into foster care mean that children
enter foster care with a high prevalence of chronic medical, mental health,
developmental, dental, and educational problems (Table 9.1 ). Thus they are
defined as children with special health care needs (CSHCN). The greatest single
healthcare need of this population is for high-quality, evidence-based trauma-
informed mental health services to address the impacts of prior and ongoing
trauma, loss, and unpredictability. In addition, children in foster care have higher
rates of asthma, growth failure, obesity, vertically transmitted infections, and
neurologic conditions than the general pediatric population. Adolescents need
access to reproductive health and substance abuse services. Up to 60% of
children <5 yr old have a developmental delay in at least 1 domain and >40% of
school-age children qualify for special education services. Unfortunately,
educational difficulties persist despite improvements in school attendance and
performance after placement in foster care. Each placement change that is
accompanied by a change in school sets children back academically by about 4
mo. Federal legislation requires child welfare to maintain children in their school
of origin when possible, even if child welfare has to provide transportation to
ensure this.
Table 9.1
Health Issues of Children in Foster Care
Chronic Medical Problems

Affect 40–60% of children.

Asthma, dermatologic, neurologic, obesity, growth failure, hearing, and
vision problems are most common.

Abuse and Neglect

>70% of children have a history of abuse and neglect at entry into foster
care.
Monitor at all health visits for abuse or neglect or poor care in the home.

Complex Chronic Medical Problems

 Involves up to 10% of children in foster care.
Children may be dependent on medical technologies or may have multiple
disabilities.

Mental Health Concerns

Affects 80% of children >4 yr of age.

Result of childhood trauma and adversity.
Most common diagnoses are adjustment disorder, posttraumatic stress
disorder, attention-deficit/hyperactivity disorder, oppositional defiant
disorder, and conduct disorder.
Externalizing problems are more likely to result in therapy.
Minority children and those in kinship care have less access to mental
health services.

Developmental Problems

60% of children <5 yr of age have at least 1 documented delay.

Typically affect communication, cognition, problem-solving, and personal-
social domains, including emotional self-regulation.

Dental Problems

20–35% of children have significant dental disease.

Adolescent Health Issues

High rates of sexually transmitted infections, high-risk behaviors, and

substance abuse.

Educational Problems

Half of special education placements relate to behavioral or emotional

issues, not cognitive.
Only 32% of adolescents eventually graduate from high school; 32%
 obtain a general equivalency diploma; 1–2% complete any amount of
college.

Family Relationship Problems

100% of children have family relationship problems.

Although children in foster care are CSHCN, they often lack access to the
services they need. Most public and private child welfare agencies do not have
formal arrangements for accessing the needed array of health services and rely
on local physicians and health clinics funded by Medicaid. Health histories are
often sparse at admission because many have lacked regular care, or their
biological parents may not be available or forthcoming. Once children enter
foster care, there is often a diffusion of responsibility across caregivers and child
welfare. Foster parents usually receive little information about a child's
healthcare needs, but they are typically expected to decide when and where
children receive healthcare services. Child welfare caseworkers are responsible
for ensuring that a child's health needs are addressed but coordination across
multiple healthcare providers may be daunting. Uncertainty about who is legally
responsible for making healthcare treatment decisions and who may have access
to health information may delay or result in the denial of healthcare services.

Healthcare for Children and Adolescents

in Foster Care
The American Academy of Pediatrics (AAP) has published detailed healthcare
standards for children in foster care, available on the Healthy Foster Care
America website. The AAP recommends that children receive healthcare
services in a medical home setting, where comprehensive healthcare is
continuous over time (Table 9.2 ). Compassionate, culturally competent
healthcare that is trauma informed means that health staff should understand,
recognize, and respond to symptoms and risk factors of traumatic stress and
provide an environment that offers physical, emotional, and psychological safety
for children and caregivers. In foster care, attention must be paid to the effects of
past trauma and the impact of ongoing uncertainty and loss on a child's health
and well-being, as well as that of their birth and foster/kinship families.

Table 9.2

Trauma-Informed Pediatric Medical Home for Children in Foster Care

CHARACTERISTIC APPLICATION IN FOSTER CARE
Comprehensive Perform comprehensive admission assessment within 30 days of entry.
healthcare Ensure access to mental health, developmental, and dental evaluation and services.
Screen and refer as needed for abuse and neglect.
Coordination of care Make timely referrals and follow up subspecialist visits.
Communicate with caseworkers, foster parents, and legal professionals.
Maintain a comprehensive medical record despite changes in placement.
Compassionate care Understand and educate children, families, and other healthcare professionals on the
impact of early childhood adversities, trauma, and ongoing uncertainties of foster
care on the developing child.
Promote positive purposeful parenting strategies and minimizing conflict among
caregivers.
Child-centered and Prioritize the needs of children first and foremost.
family-focused care Partner with families to increase understanding of a child's needs.
Focus on the strengths of children and caregivers.
Understand the conflicts for the child of belonging in multiple families.
Continuity of care Invite children to remain patients throughout their stay in foster care, and beyond when
feasible.
Cultural competence Extend this concept to include the microculture of foster care and the multiple
transitions that can further erode a child's well-being.
Understand the roles of caseworkers, foster parents, law guardians, etc.
Understand the importance of quality visitation for family reunification.
Accessibility Create a welcoming environment for children and all their families (birth, foster, kin,
preadoptive).

The trauma-informed office is one in which symptoms such as dysregulation

of sleep, behavioral problems, developmental delays, poor school function, and
somatic complaints are recognized as potential effects of childhood trauma.
Understanding the child's psychosocial context and history, as well as that of the
caregiver, and exploring their strengths, assets, and challenges are the foundation
of a trauma-informed approach. The office should have print resources for
education of families and child welfare professionals and a list of helpful local
community resources. Referral to trauma-informed pediatric mental health
services, when available, should be considered in collaboration with caregivers,
child welfare, and educators. Continuity of care is very important for the child
in foster care and includes ongoing monitoring and management of progress and
care. The AAP has several resources for caring for traumatized children.*
Several recommendations are specific to the care of children and youth in
foster care. Children should be seen early and often when they first enter a new
placement to identify all their health issues, and to support the child and
Table 9.3

Trauma-Informed Anticipatory Guidance for Children in Foster Care

SITUATION ANTICIPATORY GUIDANCE FOR FOSTER PARENTS
Preparing for Educate foster/kinship parents about impact of visitation on children and ways to improve the
visits experience for children.
Send familiar object with child to visit.
Have child draw picture to give birth parent.
Reassure child that foster parent will be there when child returns from visits.
Advise all caregivers to minimize conflict with and negativity toward each other.
Ideally, visits are coached by trained professionals.
Returning Greet child warmly and help with unpacking.
from visits Establish reentry rituals, such as quiet play, reading together, active play, having a healthy
and other snack.
transitions
Relationship Encourage caseworker to have birth parents keep child's rituals and routines consistent with
with birth those in foster/kinship home (vice versa when appropriate).
parent(s) Focus on birth parent's positive qualities; maintain a neutral or positive affect;.
Building on Encourage participation in child-directed play.
child's Time-in with child.
strengths Encourage participation in normalizing activities (e.g., hobbies, sports)
“Catch the child being good.”
Give specific praise.
Practice attentive listening.
Provide child with words for emotions.
Ignore negative behavior or redirect unless there is a safety issue.
Preparing for Foster/kinship parent, caseworker or law guardian should explain purpose of court hearings to
court dates child in simple terms.
School If changing schools, visit school together a few times, and meet teacher.
Check in regularly (weekly or monthly depending on need) with child's teacher.
Adolescent Decide what issues demand firm limits and guidelines (e.g., curfews, no smoking, party at a
friend's house), what issues are not important and can be left up to teen (e.g., hair length and
color), and what issues are ideal for negotiation (e.g., transportation to school function, style
of dress).
Encourage responsible decision-making by recognizing and complimenting it.
Encourage after-school activities.
Teach driving when age and developmentally appropriate.
Encourage teen to seek employment and teach job skills.
Help teen to identify mentors and focus on the future.

Bibliography
AAP District II Task Force on Health Care for Children in
Foster Care, District II Committee on Early Childhood,
Adoption, and Dependent Care. Fostering health: health care
for children and adolescents in foster care . AAP.: Elk Grove,
IL; 2005 [Available through the American Academy of
is limited tracking of refugees as they move to different cities or states. Thus,
many foreign-born children have had minimal pre- or postarrival screening for
infectious diseases or other health issues.
Immunization requirements and records also vary depending on entry status.
Internationally adopted children who are younger than 10 yr are exempt from
Immigration and Nationality Act regulations pertaining to immunization of
immigrants before arrival in the United States. Adoptive parents are required to
sign a waiver indicating their intention to comply with U.S.-recommended
immunizations, whereas older immigrants need only show evidence of up-to-
date, not necessarily complete, immunizations before application for permanent
resident (green card) status after arrival in the United States.
Infectious diseases are among the most common medical diagnoses identified
in immigrant children after arrival in the United States. Children may be
asymptomatic; therefore, diagnoses must be made by screening tests in addition
to history and physical examination. Because of inconsistent perinatal screening
for hepatitis B and hepatitis C viruses, syphilis, and HIV, and the high
prevalence of certain intestinal parasites and tuberculosis, all foreign-born
children should be screened for these infections on arrival in the United States.
Table 10.1 lists suggested screening tests for infectious diseases. Table 10.2 lists
incubation periods of common internationally acquired diseases. In addition to
these infections, other medical and developmental issues, including hearing,
vision, dental, and mental health assessments; evaluation of growth and
development; nutritional assessment; lead exposure risk; complete blood cell
count with red blood cell indices; microscopic urinalysis; newborn screening
(this could also be done in non-neonates) and/or measurement of thyroid-
stimulating hormone concentration; and examination for congenital anomalies
(including fetal alcohol syndrome) should be considered as part of the initial
evaluation of any immigrant child.*
Table 10.1
Screening Tests for Infectious Diseases in
International Adoptees and Foreign-Born
(Immigrant) Children
Recommended Tests

Hepatitis B virus serologic testing*

 • Hepatitis B surface antigen (HBsAg)
• Antibody to hepatitis B surface antigen (anti-HBs)
Hepatitis C virus serologic testing* †
Hepatitis A virus serologic testing †
Varicella virus serologic testing †
Syphilis serologic testing
• Nontreponemal test (RPR, VDRL, or ART)
• Treponemal test (MHA-TP or FTA-ABS)
Human immunodeficiency viruses 1 and 2 testing (ELISA if >18 mo, PCR
if <18 mo)*
Complete blood cell count with red blood cell indices and differential (if
eosinophilia, see text)
Strongyloides serology
Stool examination for O&P (2-3 specimens) †
Stool examination for Giardia lamblia and Cryptosporidium antigen (1
specimen) †
Tuberculin skin test (with CXR if >5 mm induration) or interferon-γ
release assay* †

Optional Tests (for Special Populations or Circumstances)

GC/Chlamydia
Chagas disease serology (endemic areas)
Malaria, thick and thin smears (endemic areas)
Filaria testing (endemic areas)
Urine for O&P for schistosomiasis, if hematuria present
Stool testing for enteric bacteria and viruses in children with diarrhea

ART, Automated reagin test; CXR, chest radiograph; ELISA, enzyme-linked

immunosorbent assay; FTA-ABS, fluorescent treponemal antibody absorption;
GC, gonococcus; MHA-TP, microhemagglutination test for Treponema
pallidum ; O&P, ova and parasites; PCR, polymerase chain reaction; RPR, rapid
plasma reagin; VDRL, Venereal Disease Research Laboratories.
* Repeat 3-6 mo after arrival.

† See text.

Table 10.2
Incubation Periods of Common Travel-Related Infections*

LONG
MEDIUM INCUBATION (10-21
SHORT INCUBATION (<10 DAYS) INCUBATION
DAYS)
(>21 DAYS)
Malaria Malaria Malaria
Arboviruses including dengue, yellow fever, Japanese Flaviviruses: tick-borne Schistosomiasis
encephalitis, Zika, chikungunya encephalitis and Japanese Tuberculosis
Hemorrhagic fevers: Lassa, Ebola, South American encephalitis Acute HIV
arenaviruses Hemorrhagic fevers: Lassa, Ebola, infection
Respiratory viruses including severe acute respiratory Crimean-Congo Viral hepatitis
syndrome Acute HIV infection Filariasis
Typhoid and paratyphoid Typhoid and paratyphoid Rickettsia: Q fever
Bacterial enteritis Giardia Secondary syphilis
Rickettsia : spotted fever group—Rocky Mountain Rickettsia : flea-borne, louse- Epstein-Barr virus
spotted fever, African tick typhus, Mediterranean borne, and scrub typhus, Q fever, including
spotted fever, scrub typhus, Q fever spotted fevers (rare) mononucleosis
Bacterial pneumonia including Legionella Cytomegalovirus Amoebic liver
Relapsing fever Toxoplasma disease
Amoebic dysentery Amoebic dysentery Leishmaniasis
Meningococcemia Histoplasmosis Brucella
Brucella (rarely) Brucella Bartonellosis
Leptospirosis Leptospirosis (chronic)
Fascioliasis Babesiosis Babesiosis
Rabies (rarely) Rabies Rabies
African trypanosomiasis (acute), East African (rarely) East African trypanosomiasis West African
(acute) trypanosomiasis
Hepatitis A (rarely) (chronic)
Measles Cytomegalovirus
* Diseases that commonly have variable incubation periods are shown more than once. However,
most diseases may rarely have an atypical incubation period, and this is not shown here.
HIV, Human immunodeficiency virus.
From Freedman DO: Infections in returning travelers. In Bennett JE, Dolin R, Blaser MJ, editors:
Mandell, Douglas, and Bennett's principles and practice of infectious diseases, ed 8, Philadelphia,
2015, Elsevier (Table 324-2).

Children should be examined within 1 mo of arrival in the United States, or

earlier if there are immediate health concerns, but foreign-born parents may not
access the healthcare system with their children unless prompted by illness,
school vaccination, or other legal requirements. It is important to assess the
completeness of previous medical screenings at any first visit with a foreign-born
Physicians and patients bring to their interactions diverse orientations from
multiple cultural systems. These different belief systems and practices could
have significant implications for the delivery of healthcare (Table 11.1 ).
Consequently, physician cultural awareness, sensitivity, and humility is critical
to successful patient–provider interaction.

Table 11.1
Culturally Informed Care
1. Respects the beliefs, values, and lifestyles of patients
2. Understands that health and illness are influenced by ethnic and cultural orientation, religious and spiritual
beliefs, and linguistic considerations
3. Has insight into one's own cultural biases; doesn't see “cultural issues” as something that only affects the
patient
4. Is sensitive to how differences in power and privilege affect the clinical encounter
5. Recognizes that the culturally constructed meaning of illness and health is as important a clinical issue as the
biomedical aspects of disease
6. Sensitive to within group variations in beliefs and practices; avoids stereotyping

The culturally informed physician (1) attempts to understand and respect the
beliefs, values, attitudes, and lifestyles of patients; (2) understands that health
and illness are influenced by ethnic and cultural orientation, religious and
spiritual beliefs, and linguistic considerations; (3) has insight into own cultural
biases and does not see cultural issues as something that only affects the patient;
(4) is sensitive to how differences in power and privilege may affect the quality
of the clinical encounter; (5) recognizes that in addition to the physiologic
aspects of disease, the culturally and psychologically constructed meaning of
illness and health is a central clinical issue; and (6) is sensitive to intragroup
variations in beliefs and practices and avoids stereotyping based on any group
affiliation. These core components of culturally-informed care are important for
interactions with all patients, regardless of race or ethnicity. Culturally sensitive
clinical care is essentially generally sensitive clinical care.
Becoming culturally informed is a developmental process. Fig. 11.1 displays a
framework that includes a continuum of perceptions and orientations to cultural
awareness. Individuals in the denial stage perceive their own cultural orientation
as the true one, with other cultures either undifferentiated or unnoticed. In the
defensive stage, other cultures are acknowledged but regarded as inferior to one's
own culture. The minimization stage is characterized by beliefs that fundamental
similarities among people outweigh any differences, and downplays the role of
culture as a source of human variation. The idea that one should be “color blind”
is an example of a common belief of individuals in the minimization stage.

FIG. 11.1 Development of intercultural sensitivity. (Adapted from Bennett MJ: A
developmental approach to training for intercultural sensitivity, Int J Intercultural
Relations 10(2):179–196, 1986.)

As one moves to the acceptance stage, cultural differences are acknowledged.

Further expansion and understanding lead to adaptation , where one not only
acknowledges differences but can shift frames of reference and have a level of
comfort outside one's own cultural frame. This eventually leads to further
comfort with different worldviews seen at the integration stage, where
individuals respect cultural differences and can comfortably interact across
cultures, even incorporating aspects of different cultural orientations into their
own.

Understanding Culture in the Context of

Healthcare
Cultural orientation is just one of many different perspectives that individuals
draw on as they make health and healthcare decisions. Individual psychology,
past experiences, religious and spiritual views, social position, socioeconomic
status, and family norms all can contribute to a person's health beliefs and
practices. These beliefs and practices can also change over time and may be
expressed differently in different situations and circumstances. Because of the
significant variability in health beliefs and behaviors seen among members of
the same cultural group, an approach to cultural competency that emphasizes a
knowledge set of specific cultural health practices in different cultural groups
could lead to false assumptions and stereotyping. Knowledge is important, but it
 chance of being followed by security guards at stores, or having their
bags checked. They have a greater chance of having a positive reception
in a new neighborhood, or of finding food in the supermarket that is
consistent with one's heritage. These privileges typically go unnoticed
by members of the majority culture, but their absence is painfully
recognized by members of nonmajority cultural groups. The culturally
informed physician should try to be mindful of these privileges, and how
they may influence the interaction between physicians and patients.
4. Be inquisitive. Because of the significant amount of intracultural
diversity of beliefs and practices, the only way to know a particular
patient's approach to issues concerning health and illness is through
direct and effective communication. Asking about the patient's/family's
perspective in an inquisitive and respectful manner will usually be met
with open and honest responses, as long as the patient does not feel
looked down on and the questions are asked in genuine interest.
Obtaining a health beliefs history is an effective way of understanding
clinical issues from the patient's and family's perspective (Table 11.2 ).
The health beliefs history gathers information on the patient's views on
the identification of health problems, causes, susceptibility, signs and
symptoms, concerns, treatment, and expectations. Responses gathered
from the health beliefs history can be helpful in guiding care plans and
health education interventions.
Table 11.2

The Health Beliefs His tory

• What do you think is wrong with your child?
• Why do you think your child has gotten it [the illness]?
• What do you think caused it?
• Why do you think it started when it did?
• What do you think is happening inside the body?
• What are the symptoms that make you know your child has this illness?
• What problems does this illness cause your child?
• What are you most worried about with this illness?
• How long do you think it will last?
• How do you treat it?
• What will happen if it is not treated?
• What do you expect from the treatments?

Adapted from Kleinman A, Eisenberg L, Good B: Culture, illness, and care: clinical lessons
from anthropologic and cross-cultural research, Ann Intern Med 88(2):251–258, 1978.
 Once the patient's explanatory model is elicited and understood, the clinician
should be able to assess the congruity of this model and the biomedical model,
finding similarities. Then the process of negotiating can occur. Integrating
patient-held approaches to health with evidence-based biomedical standards of
care will help place care within the lifestyle and worldview of patients, leading
to increased adherence to medical care plans, better physician–patient
communication, enhanced long-term therapeutic relationship, and improved
patient (and physician) satisfaction.

11.1
Culture-Specific Beliefs
Robert M. Kliegman

Cultural group-specific practices that affect health-seeking behaviors are noted

in Tables 11.3 and 11.4 .

Table 11.3
Cultural Values* Relevant to Health and Health-Seeking
Behavior

CULTURAL RELEVANT CULTURAL NORMS

GROUP Description of Norm Consequences of Failure to Appreciate
Latino Fatalismo: Fate is predetermined, reducing belief in Less preventive screening
the importance of screening and prevention.
Simpática: Politeness/kindness in the face of Nonadherence to therapy, failure to make
adversity—expectation that the physician should be follow-up visits
polite and pleasant, not detached.
Personalismo: Expectation of developing a warm, Refusal to divulge important parts of medical
personal relationship with the clinician, including history, dissatisfaction with treatment
introductory touching.
Respeto: Deferential behavior on the basis of age, Mistaking a deferential nod of the head/not
social stature, and economic position, including asking questions for understanding; anger at
reluctance to ask questions. not receiving due signs of respect
Familismo: Needs of the extended family outrank Unnecessary conflict, inability to reach a
those of the individual, and thus family may need to decision
 be consulted in medical decision-making.
Muslim Fasting during the holy month of Ramadan: fasting Inappropriate therapy; will not take
from sunrise to sundown, beginning during the teen medicines during daytime misinterpreted as
years. Women are exempted during pregnancy, noncompliance; misdiagnosed
lactation, and menstruation, and there are
exemptions for illness, but an exemption may be
associated with a sense of personal failure.
Modesty: Women's body, including hair, body, Deep personal outrage, seeking alternative
arms, and legs, not to be seen by men other than in care
immediate family. Female chaperone and/or
husband must be present during exam, and only that
part of the body being examined should be
uncovered.
Touch: Forbidden to touch members of the opposite Patient discomfort, seeking care elsewhere
sex other than close family. Even a handshake may
be inappropriate.
After death , body belongs to God. Postmortem Unnecessary intensification of grief and loss
examination will not be permitted unless required
by law; family may wish to perform after-death
care.
Cleanliness essential before prayer. Individual must Affront to religious beliefs
perform ritual ablutions before prayer, especially
elimination of urine and stool. Nurse may need to
assist in cleaning if patient is incapable.
God's will: God causes all to happen for a reason, Allopathic medicine will be rejected if it
and only God can bring about healing. conflicts with religious beliefs, family may
not seek healthcare.
Patriarchal , extended family. Older male typically Child's mother or even both parents may not
is head of household, and family may defer to him be able to make decisions about child's care;
for decision-making. emergency decisions may require additional
time.
Halal (permitted) vs haram (forbidden) foods and Refusal of medication, religious effrontery
medications. Foods and medicine containing
alcohol (some cough and cold syrups) or pork
(some gelatin-coated pills) are not permitted.
Native Nature provides the spiritual, emotional, physical, Spiritual living is required of Native
American social, and biologic means for human life; by caring Americans; if treatments do not reflect this
for the earth, Native Americans will be provided view, they are likely not to be followed.
for. Harmonious living is important.
Passive forbearance: Right of the individual to Mother's failure to intervene in a child's
choose his or her path. Another family member behavior and/or use of noncoercive
cannot intervene. disciplinary techniques may be mistaken for
neglect.
Natural unfolding of the individual. Parents further Many pediatric preventive practices will run
the development of their children by limiting direct counter to this philosophy.
interventions and viewing their natural unfolding.
Talking circle format to decision-making. Lecturing, excluding the views of elders, is
Interactive learning format including diverse tribal likely to result in advice that will be
members. disregarded.
African- Great heterogeneity in beliefs and culture among Risk of stereotyping and/or making
American African-Americans. assumptions that do not apply to a specific
patient or family.
Extended family and variations in family size and Advice/instructions given only to the parent
childcare arrangements are common; matriarchal and not to others involved in health decision-
decision-making regarding healthcare. making may not be effective.
 Parenting style often involves stricter adherence to Advice regarding discipline may be
rules than seen in some other cultures. disregarded if it is inconsistent with
perceived norms; other parenting styles may
not be effective.
History-based widespread mistrust of medical In patient noncompliance, physicians will be
profession and strong orientation toward culturally consulted as a last resort.
specific alternative/complementary medicine.
Greater orientation toward others; the role of an Compliance may be difficult if the needs of 1
individual is emphasized as it relates to others individual are stressed above the needs of the
within a social network. group.
Spirituality/religiosity important; church attendance
Loss of opportunity to work with the church
central in most African American families. as an ally in healthcare
East and Long history of Eastern medicines (e.g., Chinese May engage with multiple health systems
Southeast medicine) as well as more localized medical (Western biomedical and traditional) for
Asian traditions. treatment of symptoms and diseases
Extended families and care networks. Grandparents Parents may not be the only individuals a
may provide day-to-day care for children while physician needs to communicate with in
parents work outside of the home. regard to symptoms, follow-through on
treatments, and preventive behaviors.
Sexually conservative. Strong taboos for premarital Adolescents may be reluctant to talk about
sexual relationships, especially for women. issues of sexuality, pregnancy, and birth
control with physicians. Recent immigrants
or native populations may have less
knowledge regarding pregnancy prevention,
sexually transmitted infections, and HIV.
Infant/child feeding practices may overemphasize Guidelines for child nutrition and feeding
infant's or child's need to eat a certain amount of practices may not be followed out of concern
food to stay “healthy.” for child's well-being.
Saving face. This is a complex value whereby an Avoid statements that are potentially value
individual may lose prestige or respect of a 3rd laden or imply a criticism of an individual.
party when a 2nd individual makes negative or Use statements such as, “We have now found
contradictory statements. that it is better to …,” rather than criticizing
a practice.
* Adherence to these or other beliefs will vary among members of a cultural group based on

nation of origin, specific religious sect, degree of acculturation, age of patient, etc.

Table 11.4
Examples of Disease Beliefs and Health Practices in Select
Cultures

CULTURAL
BELIEF OR PRACTICE
GROUP
Latino Use of traditional medicines (nopales, or cooked prickly pear cactus, as a hypoglycemic agent)
along with allopathic medicine.
Recognition of disorders not recognized in Western allopathic medicine (empacho , in which food
adheres to the intestines or stomach), which are treated with folk remedies but also brought to the
pediatrician.
Cultural interpretation of disease (caida de mollera or “fallen fontanel”) as a cultural interpretation
of severe dehydration in infants.
Muslim Female genital mutilation: practiced in some Muslim countries; the majority do not practice it, and
it is not a direct teaching of the Koran.
Koranic faith healers: use verses from the Koran, holy water, and specific foods to bring about
recovery.
Native Traditional “interpreters” or “healers” interpret signs and answers to prayers. Their advice may be
American sought in addition or instead of allopathic medicine.
Dreams are believed to provide guidance; messages in the dream will be followed.
East and Concepts of “hot” and “cold,” whereby a combination of hot and cold foods and other
Southeast substances (e.g., coffee, alcohol) combine to cause illness. One important aspect is that
Asian Western medicines are considered “hot” by Vietnamese, and therefore nonadherence may
occur if it is perceived that too much of a medicine will make their child's body “hot.” Note:
Hot and cold do not refer to temperatures but are a typology of different foods; for example,
fish is hot and ginger is cold.
Foods, teas, and herbs are also important forms of medicine because they provide balance
between hot and cold.

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content, and method to foster critical consciousness in
medical students: a comprehensive model for cultural
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Fisher-Borne M, Cain JM, Martin SL. From mastery to
accountability: cultural humility as an alternative to cultural
competence. Soc Work Educ . 2015;34(2):165–181.
Foronda C, Baptiste DL, Reinholdt MM, Ousman K. Cultural
humility: a concept analysis. J Transcult Nurs .
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use and misuse of culture in medical education. Acad Med .
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Hook JN, Davis DE, Owen J, et al. Cultural humility:
 FIG. 12.1 Recommendations for preventive pediatric healthcare. (From Bright Futures
/American Academy of Pediatrics. Copyright 2017, American Academy of Pediatrics,
Elk Grove Village, IL. https://www.aap.org/en-us/documents/periodicity_schedule.pdf
.)

Comprehensive guides for care of well infants, children, and adolescents have
been developed based on the Periodicity Schedule to expand and further
recommend how practitioners might accomplish the tasks outlined. The current
guideline standard is The Bright Futures Guidelines for Health Supervision of
Infants, Children, and Adolescents , 4th edition
(https://brightfutures.aap.org/Pages/default.aspx ). These guidelines were
developed by AAP under the leadership of the Maternal Child Health Bureau of
the U.S. Department of Health and Human Services, in collaboration with the
National Association of Pediatric Nurse Practitioners, American Academy of
Family Physicians, American Medical Association, American Academy of
Pediatric Dentistry, Family Voices, and others.

Tasks of Well-Child Care

The well-child encounter aims to promote the physical and emotional well-being
of children and youth. Child health professionals, including pediatricians, family
medicine physicians, nurse practitioners, and physician assistants, take
CHAPTER 13

Injury Control
Brian D. Johnston, Frederick P. Rivara

In all high-income countries of the world, and increasingly in many low- and
middle-income countries, injuries are the most common cause of death during
childhood and adolescence beyond the 1st few mo of life (Table 13.1 and Fig.
13.1 ). Injuries represent one of the most important causes of preventable
pediatric morbidity and mortality in the United States. Identification of risk
factors for injuries has led to the development of successful programs for
prevention and control. Strategies for injury prevention and control should be
pursued by the pediatrician in the office, emergency department (ED), hospital,
and community setting and should be done in a multidisciplinary, multifaceted
way.

Table 13.1
Injury Deaths in the United States, 2015* [N (Rate per
100,000)]

CAUSE OF DEATH <1 yr 1-4 yr 5-9 yr 10-14 yr 15-19 yr 0-19 yr

ALL CAUSES 23,161 (583.4) 4045 (25.3) 2490 (12.2) 3013 (14.6) 10,812 (51.2) 43,521 (53.0)
ALL INJURIES 1616 (40.70) 1660 (10.40) 960 (4.70) 1468 (7.12) 8148 (39.03) 13,952 (16.99)
All unintentional 1219 (30.70) 1261 (7.90) 787 (3.85) 847 (4.11) 4152 (19.65) 8266 (10.07)
Motor vehicle occupant 26 (0.65) 80 (0.50) 111 (0.54) 144 (0.70) 748 (3.54) 1109 (1.35)
Pedestrian 12 (0.30) 175 (1.10) 98 (0.48) 117 (0.57) 329 (1.56) 731 (0.89)
Drowning 38 (0.96) 425 (2.66) 147 (0.72) 103 (0.50) 253 (1.20) 966 (1.18)
Fire and burn 13 (0.33) 107 (0.67) 78 (0.38) 52 (0.25) 35 (0.17) 285 (0.35)
Poisoning 9 (0.23) 34 (0.21) 13 (0.06) 28 (0.14) 771 (3.65) 855 (1.04)
Bicycle 0 (0.00) 6 (0.04) 15 (0.07) 38 (0.18) 45 (0.21) 104 (0.13)
Firearm 1 (0.03) 34 (0.21) 16 (0.08) 23 (0.11) 53 (0.25) 127 (0.15)
Fall 7 (0.16) 19 (0.12) 5 (0.02) 14 (0.07) 66 (0.31) 111 (0.14)
Suffocation 1023 (25.77) 118 (0.74) 35 (0.17) 39 (0.19) 43 (0.20) 1258 (1.53)
All intentional 276 (6.95) 339 (2.12) 146 (0.71) 585 (2.84) 3959 (18.74) 5305 (6.46)
Suicide 0 (0.00) 0 (0.00) 7 (0.03) 436 (2.11) 2117 (10.02) 2560 (3.12)
 Firearm suicide 0 (0.00) 0 (0.00) 0 (0.00) 160 (0.78) 942 (4.46) 1102 (1.34)
Homicide 276 (6.95) 339 (2.12) 139 (0.68) 147 (0.71) 1816 (8.59) 2717 (3.13)
Firearm homicide 11 (0.28) 64 (0.40) 68 (0.33) 95 (0.46) 1611 (7.62) 1849 (2.25)
Undetermined intent 121 (3.05) 60 (0.38) 27 (0.13) 36 (0.17) 137 (0.65) 381 (0.46)
* Injury data from US Centers for Disease Control and Prevention (CDC): Web-based Injury

Statistics Query and Reporting System (WISQARS) (website). National Center for Injury
Prevention and Control, CDC (producer). https://www.cdc.gov/injury/wisqars/ .
All-cause data from CDC, National Center for Health Statistics: Compressed Mortality File 1999–
2015, Series 20, No 2U, 2016, as compiled from data provided by the 57 vital statistics
jurisdictions through the Vital Statistics Cooperative Program, CDC WONDER online database,
October 2018.

FIG. 13.1 Global injury deaths to children, adolescents, and young adults, 0-29 yr of
age, 2012. (From WHO: Injuries and Violence: The Facts 2012. Geneva: World Health
Organization, 2014.)

Injuries have identifiable risk and protective factors that can be used to define
prevention strategies. The term accidents implies a chance event occurring
without pattern or predictability. In fact, most injuries occur under fairly
predictable circumstances to high-risk children and families. Most injuries are
preventable.
Reduction of morbidity and mortality from injuries can be accomplished not
only through primary prevention (averting the event or injury), but also through
secondary and tertiary prevention. The latter 2 approaches include appropriate
stressed families, and to live in hazardous environments.
Efforts to control injuries include education or persuasion, changes in product
design, and modification of the social and physical environment. Efforts to
persuade individuals, particularly parents, to change their behaviors have
constituted the greater part of injury control efforts. Speaking with parents
specifically about using child car-seat restraints and bicycle helmets, installing
smoke detectors, and checking the tap water temperature is likely to be more
successful than offering well-meaning but too-general advice about supervising
the child closely, being careful, and childproofing the home. This information
should be geared to the developmental stage of the child and presented in
moderate doses in the form of anticipatory guidance at well-child visits. Table
13.2 lists important topics to discuss at each developmental stage. It is important
to acknowledge that there are many barriers to prevention adherence beyond
simple knowledge acquisition; pediatricians should be familiar with low-cost
sources for safety equipment such as bicycle helmets, smoke detectors, trigger
locks, and car seats in their community.
Table 13.2
Injury Prevention Topics for Anticipatory
Guidance by the Pediatrician
Newborn

Car seats
Tap water temperature
Smoke detectors
Sleep safe environments

Infant

Car seats
Tap water temperature
Bath safety
Choking prevention

Toddler and Preschooler

 Car seats and booster seats
Water safety
Poison prevention
Fall prevention

Primary School Child

Pedestrian skills training

Water skills training
Booster seats and seat belts
Bicycle helmets
Safe storage of firearms in the home

Middle School Child

Seatbelts
Safe storage of firearms in the home
Water skills training
Sports safety and concussion prevention

High School and Older Adolescent

Seatbelts
Alcohol and drug use, especially while driving and swimming
Mobile phone use while driving
Safe storage of firearms
Sports safety and concussion prevention
Occupational injuries

The most successful injury prevention strategies generally are those involving
changes in product design . These passive interventions protect all individuals
in the population, regardless of cooperation or level of skill, and are likely to be
more successful than active measures that require repeated behavior change by
the parent or child. The most important and effective product changes have been
in motor vehicles, in which protection of the passenger compartment and use of
vehicle deaths among children and adolescents. The peak injury and death rate
for both males and females in the pediatric age-group occurs between 15 and 19
yr (see Table 13.1 ). Proper restraint use in vehicles is the single most effective
method for preventing serious or fatal injury. Table 13.3 shows the
recommended restraints at different ages. Fig. 13.5 provides examples of car
safety seats.

Table 13.3
Recommended Child-Restraint Methods
INFANTS TODDLERS (1-3) YOUNG CHILDREN
Recommended Birth to 1 yr or Older than 1 yr and weight Weight 40-80 lb and height under 4 ft 9 in;
age/weight below weight limit 20-40 lb. generally between 4 and 8 yr of age.
requirements of seat.
Type of seat Infant-only or rear-Convertible or forward- Belt-positioning booster seat.
facing convertible. facing harness seat.
Seat position Rear-facing only. Can be rear-facing until 30 Forward-facing. Place in back seat of vehicle.
Place in back seat lb if seat allows; generally
of vehicle. forward-facing. Place in
back seat of vehicle.
Notes Children should use Harness straps should be at Belt-positioning booster seats must be used
rear-facing seat or above shoulder level. with both lap and shoulder belts.
until at least 1 yr
and at least 20 lb.
Harness straps Most seats require top strap Make sure that lap belt fits low and tightly
should be at or for forward-facing use. across lap/upper thigh area, and that shoulder
below shoulder belt fits snugly, crossing chest and shoulder to
level. avoid abdominal injuries.
Data from http://www.safercar.gov/parents/CarSeats.htm .

FIG. 13.5 Car safety seats. A, Rear-facing infant seat. B, Forward-facing child harness
seat. C, Forward-facing convertible harness seat. D, Low-back booster seat. E, High-
back booster seat. (From Ebel BE, Grossman DC: Crash proof kids? An overview of
current motor vehicle child occupant safety strategies, Curr Probl Pediatr Adolesc
Health Care 33:33–64, 2003. Source: NHTSA.)

Much attention has been given to child occupants <8 yr old. Use of child-
restraint devices, infant car seats, and booster seats can be expected to reduce
fatalities by 71% and the risk of serious injuries by 67% in this age-group. All 50
depression and posttraumatic stress disorder (PTSD) as well as externalizing
problems, including delinquent behavior, aggression, and substance abuse.
The most ubiquitous source of witnessing violence for U.S. children is media
violence , sometimes referred to as virtual violence . This form of violence is
not experienced physically; rather it is experienced in realistic ways through
technology and ever more intense and realistic games. There is an ever-widening
array of screens that are part of children's everyday lives, including computers,
tablets, and cell phones, in addition to long-standing platforms, such as
televisions and movies. Recent tragic events, including mass shootings and acts
of terrorism, have increased the specter of fear among children as these events
are reenacted for them on the multiple screens they encounter. Although
exposure to media/virtual violence cannot be equated to exposure to real-life
violence, many studies confirm that media/virtual violence desensitizes children
to the meaning and impact of violent behavior. Violent video game exposure is
associated with: an increased composite aggression score; increased aggressive
behavior; increased aggressive cognitions; increased aggressive affect, increased
desensitization, and decreased empathy; and increased physiological arousal.
Violent video game use is a risk factor for adverse outcomes; however,
insufficient data exist to examine any potential link between violent video game
use and delinquency or criminal behavior. Table 14.1 lists interventions to reduce
exposure to media violence.
Table 14.1
Public Health Recommendations to Reduce
Effects of Media Violence on Children and
Adolescents

Parents should:
• Be made aware of the risks associated with children viewing
violent imagery, as it promotes aggressive attitudes, antisocial
behavior, fear, and desensitization.
• Review the nature, extent, and context of violence in media
available to their children before children view.
• Assist children's understanding of violent imagery appropriate to
their developmental level.
Professionals should:
 • Offer support and advice to parents who allow their children
unsupervised access to extreme violent imagery, as this could
be seen as a form of emotional abuse and neglect.
• Educate all young people in critical film appraisal, in terms of
realism, justification, and consequences.
• Exercise greater control over access to inappropriate violent
media entertainment by young people in secure institutions.
• Use violent film material in anger management programs under
guidance.
Media producers should:
• Reduce violent content, and promote antiviolence themes and
publicity campaigns.
• Ensure that when violence is presented, it is in context and
associated with remorse, criticism, and penalty.
• Ensure that violent action is not justified, or its consequences
understated.
Policymakers should:
• Monitor the nature, extent, and context of violence in all forms
of media, and implement appropriate guidelines, standards, and
penalties.
• Ensure that education in media awareness is a priority and a part
of school curricula.

From Browne KD, Hamilton-Giachritsis C: The influence of violent media on

children and adolescents: a public-health approach, Lancet 365:702–710, 2005.

Impacts of Violence
All types of violence have a profound impact on health and development both
psychologically and behaviorally; it may influence how children view the world
and their place in it. Children can come to see the world as a dangerous and
unpredictable place. This fear may thwart their exploration of the environment,
which is essential to learning in childhood. Children may experience
overwhelming terror, helplessness, and fear, even if they are not immediately in
danger. Preschoolers are most vulnerable to threats that involve the safety (or
perceived safety) of their caretakers. High exposure to violence in older children
Refugee Agency, reported the astounding statistic of 65.6 million people forcibly
displaced worldwide.
Mortality and morbidity related to the long-term effects of war and civil strife
are often higher than that occurring during actual fighting. War and violence are
not listed as leading causes of childhood mortality, but the regions with the
highest levels of child mortality, especially among children <5 yr of age, are the
same locations involved in military conflicts. Nations experiencing conflict
devote substantial portions of their budgets to military expenditures at the
expense of the healthcare infrastructure; a substantial proportion of deaths
attributed to malnutrition, environmentally related infectious disease, or
inadequate immunization are related to the effects of war. Children experiencing
the trauma of wartime violence are at risk for long-term health sequelae, with
greater risk for obesity, hypertension, stroke, and cardiovascular disease.
During wartime, customary patterns of behavior are forced to change,
overcrowding is frequent, and essential resources, such as water and food
staples, may be polluted or contaminated. War is associated with plagues and
epidemics, and novel disease entities can develop. Reemergence of polio or
cholera and the increased virulence of tuberculosis have been associated with
conflict-affected regions and large population displacements.
The morbidity of children exposed to conflicts is significant (Table 14.2 ).
Many more children are physically harmed than killed. Children bear the
psychological scars of war resulting from exposure to violent events, loss of
primary caregivers, and forced removal from their homes. Impressment of
children into service as soldiers or agents is a form of exploitation associated
with long-term problems of adjustment, because child soldiers often lack the
appropriate education and socialization and thus their moral compass is often
misaligned. They are often incapable of understanding the sources of conflict or
why they have been targeted. Their thought processes are more concrete; it is
easier for them to dehumanize their adversaries. Children, who themselves are
exposed to violence and cruelty, frequently become the worst perpetrators of
atrocities.
Table 14.2
Impact of War on Children
Physical
 Death
Rape
Abduction
Injuries
Amputations and fractures
Head trauma
Ballistic wounds
Blast injuries
Burns
Chemical and biologic induced
Malnutrition and starvation
Infectious disease
Displacement

Psychosocial

Loss of caregivers and family members

Separation from community
Lack of education
Inappropriate socialization
Acute stress reaction
Posttraumatic stress disorder
Depression
Maladaptive behavior

Exploitation

Conscription as soldiers
Coerced involvement in terrorist activities
Prostitution
Slavery
Forced adoption

After cessation of hostilities, children are still at risk for life-endangering

injuries from landmines , unexploded ordnance, and other explosive remnants of
war. Prior to the signing of the international treaty to ban landmines in 1997, an
relatives may traumatize children and even encourage inappropriate behavior.
Overt broadcast propaganda glorifying war and violence may sway children to
participate in militaristic or antisocial activities.

Psychological Impact of War

Exposure to war and violence can have a significant impact on a child's
psychosocial development. Displacement, loss of caregivers, physical suffering,
and the lack of appropriate socialization all contribute to abnormal child
development (see Table 14.2 ). Often the reactions are age specific (Table 14.3 ).
Preschoolers may have an increase in somatic complaints and sleep disturbances
and display acting-out behaviors such as tantrums or excessively clinging
behavior. School-age children may show regressive behavior such as enuresis
and thumb sucking. They, too, have an increase in somatic complaints; there is
often a negative impact on school performance. For teenagers, psychological
withdrawal and depression are common. Adolescents often exhibit trauma-
stimulated acting-out behavior. Motivated by the desire for revenge, they may be
quick to join in the violence and contribute to the continuation of conflict.
Table 14.3
Manifestations of Stress Reactions in
Children and Adolescents Exposed to War,
Terrorism, and Urban Violence
Children ≤6 Yr

Excessive fear of separation

Clinging behavior
Uncontrollable crying or screaming
Freezing (persistent immobility)
Sleep disorders
Terrified affect
Regressive behavior
Expressions of helplessness and passivity

Children 7-11 Yr
 Decline in school performance
Truancy
Sleep disorders
Somatization
Depressive affect
Abnormally aggressive or violent behavior
Irrational fears
Regressive and childish behavior
Expressions of fearfulness, withdrawal, and worry

Adolescents 12-17 Yr

Decline in school performance

Sleep disturbances
Flashbacks
Emotional numbness
Antisocial behavior
Substance abuse
Revenge fantasies
Suicidal ideation
Withdrawal

There is an increased incidence of both acute stress reactions and

posttraumatic stress disorder (PTSD; see Chapter 38 ). The true incidence is
difficult to assess because of the heterogeneous nature of war, degree of
exposure to violence, and methodologic challenges related to the precise
characterization of PTSD. Risk factors for having a more serious psychological
response to a violent event include severity of the incident, personal involvement
(physical injury, proximity, loss of a relative), prior history of exposure to
traumatic events, female gender, and a dysfunctional parental response to the
same event. Children may develop PTSD many years after the traumatic event.
Children do not have to be directly exposed to violent activity, and media
coverage of terrorist events may be sufficient to trigger PTSD.
The trauma experienced by children during war can have lifelong effects.
Studies on children imprisoned in concentration camps or evacuated from their
homes in London during the Battle of Britain show that these individuals were at
CHAPTER 15

Child Trafficking for Sex and Labor

V. Jordan Greenbaum

Human trafficking violates the fundamental human rights of child and adult
victims and impacts families, communities, and societies. Trafficked persons
originate from countries worldwide and may belong to any racial, ethnic,
religious, socioeconomic, or cultural group. They may be of any gender.
According to the United Nations Protocol to Prevent, Suppress and Punish
Trafficking in Persons , child trafficking refers to the “recruitment,
transportation, transfer, harboring or receipt of a person” under 18 yr old for
purposes of exploitation. Two major types of trafficking involve forced labor
and sexual exploitation (Table 15.1 ). While adult sex trafficking requires
demonstration of force, fraud, coercion, deception, or the abuse of power as a
means of exploitation, these are not required for persons younger than 18 yr.
Interpretation of the international protocol varies across the globe; U.S. law does
not require movement of a victim to qualify as human trafficking. In addition,
minors who “consent” to commercial sex in the absence of a third party
(trafficker) are victims of commercial sexual exploitation, because their age
precludes true informed consent.
Table 15.1
Types of Exploitation Included in Child
Trafficking
Sexual Exploitation

Prostitution of a child
Production of child sexual exploitation materials (child pornography)
Exploitation in context of travel and tourism
Engaging child in sex-oriented business
 Child marriage or forced marriage
Live online sexual abuse

Labor Exploitation

Occurs in a variety of sectors, such as agriculture, manufacturing, textiles,

food/hospitality services; domestic work; construction, magazine sales,
health and beauty, and cleaning services

Forced Begging
Forced Criminality
Forced Engagement in Armed Conflict
Illegal Adoption

The word victim is used in this chapter in the legal sense and refers to a person
who has been harmed as a result of a crime or other event. It is not intended to
imply any subjective interpretation of the person's feelings about his/her
situation or imply any judgment about that person's resilience.
Child trafficking may occur within the confines of the child's home country
(domestic trafficking) or may cross national borders (international , or
transnational , trafficking). Globally, victims tend to be trafficked within their
own country or to a country in the same region. In the United States, most
identified child sex trafficking victims are U.S. citizens or legal residents; few
statistical data exist on victims of child labor trafficking. Variations in definitions
of terms, problems with data collection, and underrecognition of victims
complicate estimates of the prevalence of human trafficking, but the
International Labour Organization estimates that 5.5 million of the world's
children are victims of forced labor (this includes human trafficking). In a study
of 55,000 officially identified trafficking victims, the United Nations Office on
Drugs and Crime estimated that approximately 17% were girls and 10% boys.
However, laws that define sexual exploitation in terms of girls and women, as
well as cultural views regarding gender roles, lead to underreporting of boys,
especially as victims of sex trafficking, so their numbers may be higher than
estimated.
Factors creating vulnerability to human trafficking exist at the individual,
family, community, and societal levels (Table 15.2 ). Age is an important risk
factor for adolescents since they are at a stage in their development at which they
have limited life experience, a desire to demonstrate their independence from
parental control, and a level of brain maturation that favors risk-taking and
impulsive behaviors over careful situational analysis and other executive
functions. They are also very interested in social media and are savvy at internet
use, which render them susceptible to online recruitment and solicitation.
Table 15.2
Vulnerability Factors for Child Trafficking
Individual

Member of marginalized group (racial, ethnic, sexual minority, caste, etc.)

History of sexual/physical abuse or neglect
Limited education
Substance misuse
Homeless status; runaway; told to leave home
History of child welfare and/or juvenile justice involvement (U.S., sex
trafficking)
Untreated mental health or behavioral condition
Significantly older intimate partner

Family

Poverty
Violence, substance misuse, other dysfunction
Migration

Community

Limited resources (economic, educational, social support)

Tolerance of trafficking/exploitation
Social or political upheaval
Natural disaster
Violence
Limited knowledge of trafficking/exploitation
 Increased tourism, travel to area

Societal

Cultural beliefs about roles and rights of children

Gender bias/discrimination
Tolerance of marginalization, exploitation
Sexual objectification of girls
Tolerance of violence
Economic disparities

Recruitment of child victims for labor or sex trafficking often involves false
promises of romance, job opportunities, or a better life. Children may remain in
their exploitative situation for a number of reasons, including fear of violence to
themselves or their loved ones should they attempt escape; guilt and shame for
believing the fraudulent recruitment scheme or engaging in illegal and/or
socially condemned activities; humiliation and fear of criticism by authorities;
debt bondage (believing they owe the trafficker exorbitant amounts of money
and cannot leave until the debt is paid), and fear of arrest and/or deportation.
Many children do not recognize their victimization. Girls who believe their
trafficker is a boyfriend may view their commercial sexual activities as
demonstrations of their love; boys engaging in commercial sex to obtain shelter
or food while living on the street may feel they are exploiting buyers rather than
being victimized. Traffickers may use violence, economic manipulation, and
psychological manipulation to control their victims.

Clinical Presentation
Trafficked persons may seek medical care for any of the myriad physical and
emotional consequences of exploitation. They may present with traumatic
injuries inflicted by traffickers, buyers, or others or injuries related to unsafe
working conditions. They may present with a history of sexual assault, or
symptoms/signs of sexually transmitted infections (STIs) and infections related
to overcrowded, unsanitary conditions. They may request testing for HIV or
complain of signs/symptoms of HIV or infections endemic to the victim's home
country (e.g., malaria, schistosomiasis, tuberculosis). Other clinical presentations
may involve pregnancy and complications of pregnancy or abortion;
malnutrition and/or dehydration; exhaustion; conditions related to exposure to
toxins, chemicals, and dust; and signs and symptoms of posttraumatic stress
disorder (PTSD), major depression, suicidality, behavioral problems with
aggression, and somatization. Some children may have preexisting chronic
medical conditions that have been inadequately treated before or during the
exploitation (e.g., diabetes, seizure disorder, asthma). Trafficked persons may
also seek care for medical issues related to their children.
Many of the same factors that keep victims trapped in their exploitative
conditions also preclude them from disclosing their situation to others. Most
victims presenting for medical care at clinics, hospitals, and emergency
departments do not self-identify as trafficked persons. Consequently, it is
incumbent on the medical professional to be aware of risk factors so that
potential victims may be recognized and offered services. A trafficked child may
present to a medical facility alone, in the company of a parent/guardian (who
may or may not be aware of the trafficking situation), a friend or other person
not involved in the trafficking, a person working for the trafficker (who may
pose as a friend or relative), or the trafficker. Traffickers may be male or female,
adult or juvenile, and they may be family members, acquaintances, friends, or
strangers. On occasion, children are brought in by law enforcement or child
protective services, as known or suspected victims. Table 15.3 lists possible
indicators of labor or sex trafficking. In some cases, the best indicator is the
chief complaint , which may be a condition frequently associated with
trafficking (e.g., teen pregnancy, STI symptoms/signs (especially with history of
prior STI), preventable work-related injury). The practitioner may become
concerned about possible trafficking on recognizing the presence of 1 or more
risk factors (runaway status; recent migration and current work in sector known
for labor trafficking).
Table 15.3
Possible Indicators of Child Trafficking
Indicators at Presentation

Chief complaint of acute physical or sexual assault

Chief complaint of suicide attempt
Child accompanied by unrelated adult or juvenile
 Child or parent accompanied by domineering person who appears in hurry
to leave; child/parent appears intimidated, fearful
Child or accompanying person provides inconsistent or unlikely history of
events
Child does not know city he or she is in, or address where staying

Physical Findings

Child withdrawn and with flat affect; fearful; very anxious; intoxicated; or
with inappropriate affect
Motel key(s), multiple cell phones, large amounts of cash, or a few
expensive items (clothing, nails, etc.)
Tattoos (especially with street names or sexual innuendo)
Evidence of remote or acute inflicted injury (suspicious burns, bruising,
signs of strangulation, fractures, closed head injury, thoracoabdominal
trauma)
Malnutrition and/or poor hygiene
Poor dentition and/or dental trauma
Late presentation of illness/injury

Approach to the Potentially Trafficked

Child
When interacting with a possible victim of trafficking, the medical provider
should use a trauma-informed, human rights–based, culturally appropriate,
and gender-sensitive approach (Table 15.4 ). This involves being aware that
trauma experienced by children may influence their thoughts about themselves
and others, their beliefs and perceptions of the world, and their behavior.
Hostility, withdrawal, or distrust may be reactions to trauma and should be met
with a sensitive, nonjudgmental, empathic response by the provider. Physical
safety of the patient and staff are critical, and protocols should be in place to
address security issues that may arise if the trafficker is on the premises.
Psychological safety of the patient may be facilitated by separating them from
any accompanying person when obtaining the medical history, conducting the
visit in a warm, child-friendly environment, taking adequate time to build
rapport and begin to establish trust, and ensuring that any interpreter used is not
from the same community as the patient and is trained in human trafficking.
Table 15.4
Elements of Human Rights–Based, Trauma-
Informed Approach to Patient Care
Basic Rights

Best interest of the child to be primary concern in all actions involving the
child
Protection from discrimination because of gender, race, ethnicity, culture,
socioeconomic status, disability, religion, language, country of origin, or
other status
Right to express views and be heard, appropriate to child's age and
development
Right to obtain information relevant to child, to be given in a way that
children understand
Right to privacy and confidentiality
Right to highest attainable standard of health and to access healthcare
services
Right to dignity, self-respect
Right to consideration of special needs (age, disability, etc.)
Right to respect of cultural and religious beliefs and practices

Trauma-Informed Care

Strength-based approach; facilitate patient resilience and empowerment.

Obtain medical history in private, safe place, outside presence of persons
accompanying child to visit.
Explain all processes in way child understands, and obtain assent for each
step; discuss limits of confidentiality and mandated reporting.
Encourage patient to express views and to participate in decision-making
regarding referrals and care.
Foster patient's sense of control during evaluation.
Ask only the questions needed to assess safety, health, and well-being.
Avoid asking irrelevant questions about trauma, to avoid unnecessarily
be obtained by contacting the National Human Trafficking Resource Center
(1-888-3737-888). The NHTRC has trained staff to assist victims and
professionals alike, including interpreters for over 100 languages. Additional
assistance may be obtained by contacting state or local law enforcement and
antitrafficking task forces or local child advocacy centers. In some countries,
“helplines” and “hotlines” may be used to seek assistance for suspected
trafficking victims. It is important for the healthcare provider to be aware of
local, state, and national resources for trafficking victims. Exploited persons
have numerous needs that extend beyond the range of the healthcare provider's
ability to respond. A multidisciplinary team approach is needed to ensure the
child is provided with necessary food, shelter, crisis management, language
interpretation, immigration assistance, mental health and medical care,
educational needs, and other services. Such a team may include local victim
service providers, shelter staff, behavioral health professionals, child protective
services (CPS) workers, law enforcement, child advocacy center staff, sexual
assault providers, and victim advocates. Table 15.5 lists potential health-related
referrals.
Table 15.5
Potential Health Referrals for Trafficked
Persons
Behavioral health assessment and treatment (emergent or nonurgent):
trauma-focused, preferably conducted by professional trained in trauma
therapies*
Substance abuse assessment/treatment
Obstetrician/gynecologist
Specialized medical service
Primary medical home (for immunizations including HPV, periodic STI
testing, monitoring of growth and development, family planning,
anticipatory guidance, nutrition/hygiene counseling, etc.)
Physical therapy, occupational therapy
Developmental assessment
Dentist
Optometrist or audiologist
Resources for LGBTQ
HIV clinic
 Child advocacy center (for 2nd opinion on exam; forensic interview,
behavioral health services)

HPV, Human papillomavirus; HIV, human immunodeficiency virus; LGBTQ,

lesbian, gay, bisexual, transgender, and questioning; STI, sexually transmitted
infection.

* Appropriate therapy may differ with victims from varied cultures; there is a

very limited evidence-base for effectiveness of behavioral health therapy for

trafficked children. However, therapies with an evidence base for child sexual
assault/abuse are often used in the U.S.

Trafficked victims may face considerable social stigma and discrimination .

They may be viewed as consenting participants, illegal immigrants who deserve
maltreatment, or “bad kids” who are responsible for their own actions. In some
countries, laws on sexual exploitation do not include boys, and cultural beliefs
foster the attitude that males cannot be victimized. Variations in the age of
consent may result in a child being considered an adult in one country and a
child in another. For these reasons and others, it is important for the healthcare
provider to advocate for the child's victim status when interacting with other
professionals and emphasize the need for comprehensive, sustained, trauma-
informed services.
Prior to discharge, the provider should ensure the patient understands the
results of the evaluation and the treatment plan, has a safety plan, and is aware of
options for future care. When referrals are being made, it is helpful for the
provider to take steps to ensure services are actually obtained by following up
with the referral staff, sending medical records (as appropriate and with victim
consent), and assisting the victim with arrangements as feasible. It is also helpful
to counsel the victim on their basic human rights, including their right to medical
care. If responsible for long-term care of the child, the provider should consider
that treatment needs change over time, so treatment plans must be reevaluated
periodically. Continuity of care is important but can be challenging when the
child is moved to another city, is transported back to the home country, or is re-
trafficked. Communication and collaboration with external agencies and
healthcare providers can be extremely helpful, along with assignment of a case

FIG. 16.1 Percentage of children ages 2-14 yr who experienced any
violent discipline (physical punishment and/or psychological aggression) in
the past month, by country. (United Nations Children's Fund, Hidden in
Plain Sight: A statistical analysis of violence against children. UNICEF, New
York, 2014, Fig 2. http://www.data.unicef.org/resources/hidden-in-plain-
sight .)

FIG. 16.2 Percentage of children ages 2-14 yr who experienced
psychological aggression and percentage of children ages 2-14 yr who
experienced physical punishment in the past month, by country, 2005–
2006. (United Nations Children's Fund, Hidden in Plain Sight: A statistical
analysis of violence against children. UNICEF, New York, Fig 2.
http://www.data.unicef.org/resources/hidden-in-plain-sight .)

United States
Abuse and neglect mostly occur behind closed doors and often are a well-kept
secret. Nevertheless, there were 4 million reports to CPS involving 7.2 million
children in the United States in 2015. Of the 683,000 children with substantiated
reports (9.2 per 1,000 children), 78.3% experienced neglect (including 1.9%
medical neglect), 17.2% physical abuse, 8.4% sexual abuse, and 6.2%
psychological maltreatment. While there had been a decline in rates beginning in
the early 1990s, rates increased in 2014 and 2015 from prior years. Likewise, the
rate of hospitalized children with serious physical abuse has not declined in
recent years. Medical personnel made 9.1% of all reports.
Other sources independent from the official CPS statistics cited above confirm
the prevalence of child maltreatment. In a community survey, 3% of parents
reported using very severe violence (e.g., hitting with fist, burning, using gun or
knife) against their child in the prior year. Considering a natural disinclination to
disclose socially undesirable information, such rates are both conservative and
alarming.

Etiology
Child maltreatment seldom has a single cause; rather, multiple and interacting
biopsychosocial risk factors at 4 levels usually exist. To illustrate, at the
individual level , a child's disability or a parent's depression or substance abuse
predispose a child to maltreatment. At the familial level , intimate partner (or
domestic) violence presents risks for children. Influential community factors
include stressors such as dangerous neighborhoods or a lack of recreational
facilities. Professional inaction may contribute to neglect, such as when the
treatment plan is not clearly communicated. Broad societal factors , such as
poverty and its associated burdens, also contribute to maltreatment. WHO
estimates the rate of homicide of children is approximately 2-fold higher in low-
income compared to high-income countries (2.58 vs 1.21 per 100,000
population), but clearly homicide occurs in high-income countries too. Children
in all social classes can be maltreated, and child healthcare professionals need to
guard against biases concerning low-income families.
In contrast, protective factors , such as family supports, or a mother's concern
for her child, may buffer risk factors and protect children from maltreatment.
Identifying and building on protective factors can be vital to intervening
effectively. One can say to a parent, “I can see how much you love [child's
name]. What can we do to keep her out of the hospital?” Child maltreatment
results from a complex interplay among risk and protective factors. A single
mother who has a colicky baby and who recently lost her job is at risk for
maltreatment, but a loving grandmother may be protective. A good
understanding of factors that contribute to maltreatment, as well as those that are
Table 16.1

Injury Patterns
METHOD OF
PATTERN OBSERVED
INJURY/IMPLEMENT
Grip/grab Relatively round marks that correspond to fingertips and/or thumb
Closed-fist punch Series of round bruises that correspond to knuckles of the hand
Slap Parallel, linear bruises (usually petechial) separated by areas of central sparing
Belt/electrical cord Loop marks or parallel lines of petechiae (the width of the belt/cord) with central
sparing; may see triangular marks from the end of the belt, small circular lesions
caused by the holes in the tongue of the belt, and/or a buckle pattern
Rope Areas of bruising interspersed with areas of abrasion
Other objects/household Injury in shape of object/implement (e.g., rods, switches, and wires cause linear
implements bruising)
Human bite Two arches forming a circular or oval shape, may cause bruising and/or abrasion
Strangulation Petechiae of the head and/or neck, including mucous membranes; may see
subconjunctival hemorrhages
Binding/ligature Marks around the wrists, ankles, or neck; sometimes accompanied by petechiae or
edema distal to the ligature mark
Marks adjacent to the mouth if the child has been gagged
Excessive hincar * Abrasions/burns, especially to knees
Hair pulling Traumatic alopecia; may see petechiae on underlying scalp, or swelling or tenderness
of the scalp (from subgaleal hematoma)
Tattooing or intentional Abusive cases have been described, but can also be a cultural phenomenon (e.g.,
scarring Maori body ornamentation)
*
Punishment by kneeling on salt or other rough substance.

Other conditions such as birthmarks and congenital dermal melanocytosis

(e.g., mongolian spots) can be confused with bruises and abuse. These skin
markings are not tender and do not rapidly change color or size. An underlying
medical explanation for bruises may exist, such as blood dyscrasias (hemophilia)
or connective tissue disorders (Ehlers-Danlos syndrome). The history or
examination usually provides clues to these conditions. Henoch-Schönlein
purpura, the most common vasculitis in young children, may be confused with
abuse. The pattern and location of bruises caused by abuse are usually different
from those due to a coagulopathy. Noninflicted bruises are characteristically
anterior and over bony prominences, such as shins and forehead. The presence of
a medical disorder does not preclude abuse.
Cultural practices can cause bruising. Cao gio, or coining, is a Southeast
Asian folkloric therapy. A hard object is vigorously rubbed on the skin, causing
petechiae or purpura. Cupping is another approach, popular in the Middle East.
A heated glass is applied to the skin, often on the back. As it cools, a vacuum is
 FIG. 16.4 Marks from heated objects cause burns in a pattern that
duplicates that of the object. Familiarity with the common heated objects
that are used to traumatize children facilitates recognition of possible
intentional injuries. The location of the burn is important in determining its
cause. Children tend to explore surfaces with the palmar surface of the
hand and rarely touch a heated object repeatedly for long.

FIG. 16.5 Immersion injury patterns. A, Sparing of the flexoral creases. B, Immersion
“stocking” burn. C, Immersion “glove” burn. D, Immersion buttocks burn. (From Jenny
C: Child abuse and neglect: diagnosis, treatment, and evidence, Philadelphia, 2011,
Saunders, p. 225, Fig 28-3)

Several conditions mimic abusive burns, such as brushing against a hot

radiator, car seat burns, hemangiomas, and folk remedies such as moxibustion.
Impetigo may resemble cigarette burns. Cigarette burns are usually 7-10 mm
across, whereas impetigo has lesions of varying size. Noninflicted cigarette
burns are usually oval and superficial.
Neglect frequently contributes to childhood burns. Children, home alone, may
be burned in house fires. A parent taking drugs may cause a fire and may be
unable to protect a child. Exploring children may pull hot liquids left unattended
onto themselves. Liquids cool as they flow downward so that the burn is most
severe and broad proximally. If the child is wearing a diaper or clothing, the
fabric may absorb the hot water and cause burns worse than otherwise expected.
Some circumstances are difficult to foresee, and a single burn resulting from a
momentary lapse in supervision should not automatically be seen as neglectful
parenting.
Concluding whether a burn was inflicted depends on the history, burn pattern,
and the child's capabilities. A delay in seeking healthcare may result from the
burn initially appearing minor, before blistering or becoming infected. This
circumstance may represent reasonable behavior and should not be automatically
deemed neglectful. A home investigation is often valuable (e.g., testing the water
temperature).
Fractures that strongly suggest abuse include classic metaphyseal lesions,
posterior rib fractures, and fractures of the scapula, sternum, and spinous
processes, especially in young children (Table 16.2 ). These fractures all require
more force than would be expected from a minor fall or routine handling and
activities of a child. Rib and sternal fractures rarely result from cardiopulmonary
resuscitation (CPR), even when performed by untrained adults. The
recommended 2-finger or 2-thumb technique recommended for infants since
2005 may produce anterolateral rib fractures. In abused infants, rib (Fig. 16.6 ),
metaphyseal (Fig. 16.7 ), and skull fractures are most common. Femoral and
humeral fractures in nonambulatory infants are also very worrisome for abuse.
With increasing mobility and running, toddlers can fall with enough rotational
force to cause a spiral, femoral fracture. Multiple fractures in various stages of
healing are suggestive of abuse; nevertheless, underlying conditions need to be
considered. Clavicular, femoral, supracondylar humeral, and distal extremity
fractures in children older than 2 yr are most likely noninflicted unless they are
multiple or accompanied by other signs of abuse. Few fractures are
pathognomonic of abuse; all must be considered in light of the history and the
child's developmental level. Fractures may present as an irritable fussy child.
Table 16.2
Specificity of Radiologic Findings for
Fractures
High Specificity*

Classic metaphyseal lesions

Rib fractures, especially posteromedial
Scapular fractures
Spinous process fractures
Sternal fractures

Moderate Specificity

Multiple fractures, especially bilateral

Fractures of different ages
Epiphyseal separations
Vertebral body fractures and subluxations
Digital fractures
Complex skull fractures
Pelvic fractures

Common but Low Specificity

Subperiosteal new bone formation

Clavicular fractures
Long-bone shaft fractures
Linear skull fractures

* Highest specificity applies in infants.

From Kleinman PK: Diagnostic imaging of child abuse , ed 3, Cambridge, UK,

2015, Cambridge University Press, p 24.

FIG. 16.6 High-detail oblique view of the ribs of a 6 mo old infant shows
multiple healing posteromedial rib fractures (arrowheads ). The level of
detail in this image is far greater than what would be present on a standard
chest radiograph. (From Dwek JR: The radiographic approach to child
abuse, Clin Orthop Relat Res 469:776–789, 2011, p 780, Fig 4.)

FIG. 16.7 A, Metaphyseal fracture of the distal tibia in a 3 mo old infant

admitted to the hospital with severe head injury. There is also periosteal
new bone formation of the tibia, perhaps from previous injury. B, Bone scan
 of same infant. Initial chest radiograph showed a single fracture of the right
posterior 4th rib. A radionuclide bone scan performed 2 days later revealed
multiple previously unrecognized fractures of the posterior and lateral ribs.
C, Follow-up radiographs 2 wk later showed multiple healing rib fractures.
This pattern of fracture is highly specific for child abuse. The mechanism of
these injuries is usually violent squeezing of the chest.

The differential diagnosis includes conditions that increase susceptibility to

fractures, such as osteopenia and osteogenesis imperfecta, metabolic and
nutritional disorders (e.g., scurvy, rickets), renal osteodystrophy, osteomyelitis,
congenital syphilis, and neoplasia. Some have pointed to possible rickets and
low but subclinical levels of vitamin D as being responsible for fractures thought
to be abusive. The evidence to date does not support this supposition. Features of
congenital or metabolic conditions associated with nonabusive fractures include
family history of recurrent fractures after minor trauma, abnormally shaped
cranium, dentinogenesis imperfecta, blue sclera, craniotabes, ligamentous laxity,
bowed legs, hernia, and translucent skin. Subperiosteal new bone formation is a
nonspecific finding seen in infectious, traumatic, and metabolic disorders. In
young infants, new bone formation may be a normal physiologic finding, usually
bilateral, symmetric, and <2 mm in depth.
The evaluation of a fracture should include a skeletal radiologic survey in
children <2 yr old when abuse seems possible (Table 16.3 ). Multiple
radiographs with different views are needed; “babygrams” (1 or 2 films of the
entire body) should be avoided. If the survey is normal, but concern for an occult
injury remains, a radionucleotide bone scan should be performed to detect a
possible acute injury. Follow-up films after 2 wk may also reveal fractures not
apparent initially.
Table 16.3
Radiologic Skeletal Survey for Infants and
Children Under 2 Yr of Age*
• Anteroposterior (AP) and lateral views of skull (Townes view optional; add
if any fracture seen)
• Lateral spine (cervical spine [C-spine] may be included on skull
radiographs; AP spine is included on AP chest and AP pelvis views to
include entire spine)
• AP view, right posterior oblique, left posterior oblique view of chest—rib
 technique
• AP pelvis
• AP view of each femur
• AP view of each leg
• AP view of each humerus
• AP view of each forearm
• Posteroanterior (PA) view of each hand
• AP (dorsoventral) view of each foot

* Images are checked by a radiologist before the patient leaves. Poorly

positioned or otherwise suboptimal images should be repeated. Lateral views are

added for positive or equivocal findings in the extremities. Coned views of
positive or equivocal findings (i.e., at ends of long bones, ribs) may be obtained.

Adapted from Coley BD: Caffey's pediatric diagnostic imaging , ed 12, vol 2,
Philadelphia, 2013, Mosby/Elsevier, p 1588 (Box 144-1).

In corroborating the history and the injury, the age of a fracture can be crudely
estimated (Table 16.4 ). Soft tissue swelling subsides in 2-21 days. Subperiosteal
new bone is visible within 6-21 days. Loss of definition of the fracture line
occurs in 10-21 days. Soft callus can be visible after 9 days and hard callus at
14-90 days. These ranges are shorter in infancy and longer in children with poor
nutritional status or a chronic underlying disease. Fractures of flat bones such as
the skull do not form callus and cannot be aged, although soft tissue swelling
indicates approximate recency (within the prior week).

Table 16.4
Timetable of Radiologic Changes in Children's Fractures*
(in Days)

CATEGORY EARLY PEAK LATE

1. Subperiosteal new bone formation 4-10 10-14 14-21
2. Loss of fracture line definition 10-14 14-21
3. Soft callus 10-14 14-21
4. Hard callus 14-21 21-42 42-90
* Repetitive injuries may prolong all categories. The time points tend to increase from early infancy

into childhood.
Adapted from Kleinman PK: Diagnostic imaging of child abuse , ed 3, Cambridge, UK, 2015,
Cambridge University Press, p 215.

Abusive head trauma (AHT) results in the most significant morbidity and
mortality. Abusive injury may be caused by direct impact, asphyxia, or shaking.
Subdural hematomas (Fig. 16.8 ), retinal hemorrhages, especially when
extensive and involving multiple layers, and diffuse axonal injury strongly
suggest AHT, especially when they occur together. The poor neck muscle tone
and relatively large heads of infants make them vulnerable to acceleration-
deceleration forces associated with shaking, leading to AHT. Children may lack
external signs of injury, even with serious intracranial trauma. Signs and
symptoms may be nonspecific, ranging from lethargy, vomiting (without
diarrhea), changing neurologic status or seizures, and coma. In all preverbal
children, an index of suspicion for AHT should exist when children present with
these signs and symptoms.

FIG. 16.8 CT scan indicating intracranial bleeding. A arrow, Older blood. B arrow, New
blood.

Acute intracranial trauma is best evaluated by initial and follow-up CT. MRI
is helpful in differentiating extra axial fluid, determining timing of injuries,
assessing parenchymal injury, and identifying vascular anomalies. MRI is best
obtained 5-7 days after an acute injury. Glutaric aciduria type 1 can present with
intracranial bleeding and should be considered. Other causes of subdural
hemorrhage in infants include arteriovenous malformations, coagulopathies,
birth trauma, tumor, and infections. When AHT is suspected, injuries elsewhere
—skeletal and abdominal—should be ruled out.
Retinal hemorrhages are an important marker of AHT (Fig. 16.9 ).
Whenever AHT is being considered, a dilated indirect eye examination by a
pediatric ophthalmologist should be performed. Although retinal hemorrhages
can be found in other conditions, hemorrhages that are multiple, involve >1 layer
of the retina, and extend to the periphery are very suspicious for abuse. The
mechanism is likely repeated acceleration-deceleration from shaking. Traumatic
retinoschisis points strongly to abuse.

FIG. 16.9 Retinal hemorrhages. Arrows point to hemorrhages of various sizes.

With other causes of retinal hemorrhages, the pattern is usually different than
seen in child abuse. After birth, many newborns have them, but they disappear in
2-6 wk. Coagulopathies (particularly leukemia), retinal diseases, carbon
monoxide poisoning, or glutaric aciduria may be responsible. Severe,
noninflicted, direct crush injury to the head can rarely cause an extensive
hemorrhagic retinopathy. CPR rarely, if ever, causes retinal hemorrhage in
infants and children; if present, there a few hemorrhages in the posterior pole.
Trichomonas vaginalis is by culture (Diamond media or InPouch; Biomed
Diagnostics, White City, OR) or wet mount. Wet mount requires the presence of
vaginal secretions, viewing must be immediate for optimal results, and
sensitivity is only 44–68%; therefore false-negative tests are common. Experts
have determined that insufficient data exist to recommend commercially
available Trichomonas NAATs for prepubertal children. However, there is also
no reason to suspect that test performance in children would be different from
adults.
Table 16.5
Indications for STI Screening in Children
With Suspected Sexual Abuse
1. Child has experienced penetration or has evidence of recent or healed
penetrative injury to the genitals, anus, or oropharynx.
2. Child has been abused by a stranger.
3. Child has been abused by a perpetrator known to be infected with a
sexually transmitted infection (STI) or at high risk for STIs (e.g.,
intravenous drug abusers, men who have sex with men, persons with
multiple sexual partners, those with a history of STIs).
4. Child has a sibling, other relative, or another person in the household with
an STI.
5. Child lives in an area with a high rate of STI in the community.
6. Child has signs or symptoms of STIs (e.g., vaginal discharge or pain,
genital itching or odor, urinary symptoms, genital lesions or ulcers).
7. Child or parent requests STI testing.

From Centers for Disease Control and Prevention: Sexually transmitted diseases
treatment guidelines, 2015, MMWR 64(RR3):1–137, 2015.

A number of STIs should raise concern for abuse (Table 16.6 ). In a

prepubertal child, gonorrhea or syphilis beyond the neonatal period indicates
that the child has had some contact with infected genital secretions, almost
always as a result of sexual abuse. There is some evidence to indicate that
chlamydia in children up to 3 yr of age may be perinatally acquired. Chlamydia
in children >3 yr old is diagnostic of contact with infected genital secretions,
almost always a result of sexual abuse. In children <3 yr old, sexual abuse
should still be strongly considered beyond the neonatal period. HIV is diagnostic
for sexual abuse if other means of transmission have been excluded. Because of
the potential for transmission either perinatally or through nonsexual contact, the
presence of genital warts has a low specificity for sexual abuse. The possibility
of sexual abuse should be considered and addressed with the family, especially
in children whose warts first appear beyond 5 yr of age. Type 1 or 2 genital
herpes is concerning for sexual abuse, but not diagnostic given other possible
routes of transmission. For human papillomavirus (HPV) and HSV, the
American Academy of Pediatrics (AAP) recommends reporting to CPS unless
perinatal or horizontal transmission is considered likely.

Table 16.6

Implications of Commonly Encountered Sexually Transmitted or Sexually Associated

Infections for Diagnosis and Reporting of Sexual Abuse Among Infants and
Prepubertal Children
ST/SA CONFIRMED EVIDENCE FOR SEXUAL ABUSE SUGGESTED ACTION
Gonorrhea* Diagnostic Report †
Syphilis* Diagnostic Report †
HIV ‡ Diagnostic Report †
Chlamydia trachomatis * Diagnostic Report †
Trichomonas vaginalis * Highly suspicious Report †
Genital herpes Highly suspicious (HSV-2 especially) Report † , §
Condylomata acuminata (anogenital warts)* Suspicious Consider report † , § , **
Bacterial vaginosis Inconclusive Medical follow-up
* If not likely to be perinatally acquired, and rare vertical transmission is excluded.

† Reports should be made to the agency in the community mandated to receive reports of

suspected child abuse or neglect.

‡ If not likely to be acquired perinatally or through transfusion.

§ Unless a clear history of autoinoculation exists.

** Report if evidence exists to suspect abuse, including history, physical examination, or other
identified infections.
HIV, Human immunodeficiency virus; HSV, herpes simplex virus; SA, sexually associated; ST,
sexually transmitted.
From Centers for Disease Control and Prevention: Sexually transmitted diseases treatment
guidelines, 2015, MMWR 64(RR3):1-137, 2015 (Table 6).
problems that would necessitate a behavior change to improve outcomes are
used throughout the chapter.

Unified Theory of Behavior Change

There are several theories of health-related behavior change. Each highlights a
different concept, but frameworks that unite these theories suggest that the factor
most predictive of whether one will perform a behavior is the intention to do so.
The unified theory of behavior change examines behavior along 2 dimensions:
influences on intent and moderators of the intention-behavior relationship (Fig.
17.1 ). Five main factors that influence one's decision to perform a behavior are
expectancies, social norms/normative influences, self-concept/self-image,
emotions, and self-efficacy. Table 17.1 provides specific examples on how to
explore influences of intent when guiding families in decision-making, such as
deciding to start a stimulant medication for a child diagnosed with attention-
deficit/hyperactivity disorder (ADHD). It is not necessary to ask about each
influence, but these principles are particularly useful when guiding patients who
may be resistant to change.

FIG. 17.1 The 5 constructs that influence one's intent to perform a
behavior and the 4 influences that determine whether an intent will lead to
performing the behavior. Problem identification (box at upper right) is where
the process of thinking about health behavior changes begins. A clinician
can then help the patient decide on which behavior can help the patient to
meet the health goal. Once this is decided, to help with behavior change,
clinicians should think about intent, influences of intent, and the factors that
may facilitate or impede intent from leading to action.
Table 17.1

Influences of Intent and Possible Use During a Patient Encounter (Specifically,

Starting Stimulant for ADHD)
POSSIBLE FACTORS
INFLUENCE OF STRATEGIES TO ENGAGE FAMILIES USING
INFLUENCING THE
INTENT INFLUENCES OF INTENT
DECISION
Beliefs and Ask questions about their beliefs and “I know that stimulants
expectancies experiences. helped my nephew do
Perceived advantages “What do you know already know about better in school.”
and disadvantages of stimulants?” “I heard stimulants stunt
performing a behavior. “Have you heard about other children's children's growth.”
experiences taking stimulants?”
“What do you expect will happen if your child
takes a stimulant?”
Ask permission to give information addressing
their prior beliefs or experiences.
“Is it all right if I give you some information
addressing your concerns?”
Social norms Share information about the normative nature of “Do other parents give
Pressures to (or not) the behavior and ways to cope if performing a their children stimulants
perform a behavior behavior that is not the social norm. if they are diagnosed
because of what is “I have a lot of patients who have improved in with ADHD?”
standard among social school after starting a stimulant.” “What would my
groups. mother think if she
found out my child was
taking a stimulant?”
Self-concept/self- Interact with family in a partnering, supportive, “Am I a good parent if I
image respectful manner. Identify strengths. Reframe give my child
Overall sense of self any negative images they foresee may happen medications that affect
and whether behavior is with the behavior. his brain?”
congruent with that and “I am sure your in-laws will be so happy when “What will other parents
with the image they your child is doing better in school.” at school think if I allow
want to project to my child to start a
others. stimulant? What will
my in-laws think?”
Emotions Allow patients to express their feelings. Suggest “I am so nervous about
Emotional reactions to ways to manage negative or avoidant feelings. my child starting to take
performing behaviors, “Many parents are scared to start stimulants at a stimulant.”
in intensity and first. However, once their child is succeeding in “I am so upset with how
direction (positive or school, they realize the benefits outweighed the my child is doing in
negative). risks. Let's talk more about your fears.” school and really do not
know what to do next.”
“I am so relieved that
there is a medication
that may help improve
my child's grades and
chance of going to
college.”
Self-efficacy Provide information, model the behavior, “Will I be able to
Perceived confidence encourage success, and teach skills. Explore remember to give my
they can perform the what obstacles they foresee and how confident child his medication
behavior. they are they can overcome obstacles. Help every day?”
 strategize ways to overcome obstacles. “Will I be able to make
“Do you feel confident you will be able to get sure my child has a
your child to take the medication?” large breakfast in the
“Let's brainstorm how we can prevent any of the morning before taking
side effects.” her medication?”
“Many of my patients have a large breakfast
before taking the medication. Can I help you
figure out how to fit that into your schedule?”
ADHD, Attention-deficit/hyperactivity disorder.

Once a decision to make a change is made, 4 factors determine whether an

intention leads to carrying out the behavior: knowledge and skills, environmental
facilitators and constraints, salience of the behavior, and habits. The pediatrician
can help ensure intent leads to behavior change by addressing these factors
during the visit. In the ADHD example, the clinician can help the family build
their knowledge by providing handouts on stimulants, nutritional pamphlets on
how to minimize the appetite-suppressant effects of the medication on weight,
and information on how the family can explain to others the need for medication.
Asking about morning routines will help identify potential barriers in
remembering to take the medication. Lastly, clinicians can help families think
about cues for remembering to give the medication in the morning, since their
morning routines, or habits, will have to be adjusted to adhere to this medication.
By using these principles of behavior change, pediatricians can guide their
patients toward change during an encounter by ensuring they leave with (1) a
strong positive intention to perform the behavior; (2) the perception that they
have the skills to accomplish it; (3) a belief that the behavior is socially
acceptable and consistent with their self-image; (4) a positive feeling about the
behavior; (5) specific strategies in overcoming potential barriers in performing
the behavior; and (6) a set of identified cues and enablers to help build new
habits.

Transtheoretical Model of Health

Behavior Change
It is difficult to counsel families to change a behavior when they may not agree
there is a problem or when they are not ready to build an intention to change.
The transtheoretical model of health behavior change places an individual's
motivation and readiness to change on a continuum. The premise of this model is
that behavior change is a process, and as someone attempts to change, they move
through 5 stages (although not always in a linear fashion): precontemplation (no
current intention of making a change), contemplation (considering change),
preparation (creating an intention, planning, and committing to change), action
(has changed behavior for a short time), and maintenance (sustaining long-term
change). Assessing a patient's stage of change and then targeting counseling
toward that stage can help build a therapeutic alliance , in contrast to counseling
a patient to do something she is not ready for, which can disrupt therapeutic
alliance and lead to resistance. Table 17.2 further describes stages of change and
gives examples for counseling that targets the adolescent's stage of change in
reducing marijuana smoking.

Table 17.2

Stages of Change and Strategies for Counseling*

GOAL AND
STAGE/DEFINITION SPECIFIC EXAMPLES
STRATEGY
Precontemplation Establish a “I understand you are only here because your parents are
Not considering therapeutic worried and that you don't feel that smoking marijuana is a big
change. relationship. deal.”
May be unaware Increase “Can I ask if smoking marijuana has created any problems for
that a problem awareness of you now? I know your parents were worried about your grades.”
exists. need to “It's up to you to decide if and when you are ready to cut back
change. on smoking marijuana.”
“Is it okay if I give you some information about marijuana use?”
“I know it can be hard to change a habit when you feel under
pressure. It is totally up to you to decide if cutting back is right
for you. Is it okay if I ask you about this during our next visit?”
Contemplation Identify “I'm hearing that you do agree that sometimes your marijuana
Beginning to ambivalence. use does get in the way, especially with school. However, it
consider making a Help helps relax you and it would be hard to make a change right
change, but still develop now.”
feeling ambivalent discrepancy “What would be one benefit of cutting back? What would be a
about making a between drawback to cutting back? Do you think your smoking will
change. goals and cause problems in the future?”
current “After talking about this, if you feel you want to cut back, the
behaviors. next step would be to think about how to best do that. We
Ask about wouldn't need to jump right into a plan. Why don't you think
pros and about what we discussed, and we can meet next week if you are
cons of ready to make a plan?”
changing
problem
behavior.
Support
patient
toward
making a
change.
 Preparation Help patient “It's great that you are thinking about ways to cut back on your
Preparing for set a goal smoking. I understand your initial goal is to stop smoking during
action. and prepare the week.”
Reduced a concrete “I can give you some other options of how to relax and reduce
ambivalence and plan. stress during the week.”
exploration of Offer a menu “We need to figure out how to react to your friends after school
options for change. of choices. who you normally smoke with.”
Identify “Do you have other friends who you can see after school
supports and instead, who would support this decision?”
barriers.
Action Provide “Congratulations on cutting back. Have you noticed any
Taking action; positive differences in your schoolwork? I'm so happy to hear your
actively feedback. grades improved.”
implementing plan. Identify “Has it been difficult to not see your friends after school? How
unexpected have you reacted when they get annoyed you don't want to
barriers and smoke with them?”
create “Let's continue to track your progress.”
coping
strategies.
Maintenance Reinforce “You really are committed to going to a good college and
Continues to commitment improving your grades. I'm so happy the hard work has paid
change behavior and affirm off.”
and maintains ability to “I understand that it was hard to say no to smoking with your
healthier lifestyle. change. friends last week when it was someone's birthday. How did you
Create feel after? Are there triggers that we can think about preventing
coping plans in the future?”
when relapse
does occur.
Manage
triggers.
*
This table uses an example of an adolescent who is initially resistant to cutting back on smoking
marijuana. His parents caught him smoking in his room and arranged for him to see the
pediatrician.
Adapted from Implementing mental health priorities in practice: substance use, American
Academy of Pediatrics. https://www.aap.org/en-us/advocacy-and-policy/aap-health-
initiatives/Mental-Health/Pages/substance-use.aspx .

Common Factors Approach

Conversations around behavior change are most effective when they take place
in a context of a trusting, mutually respectful relationship. The traditional
medical model assumes that patients and their families come with questions and
needs, and that the pediatrician's job is to offer specific advice and advocate for
its acceptance. This approach fails when families are reluctant, ambivalent,
demoralized, or unfamiliar with the healthcare system or the treatment choices
offered. A context more supportive of behavior change can be developed when
pediatricians use communication strategies that facilitate collaboration and
building therapeutic alliance.
The common factors approach is an evidence-based communication strategy
that is effective in facilitating behavior change. The skills central to a common
factors approach are consistent across multiple forms of psychotherapy and can
be viewed as generic aspects of treatment that can be used across a wide range of
symptoms to build a therapeutic alliance between the physician and patient. This
alliance predicts outcomes of counseling more than the specific modality of
treatment. The common factors approach has been implemented and studied in
pediatric primary care for children with mental health problems. Children who
were treated by pediatricians trained in the common factors approach had
improved functioning compared to those who saw pediatricians without this
training.
A common factors approach distinguishes between the impact of the patient–
provider alliance and the pediatrician's use of skills that influence patient
behavior change across a broad range of conditions. Interpersonal skills that help
build alliances with patients include showing empathy, warmth, and positive
regard. Skills that influence behavior change include a clinician's ability to
provide optimism, facilitate treatment engagement, and maintain the focus on
achievable goals. This can be done by clearly explaining the condition and
treatment approaches while keeping the discussion focused on immediate and
practical concerns.

Interpersonal Skills: HEL2 P3

The interpersonal skills that facilitate an affective bond between the patient and
clinician can be remembered by the HEL2 P3 mnemonic (Table 17.3 ). These
skills include providing hope , empathy , and loyalty ; using the patient's
language ; partnering with the family; asking permission to raise more
sensitive questions or to give advice; and creating a plan that is initiated by the
family. These interpersonal skills should help operationalize the common factors
approach by increasing a patient's optimism, feelings of well-being, and
willingness to work toward improved health, while also targeting feelings of
anger, ambivalence, and hopelessness.

Table 17.3

Hope, Empathy, Language, Loyalty, Permission, Partnership, Plan (HEL2 P3 )*

 SKILL EXAMPLES
Hope for improvement: Develop “I have seen other children like you with similar feelings of sadness,
strengths. and they have gotten better.”
Empathy: Listen attentively. “It must be hard for you that you no longer get pleasure in playing
soccer.”
Language: Use family's language. Check “Let me make sure I understand what you are saying. You no longer
understanding. feel like doing things that make you happy in the past?”
Loyalty: Express support and “You are free to talk to me about anything while we work through
commitment. this.”
Permission: Ask permission to “I would like to ask more questions that you may find more
explore sensitive subjects. Offer sensitive, is that okay?”
advice. “Is it okay with you if I give you my opinion on what may be the
Partnership: Identify and overcome problem here?”
barriers.
Plan: Establish a plan, or at least a first “If we work together, maybe we can think through solutions for the
step family can take. problems you identified.”
* This table illustrates the interpersonal skills highlighted in the common factors approach. In this
example the clinician is responding to an adolescent struggling with depression and resistant to
seeking help.
Adapted with data from Foy JM, Kelleher KJ, Laraque D; American Academy of Pediatrics:
Enhancing pediatric mental health care: strategies for preparing a primary care practice,
Pediatrics 125(Suppl 3):S87–S108, 2010.

Structuring a patient encounter using common factors to facilitate behavior

change uses these steps: eliciting concerns while setting an agenda and agreeing
on the nature of the problem; establishing a plan; and responding to anger and
demoralization and emphasizing hope.

Elicit Concerns: Set the Agenda and Agree on

the Problem
The first step of the visit is to elicit both the child's and the parent's concerns and
agree on the focus for the visit. This can be accomplished by using open-ended
questions and asking “anything else?” until nothing else is disclosed. It is
important to show you have time and are interested in their concerns by making
eye contact, listening attentively, minimizing distractions, and responding with
empathy and interest. Engage both the child and the parent by taking turns
eliciting their concerns. It is helpful to summarize their story to reassure them
you have heard and understand what they are saying. Keep the session
organized, and manage rambling by gently interrupting, paraphrasing, asking for
additional concerns, and refocusing the conversation.
By the end of this step in the visit, all parties should feel reassured that their
problems were heard and accurately described. The next step is to agree on the
Table 17.4
Common Factors Approach in Practice*

GOAL SPECIFIC SKILLS EXAMPLES

Elicit child and Use open-ended questions and ask, “Hi, Jacqueline and Mrs. Smith. How have things
parents' “What else?” until nothing else is been since last time? What are your biggest concerns
concerns. listed, while engaging both parties for today?”
and demonstrating empathy. “What else do you think we should put on the agenda
for today?”
“I am sorry to hear that you have had more asthma
symptoms around gym time, Jacqueline. I'd like to ask
you a few more questions to get a better understanding
of what has changed, if that's okay with you.”
“I understand this is upsetting you, Mrs. Smith, and
that you worry that Jacqueline is not going to the
nurse before gym to use her inhaler pump anymore.
Let's hear from Jacqueline.”
Agree on the problem. “Can we all agree that managing the asthma symptoms
around gym time is the most pressing issue for today?
Should we focus on that today?”
Manage rambling. “What you're saying is really important, but I want to be
sure we have time to talk about controlling your daughter's
asthma symptoms during gym. Is it okay if we go back to
that topic?”
Partner with Develop acceptable plans for “I believe we can develop a plan to help deal with
families to find treatment of further diagnoses. this. Is it okay to start talking about next steps?”
acceptable “I know these asthma symptoms are concerning to
forms of your mom. But, Jacqueline, is this something you can
treatment. act on now?”
“I am happy to give suggestions on how to more
easily use your inhaler before gym, without the other
kids noticing. But what were you thinking,
Jacqueline?”
“Let's make a specific plan on where you can keep
your inhaler so the other kids don't see it.”
Address barriers to treatment. “Is there anything that makes you worry that this may not
work?”
Increase Respond to hopelessness, anger, and “I realize it wasn't your choice to come here,
expectations frustration. Jacqueline, but I'm interested in hearing how you feel
that treatment about this issue.”
will be helpful. “It must be really hard for you, Jacqueline, when the
kids tease you about your inhaler.”
“It must be frustrating for the school nurse to call you
in the middle of the day at work, Mrs. Smith.”
“I would be angry, too, if I felt my mom didn't
understand how it felt when I got teased for going to
the nurse's office.”
Emphasize hope. “We've managed difficult things before. Remember when
Jacqueline kept getting admitted for her asthma when she
was younger? We have come a long way since then, and
I'm sure we can manage this as well.”
* Jacqueline is an adolescent female who has had asthma since she was an infant. Despite
 change and helps them to explore advantages, disadvantages, and
barriers to change. It is important to reinforce the patient's change talk.
Examples of change talk include an expression of desire (“I want to…”),
ability (“I can…”), reasons (“There are good reasons to…”), or a need
for change (“I need to…”). Clinician can use “readiness rulers” by
asking their patients to rate on a scale from 1 to 10 how important and
confident they are in making change. The clinician should then respond
by asking why the patient did not choose a lower number and should
follow up asking what it would take to bring it to a higher number.
4. The planning stage is similar to that described in the discussion of a
common factors approach and occurs once a patient is in the preparation
stage on the continuum of change. A clinician can guide their patient
through this stage by having them write down responses to statements
such as, “The changes I want to make are…,” “The most important
reasons to make this change are…,” “Some people who can support me
are…,” and “They can help me by ….” A concrete plan should include
specific actions and a way to factor in accountability and rewards. Table
17.5 uses a visit for counseling about obesity to demonstrate the process
of motivational interviewing.

Table 17.5
Counseling for Obesity Using a Motivational Interviewing (MI) Approach

SPECIFIC
ACTION EXAMPLES
SKILLS
Engagement* O pen-ended “Now that we have finished the majority of the visit, I'd
questions like to talk about your weight. Is that okay? How do
you feel about your size?”
“Mrs. Smith, how do you feel about Jimmy's weight?”
A ffirmations “You definitely have shown how strong you are having
dealt with kids teasing you about your size.”
“Remember when you were having difficulty with
school? You were able to make a few changes, and now
you are doing well. I am confident we can do the same
with your weight.”
R eflective “You are feeling like your son is the same size as
listening everyone in your family, and you aren't concerned right
now.”
“Having your family watch TV before bed really works
for your family, Mrs. Smith.”
“You're not terribly excited about having to think of
ways to cook differently.”
S ummary “So far, we have discussed how challenging it would be to
 statements lose weight and make changes for the whole family, but you
are willing to consider some simple changes.”
Focusing Set the agenda. “We could talk about increasing the amount of exercise
Jimmy has every week, reducing screen time, or
making a dietary change. What do you think would
work best?”
“Great, so we will talk about soda. What do you like
about it? How many times a week do you drink it?”
Evocation Reinforce any “Those are great reasons for thinking about cutting
change talk. back on soda.”
Change ruler. “On a scale of 1 to 10, how confident are you (or
important is it) that you can cut back on soda?”
“A 5. Why didn't you answer a 3?”
“What would it take to bring it to a 7?”
Planning Focus on how “Maybe completely eliminating soda is too difficult
to make the right now. Do you want to think of a couple of times
change, not during the week where you can reward yourself with a
“why” soda?”
anymore. “What will you drink after school instead of soda?”
Be concrete.
*
OARS is used to engage the patient and build rapport.
Adapted from Changing the conversation about childhood obesity, American Academy
of Pediatrics, Institute for Healthy Childhood Weight. https://www.aap.org/en-us/about-
the-aap/aap-press-room/pages/Changing-the-conversation-about-Childhood-
Obesity.aspx .

Shared Decision-Making
Shared decision-making has many similarities to the processes previously
described in that it emphasizes moving physicians away from a paternalistic
approach in dictating treatment to one where patients and clinicians collaborate
in making a medical decision, particularly when multiple evidence-based
treatments options exist. The pediatrician or clinician offers different treatment
options and describes the risks and benefits for each one. The patient or
caregiver expresses their values, preferences, and treatment goals, and a decision
is made together.
Shared decision-making is often facilitated by using evidence-based decision
aids such as pamphlets, videos, web-based tools, or educational workshops.
Condition-specific or more generic decision aids have been created and facilitate
the process of shared decision-making. Studies in adults show that such aids
improve knowledge and satisfaction, reduce decisional conflict, and increase the
alignment between patient preferences and treatment options. More study is
needed to assess behavioral and physiologic outcomes specifically when
temperament appears to result from genetic factors.

Table 18.1

Temperamental Characteristics: Descriptions and Examples

CHARACTERISTIC DESCRIPTION EXAMPLES*
Activity level Amount of gross motor movement “She's constantly on the move.” “He would rather sit
still than run around.”
Rhythmicity Regularity of biologic cycles “He's never hungry at the same time each day.” “You
could set a watch by her nap.”
Approach and Initial response to new stimuli “She rejects every new food at first.” “He sleeps well
withdrawal in any place.”
Adaptability Ease of adaptation to novel “Changes upset him.” “She adjusts to new people
stimulus quickly.”
Threshold of Intensity of stimuli needed to “He notices all the lumps in his food and objects to
responsiveness evoke a response (e.g., touch, them.” “She will eat anything, wear anything, do
sound, light) anything.”
Intensity of reaction Energy level of response “She shouts when she is happy and wails when she is
sad.” “He never cries much.”
Quality of mood Usual disposition (e.g., pleasant, “He does not laugh much.” “It seems like she is
glum) always happy.”
Distractibility How easily diverted from ongoing “She is distracted at mealtime when other children
activity are nearby.” “He doesn't even hear me when he is
playing.”
Attention span and How long a child pays attention “He goes from toy to toy every minute.” “She will
persistence and sticks with difficult tasks keep at a puzzle until she has mastered it.”
* Typical statements of parents, reflecting the range for each characteristic from very little to very

much.
Based on data from Chess S, Thomas A: Temperament in clinical practice, New York, 1986,
Guilford.

The concept of temperament can help parents understand and accept the
characteristics of their children without feeling responsible for having caused
them. Children who have difficulty adjusting to change may have behavior
problems when a new baby arrives or at the time of school entry. In addition,
pointing out the child's temperament may allow for adjustment in parenting
styles. Behavioral and emotional problems may develop when the
temperamental characteristics of children and parents are in conflict. For
example, if parents who keep an irregular schedule have a child who is not
readily adaptable, behavioral difficulties are more likely than if the child has
parents who have predictable routines.

Psychologic Influences: Attachment and

services, at-risk children show marked and sustained upswings in their
developmental trajectory. Early identification of children at developmental risk,
along with early intervention to support parenting, is critically important.
Children can have appropriate developmental trajectories despite childhood
trauma. Resilience is the ability to withstand, adapt to, and recover from
adversities. There are several resilience factors that can be modified: a positive
appraisal or outlook and good executive functioning (see Chapter 48 ); nurturing
parenting (see Chapter 19 ); good maternal mental health, good self-care skills,
and consistent household routines; and an understanding of trauma. The personal
histories of children who overcome poverty often include at least one trusted
adult (parent, grandparent, teacher) with whom the child has a special,
supportive, close relationship. Pediatric providers are positioned to target and
bolster resilience in their patients and families.

Developmental Domains and Theories of

Emotion and Cognition
Child development can also be tracked by the child's developmental progress in
particular domains, such as gross motor, fine motor, social, emotional, language,
and cognition. Within each of these categories are developmental lines or
sequences of changes leading up to particular attainments. Developmental lines
in the gross motor domain, from rolling to creeping to independent walking, are
clear. Others, such as the line leading to the development of conscience, are
subtler.
The concept of a developmental line implies that a child passes through
successive stages. Several psychoanalytic theories are based on stages as
qualitatively different epochs in the development of emotion and cognition
(Table 18.2 ). In contrast, behavioral theories rely less on qualitative change and
more on the gradual modification of behavior and accumulation of competence.

Table 18.2
Classic Developmental Stage Theories

SCHOOL
INFANCY TODDLERHOOD PRESCHOOL ADOLESCENCE
AGE
(0-1 YR) (2-3 YR) (3-6 YR) (12-20 YR)
(6-12 YR)
Freud: Oral Anal Phallic/oedipal Latency Genital
psychosexual
 Erikson: Basic trust vs Autonomy vs shame Initiative vs guilt Industry vs Identity vs role
psychosocial mistrust and doubt inferiority diffusion
Piaget: Sensorimotor Sensorimotor Preoperational Concrete Formal operations
cognitive operations
Kohlberg: — Preconventional: avoid Conventional: Conventional: Postconventional:
moral punishment/obtain conformity (stage law and order moral principles
rewards (stages 1 and 2) 3) (stage 4)

Psychoanalytic Theories
At the core of Freudian theory is the idea of body-centered (or broadly,
“sexual”) drives; the emotional health of both the child and the adult depends on
adequate resolution of these conflicts. Although Freudian ideas have been
challenged, they opened the door to subsequent theories of development.
Erikson recast Freud's stages in terms of the emerging personality (see Table
18.2 ). The child's sense of basic trust develops through the successful
negotiation of infantile needs. As children progress through these psychosocial
stages, different issues become salient. It is predictable that a toddler will be
preoccupied with establishing a sense of autonomy, whereas a late adolescent
may be more focused on establishing meaningful relationships and an
occupational identity. Erikson recognized that these stages arise in the context of
Western European societal expectations; in other cultures, the salient issues may
be quite different.
Erikson's work calls attention to the intrapersonal challenges facing children at
different ages in a way that facilitates professional intervention. Knowing that
the salient issue for school-age children is industry vs inferiority, pediatricians
inquire about a child's experiences of mastery and failure and (if necessary)
suggest ways to ensure adequate successes.

Cognitive Theories
Cognitive development is best understood through the work of Piaget . A central
tenet of Piaget's work is that cognition changes in quality, not just quantity (see
Table 18.2 ). During the sensorimotor stage, an infant's thinking is tied to
immediate sensations and a child's ability to manipulate objects. The concept of
“in” is embodied in a child's act of putting a block into a cup. With the arrival of
language, the nature of thinking changes dramatically; symbols increasingly take
the place of objects and actions. Piaget described how children actively construct
knowledge for themselves through the linked processes of assimilation (taking
in new experiences according to existing schemata) and accommodation
Similar or Identical Elements Within 5 Theories of Health
Behavior
GENERAL
TENET OF
THE
THEORY THEORY
CONCEPT
HEALTH BELIEF OF OF SOCIAL COGNITIVE TRANSTHEORET
CONCEPT “ENGAGING
MODEL REASONED PLANNED THEORY MODEL
IN THE
ACTION BEHAVIOR
BEHAVIOR
IS LIKELY
IF …”
ATTITUDINAL BELIEFS
Appraisal of The positive Benefits, Behavioral Behavioral Outcome Pros, cons (decision
positive and aspects barriers/health beliefs and beliefs and expectations/expectancies balance)
negative outweigh the motive evaluation of evaluation of
aspects of the negative those beliefs those beliefs
behavior and aspects. (attitudes) (attitudes)
its expected
outcome
SELF-EFFICACY BELIEFS/BELIEFS ABOUT CONTROL OVER THE BEHAVIOR
Belief in One believes Self-efficacy — Perceived Self-efficacy Self-efficacy/tempta
one's ability in one's ability behavioral
to perform to perform the control
the behavior; behavior.
confidence
NORMATIVE AND NORM-RELATED BELIEFS AND ACTIVITIES
Belief that One believes Cues from media, Normative Normative Social support Helping relationship
others want that people friends (cues to beliefs and beliefs and (process of change)
one to important to action) motivation to motivation to
engage in the one want one comply comply
behavior to engage in (subjective (subjective
(and one's the behavior; norms) norms)
motivation to person has
comply); others'
may include support.
actual
support of
others
Belief that One believes — — — Social Social liberation (pr
others (e.g., that other environment/norms; of change)
peers) are people are modeling
engaging in engaging in
the behavior the behavior.
Responses to One receives Cues from media, — — Reinforcement Reinforcement
one's positive friends (cues to management/stimul
behavior that reinforcement action) control (processes o
increase or from others or change)
decrease the creates
likelihood positive
one will reinforcements
engage in the for oneself.
behavior;
 may include
reminders
RISK-RELATED BELIEFS AND EMOTIONAL RESPONSES
Belief that One feels at Perceived — — Emotional coping Dramatic relief (pro
one is at risk risk with susceptibility/severity responses/expectancies change)
if one does regard to a (perceived threat) about environmental cues
not engage in negative
the behavior, outcome or
and that the disease.
consequences
may be
severe; may
include
actually
experiencing
negative
emotions or
symptoms
and coping
with them
INTENTION/COMMITMENT/PLANNING
Intending or One has — Behavioral Behavioral Self-control/self- Contemplation/prep
planning to formed strong intentions intentions regulation (stages of change); s
perform the behavioral liberation (process o
behavior; intentions to change)
setting goals engage in the
or making a behavior; one
commitment has set
to perform realistic goals
the behavior or made a firm
commitment
to engage in
the behavior.
From Noar SM, Zimmerman RS: Health behavior theory and cumulative knowledge regarding
health behaviors: are we moving in the right direction? Health Educ Res 20:275–290, 2005, Table
1.

Motivational interviewing is a technique often used in clinical settings to

bring about behavior change, as discussed in detail in Chapter 17 . Briefly, the
goal is to enhance an individual's motivation to change behavior by exploring
and overcoming ambivalence. The therapist is a partner rather than an authority
figure and recognizes that, ultimately, the patient has control over his or her
choices.

Statistics Used in Describing Growth and

Development
(See Chapter 27 .)
In everyday use, the term normal is synonymous with healthy . In a statistical
sense, normal means that a set of values generates a normal (bell-shaped or
gaussian) distribution. This is the case with anthropometric quantities, such as
height and weight, and with many developmental measures, such as intelligence
quotient (IQ). For a normally distributed measurement , a histogram with the
quantity (height, age) on the x axis and the frequency (the number of children of
that height, or the number who stand on their own at that age) on the y axis
generates a bell-shaped curve. In an ideal bell-shaped curve, the peak
corresponds to the arithmetic mean (average) of the sample, as well as to the
median and the mode. The median is the value above and below which 50% of
the observations lie; the mode is the value having the highest number of
observations. Distributions are termed skewed if the mean, median, and mode are
not the same number.
The extent to which observed values cluster near the mean determines the
width of the bell and can be described mathematically by the standard
deviation (SD) . In the ideal normal curve, a range of values extending from 1
SD below the mean to 1 SD above the mean includes approximately 68% of the
values, and each “tail” above and below that range contains 16% of the values. A
range encompassing ±2 SD includes 95% of the values (with the upper and
lower tails each comprising approximately 2.5% of the values), and ±3 SD
encompasses 99.7% of the values (Table 18.4 and Fig. 18.4 ).

Table 18.4
Relationship Between Standard Deviation (SD) and Normal
Range for Normally Distributed Quantities
OBSERVATIONS INCLUDED IN PROBABILITY OF A “NORMAL” MEASUREMENT DEVIATING
THE NORMAL RANGE FROM THE MEAN BY THIS AMOUNT
SD % SD %
±1 68.3 ≥1 16.0
±2 95.4 ≥2 2.3
±3 99.7 ≥3 0.13

FIG. 18.4 Relationship between percentile lines on the growth curve and frequency
distributions of height at different ages.

For any single measurement, its distance away from the mean can be
expressed in terms of the number of SDs (also called a z score ); one can then
consult a table of the normal distribution to find out what percentage of
measurements fall within that distance from the mean. Software to convert
anthropometric data into z scores for epidemiologic purposes is available. A
measurement that falls “outside the normal range”—arbitrarily defined as 2, or
sometimes 3, SDs on either side of the mean—is atypical, but not necessarily
indicative of illness. The further a measurement (height, weight, IQ) falls from
the mean, the greater is the probability that it represents not simply normal
variation, but rather a different, potentially pathologic condition.
Another way of relating an individual to a group uses percentiles. The
percentile is the percentage of individuals in the group who have achieved a
certain measured quantity (e.g., height of 95 cm) or a developmental milestone
(e.g., walking independently). For anthropometric data, the percentile cutoffs can
be calculated from the mean and SD. The 5th, 10th, and 25th percentiles
correspond to −1.65 SD, −1.3 SD, and −0.7 SD, respectively. Fig. 18.4
demonstrates how frequency distributions of a particular parameter (height) at
different ages relate to the percentile lines on the growth curve.

Bibliography
Chen Y, Baram TZ. Toward understanding how early-life stress
issues, and community violence. Evidence also suggests that some types of
challenging behavior apparent at a young age may persist. In one study, a high
percentage of preschoolers identified as having both internalizing and
externalizing behavior at age 3 yr continued to have similar difficulties at 6 yr.
Other risk factors for the development of challenging behavior include trauma
and developmental problems. Adverse childhood experiences (ACEs) , defined
as abuse and neglect, caregiver substance use, caregiver depression, and
domestic violence or criminality, are often present during childhood. In the
National Survey of Child and Adolescent Well-Being, 42% of children under 6
yr of age in the child welfare system had experienced 4 or more ACEs. Further,
there was a cumulative relationship between emotional and behavioral problems
and ACE exposure, with children exposed to 4 or more ACEs almost 5 times
more likely to have internalizing problems than children not exposed to ACEs. A
similar relationship was found for externalizing problems. Studies involving
children with developmental disabilities suggest emotional and behavioral
problems occur more frequently in this group than in typically developing
children. These children may have delays in self-regulation and communication
skills as well as increased family stress, which contribute to the increased
likelihood of behavioral challenges.

Defining Positive Parenting

The precise definition of the components of positive parenting are lacking.
Positive parenting must ensure the child's safety, health, and nutrition as well as
developmental promotion. Common attributes of positive parenting include:
caring, leading, providing, teaching, and communicating with the child in a
consistent and unconditional manner. To account for the long-term goals of
successful parenting in promoting optimal emotional, behavioral, and
developmental outcomes, some suggest the term purposeful parenting and
related characteristics (Table 19.1 ). The characterization of an ideal approach to
parenting will evolve with ever-changing societal norms, but key components
such as those in Table 19.1 will likely remain fundamental.

Table 19.1

Components of Purposeful Parenting

ATTRIBUTE DEFINING ACTIONS
 Protective Ensure the child's emotional, developmental, and physiologic needs are met.
Provide a safe environment.
Balance the need for safety with the child's need for exploration and independence.
Personal Show unconditional love and acceptance.
Be kind and gentle.
Avoid name-calling and harsh language.
Label emotions and behaviors to help children understand their feelings.
Teach and model helpful behavior rather than just saying “no.”
Progressive Adapt parenting skills and discipline to meet the child's developmental needs.
Learn about child development to know what to expect.
Notice and praise new skills and desirable behaviors.
Positive Be warm, supportive, and optimistic, even during times of misbehavior.
Avoid harsh or physical punishments.
Provide encouragement and reward effort, not just a positive result.
Playful Enjoy child-led time together to encourage exploration, foster creativity, and learn new skills.
Read together.
Purposeful Take care of your needs as a parent.
Keep the long-terms goals of parenting in mind.
Preferentially use teaching instead of punishment to encourage desirable behavior.
Be consistent with routines and expectations.
Try to understand the reason behind the child's behavior.
Adapted from the work of Andrew Garner and the Ohio Chapter, American Academy of Pediatrics.
http://ohioaap.org/wp-content/uploads/2013/07/BPoM_PurposefulParenting.pdf .

Parenting as an Intervention
The influence of parenting practices on child behavior, development, and overall
adjustment has led to efforts to teach parenting as a method of primary
prevention. The Video Interaction Project (VIP) uses a coaching and education
model with recorded parent–child interactions to foster positive parenting
behavior. These parenting behaviors range from reading aloud to encouraging
interactive play. In an urban, low-income, primary care setting, parent and child
outcomes for the VIP group were compared to those from a lower-intensity
intervention (parent mailings encouraging positive parenting behaviors) and a
control group. VIP produced the most robust impacts on socioemotional
outcomes, including increased attention and decreased distress with separation,
hyperactivity, and externalizing behavior in toddlers.
Positive parenting as a public health intervention has resulted in decreased
rates of substantiated child maltreatment cases, out-of-home placements, and
child maltreatment injuries. Other effective public health approaches include
home-visiting programs, which have been deployed to at-risk families in an
effort to improve maternal and child outcomes. The Maternal, Infant and Early
Childhood Home Visiting Program, authorized as part of the Affordable Care
Act of 2010 and again in 2015, is part of the Medicare Access and Children's
Health Insurance Program (CHIP) Reauthorization Act. A key component of
home-visiting programs is the promotion of positive parenting behavior to foster
child developmental and school readiness. Group parenting programs have been
deployed as primary prevention to promote emotional and behavioral adjustment
in young children. There is moderate-quality evidence that group-based
parenting programs may improve parent–child interactions. These programs
typically employ praise, encouragement, and affection and have been associated
with improved self-esteem and social and academic competence.
Parenting behaviors have also been employed as an intervention to treat
emotional and behavioral problems in young children. Parenting interventions
such as Incredible Years, Triple P Positive Parenting Program, and New Forrest
Parenting Program are effective for at least short-term improvements in child
conduct problems, parental mental health, and parenting practices. Also called
parent training programs , most teach the importance of play, rewards, praise,
and consistent discipline and allow parents to practice new skills. This active-
learning component distinguishes parent training programs from educational
programs, which have been shown to be less effective.
Teaching emotional communication skills and positive parent–child
interaction skills are associated with parent training programs that demonstrate a
greater increase in parenting skills (Table 19.2 ). Several components are
associated with programs that show greater improvements in child externalizing
behavior: teaching parents to use time-out correctly, respond consistently, and
interact positively with their children. All successful programs require parents to
practice parenting skills during the program.

Table 19.2

Parent Training Program Components

COMPONENT ACTIVITIES
Knowledge about child development and Providing developmentally-appropriate environment
behavior Learning about child development
Promoting positive emotional development
Positive parent–child interactions Learning the importance of positive, non–discipline-focused
interactions
Using skills that promote positive interactions
Providing positive attention
Responsiveness and warmth Responding sensitively to the child's emotional needs
Providing appropriate physical contact and affection
Emotional communication Using active listening to foster communication
 Helping children identify and express emotion
Disciplinary communication Setting clear, appropriate, and consistent expectations
Establishing limits and rules
Choosing and following through with appropriate
consequences
Discipline and behavior management Understanding child misbehavior
Understanding appropriate discipline strategies
Using safe and appropriate monitoring and supervision
practices
Using reinforcement techniques
Using problem solving for challenging behavior
Being consistent
Promoting children's social skills and prosocial Teaching children to share, cooperate, and get along with
behavior others
Using good manners
Promoting children's cognitive or academic Fostering language and literacy development
skills Promoting school readiness
Adapted from US Centers for Disease Control and Prevention: Parent training programs: insight
for practitioners, Atlanta, 2009, CDC.

Parents have been found to benefit from participation in parenting programs.

Before their participation, parents experienced a loss of control, self-blame,
social isolation, and difficulty dealing with their child's emotional and behavioral
problems, all of which improved after participation. The few studies that have
assessed the long-term efficacy of parent-training programs suggest overall
positive child outcomes, but also periods of relapse during which the use of
positive parenting skills decreased. Use of social supports is associated with
positive child outcomes and may be an important program component when
considering long-term success.

The Role of the Pediatrician

Pediatricians and other pediatric practitioners have a primary responsibility to
support the needs of parents and their children. Numerous programs and
interventions have been developed to be delivered effectively and efficiently in
the primary care setting.
The American Academy of Pediatrics published Bright Futures and the
associated Guidelines for Preventive Care to standardize child health promotion
and prevention in primary care. A substantial amount of the content in Bright
Futures maps to the positive-parenting domains of safety, feeding,
developmental promotion, and protection. Implementing Bright Futures
guidelines in health supervision visits is an important way for pediatric
practitioners to support the promotion of positive parenting in practice.
Table 20.1

Milestones of Prenatal Development

WK DEVELOPMENTAL EVENTS
1 Fertilization and implantation; beginning of embryonic period
2 Endoderm and ectoderm appear (bilaminar embryo)
3 First missed menstrual period; mesoderm appears (trilaminar embryo); somites begin to form
4 Neural folds fuse; folding of embryo into human-like shape; arm and leg buds appear; crown-rump length
4-5 mm
5 Lens placodes, primitive mouth, digital rays on hands
6 Primitive nose, philtrum, primary palate
7 Eyelids begin; crown-rump length 2 cm
8 Ovaries and testes distinguishable
9 Fetal period begins; crown-rump length 5 cm; weight 8 g
12 External genitals distinguishable
20 Usual lower limit of viability; weight 460 g; length 19 cm
25 Third trimester begins; weight 900 g; length 24 cm
28 Eyes open; fetus turns head down; weight 1,000-1,300 g
38 Term

During wk 4-8, lateral folding of the embryologic plate, followed by growth at

the cranial and caudal ends and the budding of arms and legs, produces a human-
like shape. Precursors of skeletal muscle and vertebrae (somites) appear, along
with the branchial arches that will form the mandible, maxilla, palate, external
ear, and other head and neck structures. Lens placodes appear, marking the site
of future eyes; the brain grows rapidly. By the end of wk 8, as the embryonic
period closes, the rudiments of all major organ systems have developed; the
crown-rump length is 3 cm.

Fetal Period
From the 9th wk on (fetal period), somatic changes consist of rapid body growth
as well as differentiation of tissues, organs, and organ systems. Fig. 20.1 depicts
changes in body proportion. By wk 10, the face is recognizably human. The
midgut returns to the abdomen from the umbilical cord, rotating
counterclockwise to bring the stomach, small intestine, and large intestine into
their normal positions. By wk 12, the gender of the external genitals becomes
clearly distinguishable. Lung development proceeds, with the budding of
bronchi, bronchioles, and successively smaller divisions. By wk 20-24, primitive
alveoli have formed and surfactant production has begun; before that time, the
absence of alveoli renders the lungs useless as organs of gas exchange.
CHAPTER 21

The Newborn
John M. Olsson

(See also Chapter 113 .)

Regardless of gestational age, the newborn (neonatal) period begins at birth
and includes the 1st mo of life. During this time, marked physiologic transitions
occur in all organ systems, and the infant learns to respond to many forms of
external stimuli. Because infants thrive physically and psychologically only in
the context of their social relationships, any description of the newborn's
developmental status has to include consideration of the parents' role as well.

Parental Role in Mother–Infant

Attachment
Parenting a newborn infant requires dedication because a newborn's needs are
urgent, continuous, and often unclear. Parents must attend to an infant's signals
and respond empathically. Many factors influence parents' ability to assume this
role.

Prenatal Factors
Pregnancy is a period of psychologic preparation for the profound demands of
parenting. Women may experience ambivalence, particularly (but not
exclusively) if the pregnancy was unplanned. If financial concerns, physical
illness, prior miscarriages or stillbirths, or other crises interfere with psychologic
preparation, the neonate may not be welcomed. For adolescent mothers, the
demand that they relinquish their own developmental agenda, such as an active
social life, may be especially burdensome.
 The early experience of being mothered may establish unconsciously held
expectations about nurturing relationships that permit mothers to “tune in” to
their infants. These expectations are linked with the quality of later infant–parent
interactions. Mothers whose early childhoods were marked by traumatic
separations, abuse, or neglect may find it especially difficult to provide
consistent, responsive care. Instead, they may reenact their childhood
experiences with their own infants, as if unable to conceive of the mother–child
relationship in any other way. Bonding may be adversely affected by several risk
factors during pregnancy and in the postpartum period that undermine the
mother–child relationship and may threaten the infant's cognitive and emotional
development (Table 21.1 ).
Table 21.1
Prenatal Risk Factors for Attachment
Recent death of a loved one
Previous loss of or serious illness in another child
Prior removal of a child
History of depression or serious mental illness
History of infertility or pregnancy loss
Troubled relationship with parents
Financial stress or job loss
Marital discord or poor relationship with the other parent
Recent move or no community ties
No friends or social network
Unwanted pregnancy
No good parenting model
Experience of poor parenting
Drug and/or alcohol abuse
Extreme immaturity

From Dixon SD, Stein MT: Encounters with children: pediatric behavior and
development, ed 4, Philadelphia, 2006, Mosby, p 131.

Social support during pregnancy, particularly support from the father and
close family members, is also important. Conversely, conflict with or
abandonment by the father during pregnancy may diminish the mother's ability
to become absorbed with her infant. Anticipation of an early return to work may
make some women reluctant to fall in love with their babies because of
anticipated separation. Returning to work should be delayed for at least 6 wk, by
which time feeding and basic behavioral adjustments have been established.
Many decisions have to be made by parents in anticipation of the birth of their
child. One important choice is that of how the infant will be nourished. Among
the important benefits of breastfeeding is its promotion of bonding. Providing
breastfeeding education for the parents at the prenatal visit by the pediatrician
and by the obstetrician during prenatal care can increase maternal confidence in
breastfeeding after delivery and reduce stress during the newborn period (see
Chapter 56 ).

Peripartum and Postpartum Influences

The continuous presence during labor of a woman trained to offer friendly
support and encouragement (a doula ) results in shorter labor, fewer obstetric
complications (including cesarean section), and reduced postpartum hospital
stays. Early skin-to-skin contact between mothers and infants immediately after
birth may correlate with an increased rate and longer duration of breastfeeding.
Most new parents value even a brief period of uninterrupted time in which to get
to know their new infant, and increased mother–infant contact over the 1st days
of life may improve long-term mother–child interactions. Nonetheless, early
separation, although predictably very stressful, does not inevitably impair a
mother's ability to bond with her infant. Early discharge home from the
maternity ward may undermine bonding, particularly when a new mother is
required to resume full responsibility for a busy household.
Postpartum depression may occur in the 1st wk or up to 6 mo after delivery
and can adversely affect neonatal growth and development. Screening tools,
such as the Edinburgh Postnatal Depression Scale (EPDS) , are available for
use during neonatal and infant visits to the pediatric provider. On the EPDS,
scores of 0-8 indicate a low likelihood of depression (Table 21.2 ). Cutoff-score
recommendations for further evaluation of depression have ranged from 9 to 13;
thus any woman scoring 9 or above should be evaluated further. If postpartum
depression is present, referral for mental healthcare will greatly accelerate
recovery.
Table 21.2
Edinburgh Postnatal Depression Scale
Instructions for Users

1. The mother is asked to underline the response that comes closest to how
she has been feeling in the previous 7 days.
2. All 10 items must be completed.
3. Care should be taken to avoid the possibility of the mother discussing her
answers with others.
4. The mother should complete the scale herself, unless she has limited
English or has difficulty with reading.
5. The Edinburgh Postnatal Depression Scale may be used at 6-8 wk to
screen postnatal women. The child health clinic, a postnatal checkup, or a
home visit may provide a suitable opportunity for its completion.

Edinburgh Postnatal Depression Scale

Name:
Address:
Baby's age:
Because you have recently had a baby, we would like to know how you are
feeling. Please underline the answer that comes closest to how you have
felt in the past 7 days, not just how you feel today.
Here is an example, already completed.
I have felt happy:
Yes, all the time
Yes, most of the time
No, not very often
No, not at all
This would mean: “I have felt happy most of the time” during the past
week. Please complete the other questions in the same way.
In the past 7 days:
1. I have been able to laugh and see the funny side of things
As much as I always could
Not quite so much now
Definitely not so much now
 Not at all
2. I have looked forward with enjoyment to things
As much as I ever did
Rather less than I used to
Definitely less than I used to
Hardly at all
*3. I have blamed myself unnecessarily when things went wrong
Yes, most of the time
Yes, some of the time
Not very often
No, never
4. I have been anxious or worried for no good reason
No, not at all
Hardly ever
Yes, sometimes
Yes, very often
*5. I have felt scared or panicky for no very good reason
Yes, quite a lot
Yes, sometimes
No, not much
No, not at all
*6. Things have been getting on top of me
Yes, most of the time I haven't been able to cope at all
Yes, sometimes I haven't been coping as well as usual
No, most of the time I have coped quite well
No, I have been coping as well as ever
*7. I have been so unhappy that I have had difficulty sleeping
Yes, most of the time
Yes, sometimes
Not very often
No, not at all
*8. I have felt sad or miserable
Yes, most of the time
Yes, quite often
Not very often
No, not at all
*9. I have been so unhappy that I have been crying
 Yes, most of the time
Yes, quite often
Only occasionally
No, never
*10. The thought of harming myself has occurred to me
Yes, quite often
Sometimes
Hardly ever
Never

Response categories are scored 0, 1, 2, and 3 according to increased severity

of the symptom. Items marked with an asterisk (*) are reverse-scored (i.e., 3, 2,
1, and 0). The total score is calculated by adding the scores for each of the 10
items. Users may reproduce the scale without further permission provided they
respect copyright (which remains with the British Journal of Psychiatry ) by
quoting the names of the authors, the title, and the source of the paper in all
reproduced copies.

From Currie ML, Rademacher R: The pediatrician's role in recognizing and

intervening in postpartum depression, Pediatr Clin North Am 51:785–801, 2004.

The Infant's Role in Mother–Infant

Attachment
The in utero environment contributes greatly but not completely to the future
growth and development of the fetus. Abnormalities in maternal-fetal placental
circulation and maternal glucose metabolism or the presence of maternal
infection can result in abnormal fetal growth. Infants may be small or large for
gestational age as a result. These abnormal growth patterns not only predispose
infants to an increased requirement for medical intervention, but also may affect
their ability to respond behaviorally to their parents.

Physical Examination
Examination of the newborn should include an evaluation of growth (see
Chapter 20 ) and an observation of behavior . The average term newborn
interactions with caregivers or the wider environment may alter experience-
dependent processes that are critical to brain structure development and function
during infancy. Although for some processes, subsequent stimulation may allow
catch-up, as the periods of plasticity close during the rapid developmental
changes occurring in infancy, more permanent deficits may result.
The infant acquires new competences in all developmental domains. The
concept of developmental trajectories recognizes that complex skills build on
simpler ones; it is also important to realize how development in each domain
affects functioning in all the others. All growth parameters should be plotted
using the World Health Organization charts, which show how children from birth
through 72 mo “should” grow under optimal circumstances (see Chapter 23 ,
Figs. 23.1 and 23.2 ). Table 22.1 presents an overview of key milestones by
domain; Table 22.2 presents similar information arranged by age. Table 22.3
presents age at time of x-ray appearance of centers of ossification. Parents often
seek information about “normal development” during this period and should be
directed to reliable sources, including the American Academy of Pediatrics
website (healthychildren.org ).

Table 22.1
Developmental Milestones in 1st 2 Yr of Life

AVERAGE AGE OF
MILESTONE DEVELOPMENTAL IMPLICATIONS
ATTAINMENT (MO)
GROSS MOTOR
Holds head steady while sitting 2 Allows more visual interaction
Pulls to sit, with no head lag 3 Muscle tone
Brings hands together in midline 3 Self-discovery of hands
Asymmetric tonic neck reflex gone 4 Can inspect hands in midline
Sits without support 6 Increasing exploration
Rolls back to stomach 6.5 Truncal flexion, risk of falls
Walks alone 12 Exploration, control of proximity to parents
Runs 16 Supervision more difficult
FINE MOTOR
Grasps rattle 3.5 Object use
Reaches for objects 4 Visuomotor coordination
Palmar grasp gone 4 Voluntary release
Transfers object hand to hand 5.5 Comparison of objects
Thumb-finger grasp 8 Able to explore small objects
Turns pages of book 12 Increasing autonomy during book time
Scribbles 13 Visuomotor coordination
Builds tower of 2 cubes 15 Uses objects in combination
Builds tower of 6 cubes 22 Requires visual, gross, and fine motor
coordination
COMMUNICATION AND LANGUAGE
Smiles in response to face, voice 1.5 More active social participant
Monosyllabic babble 6 Experimentation with sound, tactile sense
Inhibits to “no” 7 Response to tone (nonverbal)
Follows 1-step command with 7 Nonverbal communication
gesture
Follows 1-step command without 10 Verbal receptive language (e.g., “Give it to
gesture me”)
Says “mama” or “dada” 10 Expressive language
Points to objects 10 Interactive communication
Speaks first real word 12 Beginning of labeling
Speaks 4-6 words 15 Acquisition of object and personal names
Speaks 10-15 words 18 Acquisition of object and personal names
Speaks 2-word sentences (e.g., 19 Beginning grammatization, corresponds with
“Mommy shoe”) 50-word vocabulary
COGNITIVE
Stares momentarily at spot where 2 Lack of object permanence (out of sight, out of
object disappeared mind; e.g., yarn ball dropped)
Stares at own hand 4 Self-discovery, cause and effect
Bangs 2 cubes 8 Active comparison of objects
Uncovers toy (after seeing it 8 Object permanence
hidden)
Egocentric symbolic play (e.g., 12 Beginning symbolic thought
pretends to drink from cup)
Uses stick to reach toy 17 Able to link actions to solve problems
Pretend play with doll (e.g., gives 17 Symbolic thought
doll bottle)

Table 22.2
Emerging Patterns of Behavior During the 1st Yr of Life*
NEONATAL PERIOD (1ST 4 WK)
Prone: Lies in flexed attitude; turns head from side to side; head sags on ventral suspension
Supine: Generally flexed and a little stiff
Visual: May fixate face on light in line of vision; doll's eye movement (oculocephalic reflex) of eyes on
turning of the body
Reflex: Moro response active; stepping and placing reflexes; grasp reflex active
Social: Visual preference for human face
AT 1 MO
Prone: Legs more extended; holds chin up; turns head; head lifted momentarily to plane of body on ventral
suspension
Supine: Tonic neck posture predominates; supple and relaxed; head lags when pulled to sitting position
Visual: Watches person; follows moving object
Social: Body movements in cadence with voice of other in social contact; beginning to smile
AT 2 MO
Prone: Raises head slightly farther; head sustained in plane of body on ventral suspension
Supine: Tonic neck posture predominates; head lags when pulled to sitting position
Visual: Follows moving object 180 degrees
Social: Smiles on social contact; listens to voice and coos
AT 3 MO
 Prone: Lifts head and chest with arms extended; head above plane of body on ventral suspension
Supine: Tonic neck posture predominates; reaches toward and misses objects; waves at toy
Sitting: Head lag partially compensated when pulled to sitting position; early head control with bobbing
motion; back rounded
Reflex: Typical Moro response has not persisted; makes defensive movements or selective withdrawal
reactions
Social: Sustained social contact; listens to music; says “aah, ngah”
AT 4 MO
Prone: Lifts head and chest, with head in approximately vertical axis; legs extended
Supine: Symmetric posture predominates, hands in midline; reaches and grasps objects and brings them to
mouth
Sitting: No head lag when pulled to sitting position; head steady, tipped forward; enjoys sitting with full
truncal support
Standing: When held erect, pushes with feet
Adaptive: Sees raisin, but makes no move to reach for it
Social: Laughs out loud; may show displeasure if social contact is broken; excited at sight of food
AT 7 MO
Prone: Rolls over; pivots; crawls or creep-crawls (Knobloch)
Supine: Lifts head; rolls over; squirms
Sitting: Sits briefly, with support of pelvis; leans forward on hands; back rounded
Standing: May support most of weight; bounces actively
Adaptive: Reaches out for and grasps large object; transfers objects from hand to hand; grasp uses radial palm;
rakes at raisin
Language: Forms polysyllabic vowel sounds
Social: Prefers mother; babbles; enjoys mirror; responds to changes in emotional content of social contact
AT 10 MO
Sitting: Sits up alone and indefinitely without support, with back straight
Standing: Pulls to standing position; “cruises” or walks holding on to furniture
Motor: Creeps or crawls
Adaptive: Grasps objects with thumb and forefinger; pokes at things with forefinger; picks up pellet with
assisted pincer movement; uncovers hidden toy; attempts to retrieve dropped object; releases object
grasped by other person
Language: Repetitive consonant sounds (“mama,” “dada”)
Social: Responds to sound of name; plays peek-a-boo or pat-a-cake; waves bye-bye
AT 1 YR
Motor: Walks with one hand held; rises independently, takes several steps (Knobloch)
Adaptive: Picks up raisin with unassisted pincer movement of forefinger and thumb; releases object to other
person on request or gesture
Language: Says a few words besides “mama,” “dada”
Social: Plays simple ball game; makes postural adjustment to dressing
* Data are derived from those of Gesell (as revised by Knobloch), Shirley, Provence, Wolf, Bailey,
and others.
Data from Knobloch H, Stevens F, Malone AF: Manual of developmental diagnosis, Hagerstown,
MD, 1980, Harper & Row.

Table 22.3
Time of Radiographic Appearance of Centers of
Ossification in Infancy and Childhood
 BOYS—AGE AT BONES AND EPIPHYSEAL GIRLS—AGE AT
APPEARANCE* CENTERS APPEARANCE*
HUMERUS, HEAD
3 wk 3 wk
CARPAL BONES
2 mo ± 2 mo Capitate 2 mo ± 2 mo
3 mo ± 2 mo Hamate 2 mo ± 2 mo
30 mo ± 16 mo Triangular † 21 mo ± 14 mo
42 mo ± 19 mo Lunate † 34 mo ± 13 mo
67 mo ± 19 mo Trapezium † 47 mo ± 14 mo
69 mo ± 15 mo Trapezoid † 49 mo ± 12 mo
66 mo ± 15 mo Scaphoid † 51 mo ± 12 mo
No standards available Pisiform † No standards available
METACARPAL BONES
18 mo ± 5 mo II 12 mo ± 3 mo
20 mo ± 5 mo III 13 mo ± 3 mo
23 mo ± 6 mo IV 15 mo ± 4 mo
26 mo ± 7 mo V 16 mo ± 5 mo
32 mo ± 9 mo I 18 mo ± 5 mo
FINGERS (EPIPHYSES)
16 mo ± 4 mo Proximal phalanx, 3rd finger 10 mo ± 3 mo
16 mo ± 4 mo Proximal phalanx, 2nd finger 11 mo ± 3 mo
17 mo ± 5 mo Proximal phalanx, 4th finger 11 mo ± 3 mo
19 mo ± 7 mo Distal phalanx, 1st finger 12 mo ± 4 mo
21 mo ± 5 mo Proximal phalanx, 5th finger 14 mo ± 4 mo
24 mo ± 6 mo Middle phalanx, 3rd finger 15 mo ± 5 mo
24 mo ± 6 mo Middle phalanx, 4th finger 15 mo ± 5 mo
26 mo ± 6 mo Middle phalanx, 2nd finger 16 mo ± 5 mo
28 mo ± 6 mo Distal phalanx, 3rd finger 18 mo ± 4 mo
28 mo ± 6 mo Distal phalanx, 4th finger 18 mo ± 5 mo
32 mo ± 7 mo Proximal phalanx, 1st finger 20 mo ± 5 mo
37 mo ± 9 mo Distal phalanx, 5th finger 23 mo ± 6 mo
37 mo ± 8 mo Distal phalanx, 2nd finger 23 mo ± 6 mo
39 mo ± 10 mo Middle phalanx, 5th finger 22 mo ± 7 mo
152 mo ± 18 mo Sesamoid (adductor pollicis) 121 mo ± 13 mo
HIP AND KNEE
Usually present at birth Femur, distal Usually present at birth
Usually present at birth Tibia, proximal Usually present at birth
4 mo ± 2 mo Femur, head 4 mo ± 2 mo
46 mo ± 11 mo Patella 29 mo ± 7 mo
FOOT AND ANKLE ‡
* To nearest month.

† Except for the capitate and hamate bones, the variability of carpal centers is too great to make
them very useful clinically.
‡ Standards for the foot are available, but normal variation is wide, including some familial
variants, so this area is of little clinical use.
Values represent mean ± standard deviation, when applicable.
The norms present a composite of published data from the Fels Research Institute, Yellow
 B, Length for age and weight for age for girls, birth to 24 mo.
(Courtesy World Health Organization: WHO Child Growth
Standards, 2014.)

FIG. 23.2 The World Health Organization Growth Charts.

Most children begin to walk independently at about 12-15 mo of age. Early

walking is not associated with advanced development in other domains. Infants
initially toddle with a wide-based gait, with the knees bent and the arms flexed at
the elbow; the entire torso rotates with each stride; the toes may point in or out,
and the feet strike the floor flat. The appearance is that of genu varum (bowleg ).
Subsequent refinement leads to greater steadiness and energy efficiency. After
several months of practice, the center of gravity shifts back and the torso
stabilizes, while the knees extend and the arms swing at the sides for balance.
The feet are held in better alignment, and the child is able to stop, pivot, and
stoop without toppling over (see Chapters 692 and 693 ).

Cognitive Development
Exploration of the environment increases in parallel with improved dexterity
(reaching, grasping, releasing) and mobility. Learning follows the precepts of
Piaget's sensorimotor stage (see Chapter 18 ). Toddlers manipulate objects in
novel ways to create interesting effects, such as stacking blocks or filling and
dumping buckets. Playthings are also more likely to be used for their intended
purposes (combs for hair, cups for drinking). Imitation of parents and older
siblings or other children is an important mode of learning. Make-believe play
(symbolic play ) centers on the child's own body, such as pretending to drink
from an empty cup (Table 23.1 ; see also Table 22.1 ).

Table 23.1
Emerging Patterns of Behavior From 1-5 Yr of Age*
15 MO
Motor: Walks alone; crawls up stairs
Adaptive: Makes tower of 3 cubes; makes a line with crayon; inserts raisin in bottle
Language: Jargon; follows simple commands; may name a familiar object (e.g., ball); responds to his/her name
Social: Indicates some desires or needs by pointing; hugs parents
18 MO
Motor: Runs stiffly; sits on small chair; walks up stairs with 1 hand held; explores drawers and wastebaskets
 Adaptive: Makes tower of 4 cubes; imitates scribbling; imitates vertical stroke; dumps raisin from bottle
Language: 10 words (average); names pictures; identifies 1 or more parts of body

Social: Feeds self; seeks help when in trouble; may complain when wet or soiled; kisses parent with pucker
24 MO
Motor: Runs well, walks up and down stairs, 1 step at a time; opens doors; climbs on furniture; jumps
Adaptive: Makes tower of 7 cubes (6 at 21 mo); scribbles in circular pattern; imitates horizontal stroke; folds
paper once imitatively
Language: Puts 3 words together (subject, verb, object)
Social: Handles spoon well; often tells about immediate experiences; helps to undress; listens to stories when
shown pictures
30 MO
Motor: Goes up stairs alternating feet
Adaptive: Makes tower of 9 cubes; makes vertical and horizontal strokes, but generally will not join them to
make cross; imitates circular stroke, forming closed figure
Language: Refers to self by pronoun “I”; knows full name
Social: Helps put things away; pretends in play
36 MO
Motor: Rides tricycle; stands momentarily on 1 foot
Adaptive: Makes tower of 10 cubes; imitates construction of “bridge” of 3 cubes; copies circle; imitates cross
Language: Knows age and sex; counts 3 objects correctly; repeats 3 numbers or a sentence of 6 syllables; most of
speech intelligible to strangers
Social: Plays simple games (in “parallel” with other children); helps in dressing (unbuttons clothing and puts
on shoes); washes hands
48 MO
Motor: Hops on 1 foot; throws ball overhand; uses scissors to cut out pictures; climbs well
Adaptive: Copies bridge from model; imitates construction of “gate” of 5 cubes; copies cross and square; draws
man with 2-4 parts besides head; identifies longer of 2 lines
Language: Counts 4 pennies accurately; tells story
Social: Plays with several children, with beginning of social interaction and role-playing; goes to toilet alone
60 MO
Motor: Skips
Adaptive: Draws triangle from copy; names heavier of 2 weights
Language: Names 4 colors; repeats sentence of 10 syllables; counts 10 pennies correctly
Social: Dresses and undresses; asks questions about meaning of words; engages in domestic role-playing
* Data derived from those of Gesell (as revised by Knobloch), Shirley, Provence, Wolf, Bailey, and
others. After 6 yr, the Wechsler Intelligence Scales for Children (WISC-IV) and other scales offer
the most precise estimates of cognitive development. To have their greatest value, they should be
administered only by an experienced and qualified person.

Emotional Development
Infants who are approaching the developmental milestone of taking their 1st
steps may be irritable. Once they start walking, their predominant mood changes
markedly. Toddlers are often elated with their new ability and with the power to
control the distance between themselves and their parents. Exploring toddlers
orbit around their parents, moving away and then returning for a reassuring
touch before moving away again. A child with secure attachment will use the
process is reciprocal between the child and the school. It is developmentally
based, recognizing the importance of early experiences for later development.
Rather than delaying school entry, high-quality early-education programs may be
the key to ultimate school success.
School makes increasing cognitive demands on the child. Mastery of the
elementary curriculum requires that many perceptual, cognitive, and language
processes work efficiently (Table 25.1 ), and children are expected to attend to
many inputs at once. The 1st 2-3 yr of elementary school are devoted to
acquiring the fundamentals: reading, writing, and basic mathematics skills. By
3rd grade, children need to be able to sustain attention through a 45 min period,
and the curriculum requires more complex tasks. The goal of reading a
paragraph is no longer to decode the words, but to understand the content; the
goal of writing is no longer spelling or penmanship, but composition. The
volume of work increases along with the complexity.

Table 25.1
Selected Perceptual, Cognitive, and Language Processes
Required for Elementary School Success

PROCESS DESCRIPTION ASSOCIATED PROBLEMS

PERCEPTUAL
Visual Ability to break a complex figure into Persistent letter confusion (e.g., between b, d, and g
analysis components and understand their spatial ); difficulty with basic reading and writing and
relationships limited “sight” vocabulary
Proprioception Ability to obtain information about body Poor handwriting, requiring inordinate effort, often
and motor position by feel and unconsciously program with overly tight pencil grasp; special difficulty
control complex movements with timed tasks
Phonologic Ability to perceive differences between Delayed receptive language skill; attention and
processing similar-sounding words and to break down behavior problems secondary to not understanding
words into constituent sounds directions; delayed acquisition of letter-sound
correlations (phonetics)
COGNITIVE
Long-term Ability to acquire skills that are “automatic” Delayed mastery of the alphabet (reading and
memory, both (i.e., accessible without conscious thought) writing letters); slow handwriting; inability to
storage and progress beyond basic mathematics
recall
Selective Ability to attend to important stimuli and Difficulty following multistep instructions,
attention ignore distractions completing assignments, and behaving well;
problems with peer interaction
Sequencing Ability to remember things in order; facility Difficulty organizing assignments, planning,
with time concepts spelling, and telling time
LANGUAGE
Receptive Ability to comprehend complex Difficulty following directions; wandering attention
language constructions, function words (e.g., if, during lessons and stories; problems with reading
 when, only, except), nuances of speech, and comprehension; problems with peer relationships
extended blocks of language (e.g.,
paragraphs)
Expressive Ability to recall required words effortlessly Difficulty expressing feelings and using words for
language (word finding), control meanings by varying self-defense, with resulting frustration and physical
position and word endings, and construct acting out; struggling during “circle time” and in
meaningful paragraphs and stories language-based subjects (e.g., English)

Cognitive abilities interact with a wide array of attitudinal and emotional

factors in determining classroom performance. These factors include external
rewards (eagerness to please adults and approval from peers) and internal
rewards (competitiveness, willingness to work for a delayed reward, belief in
one's abilities, and ability to risk trying when success is not ensured). Success
predisposes to success, whereas failure impacts self-esteem and reduces self-
efficacy, diminishing a child's ability to take future risks.
Children's intellectual activity extends beyond the classroom. Beginning in the
3rd or 4th grade, children increasingly enjoy strategy games and wordplay (puns
and insults) that exercise their growing cognitive and linguistic mastery. Many
become experts on subjects of their own choosing, such as sports trivia, or
develop hobbies, such as special card collections. Others become avid readers or
take on artistic pursuits. Whereas board and card games were once the usual
leisure-time activity of youth, video, computer, and other electronic games
currently fill this need.

Implications for Parents and Pediatricians

Pediatricians have an important role in preparing their patients for school
entrance by promoting health through immunizations, adequate nutrition,
appropriate recreation, and screening for physical, developmental, and cognitive
disorders. The American Academy of Pediatrics recommends that pediatric
providers promote the “5 Rs” of early education: (1) reading as a daily family
activity; (2) rhyming, playing, and cuddling together; (3) routines and regular
times for meals, play, and sleep; (4) reward through praise for successes; and (5)
reciprocal nurturing relationships.
Concrete operations allow children to understand simple explanations for
illnesses and necessary treatments, although they may revert to prelogical
thinking when under stress. A child with pneumonia may be able to explain
about white cells fighting the “germs” in the lungs, but may still secretly harbor
the belief that the sickness is a punishment for disobedience.
As children are faced with more abstract concepts, academic and classroom
paper at the foot and head of a supine infant or using a tape measure or wall
growth chart with a book or ruler on the head can lead to inaccuracy and render
the measurement useless.
Measurements for height and weight should be plotted on the age-appropriate
growth curve. Comparing measurements with previous growth trends, repeating
measures that are inconsistent, and plotting results longitudinally are essential
for monitoring growth. Calculation of interim linear height velocity, such as
centimeters per year (cm/yr), allows more precise comparison of growth rate to
the norm (Table 27.1 ).

Table 27.1
Growth Velocity and Other Growth Characteristics by Age

INFANCY CHILDHOOD ADOLESCENCE

Birth-12 mo: 24 6 cm/yr Sigmoid-shaped growth
cm/yr Slowly decelerates before pubertal Adolescent growth spurt accounts for about 15% of
12-24 mo: 10 onset adult height
cm/yr Height typically does not cross Peak height velocity
24-36 mo: 8 cm/yr percentile lines Girls: 8 cm/yr
Boys: 10 cm/yr

If a child is growing faster or more slowly than expected, measurement of

body proportions, which follow a predictable sequence of changes with
development, are useful. The head and trunk are relatively large at birth, with
progressive lengthening of the limbs throughout development, particularly
during puberty. The upper-to-lower body segment ratio (U/L ratio ) provides
an assessment of truncal growth relative to limb growth. The lower-body
segment is defined as the length from the top of the symphysis pubis to the floor,
and the upper-body segment is the total height minus the lower-body segment.
The U/L ratio equals approximately 1.7 at birth, 1.3 at 3 yr, and 1.0 after 7 yr.
Higher U/L ratios are characteristic of short-limb dwarfism, as occurs with
Turner syndrome or bone disorders, whereas lower ratios suggest hypogonadism
or Marfan syndrome.
Arm span also provides assessment of proportionality and is measured as the
distance between the tips of the middle fingers while the patient stands with the
back against the wall with arms outstretched horizontally at a 90-degree angle to
the trunk. This span should be close to height, although the proportion changes
with age.
 short stature: postnatal onset pathologic short stature, constitutional growth
delay, familial short stature, and prenatal onset short stature. (From
Mahoney CP: Evaluating the child with short stature, Pediatr Clin North Am
34:825, 1987.)

For premature infants , overdiagnosis of growth failure can be avoided by

using growth charts developed specifically for this population. A cruder method,
subtracting the weeks of prematurity from the postnatal age when plotting
growth parameters, does not capture the variability in growth velocity that very-
low-birthweight (VLBW) infants demonstrate. Although VLBW infants may
continue to show catch-up growth through early school age, most achieve
weight catch-up during the 2nd year and height catch-up by 3-4 yr, barring
medical complications (see Chapter 117 ).
Abnormal growth may be caused by a variety of factors, including congenital
conditions, systemic disease, endocrine disorders, nutritional deficiency (see
Chapter 57 ), psychosocial conditions, constitutional delay, or familial disorders
(Tables 27.2 and 27.3 ). In congenital pathologic short stature, an infant may or
may not be born small, but growth gradually tapers throughout infancy (Fig.
27.3 ). Causes include chromosome or genetic abnormalities (Turner syndrome,
skeletal dysplasia, trisomy 21; see Chapter 98 ), perinatal infection, extreme
prematurity, and teratogens (phenytoin, alcohol) (see Chapter 115.5 ). Linear
growth deceleration with or without changes in weight can occur at the onset or
as a result of a systemic illness or chronic inflammation. Medications such as
high-dose glucocorticoids may also impact growth. Analysis of growth patterns
requires consideration of weight status. Poor linear growth in the setting of
decreasing BMI suggests a nutritional or gastrointestinal issue, whereas poor
linear growth in the context of good or robust BMI suggests a hormonal
condition (hypothyroidism, growth hormone deficiency, cortisol excess).
Table 27.2
Common Causes of Decreased Growth and
Short Stature
Variation of normal
Familial short stature
Constitutional delay
Delayed puberty
Nutrition and gastrointestinal conditions
 Malnutrition
Celiac disease
Inflammatory bowel disease
Genetic conditions
Turner syndrome
Prader-Willi syndrome
22q deletion syndrome
Trisomy 21
Skeletal dysplasias: achondroplasia, SHOX haploinsufficiency,
osteogenesis imperfecta
Endocrine conditions
Hypothyroidism
Growth hormone deficiency
Poorly controlled diabetes mellitus
Poorly controlled diabetes insipidus
Metabolic bone disease: rickets, hypophosphatasia
Glucocorticoid excess
Psychosocial causes
Renal conditions
Renal tubular acidosis
Nephrotic syndrome
Medications
Glucocorticoids
Inappropriate sex steroid exposure
Antiepileptic medications
Table 27.3
Common Causes of Increased Growth and Tall
Stature

Variation of normal
Constitutional tall stature
Familial tall stature
Endocrine conditions
Growth hormone excess
Precocious puberty
Congenital adrenal hyperplasia
 Obesity
Genetic conditions
Marfan syndrome
Klinefelter syndrome
Sotos syndrome

Not all decreased growth is abnormal; variations of growth include

constitutional growth (and pubertal) delay and familial short stature. In
constitutional growth delay , weight and height decrease near the end of
infancy, parallel the norm through middle childhood, and accelerate toward the
end of adolescence with achievement of normal adult height. In familial short
stature , both the infant/child and the parent(s) are small; growth runs parallel to
and just below the normal curves.
Although tall or accelerated growth may be a variation of normal,
unexpected increase in growth may also signal an underlying condition (Table
27.3 ). Typically, obese individuals grow more quickly than their peers because
of peripheral aromatization of estrogen and effects on bone maturation. Despite
early taller stature, obese children are not ultimately taller than anticipated for
genetic height. Early onset of puberty, growth hormone excess, and sex steroid
exposure can also lead to accelerated growth. Several of these conditions may
ultimately lead to short stature in adulthood. Genetic conditions associated with
tall stature and overgrowth include Sotos, Klinefelter, and Marfan syndromes
(see Chapter 576 ).

Evaluation of Abnormal Growth

Evaluation of abnormal growth should include confirmation that the data are
accurate and plotted correctly. Comparisons should be made with previous
measurements. If poor or rapid growth or short or tall stature is a concern, a
radiograph of the left hand and wrist, the bone age , can provide information
about skeletal maturation. Skeletal development represents physiologic rather
than chronological age. Reference standards for bone maturation facilitate
estimation of bone age (see Table 22.3 ). A delayed bone age (skeletal age
younger than chronological age) suggests catch-up potential for linear growth.
Advanced bone age suggests a rapid maturation of the skeleton that may lead to
earlier cessation of growth. Bone age should be interpreted with the guidance of
a pediatric endocrinologist. Skeletal age correlates well with stage of pubertal
adiposity. Other methods of measuring fat, such as hydrodensitometry,
bioelectrical impedance, and total body water measurement, are used in research,
but not in clinical evaluation, but whole body dual-energy x-ray absorptiometry
(DXA) is beginning to emerge as a tool for measuring body fat and lean body
mass.

Dental Development
Dental development includes mineralization, eruption, and exfoliation (Table
27.4 ). Initial mineralization begins as early as the 2nd trimester (mean age for
central incisors, 14 wk) and continues through 3 yr of age for the primary
(deciduous) teeth and 25 yr of age for the secondary (permanent) teeth.
Mineralization begins at the crown and progresses toward the root. Eruption
begins with the central incisors and progresses laterally. Exfoliation begins at
about 6 yr of age and continues through 12 yr. Eruption of the permanent teeth
may follow exfoliation immediately or may lag by 4-5 mo. The timing of dental
development is poorly correlated with other processes of growth and maturation.
Delayed eruption is usually considered when no teeth have erupted by
approximately 13 mo of age (mean + 3 SD). Common causes include congenital
or genetic disorders, endocrine disorders (e.g., hypothyroidism,
hypoparathyroidism), familial conditions, and (the most common) idiopathic
conditions. Individual teeth may fail to erupt because of mechanical blockage
(crowding, gum fibrosis). Causes of early exfoliation include hypophosphatasia,
histiocytosis X, cyclic neutropenia, leukemia, trauma, and idiopathic factors.
Nutritional and metabolic disturbances, prolonged illness, and certain
medications (tetracycline) frequently result in discoloration or malformations of
the dental enamel. A discrete line of pitting on the enamel suggests a time-
limited insult.

Table 27.4
Chronology of Human Dentition of Primary (Deciduous)
and Secondary (Permanent) Teeth

CALCIFICATION AGE AT ERUPTION AGE AT SHEDDING

Begins at Complete at Maxillary Mandibular Maxillary Mandibular
PRIMARY TEETH
Central incisors 5th fetal mo 18-24 mo 6-8 mo 5-7 mo 7-8 yr 6-7 yr
Lateral incisors 5th fetal mo 18-24 mo 8-11 mo 7-10 mo 8-9 yr 7-8 yr
 Cuspids (canines) 6th fetal mo 30-36 mo 16-20 mo 16-20 mo 11-12 yr 9-11 yr
First molars 5th fetal mo 24-30 mo 10-16 mo 10-16 mo 10-12 yr 10-12 yr
Second molars 6th fetal mo 36 mo 20-30 mo 20-30 mo 10-12 yr 11-13 yr
SECONDARY TEETH
Central incisors 3-4 mo 9-10 yr 7-8 yr 6-7 yr
Lateral incisors Max, 10-12 mo 10-11 yr 8-9 yr 7-8 yr
Mand, 3-4 mo
Cuspids (canines) 4-5 mo 12-15 yr 11-12 yr 9-11 yr
First premolars (bicuspids) 18-21 mo 12-13 yr 10-11 yr 10-12 yr
Second premolars (bicuspids) 24-30 mo 12-14 yr 10-12 yr 11-13 yr
First molars Birth 9-10 yr 6-7 yr 6-7 yr
Second molars 30-36 mo 14-16 yr 12-13 yr 12-13 yr
Third molars Max, 7-9 yr 18-25 yr 17-22 yr 17-22 yr
Mand, 8-10 yr
Mand, Mandibular; Max, maxillary.
Adapted from a chart prepared by P.K. Losch, Harvard School of Dental Medicine, who provided
the data for this table.

Bibliography
Centers for Disease Control and Prevention, National Center for
Health Statistics. CDC growth charts (website) .
http://www.cdc.gov/growthcharts/ .
De Onis M, Garza C, Onyango AW, et al. Comparison of the
WHO child growth standards and the CDC 2000 growth
charts. J Nutr . 2007;137:144–148.
Foote JM, Kirouac N, Lipman TH. PENS position statement on
linear growth measurement of children. J Pediatr Nurs .
2015;30(2):425–426.
Grummer-Strawn LM, Reinold C, Krebs NF, Centers for
Disease Control and Prevention. Use of World Health
Organization and CDC growth charts for children aged 0-59
months in the United States. MMWR Recomm Rep .
2010;59(RR–9):1–15.
Guo SS, Roche AF, Chumlea WC, et al. Growth in weight,
recumbent length and head circumference for preterm low-
birthweight infants during the first three years of life using
gestation-adjusted ages. Early Hum Dev . 1997;47:305–325.
incumbent on the pediatric clinician to conduct regular developmental
surveillance and periodic developmental screening at primary care health
supervision visits aimed at early identification and treatment.
Among the many types of developmental or behavioral conditions, the most
common include language problems, affecting at least 1 in 10 children (see
Chapter 52 ); behavior or emotional disorders, affecting up to 25% of children,
with 6% considered serious; attention-deficit/hyperactivity disorder, affecting 1
in 10 children (Chapter 49 ); and learning disabilities, affecting up to 10%
(Chapters 50 and 51 ). Less common and more disabling are the intellectual
disabilities (1–2%; Chapter 53 ); autism spectrum disorders (1 in 59 children;
Chapter 54 ); cerebral palsy and related motor impairments (0.3%, or 1 in 345
children; Chapter 616 ); hearing impairment, also referred to as deafness, hard-
of-hearing, or hearing loss (0.12%; Chapter 655 ); and nonrefractive vision
impairment (0.8%; Chapter 639 ).

Developmental and Behavioral

Surveillance
General health surveillance is a critical responsibility of the primary care
clinician and is a key component of health supervision visits. Regular
developmental and behavioral surveillance should be performed at every health
supervision visit from infancy through young adulthood. Surveillance of a child's
development and behavior includes both obtaining historical information on the
child and family and making observations at the office visit (Tables 28.1 and
28.2 ).
Table 28.1
Key Components of Developmental and
Behavioral Surveillance
History

1. Parental developmental concerns

2. Developmental history
a. Streams of developmental milestone achievement
i. Gross motor
 ii. Fine motor
iii. Verbal speech and language
(1) Expressive
(2) Receptive
iv. Social language and self-help
b. Patterns of abnormality
i. Delay
ii. Dissociation
iii. Deviancy or deviation
iv. Regression
3. Behavior history
a. Interactions
i. Familiar settings (e.g. home, school): parents, siblings,
other familiar people, peers, other children
ii. Interaction in unfamiliar settings (e.g., community):
unfamiliar adults and children
b. Patterns of abnormality
i. Noncompliance, disruption (including tantrums),
aggression, impulsivity, increased activity, decreased
attention span, decreased social engagement, decreased
auditory or visual attention
ii. Deviation or atypical behaviors
(1) Repetitive play, rituals, perseverative
thought or action, self-injury
4. Risk factor identification: medical, family, and social history (including
social determinants of health)
5. Protective factor identification (also including social determinants)

Developmental Observation

1. Movement: gross and fine motor skills

2. Verbal communication: expressive speech and language, language
understanding
3. Social engagement and response
4. Behavior: spontaneous and responsive with caregiver and with staff
5. Related neurologic function on physical examination
Table 28.2
“Red Flags” in Developmental Screening and
Surveillance*
These indicators suggest that development is seriously disordered and that the
child should be promptly referred to a developmental or community
pediatrician.
Positive Indicators
Presence of Any of the Following:

Loss of developmental skills at any age

Parental or professional concerns about vision, fixing, or following an
object or a confirmed visual impairment at any age (simultaneous referral
to pediatric ophthalmology)
Hearing loss at any age (simultaneous referral for expert audiologic or ear,
nose, and throat assessment)
Persistently low muscle tone or floppiness
No speech by 18 mo, especially if the child does not try to communicate by
other means, such as gestures (simultaneous referral for urgent hearing
test)
Asymmetry of movements or other features suggestive of cerebral palsy,
such as increased muscle tone
Persistent toe walking
Complex disabilities
Head circumference above the 99.6th centile or below 0.4th centile; also, if
circumference has crossed 2 centiles (up or down) on the appropriate
chart or is disproportionate to parental head circumference
An assessing clinician who is uncertain about any aspect of assessment but
thinks that development may be disordered

Negative Indicators
Activities That the Child Cannot Do:

Sit unsupported by 12 mo
Walk by 18 mo (boys) or 2 yr (girls) (check creatine kinase urgently)
 Walk other than on tiptoes
Run by 2.5 yr
Hold object placed in hand by 5 mo (corrected for gestation)
Reach for objects by 6 mo (corrected for gestation)
Point at objects to share interest with others by 2 yr

* Most children do not have “red flags” and thus require quality screening to

detect any problems.

Adapted from Horridge KA. Assessment and investigation of the child with
disordered development. Arch Dis Child Educ Pract Ed 96:9–20, 2011.

Key historical elements include (1) eliciting and attending to the parents' or
caregivers' concerns around the child's development or behavior; (2) obtaining a
history of the child's developmental skills and behavior at home, with peers, in
school, and in the community; and (3) identifying the risks, strengths, and
protective factors for development and behavior in the child and family,
including the social determinants of health. During the office visit, the clinician
should make and document direct observations of the child's developmental
skills and behavioral interactions. Skills in all streams of development should be
considered along with observations of related neurologic functioning made on
physical examination.
With this history and observation, the clinician should create and maintain a
longitudinal record of the child's development and behavior for tracking the
child across visits. It is often helpful to obtain information from and share
information with other professionals involved with the child, including childcare
professionals, home visitors, teachers, after-school providers, and developmental
therapists. This provides a complete picture of the child's development and
behavior and allows collaborative tracking of the child's progress.

The Developmental and Behavioral Histories

Developmental surveillance includes tracking a child's achievement of
milestones, which represent key readily recognizable skills that usually occur in
a predictable sequence and at predictable age ranges during childhood. The
care visit at 9 m, 18 mo, and 30 mo. Tests recommended at these ages screen
development across all the streams. In addition, an autism screening test is
recommended at the 18 and 24 mo visits. Table 28.3 provides recommended
screening tests for general development and for autism. It is also recommended
that a child have a screening test administered any time that a parent, guardian,
or child health or early childhood professional has concerns identified during
developmental surveillance, or through screening performed at early childhood
programs. Although routine formal screening before the child's entry into
elementary school is not included in current guidelines, the primary care
clinician should be vigilant about surveillance regarding development at the 4 or
5 yr old visit and perform formal screening if concerns are identified, because of
the potential impact on learning and school services.

Table 28.3
Standardized Tools for General Developmental Screening

SCREENING AGE NUMBER ADMINISTRATION PUBLICATION

REF*
TEST RANGE OF ITEMS TIME INFORMATION
Ages & Stages 2-60 mo 30 10-15 min Paul H. Brookes Publishing 1
Questionnaires-3 800-638-3775
(ASQ3) www.brookespublishing.com
Parents' 0-8 y 10 2-10 min Ellsworth & Vandermeer 2
Evaluation of Press
Developmental 888-729-1697
Status (PEDS) www.pedstest.com
Parents' 0-8 y 6-8 items at 4-6 min Ellsworth & Vandermeer 2
Evaluation of each age Press
Developmental level 888/729-1697 or
Status: www.pedstest.com
Developmental
Milestones
(PEDS:DM)
Screening Version
Survey of Well- Dev: 1- Dev: 10 Dev: <5 min www.theswyc.org 3-6
being of Young 65 mo Autism: Autism: <5 min
Children (SWYC) Autism: 7
† 16-35
mo
* Key reference sources:

1. Squires J, Potter L, Bricker D: The ASQ user's guide,

ed 3, Baltimore, MD, 2009, Paul H Brookes
Publishing.
identify children in need of screening or evaluation for problems in learning,
attention, and behavior.
Additional screening for behavioral conditions should be considered, although
there is currently no recommended consensus on the ages at which behavioral
screening should occur. One possibility would be to provide behavioral
screening at the 30 mo, 4 or 5 yr, and 8 yr visits to identify problems emerging in
the toddler, preschool, and early elementary years. For older children, visits
during preadolescent or adolescent ages also offer an opportunity for
surveillance and possible screening for behavioral and emotional problems
meriting professional assistance or intervention. Table 28.4 provides
recommended behavior screening tools.

Table 28.4
Standardized Tools for General Behavioral Screening

SCREENING AGE NUMBER ADMINISTRATION PUBLICATION

REF*
TEST RANGE OF ITEMS TIME INFORMATION
Ages & Stages 2-60 mo 9 age- 10 min Paul H. Brookes 1, 2
Questionnaire: specific Publishing,
Social-Emotional-2 forms with 800-638-3775
(ASQ:SE-2) (2015) 19-33 items www.agesandstages.com
Brief Infant Toddler 12-36 mo 42 7-10 min Pearson Assessments † 3
Social Emotional
Assessment
(BITSEA)
Pediatric Symptom 4-16 yr 17 <5 min Website ‡ 4
Checklist–17 items PSC-35
(PSC-17b)) Youth
self-
report:
≥11 yr
Strengths and 4-17 yr 25; 22 for 3- 5-10 min www.sdqinfo.org 5
Difficulties 3-4 yr old 4 yr olds
Questionnaire version
(SDQ) available
Youth
self-report
11-16 yr
* Key reference sources:

1. Squires J, Bricker DD, Twombly E: Ages & Stages

Questionnaires: Social-Emotional-2 (ASQ:SE-2): a
parent-completed, child-monitoring system for social-
anticipatory guidance, safety and injury prevention, and developmental
promotion), tools relying on parent completion with office staff administration
and scoring are well suited for primary care settings. Such tests may be
completed in advance of appointments, either online or in writing, whether at
home or while waiting for the pediatric visit to begin. If a test is scored in
advance of the visit, the pediatric clinician can enter the room with results in
hand for review and discussion, including a description of the child's
development and behavior compared with peers, general information on child
development and behavior, any areas of concern, referrals needed, and
information to share with the child's daycare, preschool, or other community
providers, when applicable.

Table 28.5
Standardized Tools for Language and Autism Screening

NUMBER
AGE ADMINISTRATION PURCHASE/ OBTAINMENT
SCREENING TEST OF REF*
RANGE TIME INFORMATION
ITEMS
LANGUAGE
Communication and 6-24 mo 24 5-10 min Paul H. Brookes Publishing 1
Symbolic Behavior Co
Scales: Developmental 800/638-3775
Profile (CSBS-DP): www.brookespublishing.com
Infant Toddler
Checklist
AUTISM
Modified Checklist for 16-48 20 (avg) 5-10 min www.m-chat.org/ 2
Autism in Toddlers, mo Follow up interview †
Revised with Follow-
up (M-CHAT-R/F)
Social Communication 4+ yr 40 (avg) 5-10 min Western Psychological 3, 4
Questionnaire (SCQ) Services
www.wpspublish.com
* Key reference sources:

1. Wetherby AM, Prizant BM: Communication and

Symbolic Behavior Scales: Developmental Profile,
Baltimore, MD, 2002, Paul H Brookes Publishing.
2. Robins DL, Casagrande K, Barton M, et al: Validation
of the Modified Checklist for Autism in Toddlers,
Revised with Follow-up (M-CHAT-R/F), Pediatrics
symptoms or illness (Table 29.1 ).

Table 29.1
Conditions That Do and Do Not Require Exclusion From
Group Childcare Settings

CONDITIONS THAT REQUIRE EXCLUSION COMMENTS

If any of these 3 key criteria for exclusion of children who are ill are met, the child should be temporarily
excluded, regardless of the type of illness:
Illness preventing the child from participating Providers should specify in their policies, approved
comfortably in activities, as determined by the by the facility's healthcare consultant, what severity
childcare provider level of illness the facility can manage, and how
much and what types of illness will be addressed:
• Severity level 1 consists of children whose health
condition is accompanied by high interest and complete
involvement in activity, associated with an absence of
symptoms of illness (e.g., children recovering from
pinkeye, rash, or chickenpox) but who need further
recuperation time.
• Severity level 2 encompasses children whose health
condition is accompanied by a medium activity level
because of symptoms (e.g., children with low-grade
fever, children at beginning of illness, children in early
recovery period of illness)
• Severity level 3 consists of children whose health
condition is accompanied by a low activity level
because of symptoms that preclude much involvement.
Illness resulting in a greater need for care than the
childcare staff can provide without compromising the
health and safety of the other children, as determined
by the childcare provider
Illness that poses a risk of spread of harmful diseases
to others
In addition to the above key criteria, temporary exclusion is recommended when the child has any of the
following conditions:
Fever (temperature above 38°C [101°F] orally, above Accompanied by behavior changes or other signs or
38.9°C [102°F] rectally, or above 37.8°C [100°F] or symptoms of illness until medical professional evaluation
higher taken axillary [armpit] or measured by an finds the child able to be included at the facility
equivalent method) and behavior change or other signs
and symptoms (e.g., sore throat, rash, vomiting,
diarrhea)
Acute change in behavior including lethargy/lack of Until evaluation by a medical professional finds the child
responsiveness, inexplicable irritability or persistent able to be included at the facility
crying, difficult breathing, or having a quickly
spreading rash
Diarrhea (defined by watery stools or decreased form Readmission after diarrhea can occur when diapered
of stool that is not associated with changes of diet). children have their stool contained by the diaper
Exclusion is required for all diapered children whose (even if the stools remain loose) and when toilet-
stool is not contained in the diaper and toilet-trained trained children are continent. Special circumstances
children if the diarrhea is causing soiled pants or that require specific exclusion criteria include the
clothing. following:
 • Toxin-producing Escherichia coli or Shigella infection,
until stools are formed and test results of 2 stool
cultures obtained from stools produced 24 hr apart do
not detect these organisms
• Salmonella serotype Typhi infection, until diarrhea
resolves and, in children <5 yr old, 3 negative stool
cultures obtained at 24 hr intervals
Blood or mucus in stool Not explained by dietary change, medication, or hard
stools
Vomiting illness More than 2 times in previous 24 hr, unless vomiting is
determined to be caused by a noninfectious condition and
child remains adequately hydrated
Abdominal pain Persistent (continues >2 hr) or intermittent associated
with fever or other signs or symptoms
Mouth sores with drooling Unless the child's primary care provider or local health
department authority states that the child is noninfectious
Rash with fever or behavior changes Until the primary care provider has determined that the
illness is not an infectious disease
Active tuberculosis Until the child's primary care provider or local health
department states child is on appropriate treatment and
can return
Impetigo Until treatment has been started
Streptococcal pharyngitis (i.e., strep throat or other Until 24 hr after treatment has been started
streptococcal infection)
Purulent conjunctivitis Defined as pink or red conjunctiva with white or yellow
eye discharge, until after treatment has been initiated
Pediculosis (head lice) Until after 1st treatment
Note: Exclusion is not necessary before end of the
program day.
Scabies Until after treatment has been given
Varicella-zoster virus (chickenpox) Until all lesions have dried or crusted (usually 6 days
after onset of rash)
Rubella Until 6 days after onset of rash
Pertussis Until 5 days of appropriate antibiotic treatment
Mumps Until 5 days after onset of parotid gland swelling
Measles Until 4 days after onset of rash
Hepatitis A virus Until 1 wk after onset of illness or jaundice if child's
symptoms are mild or as directed by health department
Any child determined by the local health department
to be contributing to the transmission of illness during
an outbreak
CONDITIONS THAT DO NOT REQUIRE COMMENTS
EXCLUSION
Common colds, runny noses Regardless of color or consistency of nasal discharge
A cough not associated with an infectious disease or a
fever
Watery, yellow or white discharge or crusting eye
discharge without fever, eye pain, or eyelid redness
Presence of bacteria or viruses in urine or feces in the Exceptions include children infected with highly
absence of illness symptoms (e.g., diarrhea) contagious organisms capable of causing serious illness.
Pinkeye (bacterial conjunctivitis), indicated by pink or If 2 unrelated children in the same program have
red eyelids after sleep conjunctivitis, the organism causing the conjunctivitis
may have a higher risk for transmission, and a child
healthcare professional should be consulted.
 Fever without any signs or symptoms of illness in If the child is behaving normally but has fever <38.9°C
children >6 mo old regardless of whether (102°F) rectally or the equivalent, child should be
acetaminophen or ibuprofen was given monitored but does not need to be excluded for fever
alone.
Rash without fever and without behavioral changes
Lice or nits Exclusion for treatment of an active lice infestation may
be delayed until end of the day.
Ringworm Exclusion for treatment may be delayed until end of the
day.
Molluscum contagiosum Do not require exclusion or covering of lesions
Thrush (i.e., white spots or patches in mouth or on
cheeks or gums)
Fifth disease Once the rash has appeared
Methicillin-resistant Staphylococcus aureus (MRSA) Known MRSA carriers or colonized individuals should
without an infection or illness that would otherwise not be excluded.
require exclusion
Cytomegalovirus infection
Chronic hepatitis B infection
HIV infection
Asymptomatic children who have been previously Children who are continent of stool or who are diapered
evaluated and found to be shedding potentially with formed stools that can be contained in the diaper
infectious organisms in the stool may return to care
Children with chronic infections conditions who can ADA requires that childcare programs make reasonable
be accommodated in the program according to federal accommodations for children with disabilities and/or
legal requirement in Americans with Disabilities Act chronic illnesses, considering each child individually.
(ADA)
Adapted from American Academy of Pediatrics (AAP), American Public Health Association,
National Resource Center for Health and Safety in Child Care and Early Education: Stepping
stones to caring for our children: national health and safety performance standards—guidelines
for early care and education programs , ed 3, Elk Grove Village, IL, 2013, AAP, pp 46–52.
http://nrckids.org/index.cfm/products/stepping-stones-to-caring-for-our-children-3rd-edition-
ss3/stepping-stones-to-caring-for-our-children-3rd-edition-ss3/ .

The caregiver/teacher should determine if the illness (1) prevents the child
from participating comfortably in activities; (2) results in a need for care that is
greater than the staff can provide without compromising the health and safety of
other children; (3) poses a risk of spread of harmful diseases to others; or (4)
causes a fever and behavior change or other signs and symptoms (e.g., sore
throat, rash, vomiting, diarrhea). An unexplained temperature above 100°F
(37.8°C) (armpit) in a child <6 mo old should be medically evaluated. Any
infant <2 mo old with fever should receive immediate medical attention.
Most families need to arrange to keep sick children at home, such as staying
home from work or having backup plans with an alternative caregiver.
Alternative care arrangements outside the home for sick children are relatively
rare but may include either (1) care in the child's own center, if it offers special
provisions designed for the care of ill children (sometimes called the infirmary
model or sick daycare ), or (2) care in a center that serves only children with
pediatricians can help parents determine how to adjust childcare arrangements to
best meet their child's specific needs (e.g., allergies, eating and sleeping habits,
temperament and stress-regulation capacities). For most parents, finding
childcare that they can afford, access, manage, and accept as a good environment
for their child is a difficult and often distressing process. Many parents also
worry about how their child will fare in childcare (e.g., Will their child feel
distressed by group settings, suffer from separation from the parents, or even be
subjected to neglect or abuse?). These worries are especially likely among low-
income parents with fewer family and community resources. A few parents may
think of childcare only as “babysitting” and may not consider the consequences
for their child's cognitive, linguistic, and social development, focusing solely on
whether the child is safe and warm. These parents may be less likely to select a
high-quality childcare arrangement, which is especially problematic if the family
is facing socioeconomic challenges that already place them at risk of receiving
lower-quality care for their children. For these parents, it is vital to stress the
importance of quality and its implications for their child's cognitive, language,
and behavioral development and school readiness.

Table 29.2

Childcare Information Resources

ORGANIZATION SPONSOR WEBSITE AND CONTACT INFORMATION
Child Care Aware Child Care Aware of http://www.childcareaware.org
America (formerly
National
Association of Child
Care Resource and
Referral Agencies)
Healthy Child Care American Academy http://www.healthychildcare.org
America of Pediatrics (AAP)
National http://www.naeyc.org
Association for the
Education of Young
Children (NAEYC)
National http://www.nascd.com
Association for
Sick Child Daycare
(NASCD)
National Resource http://www.nrckids.org
Center for Health For 2013 report from AAP, APHA, NRC, Stepping Stones to
and Safety in Child Caring for Our Children: National Health and Safety
Care and Early Performance Standards—Guidelines for Early Care and
Education (NRC) Education Programs, ed 3, go to:
http://nrckids.org/index.cfm/products/stepping-stones-to-caring-
 for-our-children-3rd-edition-ss3/stepping-stones-to-caring-for-
our-children-3rd-edition-ss3/
Office of Child U.S. Department of http://www.acf.hhs.gov/programs/occ
Care (OCC) Health and Human
Services,
Administration for
Children and
Families
Office of Child U.S. Department of https://childcareta.acf.hhs.gov/
Care Technical Health and Human
Assistance Network Services,
(CCTAN) Administration for
Children and
Families, Office of
Child Care

Advising Parents on Childcare Health Issues

Parents of infants should be advised to ensure that childcare providers put infants
on their back to sleep to prevent SIDS. Also, pediatricians should emphasize the
importance of following vaccination schedules; most states require compliance
for children to participate in licensed group childcare settings.
When children are ill, parents should be advised to follow guidelines for
inclusion and exclusion (see Table 29.1 ). Parents may disagree with childcare
staff about whether a child meets or does not meet the exclusion criteria.
However, professional guidelines state that “if … the reason for exclusion relates
to the child's ability to participate or the caregiver's/teacher's ability to provide
care for the other children, the caregiver/teacher should not be required to accept
responsibility for the care of the child.”*

Helping Children With Special Needs

Pediatricians should work with parents and communicate with other service
providers and early intervention staff to identify problems, remove access
barriers, and coordinate service delivery for children with special needs. They
should also encourage involvement of parents and childcare providers in IFSP or
IEP plan development.

Consulting and Partnering With Childcare

Providers
Most state regulations mandate that licensed programs have a formal relationship
 larger discrepancies between school night and non–school night
bedtimes and wake times, and increased “weekend oversleep” in an
attempt to compensate for chronic weekday sleep insufficiency. This
phenomenon, often referred to as “social jet lag,” not only fails to
adequately address performance deficits associated with insufficient
sleep on school nights, but further exacerbates the normal adolescent
phase delay and results in additional circadian disruption (analogous to
that experienced by shift workers).

Table 31.1 lists normal developmental changes in children's sleep.

Table 31.1
Normal Developmental Changes in Children's Sleep

SLEEP
AGE DURATION*
ADDITIONAL SLEEP ISSUES SLEEP DISORDERS
CATEGORY AND SLEEP
PATTERNS
Newborn (0-2 Total sleep: American Academy of Most sleep issues perceived as
mo) 10-19 hr per Pediatrics issued a revised problematic at this stage represent a
24 hr (average, recommendation in 2016 discrepancy between parental
13-14.5 hr), advocating against bed- expectations and developmentally
may be higher sharing in the 1st yr of life, appropriate sleep behaviors. Newborns
in premature instead encouraging who are extremely fussy and persistently
babies proximate but separate difficult to console, as noted by parents,
Bottle-fed sleeping surfaces for mother are more likely to have underlying
babies and infant for at least the 1st 6 medical issues such as colic,
generally sleep mo and preferably 1st yr of gastroesophageal reflux, and formula
for longer life. intolerance.
periods (2-5 hr Safe sleep practices for
bouts) than infants:
breastfed • Place baby on his or her back to
babies (1-3 sleep at night and during nap
hr). times.
Sleep periods • Place baby on a firm mattress
are separated with well-fitting sheet in safety-
by 1-2 hr approved crib.
awake. • Do not use pillows or comforters.
No established • Standards require crib bars to be
nocturnal-
no farther apart than in.
diurnal pattern
• Make sure baby's face and head
in 1st few wk;
stay uncovered and clear of
sleep is evenly
blankets and other coverings
distributed
during sleep.
throughout the
day and night,
averaging 8.5
 hr at night and
5.75 hr during
day.
Infant (2-12 Recommended Sleep regulation or self- Behavioral insomnia of childhood;
mo) sleep duration (4- soothing involves the infant's sleep-onset association type
12 mo) is 12-16 hr ability to negotiate the sleep– Sleep-related rhythmic movements
(note that there is wake transition, both at sleep (head banging, body rocking)
great individual onset and following normal
variability in sleep awakenings throughout the
times during night. The capacity to self-
infancy). soothe begins to develop in
the 1st 12 wk of life and is a
reflection of both
neurodevelopmental
maturation and learning.
Sleep consolidation, or
“sleeping through the night,”
is usually defined by parents
as a continuous sleep episode
without the need for parental
intervention (e.g., feeding,
soothing) from the child's
bedtime through the early
morning. Infants develop the
ability to consolidate sleep
between 6 wk and 3 mo.
Toddler (1-2 Recommended Cognitive, motor, social, and Behavioral insomnia of childhood,
yr) sleep amount language developmental sleep-onset association type
is 11-14 hr issues impact sleep. Behavioral insomnia of childhood,
(including Nighttime fears develop; limit-setting type
naps). transitional objects and
Naps decrease bedtime routines are
from 2 to 1 important.
nap at average
age of 18 mo.
Preschool (3- Recommended Persistent cosleeping tends to be Behavioral insomnia of childhood, limit-
5 yr) sleep amount highly associated with sleep setting type
is 10-13 hr problems in this age-group.
(including Sleep problems may become Sleepwalking, sleep terrors, nighttime
naps). chronic. fears/nightmares, obstructive sleep
Overall, 26% apnea syndrome
of 4 yr olds
and just 15%
of 5 yr olds
nap.
Middle Recommended School and behavior problems Nightmares
childhood (6- sleep amount is 9- may be related to sleep problems.
12 yr) 12 hr. Media and electronics, such as Obstructive sleep apnea syndrome
television, computer, video Insufficient sleep
games, and the Internet,
increasingly compete for sleep
time.
Irregularity of sleep–wake
schedules reflects increasing
discrepancy between school
 and non–school night
bedtimes and wake times.
Adolescence Recommended Puberty-mediated phase delay Insufficient sleep
(13-18 yr) sleep amount (later sleep onset and wake Delayed sleep–wake phase disorder
is 8-10 hr. times), relative to sleep-wake Narcolepsy
Later cycles in middle childhood Restless legs syndrome/periodic
bedtimes; Earlier required wake times limb movement disorder
increased Environmental competing
discrepancy priorities for sleep
between sleep
patterns on
weekdays and
weekends
* All recommended sleep amounts from Paruthi S, Brooks LJ, D'Ambrosio C, et al: Recommended

amount of sleep for pediatric populations: a consensus statement of the American Academy of
Sleep Medicine. J Clin Sleep Med 12:785–786, 2016.

Common Sleep Disorders

Childhood sleep problems may be conceptualized as resulting from (1)
inadequate duration of sleep for age and sleep needs (insufficient sleep quantity);
(2) disruption and fragmentation of sleep (poor sleep quality) as a result of
frequent, repetitive, and brief arousals during sleep; and (3) misalignment of
sleep–wake timing with circadian rhythms or CNS-mediated hypersomnia
(excessive daytime sleepiness and increased sleep needs). Insufficient sleep is
usually the result of difficulty initiating (delayed sleep onset ) or maintaining
sleep (prolonged night wakings ), but, especially in older children and
adolescents, may also represent a conscious lifestyle decision to sacrifice sleep
in favor of competing priorities, such as homework and social activities. The
underlying causes of delayed sleep onset/prolonged night wakings or sleep
fragmentation may in turn be related to primarily behavioral factors (e.g.,
bedtime resistance resulting in shortened sleep duration) or medical causes (e.g.,
obstructive sleep apnea causing frequent, brief arousals).
Certain pediatric populations are relatively more vulnerable to acute or
chronic sleep problems. These include children with medical problems, such as
chronic illnesses or pain conditions (e.g., cystic fibrosis, asthma, idiopathic
juvenile arthritis) and acute illnesses (e.g., otitis media); children taking
stimulants s (e.g., psychostimulants, caffeine), sleep-disrupting medications
(e.g., corticosteroids), or daytime-sedating medications (some anticonvulsants,
α-agonists); hospitalized children; and children with a variety of psychiatric
disorders, including attention-deficit/hyperactivity disorder (ADHD), depression,
the child's resistance at bedtime is the result of an underlying problem in falling
asleep that is caused by other factors (medical conditions such as asthma or
medication use; a sleep disorder such as restless legs syndrome; anxiety) or a
mismatch between the child's intrinsic circadian rhythm (“night owl”) and
parental expectations regarding an “appropriate” bedtime.
Successful treatment of limit-setting sleep problems generally involves a
combination of parent education regarding appropriate limit setting, decreased
parental attention for bedtime-delaying behavior, establishment of bedtime
routines, and positive reinforcement (sticker charts) for appropriate behavior at
bedtime. Other behavioral management strategies that have empirical support
include bedtime fading , or temporarily setting the bedtime closer to the actual
sleep-onset time and then gradually advancing the bedtime to an earlier target
bedtime. Older children may benefit from being taught relaxation techniques to
help themselves fall asleep more readily. Following the principles of healthy
sleep practices for children is essential (Table 31.2 ).
Table 31.2
Basic Principles of Healthy Sleep for Children
1. Have a set bedtime and bedtime routine for your child.
2. Bedtime and wake-up time should be about the same time on school
nights and non–school nights. There should not be more than about 1 hr
difference from one day to another.
3. Make the hour before bed shared quiet time. Avoid high-energy
activities, such as rough play, and stimulating activities, such as watching
television or playing computer games, just before bed.
4. Don 't send your child to bed hungry. A light snack (e.g., milk and
cookies) before bed is a good idea. Heavy meals within 1 hr or 2 of
bedtime, however, may interfere with sleep.
5. Avoid products containing caffeine for at least several hours before
bedtime. These include caffeinated sodas, coffee, tea, and chocolate.
6. Make sure your child spends time outside every day, whenever
possible, and is involved in regular exercise.
7. Keep your child 's bedroom quiet and dark. A low-level night light is
acceptable for children who find completely dark rooms frightening.
8. Keep your child 's bedroom at a comfortable temperature during the
night (<24°C [75°F]).
 9. Don 't use your child 's bedroom for time-out or punishment.
10. Keep the television set out of your child 's bedroom. Children can
easily develop the bad habit of “needing” the television to fall asleep. It is
also much more difficult to control your child's viewing if the set is in the
bedroom.

A 3rd type of childhood insomnia is related to a mismatch between parental

expectations regarding time in bed and the child's intrinsic sleep needs. If, as
illustrated in Fig. 31.1 , a child's typical sleep time is 10 hr but the “sleep
window” is set for 12 hr (7 PM to 7 AM ), the result is likely to be a prolonged
sleep onset of 2 hr, an extended period of wakefulness during the night, or early
morning waking (or a combination); these periods are usually characterized by
“normal” wakefulness in the child that is not accompanied by excessive distress.
This situation is important to recognize because the solution—reducing the time
in bed to actual sleep time—is typically simple and effective.

FIG. 31.1 Mismatch between sleep needs/duration and time in bed,
resulting in insomnia.

Another form of insomnia that is more common in older children and

adolescents is often referred to as psychophysiologic, primary, or learned
insomnia. Primary insomnia occurs mainly in adolescents and is characterized
by a combination of learned sleep-preventing associations and heightened
physiologic arousal resulting in a complaint of sleeplessness and decreased
daytime functioning. A hallmark of primary insomnia is excessive worry about
sleep and an exaggerated concern of the potential daytime consequences. The
physiologic arousal can be in the form of cognitive hypervigilance , such as
“racing” thoughts; in many individuals with insomnia, an increased baseline
level of arousal is further intensified by this secondary anxiety about
sleeplessness. Treatment usually involves educating the adolescent about the
principles of healthy sleep practices (Table 31.3 ), institution of a consistent
sleep–wake schedule, avoidance of daytime napping, instructions to use the bed
for sleep only and to get out of bed if unable to fall asleep (stimulus control ),
restricting time in bed to the actual time asleep (sleep restriction ), addressing
maladaptive cognitions about sleep, and teaching relaxation techniques to reduce
anxiety.
Table 31.3
Basic Principles of Healthy Sleep for
Adolescents
1. Wake up and go to bed at about the same time every night. Bedtime
and wake-up time should not differ from school to non–school nights by
more than approximately 1 hr.
2. Avoid sleeping in on weekends to “catch up” on sleep. This makes it
more likely that you will have problems falling asleep.
3. If you take naps , they should be short (no more than 1 hr) and scheduled
in the early to mid-afternoon . However, if you have a problem with
falling asleep at night, napping during the day may make it worse and
should be avoided.
4. Spend time outside every day. Exposure to sunlight helps to keep your
body's internal clock on track.
5. Exercise regularly. Exercise may help you fall asleep and sleep more
deeply.
6. Use your bed for sleeping only. Don't study, read, listen to music, or
watch television on your bed.
7. Make the 30-60 minutes before bedtime a quiet or wind-down time .
Relaxing, calm, enjoyable activities, such as reading a book or listening
to calm music, help your body and mind slow down enough to let you get
to sleep. Don't study, watch exciting/scary movies, exercise, or get
involved in “energizing” activities just before bed.
8. Eat regular meals, and don 't go to bed hungry . A light snack before bed
 is a good idea; eating a full meal within 1 hr before bed is not.
9. Avoid eating or drinking products containing caffeine from dinnertime to
bedtime. These include caffeinated sodas, coffee, tea, and chocolate.
10. Do not use alcohol. Alcohol disrupts sleep and may cause you to awaken
throughout the night.
11. Smoking (e.g., cigarettes) disturbs sleep. Although you should not smoke
at all, if you do, do not smoke at least 2 hr before bed .
12. Do not use sleeping pills, melatonin, or other nonprescription sleep
aids to help you sleep unless specifically recommended by your doctor.
These can be dangerous, and the sleep problems often return when you
stop taking the medicine.

Behavioral treatments for insomnia, even in young children, appear to be

highly effective and well tolerated. Several studies have failed to demonstrate
long-term negative effects of behavioral strategies such as “sleep training” on
parent–child relationships and attachment, psychosocial-emotional functioning,
and chronic stress. In general, hypnotic medications or supplements such as
melatonin are infrequently needed as an adjunct to behavioral therapy to treat
insomnia in typically developing and healthy children.

Obstructive Sleep Apnea Syndrome

Sleep-related breathing disorder (SRBD ) in children encompasses a broad
spectrum of respiratory disorders that occur exclusively in sleep or that are
exacerbated by sleep, including primary snoring and upper airway resistance
syndrome, as well as apnea of prematurity (see Chapter 122.2 ) and central
apnea (see Chapter 446.2 ). Obstructive sleep apnea syndrome (OSAS) , the
most important clinical entity within the SRBD spectrum, is characterized by
repeated episodes of prolonged upper airway obstruction during sleep despite
continued or increased respiratory effort, resulting in complete (apnea ) or
partial (hypopnea ; ≥30% reduction in airflow accompanied by ≥3% O2
desaturation and/or arousal) cessation of airflow at the nose and/or mouth, as
well as in disrupted sleep. Both intermittent hypoxia and the multiple arousals
resulting from these obstructive events likely contribute to significant metabolic,
cardiovascular, and neurocognitive-neurobehavioral morbidity.
Primary snoring is defined as snoring without associated ventilatory
abnormalities on overnight polysomnogram (e.g., apneas or hypopneas,
hypoxemia, hypercapnia) or respiratory-related arousals and is a manifestation of
the vibrations of the oropharyngeal soft tissue walls that occur when an
individual attempts to breathe against increased upper airway resistance during
sleep. Although generally considered nonpathologic, primary snoring in children
may still be associated with subtle breathing abnormalities during sleep,
including evidence of increased respiratory effort, which in turn may be
associated with adverse neurodevelopmental outcomes.

Etiology
OSAS results from an anatomically or functionally narrowed upper airway; this
typically involves some combination of decreased upper airway patency (upper
airway obstruction and/or decreased upper airway diameter), increased upper
airway collapsibility (reduced pharyngeal muscle tone), and decreased drive to
breathe in the face of reduced upper airway patency (reduced central ventilatory
drive) (Table 31.4 ). Upper airway obstruction varies in degree and level (i.e.,
nose, nasopharynx/oropharynx, hypopharynx) and is most frequently caused by
adenotonsillar hypertrophy, although tonsillar size does not necessarily correlate
with degree of obstruction, especially in older children. Other causes of airway
obstruction include allergies associated with chronic rhinitis or nasal obstruction;
craniofacial abnormalities, including hypoplasia or displacement of the maxilla
and mandible; gastroesophageal reflux with resulting pharyngeal reactive edema
(see Chapter 349 ); nasal septal deviation (Chapter 404 ); and velopharyngeal
flap cleft palate repair. Reduced upper airway tone may result from
neuromuscular diseases, including hypotonic cerebral palsy and muscular
dystrophies (see Chapter 627 ), or hypothyroidism (Chapter 581 ). Reduced
central ventilatory drive may be present in some children with Arnold-Chiari
malformation (see Chapter 446 ); rapid-onset obesity with hypothalamic
dysfunction, hypoventilation, and autonomic dysregulation (Chapter 60.1 ); and
meningomyelocele (Chapter 609.4 ). In other situations the etiology is mixed;
individuals with Down syndrome (see Chapter 98.2 ), because of their facial
anatomy, hypotonia, macroglossia, and central adiposity, as well as the increased
incidence of hypothyroidism, are at particularly high risk for OSAS, with some
estimates of prevalence as high as 70%.
Table 31.4
Anatomic Factors That Predispose to
Obstructive Sleep Apnea Syndrome and
Hypoventilation in Children
Nose

Anterior nasal stenosis

Choanal stenosis/atresia
Deviated nasal septum
Seasonal or perennial rhinitis
Nasal polyps, foreign body, hematoma, mass lesion

Nasopharyngeal and Oropharyngeal

Adenotonsillar hypertrophy
Macroglossia
Cystic hygroma
Velopharyngeal flap repair
Cleft palate repair
Pharyngeal mass lesion

Craniofacial

Micrognathia/retrognathia
Midface hypoplasia (e.g., trisomy 21, Crouzon disease, Apert syndrome)
Mandibular hypoplasia (Pierre Robin, Treacher Collins, Cornelia de Lange
syndromes)
Craniofacial trauma
Skeletal and storage diseases
Achondroplasia
Storage diseases (e.g., glycogen; Hunter, Hurler syndromes)

Although many children with OSAS are of normal weight, an increasingly

large percentage are overweight or obese, and many of these children are school-
age or younger (see Chapter 60 ). There is a significant correlation between
weight and SRBD (e.g., habitual snoring, OSAS, sleep-related hypoventilation).
micrognathia, and midfacial hypoplasia, best appreciated by inspection of the
lateral facial profile, increase the likelihood of OSAS and should be noted. In
severe cases the child may have evidence of pulmonary hypertension, right-sided
heart failure, and cor pulmonale; systemic hypertension may occur, especially in
obese children.
Table 31.5
American Academy of Pediatrics Clinical
Practice Guideline: Diagnosis and
Management of Childhood Obstructive Sleep
Apnea Syndrome (OSAS)
Key Action Statement 1: Screening for OSAS

As part of routine health maintenance visits, clinicians should inquire

whether the child or adolescent snores. If the answer is affirmative or if a
child or adolescent presents with signs or symptoms of OSAS, clinicians
should perform a more focused evaluation. (Evidence Quality: Grade B;
Recommendation Strength: Recommendation.)

Key Action Statement 2A: Polysomnography

If a child or adolescent snores on a regular basis and has any of the

complaints or findings of OSAS, clinicians should either (1) obtain a
polysomnogram (Evidence Quality: Grade A; Recommendation Strength:
Recommendation) or (2) refer the patient to a sleep specialist or
otolaryngologist for a more extensive evaluation (Evidence Quality:
Grade D; Recommendation Strength: Option.)

Key Action Statement 2B: Alternative Testing

If polysomnography is not available, clinicians may order alternative

diagnostic tests, such as nocturnal video recording, nocturnal oximetry,
daytime nap polysomnography, or ambulatory polysomnography.
(Evidence Quality: Grade C; Recommendation Strength: Option.)
Key Action Statement 3: Adenotonsillectomy

If a child is determined to have OSAS, has a clinical examination

consistent with adenotonsillar hypertrophy, and does not have a
contraindication to surgery, the clinician should recommend
adenotonsillectomy as the first line of treatment. If the child has OSAS
but does not have adenotonsillar hypertrophy, other treatment should be
considered (see Key Action Statement 6 ). Clinical judgment is required
to determine the benefits of adenotonsillectomy compared with other
treatments in obese children with varying degrees of adenotonsillar
hypertrophy. (Evidence Quality: Grade B; Recommendation Strength:
Recommendation.)

Key Action Statement 4: High-Risk Patients Undergoing

Adenotonsillectomy

Clinicians should monitor high-risk patients undergoing

adenotonsillectomy as inpatients postoperatively. (Evidence Quality:
Grade B; Recommendation Strength: Recommendation.)

Key Action Statement 5: Reevaluation

Clinicians should clinically reassess all patients with OSAS for persisting
signs and symptoms after therapy to determine whether further treatment
is required. (Evidence Quality: Grade B; Recommendation Strength:
Recommendation.)

Key Action Statement 5B: Reevaluation of High-Risk Patients

Clinicians should reevaluate high-risk patients for persistent OSAS after

adenotonsillectomy, including those who had a significantly abnormal
baseline polysomnogram, have sequelae of OSAS, are obese, or remain
symptomatic after treatment, with an objective test (see Key Action
Statement 2 ), or refer such patients to a sleep specialist. (Evidence
Quality: Grade B; Recommendation Strength: Recommendation.)
Key Action Statement 6: Continuous Positive Airway Pressure (CPAP)

Clinicians should refer patients for CPAP management if symptoms/signs

or objective evidence of OSAS persists after adenotonsillectomy or if
adenotonsillectomy is not performed. (Evidence Quality: Grade B;
Recommendation Strength: Recommendation.)

Key Action Statement 7: Weight Loss

Clinicians should recommend weight loss in addition to other therapy if a

child/adolescent with OSAS is overweight or obese. (Evidence Quality:
Grade C; Recommendation Strength: Recommendation.)

Key Action Statement 8: Intranasal Corticosteroids

Clinicians may prescribe topical intranasal corticosteroids for children with

mild OSAS in whom adenotonsillectomy is contraindicated or for
children with mild postoperative OSAS. (Evidence Quality: Grade B;
Recommendation Strength: Option.)

Adapted from Marcus CL, Brooks LJ, Draper KA, et al: Diagnosis and
management of childhood obstructive sleep apnea syndrome. Pediatrics
130:576–584, 2012.

Because no combination of clinical history and physical findings can

accurately predict which children with snoring have OSAS, the gold standard for
diagnosing OSAS remains an in-lab overnight polysomnogram (PSG) .
Overnight PSG is a technician-supervised, monitored study that documents
physiologic variables during sleep; sleep staging, arousal measurement,
cardiovascular parameters, and body movements (electroencephalography,
electrooculography, chin and leg electromyography, electrocardiogram, body
position sensors, and video recording), and a combination of breathing monitors
(oronasal thermal sensor and nasal air pressure transducer for airflow),
chest/abdominal monitors (e.g., inductance plethysmography for respiratory
effort, pulse oximeter for O2 saturation, end-tidal or transcutaneous CO2 for CO2
retention, snore microphone). The PSG parameter most often used in evaluating
should be paid to education of the child and family, and desensitization protocols
should usually be implemented to increase the likelihood of adherence. Efficacy
studies at the current pressure and retitrations should be conducted periodically
with long-term use (at least annually) or in association with significant weight
changes or resurgence of SRBD symptoms.

Parasomnias
Parasomnias are episodic nocturnal behaviors that often involve cognitive
disorientation and autonomic and skeletal muscle disturbance. Parasomnias may
be further characterized as occurring primarily during non-REM sleep (partial
arousal parasomnias) or in association with REM sleep, including nightmares,
hypnogogic hallucinations, and sleep paralysis; other common parasomnias
include sleep-talking and hypnic jerks or “sleep starts.”

Etiology
Partial arousal parasomnias represent a dissociated sleep–wake state, the
neurobiology of which remains unclear, although genetic factors and an intrinsic
oscillation of subcortical-cortical arousal with sleep have been proposed. These
episodic events, which include sleepwalking, sleep terrors, and confusional
arousals, are more common in preschool and school-age children because of the
relatively higher percentage of SWS in younger children. Partial arousal
parasomnias typically occur when SWS predominates, in the 1st third of the
night. In contrast, nightmares , which are much more common than partial
arousal parasomnias but are often confused with them, tend to be concentrated in
the last third of the night, when REM sleep is most prominent. Any factor
associated with an increase in the relative percentage of SWS (certain
medications, previous sleep restriction) may increase the frequency of events in
a predisposed child. There appears to be a genetic predisposition for both
sleepwalking and night terrors. Partial arousal parasomnias may also be difficult
to distinguish from nocturnal seizures. Table 31.6 summarizes similarities and
differences among these nocturnal arousal events.

Table 31.6
Key Similarities and Differentiating Features Between Non-
REM and REM Parasomnias as Well as Nocturnal Seizures
 CONFUSIONAL SLEEP NOCTURNAL
SLEEPWALKING NIGHTMARES
AROUSALS TERRORS SEIZURES
Time Early Early Early-mid Late Any
Sleep stage SWA SWA SWA REM Any
EEG − − − − +
discharges
Scream − ++++ − ++ +
Autonomic + ++++ + + +
activation
Motor − + +++ + ++++
activity
Awakens − − − + +
Duration 0.5-10; more gradual 1-10; more 2-30; more gradual 3-20 5-15; abrupt
(min) offset gradual offset offset onset and offset
Postevent + + + − +
confusion
Age Child Child Child Child, young Adolescent,
adult young adult
Genetics + + + − ±
Organic CNS − − − − ++++
lesion
CNS, Central nervous system; EEG, electroencephalogram; REM, rapid eye movement; SWA,
slow-wave arousal.
From Avidan A, Kaplish N: The parasomnias: epidemiology, clinical features and diagnostic
approach. Clin Chest Med 31:353–370, 2010.

Epidemiology
Many children sleepwalk on at least one occasion; the lifetime prevalence by age
10 yr is 13%. Sleepwalking (somnambulism) may persist into adulthood, with
the prevalence in adults of approximately 4%. The prevalence is approximately
10 times greater in children with a family history of sleepwalking. The peak
prevalence of sleep terrors is 34% at age 1-5 yr, decreasing to 10% by age 7;
the age at onset is usually between 4 and 12 yr. Because of the common genetic
predisposition, the likelihood of developing sleepwalking after age 5 is almost 2-
fold higher in children with a history of sleep terrors. Although sleep terrors can
occur at any age from infancy through adulthood, most individuals outgrow
sleep terrors by adolescence. Confusional arousals (sleep drunkenness, sleep
inertia) usually occur with sleepwalking and sleep terrors; prevalence rates have
been estimated at >15% in children age 3-13 yr.

Clinical Manifestations
The partial arousal parasomnias have several features in common. Because they
typically occur at the transition out of “deep” sleep or SWS, partial arousal
neurologic disorder characterized by an almost irresistible urge to move the legs,
often accompanied by uncomfortable sensations in the lower extremities. Both
the urge to move and the sensations are usually worse at rest and in the evening
and are at least partially relieved by movement, including walking, stretching,
and rubbing, but only if the motion continues. RLS is a clinical diagnosis that is
based on the presence of these key symptoms (Table 31.7 ).
Table 31.7
Diagnostic Criteria for Restless Legs
Syndrome
A. An urge to move legs, usually accompanied by or in response to
uncomfortable and unpleasant sensations in the legs, characterized by the
following:
1. The urge to move the legs begins or worsens during periods of
rest or inactivity.
2. The urge to move the legs is partially or totally relieved by
movement.
3. The urge to move the legs is worse in the evening or at night than
during the day, or occurs only in the evening or at night.
B. The symptoms in Criterion A occur at least three times per week and have
persisted for at least 3 months.
C. The symptoms in Criterion A are accompanied by significant distress or
impairment in social, occupational, educational, academic, behavioral, or
other important areas of functioning.
D. The symptoms in Criterion A are not attributable to another mental
disorder or medical condition (e.g., arthritis, leg edema, peripheral
ischemia, leg cramps) and are not better explained by a behavioral
condition (e.g., positional discomfort, habitual foot tapping).
E. The symptoms are not attributable to the physiological effects of a drug or
abuse or medication (e.g., akathisia).

From American Psychiatric Association: Diagnostic and Statistical Manual of

Mental Disorders, 5th ed, 2013, p 410.
typically visual hallucinations and sleep paralysis, may be conceptualized as
representing the “intrusion” of REM sleep features into the waking state. Other
REM-related features include observance of eye movements and twitches at
sleep onset and vivid dreams. Rapid weight gain, especially near symptom onset,
is frequently observed, and young children with narcolepsy have been reported
to develop precocious puberty.
Table 31.8
Diagnostic Criteria for Narcolepsy
A. Recurrent periods of an irrepressible need to sleep, lapsing into sleep, or
napping occurring within the same day. These must have been occurring at
least three times per week over the past 3 months.
B. The presence of at least one of the following:
1. Episodes of cataplexy, defined as either (a) or (b), occurring at
least a few time per month:
a. In individuals with long-standing disease, brief (seconds
to minutes) episodes of sudden bilateral loss of muscle
tone with maintained consciousness that are precipitated
by laughter or joking.
b. In children or individuals within 6 months of onset,
spontaneous grimaces or jaw-opening episodes with
tongue thrusting or a global hypotonia, without any
obvious emotional triggers.
2. Hypocretin deficiency, as measured using cerebrospinal fluid
(CSF) hypocretin-1 immunoreactivity values (less than or equal
to one-third of values obtained in healthy subjects tested using
the same assay, or less than or equal to 110 pg/mL). Low CSF
levels of hypocretin-1 must not be observed in the context of
acute brain injury, inflammation, or infection.
3. Nocturnal sleep polysomnography showing rapid eye movement
(REM) sleep latency less than or equal to 15 minutes, or a
multiple sleep latency test showing a mean sleep latency less than
or equal to 8 minutes and two or more sleep-onset REM periods.

Specify whether:
 Narcolepsy without cataplexy but with hypocretin deficiency: Criterion
B requirements of low CSF hypocretin-1 levels and positive
polysomnography/multiple sleep latency test are met, but no cataplexy is
present (Criterion B1 not met).
Narcolepsy with cataplexy but without hypocretin deficiency: In this
rare sub-type (less than 5% of narcolepsy cases), Criterion B
requirements of cataplexy and positive polysomnography/multiple sleep
latency test are met, but CSF hypocretin-1 levels are normal (Criterion
B2 not met).
Autosomal dominant cerebellar ataxia, deafness, and narcolepsy: This
sub-type is caused by exon 21 DNA (cytosine-5)-methyltransferase-1
mutations and is characterized by late-onset (age 30-40 years) narcolepsy
(with low or intermediate CSF hypocretin-1 levels), deafness, cerebellar
ataxia, and eventually dementia.
Autosomal dominant narcolepsy, obesity, and type 2 diabetes:
Narcolepsy, obesity, and type 2 diabetes are low CSF hypocretin-1 levels
have been described in rare cases and are associated with a mutation in
the myelin oligodendrocyte glycoprotein gene.
Narcolepsy without cataplexy but with hypocretin deficiency: This sub-
type is for narcolepsy that develops secondary to medical conditions that
cause infectious (e.g., Whipple's disease, sarcoidosis), traumatic, or
tumoral destruction of hypocretin neurons.

Severity:

Mild: Infrequent cataplexy (less than once per week), need for naps only
once or twice per day, and less disturbed nocturnal sleep.
Moderate: Cataplexy once daily or every few days, disturbed nocturnal
sleep and need for multiple naps daily.
Severe: Drug-resistant cataplexy with multiple attacks daily, nearly
constant sleepiness, and disturbed nocturnal sleep (i.e., movements,
insomnia, and vivid dreaming).

From American Psychiatric Association: Diagnostic and Statistical Manual of

Mental Disorders, 5th ed, 2013, pp 372–373.
problems, especially ADHD.

Table 31.9
BEARS Sleep Screening Algorithm
The BEARS instrument is divided into 5 major sleep domains, providing a comprehensive screen for the
major sleep disorders affecting children 2-18 yr old. Each sleep domain has a set of age-appropriate “trigger
questions” for use in the clinical interview.
B = Bedtime problems
E = Excessive daytime sleepiness
A = Awakenings during the night
R = Regularity and duration of sleep
S = Snoring
EXAMPLES OF DEVELOPMENTALLY APPROPRIATE TRIGGER QUESTIONS
Toddler/Preschool Child School-Age Child (6-12 yr) Adolescent (13-18 yr)
(2-5 yr)
1. Bedtime Does your child have any Does your child have any Do you have any problems
problems problems going to bed? problems at bedtime? (P) falling asleep at bedtime? (C)
Falling asleep? Do you any problems going to
bed? (C)
2. Excessive Does your child seem Does your child have difficulty Do you feel sleepy a lot during
daytime overtired or sleepy a lot waking in the morning, seem the day? In school? While
sleepiness during the day? Does your sleepy during the day, or take driving? (C)
child still take naps? naps? (P)
Do you feel tired a lot? (C)
3. Awakenings Does your child wake up a Does your child seem to wake Do you wake up a lot at night?
during the lot at night? up a lot at night? Any Do you have trouble getting
night sleepwalking or nightmares? (P) back to sleep? (C)
Do you wake up a lot at night?
Do you have trouble getting
back to sleep? (C)
4. Regularity Does your child have a What time does your child go to bed What time do you usually go
and regular bedtime and wake and get up on school days? to bed on school nights?
duration of time? What are they? Weekends? Do you think your child Weekends? How much sleep
sleep is getting enough sleep? (P) do you usually get? (C)
5. Snoring Does your child snore a Does your child have loud or nightly Does your teenager snore
lot or have difficulty snoring or any breathing difficulties loudly or nightly? (P)
breathing at night? at night? (P)
C, Child; P, parent.

Effective preventive measures include educating parents of newborns about

normal sleep amounts and patterns. The ability to regulate sleep, or control
internal states of arousal to fall asleep at bedtime and to fall back asleep during
the night, begins to develop in the 1st 8-12 wk of life. Thus it is important to
recommend that parents put their 2-4 mo old infants to bed “drowsy but awake”
if they want to avoid dependence on parental presence at sleep onset and foster
the infant's ability to self-soothe. Other important sleep issues include discussing
the importance of regular bedtimes, bedtime routines, and transitional objects for
undirected presentation of the primary problem, it is important to shift to direct
questioning to clarify the duration, frequency, and severity of symptoms,
associated distress or functional impairment, and the developmental and
environmental context in which the symptoms occur.
Because of the high degree of comorbidity of psychosocial problems in
children, after eliciting the presenting problem, the pediatric practitioner should
then briefly screen for problems in all the major developmentally appropriate
categories of cognitive, developmental, emotional, behavioral, and social
disturbance, including problems with mood, anxiety, attention, behavior,
thinking and perception, substance use, social relatedness, eating, elimination,
development, language, and learning. This can be preceded by a transition
statement such as, “Now I'd like to ask about some other issues that I ask all
parents and kids about.”
A useful guide for this area of inquiry is provided by the 11 Action Signs
(Table 32.1 ), designed to give frontline clinicians the tools needed to recognize
early symptoms of mental disorders. Functional impairment can be assessed by
inquiring about symptoms and function in the major life domains, including
home and family, school, peers, and community. These domains are included in
the HEADSS (Home, Education, Activities, Drugs, Sexuality,
Suicide/Depression) Interview Guide, often used in the screening of adolescents
(Table 32.2 ).
Table 32.1
Mental Health Action Signs
• Feeling very sad or withdrawn for more than 2 weeks
• Seriously trying to harm or kill yourself, or making plans to do so
• Sudden overwhelming fear for no reason, sometimes with a racing heart or
fast breathing
• Involvement in many fights, using a weapon, or wanting to badly hurt others
• Severe out-of-control behavior that can hurt yourself or others
• Not eating, throwing up, or using laxatives to make yourself lose weight
• Intense worries or fears that get in the way of your daily activities
• Extreme difficulty in concentrating or staying still that puts you in physical
danger or causes school failure
• Repeated use of drugs or alcohol
 • Severe mood swings that cause problems in relationships
• Drastic changes in your behavior or personality

From The Action Signs Project, Center for the Advancement of Children's
Mental Health at Columbia University.
Table 32.2
HEADSS* Screening Interview for Taking a
Rapid Psychosocial History
Parent Interview
Home

• How well does the family get along with each other?

Education

• How well does your child do in school?

Activities

• What does your child like to do?

• Does your child do anything that has you really concerned?
• How does your child get along with peers?

Drugs

• Has your child used drugs or alcohol?

Sexuality

• Are there any issues regarding sexuality or sexual activity that are of
concern to you?
Suicide/Depression

• Has your child ever been treated for an emotional problem?

• Has your child ever intentionally tried to hurt him/herself or made threats to
others?

Adolescent Interview
Home

• How do you get along with your parents?

Education

• How do you like school and your teachers?

• How well do you do in school?

Activities

• Do you have a best friend or group of good friends?

• What do you like to do?

Drugs

• Have you used drugs or alcohol?

Sexuality

• Are there any issues regarding sexuality or sexual activity that are of
concern to you?

Suicide/Depression

• Everyone feels sad or angry some of the time. How about you?
• Did you ever feel so upset that you wished you were not alive or so angry
 you wanted to hurt someone else badly?

* HEADSS, Home, Education, Activities, Drugs, Sexuality, Suicide/Depression.

From Cohen E, MacKenzie RG, Yates GL: HEADSS, a psychosocial risk

assessment instrument: implications for designing effective intervention
programs for runaway youth, J Adolesc Health 12:539–544, 1991.

The nature and severity of the presenting problem(s) can be further

characterized through a standardized self-, parent-, or teacher-informant
symptom rating scale; Table 32.3 lists selected scales in the public domain. A
rating scale is a type of measure that provides a relatively rapid assessment of a
specific construct with an easily derived numerical score that is readily
interpreted. The use of symptom rating scales can ensure efficient, systematic
coverage of relevant symptoms, quantify symptom severity, and document a
baseline against which treatment effects can be measured. Functional
impairment also can be assessed with self- and other-reported rating scales.

Table 32.3
Select List of Mental Health Rating Scales in the Public
Domain

FOR INFORMANT: TIME TO

INSTRUMENTS AGES NUMBER OF COMPLETE AVAILABLE AT
(yr) ITEMS (min)
BROAD BAND
Pediatric 4-18 Parent: 35, 5-10 www.massgeneral.org/psychiatry/services/psc_home.aspx
Symptom 17
Checklist (PSC) Youth: 35,
17
SNAP-IV Rating 6-18 Parent, Teacher: 10 http://www.crfht.ca/files/8913/7597/8069/SNAPIV_000.pdf
Scale 90
Strengths and 4-18 Parent, Teacher, 5 www.sdqinfo.com
Difficulties Child: 25
Questionnaire
(SDQ)
NARROW BAND
Anxiety
Self-Report for 8-18 Parent, Child: 5 http://www.pediatricbipolar.pitt.edu/content.asp?id=2333#3304
Childhood 41
Anxiety Related
 Emotional
Disorders
(SCARED)
Attention and Behavior
Vanderbilt ADHD 6-12 Parent: 55 10 http://www.nichq.org/childrens-health/adhd/resources/vanderbilt-asses
Diagnostic Rating Teacher: 43 scales
Scale
Autism
Modified 16-30 Parent: 23 5-10 https://www.m-chat.org/index.php
Checklist for mo
Autism in
Toddlers (M-
CHAT)
Depression
Center for 6-18 Child: 20 5 https://www.brightfutures.org/mentalhealth/pdf/professionals/bridges/c
Epidemiological
Studies
Depression Scale
for Children
(CES-DC)
Mood and 7-18 Parent: 34 <5 www.devepi.duhs.duke.edu/mfq.html
Feelings Child: 33
Questionnaire
(MFQ)–Short
Version
Patient Health 12/13+ 9 <5 http://www.phqscreeners.com/sites/g/files/g10016261/f/201412/PHQ-
Questionnaire–9 9_English.pdf
(PHQ-9)
ADHD, Attention-deficit/hyperactivity disorder.

Clinical experience and methodological studies suggest that parents and

teachers are more likely than the child to report externalizing problems
(disruptive, impulsive, overactive, or antisocial behavior). Children may be more
likely to report anxious or depressive feelings, including suicidal thoughts and
acts, of which the parents may be unaware. Discrepancies across informants are
common and can shed light on whether the symptoms are pervasive or
contextual. Although concerns have been raised about children's competence as
self-reporters (because of limitations in linguistic skills; self-reflection;
emotional awareness; ability to monitor behavior, thoughts, and feelings;
tendency toward social desirability), children and adolescents can be reliable and
valid self-reporters.
Clinicians are encouraged to become familiar with the psychometric
characteristics and appropriate use of at least 1 broad-band symptom rating
scale, such as the Strengths and Difficulties Questionnaire (SDQ),* the Pediatric
Symptom Checklist (PSC), † or the Swanson, Nolan, and Pelham–IV (SNAP-IV).
‡ These measures are available in multiple languages. If the clinical interview or
CHAPTER 33

Psychopharmacology
David R. DeMaso, Heather J. Walter

Psychopharmacology is the first-line treatment for several child and adolescent

psychiatric disorders (e.g., ADHD, schizophrenia, bipolar) and is used
adjunctively with psychosocial treatments for other disorders (or coexisting
conditions), including anxiety, depression, autism spectrum, tic, trauma-related,
and obsessive-compulsive disorders. Although pediatric primary care
practitioners (PCPs) may routinely manage medications for attention-
deficit/hyperactivity disorder (ADHD), anxiety, and depression, they may be
called on to manage psychotropic medications with which they have had less
experience. As such, it is useful for PCPs to be familiar with basic information
about child and adolescent psychopharmacology. Before prescribing a
psychotropic medication, PCPs should review full prescribing information for
each medication (in package inserts or at reliable websites such as the National
Institutes of Health DailyMed * ) to obtain complete and up-to-date information
about indications, contraindications, warnings, interactions, and precautions.
Pediatric prescribers should be aware of “best practice” principles that
underlie medication assessment and management by child and adolescent
psychiatrists (Table 33.1 ), so as to consider extrapolation of these principles to
prescribing in the primary care setting. The use of medication involves a series
of interconnected steps, including performing an assessment, constructing
working diagnoses and an explanatory formulation, deciding on treatment and a
monitoring plan, obtaining treatment assent/consent, and implementing
treatment.
Table 33.1
Best Principles for Use of Psychotropic
Medications With Children and Adolescents
 1. Before initiating pharmacotherapy, a psychiatric evaluation is completed.
2. Before initiating pharmacotherapy, a medical history is obtained, and a
medical evaluation is considered when appropriate.
3. The prescriber communicates with other professionals to obtain collateral
history and collaborate in the monitoring of outcome and side effects
during the medication trial.
4. The prescriber develops a psychosocial and psychopharmacologic
treatment plan based on the best available evidence.
5. The prescriber develops a plan to monitor the patient during the
medication trial.
6. The prescriber is cautious when the medication trial cannot be
appropriately monitored.
7. The prescriber educates the patient and family about the patient's
diagnosis and treatment plan.
8. The prescriber obtains and documents informed consent before initiating
the medication trial and at appropriate intervals during the trial.
9. The informed-consent process focuses on the risks and benefits of the
proposed and alternative treatments.
10. The medication trial should involve an adequate dose of medication for an
adequate duration.
11. The prescriber reassesses the patient if the patient fails to respond to the
medication trial as expected.
12. The prescriber has a clear rationale for using medication combinations.
13. The prescriber has a specific plan for medication discontinuation.

Adapted from American Academy of Child and Adolescent Psychiatry: Practice

parameter on the use of psychotropic medication in children and adolescents. J
Am Acad Child Adolesc Psychiatry 48(9):961–973, 2009.

Questions remain about the quality of the evidence supporting the use of many
psychotropic medications in children and adolescents. Therefore, cognitive,
emotional, and behavioral symptoms are targets for medication treatment when
(1) there is no or insufficient response to available evidence-based psychosocial
interventions, (2) the patient's symptoms convey significant risk of harm, or (3)
the patient is experiencing significant distress or functional impairment.
Common target symptoms include agitation, aggression, anxiety, depression,
hyperactivity, inattention, impulsivity, mania, obsessions, compulsions, and
psychosis (Table 33.2 ). All these can be quantitatively measured with
standardized symptom rating scales to establish baseline symptom severity and
facilitate “treating to target.”

Table 33.2

Target Symptom Approach to Psychopharmacologic Management

TARGET SYMPTOM MEDICATION CONSIDERATIONS
Agitation Atypical antipsychotic
Typical antipsychotic
Anxiolytic
Aggression Stimulant
Atypical antipsychotic
Anxiety Antidepressant
Anxiolytic (only situational anxiety)
Depression Antidepressant
Hyperactivity, inattention, impulsivity Stimulant
α-Agonist
Atomoxetine
Mania Atypical antipsychotic
Lithium
Obsessions, compulsions Antidepressant
Psychosis Atypical antipsychotic
Typical antipsychotic
Tics α-Agonist
Atypical antipsychotic
Typical antipsychotic
Adapted from Shaw RJ, DeMaso DR: Clinical manual of pediatric psychosomatic medicine:
mental health consultation with physically ill children and adolescents, Washington, DC, 2006,
American Psychiatric Press, p 306.

Stimulants and Other ADHD Medications

Stimulants are sympathomimetic drugs that act both in the central nervous
system (CNS) and peripherally by enhancing dopaminergic and noradrenergic
transmission (Table 33.3 ). Strong evidence exists for the effectiveness of these
medications for the treatment of ADHD and aggression, as well as moderate
evidence for the treatment of hyperactivity in autism spectrum disorder (ASD).
In some cases, stimulants are used adjunctively with antidepressants in the
treatment of depression and as monotherapy for fatigue or malaise associated
with chronic physical illnesses.
Table 33.3
Select Medications for Attention-Deficit/Hyperactivity
Disorder (ADHD) Symptoms

FDA SELECT
GENERIC (BRAND) DAILY
APPROVED DAILY MEDICAL
APPROXIMATE TARGET THERAPEUTIC
(Pediatric STARTING MONITORING
DURATION OF SYMPTOMS DOSAGE
age range in DOSE AND
ACTION RANGE*
years) PRECAUTIONS
STIMULANTS
Long Acting
OROS ADHD (6+) Inattention 18 mg Age 6-12: Personal and
methylphenidate Hyperactivity 18-54 mg family CV
(Concerta) Impulsivity Age >12: 18- history; personal
12 hr 72 mg seizure history;
Ht, Wt, BP, P;
bipolar or
psychotic
symptoms;
substance abuse;
potential for GI
obstruction
Dexmethylphenidate ADHD (6+) Inattention 5 mg 5-30 mg Personal and
(Focalin XR) † Hyperactivity family CV
10-12 hr Impulsivity history; personal
seizure history;
Ht, Wt, BP, P;
bipolar or
psychotic
symptoms;
substance abuse
Amphetamine ADHD (6+) Inattention 5 mg 5-30 mg Personal and
combination Hyperactivity family CV
(Adderall XR) † Impulsivity history; personal
12 hr seizure history;
Ht, Wt, BP, P;
bipolar or
psychotic
symptoms;
substance abuse
Lisdexamfetamine ADHD (6+) Inattention 20 mg 20-70 mg Personal and
(capsule † and Hyperactivity family CV
chewable) Impulsivity history; personal
(Vyvanse) seizure history;
12 hr Ht, Wt, BP, P;
bipolar or
psychotic
symptoms;
substance abuse
Methylphenidate ADHD (6+) Inattention 10 mg 10-30 mg Personal and
transdermal Hyperactivity family CV
(Daytrana) Impulsivity history; personal
 12 hr seizure history;
Ht, Wt, BP, P;
bipolar or
psychotic
symptoms;
substance abuse;
skin reactions
Methylphenidate ADHD (6+) Inattention 20 mg 20-60 mg Personal and
suspension Hyperactivity family CV
(Quillivant XR) Impulsivity history; personal
12 hr seizure history;
Ht, Wt, BP, P;
bipolar or
psychotic
symptoms;
substance abuse
Intermediate Acting
Methylphenidate ADHD (6+) Inattention 10 mg 10-60 mg Personal and
(Metadate CD, Hyperactivity family CV
Ritalin LA) Impulsivity history; personal
8 hr seizure history;
Ht, Wt, BP, P;
bipolar or
psychotic
symptoms;
substance abuse
Dextroamphetamine ADHD (6+) Inattention 5 mg 5-40 mg Personal and
(Dexedrine Hyperactivity family CV
Spansule) Impulsivity history; personal
8 hr seizure history;
Ht, Wt, BP, P;
bipolar or
psychotic
symptoms;
substance abuse
Methylphenidate ADHD (6+) Inattention 20 mg 20-60 mg Personal and
chewable Hyperactivity family CV
(Quillichew ER) Impulsivity history; personal
8 hr seizure history;
Ht, Wt, BP, P;
bipolar or
psychotic
symptoms;
substance abuse
Short Acting
Dexmethylphenidate ADHD (6+) Inattention 5 mg 5-20 mg Personal and
(Focalin) Hyperactivity family CV
4-5 hr Impulsivity history; personal
seizure history;
Ht, Wt, BP, P;
bipolar or
psychotic
symptoms;
substance abuse
Methylphenidate ADHD (6+) Inattention 5 mg 5-60 mg Personal and
 (Ritalin, Methylin) Hyperactivity family CV
4 hr Impulsivity history; personal
seizure history;
Ht, Wt, BP, P;
bipolar or
psychotic
symptoms;
substance abuse
Amphetamine ADHD (3+) Inattention Age 3-5: 5-40 mg Personal and
combination Hyperactivity 2.5 mg family CV
(Adderall) Impulsivity Age ≥6: 5 history; personal
4-5 hr mg seizure history;
Ht, Wt, BP, P;
bipolar or
psychotic
symptoms;
substance abuse
Dextroamphetamine ADHD (3+) Inattention Age 3-5: 5-40 mg Personal and
(Dexedrine) Hyperactivity 2.5 mg family CV
4 hr Impulsivity Age ≥6: 5 history; personal
mg seizure history;
Ht, Wt, BP, P;
bipolar or
psychotic
symptoms;
substance abuse
SELECTIVE NOREPINEPHRINE REUPTAKE INHIBITOR
Atomoxetine ADHD (6+) Inattention <70 kg: <70 kg: 0.5- Personal and
(Strattera) Hyperactivity 0.5 1.2 family CV
24 hours Impulsivity mg/kg/day mg/kg/day history; BP, P;
>70 kg: >70 kg: 40- liver injury;
40 mg 100 mg suicidal ideation;
bipolar or
psychotic
symptoms
ALPHA (α)-AGONISTS
Short Acting
Clonidine None Inattention 0.05 mg 27-40.5 kg: CV history; BP,
(Catapres) Hyperactivity 0.05-0.2 mg P; rebound
4 hr Impulsivity 40.5-45 kg: hypertension;
0.05-0.3 mg cardiac
>45 kg: 0.05- conduction
0.4 mg abnormalities
Guanfacine (Tenex) None Inattention 0.5 mg 27-40.5 kg: CV history; BP,
6 hr Hyperactivity 0.5-2 mg P; rebound
Impulsivity 40.5-45 kg: hypertension;
0.5-3 mg cardiac
>45 kg: 0.5-4 conduction
mg abnormalities
Long Acting
Clonidine (Kapvay) ADHD (6+) Inattention 0.1 mg 0.1-0.4 mg CV history; BP,
12 hr Hyperactivity P; rebound
Impulsivity hypertension;
cardiac
conduction
 abnormalities
Guanfacine ADHD (6+) Inattention 1 mg Monotherapy CV history; BP,
(Intuniv) Hyperactivity : P; rebound
24 hr Impulsivity 25-33.9 kg: hypertension,
2-3 mg cardiac
34-41.4 kg: conduction
2-4 mg abnormalities
41.5-49.4 kg:
3-5 mg
49.5-58.4 kg:
3-6 mg
58.5-91 kg:
4-7 mg
>91 kg: 5-7
mg
Adjunctive
(with
stimulant):
0.05-0.12
mg/kg/day

* Doses shown in table may exceed maximum recommended dose for some children.

† Capsule contents may be sprinkled on soft food.

FDA, U.S. Food and Drug Administration; CV, cardiovascular; Ht, height; Wt, weight; BP, blood
pressure; P, pulse; GI, gastrointestinal.

No major differences in efficacy or tolerability have been found between

different classes of stimulants, and no consistent patient profile identifies those
who will respond preferentially to one class over another. The most common
(generally dose-dependent) side effects of stimulants include headache,
stomachache, appetite suppression, weight loss, blood pressure (BP) and heart
rate increases, and delayed sleep onset. Less common side effects include
irritability (particularly prominent in younger children), aggression, social
withdrawal, and hallucinations (visual or tactile). Amphetamine preparations
prescribed concurrently with serotonergic antidepressants can be associated with
the development of serotonin syndrome.
Stimulants have been associated with elevations in mean BP (<5 mm Hg) and
pulse (<10 beats/min); a subset of individuals (5–10%) may have greater
increases. The rate of sudden death in pediatric patients taking stimulants is
comparable to children in the general population; the hazard ratio for serious
cardiovascular (CV) events is 0.75 (although up to a 2-fold increase in risk could
not be ruled out). Moreover, a case series analysis of children with a CV incident
and treatment with methylphenidate demonstrated an increased risk of
arrhythmia (incidence rate ratio, 1.61) that was highest in the presence of
congenital heart disease. The U.S. Food and Drug Administration (FDA)
 Sedation, somnolence, headache, abdominal pain, hypotension, bradycardia,
cardiac conduction abnormalities, dry mouth, depression, and confusion are
potential side effects of clonidine and guanfacine. Abrupt withdrawal can result
in rebound hypertension; overdose can result in death.

Antidepressants
Antidepressant drugs act on pre- and postsynaptic receptors affecting the release
and reuptake of brain neurotransmitters, including norepinephrine, serotonin,
and dopamine (Table 33.4 ). There is strong evidence for the effectiveness of
antidepressant medications in the treatment of anxiety and obsessive-compulsive
disorders and weaker evidence for the treatment of depressive disorders. Suicidal
thoughts have been reported during treatment with all antidepressants. The
overall risk difference of suicidal ideation/attempts across all randomized
controlled trials (RCTs) of antidepressants and indications has been reported as
0.7%, corresponding to a number needed to harm of 143. All antidepressants
carry an FDA warning for suicidality; careful monitoring is recommended during
the initial stages of treatment and following dose adjustments.

Table 33.4
Select Medications for Depression and Anxiety in Children
and Adolescents

FDA SELECT
DAILY
APPROVED DAILY MEDICAL
GENERIC THERAPEUTIC
(Pediatric age TARGET SYMPTOMS STARTING MONITORING
(BRAND) DOSAGE
range in DOSE AND
RANGE*
years) PRECAUTIONS
SELECTIVE SEROTONIN REUPTAKE INHIBITORS
Citalopram None Depression 10 mg 10-40 mg Suicidal ideation;
(Celexa) Anxiety QT prolongation
Obsessions/compulsions at doses >40 mg;
abnormal
bleeding; mania;
SS, DS
Escitalopram Depression Depression 5 mg 5-20 mg Suicidal ideation;
(Lexapro) (12-17) Anxiety abnormal
Obsessions/compulsions bleeding; mania;
SS, DS
Fluoxetine Depression Depression Age 6- Depression: Suicidal ideation;
(Prozac) (8-17) Anxiety 12: 10 10-20 mg abnormal
OCD (7- Obsessions/compulsions mg Anxiety, bleeding; mania;
 17) Age 13- OCD: 10-60 SS
17: 20 mg
mg
Sertraline OCD (6-17) Depression Age 6- 12.5-200 mg Suicidal ideation;
(Zoloft) Anxiety 12: abnormal
Obsessions/compulsions 12.5-25 bleeding; mania;
mg SS, DS
Age 13-
17: 25-
50 mg
ATYPICAL ANTIDEPRESSANTS
Bupropion None Depression 150 mg 150-300 mg Suicidal ideation;
(Wellbutrin neuropsychiatric
XL) reaction, seizures
(>300 mg/day),
BP; mania;
contraindicated in
patients with
seizure and eating
disorders
Duloxetine Anxiety (7-17) Depression 30 mg 30-60 mg Suicidal ideation;
(Cymbalta) Anxiety BP, P; liver
damage; severe
skin reactions;
abnormal
bleeding; mania;
SS, DS
Mirtazapine None Depression 7.5 mg 7.5-45 mg Suicidal ideation;
(Remeron) weight;
somnolence;
agranulocytosis;
QT prolongation;
mania; SS, DS
Venlafaxine None Depression 37.5 mg 37.5-225 mg Suicidal ideation;
(Effexor XR) Anxiety BP; abnormal
bleeding; mania;
SS, DS
TRICYCLIC ANTIDEPRESSANTS
Clomipramine OCD (10-17) Obsessions 25 mg 25-200 mg Suicidal ideation;
(Anafranil) Compulsions BP; P; ECG;
blood level;
mania; SS;
seizures; DS
ANXIOLYTIC AGENTS (SITUATIONAL USE)
Lorazepam None Anxiety 0.5 mg 0.5-2 mg Respiratory
(Ativan) depression;
sedation; physical
and psychological
dependence;
paradoxical
reactions
Clonazepam None Panic 0.5 mg 0.5-1 mg Respiratory
(Klonopin) depression;
sedation; physical
and psychological
 dependence;
paradoxical
reactions; suicidal
ideation
Hydroxyzine Anxiety Anxiety 50 mg Age <6: 50 QT prolongation
(Atarax, mg
Vistaril) Age >6: 50-
100 mg
* Doses shown in table may exceed maximum recommended dose for some children.

OCD, Obsessive-compulsive disorder; BP, blood pressure; P, pulse; ECG, electrocardiogram; SS,
serotonin syndrome; DS, discontinuation syndrome.

The selective serotonin reuptake inhibitor (SSRI) fluoxetine outperforms all

other antidepressants (both SSRI and non-SSRI) studied and is the only SSRI
separating from placebo in studies of depressed preadolescents . SSRIs have a
large margin of safety. Side effects to SSRIs generally manifest in the first few
weeks of treatment, and many will resolve with time. More common side effects
include nausea, irritability, insomnia, appetite changes, weight loss/gain,
headaches, dry mouth, dizziness, bruxism, diaphoresis, tremors, akathisia,
restlessness, and behavioral activation. Approximately 5% of youth taking
SSRIs, particularly children, develop behavioral activation (increased
impulsivity, agitation, and irritability) that can be confused with mania, but the
activation symptoms typically resolve when the dose is decreased or the
medication discontinued. Sexual side effects are common, including decreased
libido, anorgasmia, and erectile dysfunction. There is an increased risk of
bleeding, especially when used with aspirin or nonsteroidal antiinflammatory
drugs (NSAIDs).
SSRIs can be associated with abnormal heart rhythms, and citalopram causes
dose-dependent QT-interval prolongation, contraindicating doses >40 mg/day.
Patients with diabetes may experience hypoglycemia during SSRI treatment and
hyperglycemia on discontinuation. Discontinuation symptoms (e.g., dysphoric
mood, irritability, agitation, dizziness, sensory disturbances, anxiety, confusion,
headache, lethargy, emotional lability, insomnia, hypomania) are common with
short-acting SSRIs (sertraline, citalopram, escitalopram), leading to a
recommendation for divided doses if these medications are used at higher doses
and graduated reduction if discontinued.
The serotonin syndrome is characterized by the triad of mental status
changes (e.g., agitation, hallucinations, delirium, coma), autonomic instability
(e.g., tachycardia, labile BP, dizziness, diaphoresis, flushing, hyperthermia), and
neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia,
Antipsychotics
Based on their mechanism of action, antipsychotic medications can be divided
into first-generation (blocking dopamine D2 receptors) and second-generation
(mixed dopaminergic and serotonergic antagonists) agents (Table 33.5 ).

Table 33.5
Select Medications for Psychosis, Mania, Irritability,
Agitation, Aggression, and Tourette Disorder in Children
and Adolescents

SELECT
FDA DAILY
DAILY MEDICAL
GENERIC APPROVED TARGET THERAPEUTIC
STARTING MONITORING
(BRAND) (Pediatric age SYMPTOMS DOSAGE
DOSE AND
range in years) RANGE*
PRECAUTIONS
SECOND-GENERATION ANTIPSYCHOTICS
Aripiprazole Bipolar (10- Mania Bipolar, Bipolar, BMI, BP, P,
(Abilify) 17) Psychosis schizophrenia: schizophrenia: fasting glucose
Available in Schizophrenia Irritability 2 mg 10-30 mg and lipids,
liquid (13-17) Aggression Autism: 2 mg Autism: 5-15 abnormal
preparation Irritability in Agitation Tourette: 2 mg movements;
autism (6-17) Vocal/motor mg Tourette: 5-20 compulsive
Tourette (6- tics mg behaviors;
17) neuroleptic
malignant
syndrome;
leukopenia,
neutropenia,
agranulocytosis;
seizures
Olanzapine Bipolar (13- Mania 2.5 mg 2.5-20 mg BMI, BP, P,
(Zyprexa) 17) Psychosis fasting glucose
Available in Schizophrenia Agitation and lipids,
liquid, (13-17) abnormal
dissolvable, movements; skin
and IM rash (DRESS);
preparations neuroleptic
malignant
syndrome;
leukopenia,
neutropenia,
agranulocytosis;
seizures
Quetiapine Bipolar (10- Mania 25 mg bid Bipolar: 400- BMI, BP, P,
(Seroquel) 17) Psychosis 600 mg fasting glucose
Schizophrenia Agitation Schizophrenia: and lipids,
(13-17) 400-800 mg abnormal
 movements;
ophthalmologic
exam; neuroleptic
malignant
syndrome;
leukopenia,
neutropenia,
agranulocytosis;
seizures; QT
prolongation
Risperidone Bipolar (10- Mania Bipolar, Bipolar, BMI, BP, P,
(Risperdal) 17) Psychosis schizophrenia: schizophrenia: fasting glucose
Available in Schizophrenia Irritability 0.5 mg 1-6 mg and lipids,
liquid and (13-17) Aggression Autism: Autism: 0.5-3 prolactin,
dissolvable Irritability in Agitation <20 kg: 0.25 mg abnormal
preparations autism (5-17) mg movements;
≥20 kg: 0.5 neuroleptic
mg malignant
syndrome;
leukopenia,
neutropenia,
agranulocytosis;
seizures
Paliperidone Schizophrenia Psychosis 3 mg <51 kg: 3-6 BMI, BP, P,
(Invega) (12-17) mg fasting glucose
Available in ≥51 kg: 3-12 and lipids,
liquid and mg prolactin,
IM abnormal
preparations movements, QT
prolongation;
neuroleptic
malignant
syndrome;
potential for GI
obstruction;
leukopenia,
neutropenia,
agranulocytosis;
seizures
Lurasidone Schizophrenia Psychosis 40 mg 40-80 mg BMI, BP, P,
(Latuda) (13-17) fasting glucose
and lipids,
prolactin,
abnormal
movements;
neuroleptic
malignant
syndrome;
leukopenia,
neutropenia,
agranulocytosis;
seizures
Asenapine Bipolar (10-17) Mania 2.5 mg twice daily 5-20 mg BMI, BP, P,
(Saphris) Psychosis fasting glucose
and lipids,
prolactin,
 abnormal
movements; QT
prolongation;
neuroleptic
malignant
syndrome;
leukopenia,
neutropenia,
agranulocytosis;
seizures
FIRST-GENERATION ANTIPSYCHOTIC
Haloperidol Psychosis Mania 0.05 mg/kg/day 0.05-0.15 BP, P; abnormal
(Haldol) Tourette Psychosis mg/kg/day movements; QT
Available in disorder Irritability prolongation;
liquid and Severe Aggression neuroleptic
IM behavioral Agitation malignant
preparations disorders Vocal/motor syndrome;
Agitation (3- tics encephalopathy
17) when combined
with lithium;
leukopenia,
neutropenia,
agranulocytosis
MOOD STABILIZER
Lithium Bipolar (12-17) Mania Acute mania: Long-term Serum level,
carbonate 1800 mg/day control: 900- CBC/diff, thyroid
Available in Target level: 1200 mg/day function,
liquid 1.0-1.5 Target level: BUN/creatine,
preparation mEq/L 0.6-1.2 mEq/L UA, electrolytes,
FBS; ECG;
encephalopathy
when combined
with haloperidol
*
Doses shown in table may exceed maximum recommended dose for some children.
BMI, Body mass index; BP, blood pressure; P, pulse; IM, intramuscular; GI, gastrointestinal;
CBC/diff, complete blood count with differential; BUN, blood urea nitrogen; UA, urinalysis; FBS,
fasting blood sugar; ECG, electrocardiogram.

The second-generation (or atypical ) antipsychotics (SGAs) have relatively

strong antagonistic interactions with 5-HT2 receptors and perhaps more variable
activity at central adrenergic, cholinergic, and histaminic sites, which might
account for the varying side effects, particularly metabolic, noted among these
agents. The SGAs have moderate evidence for the treatment of agitation in
autism and for the treatment of schizophrenia, bipolar disorder, and aggression.
Haloperidol is a high-potency antipsychotic that is the first-generation (or
typical ) antipsychotic most commonly used in treatment of agitation and
schizophrenia.
The SGAs have significant side effects, including sedation, extrapyramidal
symptoms, weight gain, metabolic syndrome, diabetes, hyperlipidemia,
hyperprolactinemia, hematologic effects (e.g., leukopenia, neutropenia), elevated
liver transaminases, seizures, and CV effects (Table 33.6 ). They have an FDA
warning for increased risk of diabetes. Youth appear to be more sensitive to
sedation, extrapyramidal side effects (except akathisia), withdrawal dyskinesia,
prolactin abnormalities, weight gain, hepatotoxicity, and metabolic
abnormalities. The development of diabetes or tardive dyskinesia appears less
prevalent than in adults, although this may be a function of short follow-up
periods because these side effects may not emerge until adulthood.

Table 33.6
Adverse Effects for Select Antipsychotic Medications

ADVERSE ARIPIPRAZOLE OLANZAPINE QUETIAPINE RISPERIDONE PALIPERIDONE

EFFECT (ABILIFY) (ZYPREXA) (SEROQUEL) (RISPERDAL) (INVEGA)
Weight gain 0/+ +++ ++ ++ ++
QTc interval 0/+ 0/+ + + +
Sedation 0/+ +/++ ++ + 0/+
Prolactin 0 + 0 +++ +++
increase
Lipid increase 0/+ +++ ++ + +
Diabetes 0/+ +++ ++ + +
Anticholinergic 0 ++ +/++ 0 0
Acute + 0/+ 0 ++ ++
parkinsonism
Akathisia ++ + + + +
Tardive 0/+ 0/+ 0/+ 0/+ 0/+
dyskinesia
Withdrawal +/++ 0/+ 0/+ + +
dyskinesia
Orthostasis 0/+ ++ ++ + +
Seizures 0/+ 0/+ 0/+ 0/+ 0/+
0 = none; 0/+ = minimal; + = mild; ++ = moderate; +++ = severe.
Adapted from Correll CU: Antipsychotic medications. In Dulcan MK, editor: Dulcan's textbook of
child and adolescent psychiatry, ed 2, Washington, DC, 2016, American Psychiatric Press, pp
795–846.

The management of adverse effects should be proactive with baseline

assessment and ongoing monitoring (Table 33.7 ). Abnormal movements
(dystonia, akathisia, tardive dyskinesia) need periodic assessment using a
standardized instrument such as the Abnormal Involuntary Movement Scale
(AIMS). Valbenazine is FDA approved for the treatment of tardive dyskinesia in
adults. The need for antiparkinsonian agents may be a consideration, particularly
for patients at risk for acute dystonia or who have a previous history of dystonic
reactions. CV effects of SGAs include prolongation of the QTc interval,
tachycardia, orthostatic hypertension, and pericarditis. In patients with a personal
or family history of cardiac abnormalities, including syncope, palpitations,
arrhythmias, or sudden unexplained death, a baseline ECG with subsequent
monitoring should be considered, along with cardiology consultation before
prescribing. Alternative pharmacology should be considered if the resting heart
rate exceeds 130 beats/min, or the PR, QRS, and QTc exceed 200, 120, and 460
milliseconds (msec), respectively.

Table 33.7
Metabolic Monitoring Parameters Based on ADA/APA
Consensus Guidelines

WEEK WEEK WEEK EVERY 3 MO

BASELINE ANNUALLY
4 8 12 THEREAFTER
Medical history* X X X
Weight (BMI) X X X X X X
Waist circumference X X X
Blood pressure X X X
Fasting X X X
glucose/HbA1c
Fasting lipids X X X
*
Personal and family history of obesity, hypertension, and cardiovascular disease.
BMI, Body mass index; Hb, hemoglobin.
From American Diabetes Association (ADA), American Psychiatric Association (APA), American
Association of Clinical Endocrinologists, North American Association for the Study of Obesity.
Consensus development conference on antipsychotic drugs and obesity and diabetes, Diabetes
Care 27:596–601, 2004.

The cytochrome P450 (CYP) enzymes metabolize the antipsychotics and as

such necessitate that the PCP and psychiatrist are alert for potential drug-drug
interactions that may impact the serum levels of all patient medications.
CYP3A4 is mainly relevant to lurasidone, quetiapine, olanzapine, and
haloperidol, whereas CYP2D6 predominately clears aripiprazole and
risperidone. Asenapine is metabolized by CYP1A2 as well as direct
glucuronidation by UGT1A4. Because <10% of paliperidone undergoes CYP
first-pass metabolism, there is a lower likelihood of drug-drug interactions.
Primary prevention strategies to manage weight and metabolic dysfunction
include educating the youth and family about healthy lifestyle behaviors and
Principles for Psychotropic Prescribing in
Primary Care
Because nonpsychiatrist physicians (predominantly pediatricians) provide three
quarters and two thirds, respectively, of all child and adolescent mental health
visits in which new psychotropic medications are initiated, it can be helpful for
PCPs to develop consultative relationships with child and adolescent
psychiatrists who can advise about safe and effective psychotropic prescribing. If
such consultation is not readily available, PCPs may benefit from following a
standardized approach to prescribing that is feasible in the primary care setting
(Table 33.8 ). This approach emphasizes baseline assessment with standardized
rating scales to identify target symptoms and their level of severity; selection of
FDA-approved medications for the target symptom and patient age range;
adherence to recommendations regarding therapeutic dosage ranges; follow-up
rating scale assessment to monitor medication response; sufficient duration of
the medication trial; and switching to an alternative FDA-approved medication if
the first medication trial is ineffective. Generally, consultation with a physician
experienced in managing the child's disorder should occur if one is considering
using multiple psychotropic medications, doses outside of therapeutic range, or
non-FDA-approved medications.
Table 33.8
Principles for Psychotropic Prescribing in
Primary Care
1. Identify potential target symptoms through the systematic use (e.g., at all
well-child visits) of broad-band mental health screening instruments,
such as the Pediatric Symptom Checklist or the Strengths and Difficulties
Questionnaire.
2. Establish the baseline severity of identified target symptom(s) through the
use of narrow-band symptom rating scales, such as the following
(selected from instruments in the public domain):
a. Depression
• Mood and Feelings Questionnaire
• Centers for Epidemiologic Studies Depression Scale
• Patient Health Questionnaire-9
 b. Anxiety
• Screen for Child Anxiety Related Disorders
c. ADHD, Behavior Problems
• Vanderbilt ADHD Diagnostic Rating Scale
• SNAP-IV 19
d. Aggression
• Outburst Monitoring Scale
3. Select a medication that is FDA approved for the target symptom and age
range; titrate as tolerated from starting dose to therapeutic dosage range.
4. Treat to target : Readminister baseline symptom rating scale at regular
intervals (at least monthly) to assess treatment response (reduction in
rating scale score), with the goal of remission (rating scale score below
clinical cutpoint).
5. If medication trial is unsuccessful after adherence to therapeutic dose for
adequate duration (typically 1-2 mo), consider 2nd trial of alternative
medication with FDA approval for target symptom and age range,
following same principles as for 1st trial.
6. If 2nd medication trial is unsuccessful, consultation with a child and
adolescent psychiatrist is recommended before resorting to medication
doses outside therapeutic range, polypharmacy, or non–FDA-approved
medications.

ADHD, Attention-deficit/hyperactivity disorder; FDA, U.S. Food and Drug

Administration.

Bibliography
American Diabetes Association, American Psychiatric
Association, American Association of Clinical
Endocrinologists, North American Association for the Study
of Obesity. Consensus development conference on
antipsychotic drugs and obesity and diabetes. Diabetes Care .
2004;27:596–601.
American Academy of Child Adolescent Psychiatry. Practice
parameter for the use of atypical antipsychotic medications in
may be less pronounced in practice than in theory. The quality of the therapist–
patient alliance is consistently an important predictor of treatment outcome. A
positive working relationship, expecting change to occur, facing problems
assertively, increasing mastery, and attributing change to the participation in the
therapy have all been connected to effective therapy.

Table 34.1
Effective Psychotherapies for Specific Behavioral Health
Disorders

DISORDER WELL ESTABLISHED* PROBABLY EFFICACIOUS †

Anorexia Family therapy: behavioral Family therapy: systemic
Individual insight-oriented
psychotherapy
Anxiety Individual CBT CBT + parent component
CBT + medication
ADHD Behavioral parent training Combined training interventions
Behavioral classroom management
Behavioral peer interventions
Organization (executive function) training
Autism Individual, comprehensive ABA Individual, focused ABA + DSP
Teacher-implemented ABA + DSP Focused DSP parent training
Bipolar None Family psychoeducation + skill
building
Depression, child Group CBT Behavior therapy
Group CBT + parent component
Depression adolescent Group CBT Group CBT + parent component
Individual interpersonal psychotherapy Individual CBT
Individual CBT + parent/family
component
Insomnia Individual CBT
ODD and CD, child Individual/parent management training Group CBT
Individual CBT Group/parent management training
Problem-solving skill training
Group assertiveness training
Multidimensional treatment foster care
Multisystemic therapy
ODD and CD, Combined behavioral therapy, CBT, and family CBT
adolescent therapy
Treatment foster care
OCD None Individual CBT
Family-focused individual CBT
Personality Disorders None Dialectical behavioral therapy
PTSD Trauma-focused CBT Group CBT
Social phobia None Group CBT
Specific phobia None None
Substance use Group CBT Family-based treatment, behavioral
 Individual CBT Motivational interviewing
Family-based treatment, ecologic
Self-injury Individual + family CBT + parent training Family-based therapy
Psychodynamic individual + family
* Two or more consistent randomized controlled trials demonstrating superiority of treatment over

control groups; conducted by independent investigators working at different research settings.

† Same as above, but lacking independent investigator criterion.

ADHD, Attention-deficit/hyperactivity disorder CBT, cognitive-behavioral therapy; ABA, applied

behavioral analysis; DSP, developmental social-pragmatic; ODD, oppositional defiant disorder;
CD, conduct disorder; OCD, obsessive-compulsive disorder; PTSD, posttraumatic stress disorder.
Adapted from Society of Clinical Child and Adolescent Psychology: Effective child psychotherapy.
http://effectivechildtherapy.org/content/ebp-options-specific-disorders . Accessed March 5, 2017.

All psychotherapy interventions involve a series of interconnected steps,

including performing an assessment, constructing working diagnoses and an
explanatory formulation, deciding on treatment and a monitoring plan, obtaining
treatment assent/consent, and implementing treatment. Psychotherapists ideally
develop a treatment plan by combining known evidence-based therapies with
clinical judgment and patient/family preference to arrive at a specific
intervention plan for the individual patient.

Behavior Therapy
Behavior therapy is based on both classic (Pavlovian) and operant (Skinnerian)
conditioning. Both approaches do not concern themselves with the inner motives
of the individual, but instead address the antecedent stimuli and consequent
responses. The treatment begins with a behavioral assessment with interview,
observation, diary, and rating scale components, along with a functional analysis
of the setting context, immediately preceding external events, and real-world
consequences of the behavior. A treatment plan is developed to modify the
maladaptive functions of the behavior, using tools such as positive and negative
reinforcement, social and tangible rewards, shaping, modeling, and prompting to
increase positive behavior, and extinction, stimulus control, punishment,
response cost, overcorrection, differential reinforcement of incompatible
behavior, graded exposure/systematic desensitization, flooding, modeling, and
role-playing to decrease negative behavior.
Behavior therapy has shown applicability to anxiety disorders, obsessive-
compulsive and related disorders, behavior disorders, A DHD, and autism
spectrum disorder.
Cognitive-Behavioral Therapy
Cognitive-behavioral therapy (CBT) is based on social and cognitive learning
theories and extends behavior therapy to address the influence of cognitive
processes on behavior. CBT is a problem-oriented treatment centered on
correcting problematic patterns in thinking and behavior that lead to emotional
difficulties and functional impairments. The CBT therapist seeks to identify and
change cognitive distortions (e.g., learned helplessness, irrational fears), identify
and avoid distressing situations, and identify and practice distress-reducing
behavior. Self-monitoring (daily thought records), self-instruction (brief
sentences asserting thoughts that are comforting and adaptive), and self-
reinforcement (rewarding oneself) are key tools used to facilitate achievement of
the CBT goals. Table 34.2 outlines the key descriptive features of CBT that can
be used by PCPs when describing CBT to patients and their family members.
Table 34.2
Core Components and Characteristics of
Cognitive-Behavioral Therapy
• One 60- to 90-minute session each week, typically for 6-12 weeks
• Symptom measures typically are collected frequently.
• Treatment is goal-oriented and collaborative with patient as an active
participant.
• Treatment is focused on changing current problematic thoughts or
behaviors.
• Weekly homework typically is assigned.

From Coffey SF, Banducci AN, Vinci C: Common questions about cognitive
behavior therapy for psychiatric disorders. Am Fam Physician 92:807–812,
2015.

CBT has good-quality evidence for the treatment of depression, anxiety,

obsessive-compulsive disorders (OCDs), behavior disorders, substance abuse,
and insomnia (see Table 34.1 ). For many childhood psychiatric disorders, CBT
alone provides outcomes comparable to psychotropic medication alone, and the
combination of both may convey additional benefit in symptom and harm
“right person” in the “right setting,” and delivering the intervention in the “right
way” (to meet the needs of patients and families). This challenge has led to
interest in identifying common practice elements across efficacious evidence-
based therapies that could be “matched” in a flexible way to patients of a certain
age, gender, and race/ethnicity who have certain psychiatric disorders. Table
34.3 provides the major practice elements for 3 of the most common child and
adolescent psychiatric disorders: anxiety, depression, and disruptive behaviors.
These practice elements, when made available to patients with psychiatric
disorders in a system of care, are estimated to be relevant to approximately two
thirds of the patients. Six of the practice elements—problem-solving skills,
psychoeducation of the parent, relaxation skills, self-monitoring,
cognitive/coping skills, and psychoeducation of the child—are applicable to all 3
disorders and as such could be considered “core skills” for the child and
adolescent psychotherapist.

Table 34.3
Practice Elements in Interventions for 3 Common Child and
Adolescent Psychiatric Disorders

ANXIETY DISORDERS DEPRESSION DISRUPTIVE BEHAVIOR

Directed play X
Limit setting X
Time-out X
Cost response X
Activity scheduling X
Maintenance X X
Skill building X
Social skills training X X
Therapist praise/rewards X
Natural and logical consequences X X
Communication skills X X
Assertiveness training X
Parent monitoring X X
Modeling X
Ignoring X X
Parent praise X X
Problem solving X X X
Parent coping X X
Psychoeducation, parent X X X
Relaxation X X X
Tangible rewards X X
Self-monitoring X X X
Cognitive/coping X X X
Psychoeducation, child X X X
 Exposure X
Adapted from Chorpita BF, Daleiden EL, Weisz JR: Identifying and selecting the common
elements of evidence based interventions: a distillation and matching model, Ment Health Serv
Res 7(1):5–20, 2005.

Psychoeducation is the education of the parent and child about the cause,
course, prognosis, and treatment of the disorder. Problem solving is techniques,
discussions, or activities designed to bring about solutions to targeted problems,
with the intention of imparting a skill for how to approach and solve future
problems in a similar manner. Relaxation is techniques designed to create and
maintain the physiologic relaxation response. Self-monitoring is the repeated
measurement of a target metric by the child. Cognitive/coping skills consist of
techniques designed to alter interpretations of events through examination of the
child's reported thoughts, accompanied by exercises designed to test the validity
of the reported thoughts. PCPs can incorporate some of these elements into their
anticipatory guidance work with pediatric patients.

Modular Therapy Packages

Of considerable importance to day-to-day clinical work is the manner in which
common therapy practice elements are selected, sequenced, repeated, or
selectively applied. This coordination of psychotherapeutic elements is
particularly relevant for patients presenting with multiple concurrent psychiatric
disorders. The Modular Approach to Therapy for Children (MATCH) is a
multidisorder intervention system that incorporates treatment procedures
(practice elements) and treatment logic (coordination) corresponding to
efficacious interventions for childhood anxiety, depression, and behavior
problems, with modifications to allow the system to operate as a single protocol.
Compared with standard manualized treatments for individual disorders and with
usual care, the modular package outperformed both comparators on multiple
clinical and service outcome measures when assessed over a 2-yr period,
although additional, independently derived evidence is needed to categorize this
treatment approach as well established.

Common Elements of Treatment Engagement

Interventions
Treatment engagement is conceptualized as a multidimensional construct
targeting cognitive, attendance, and adherence domains. Research has identified
several key factors addressing these domains that are associated with treatment
engagement: accessibility promotion, psychoeducation about services,
appointment reminders, assessment of treatment barriers, patient assessment,
expectation setting, modeling, and homework assignments (Table 34.4 ). To
promote treatment engagement, the first 7 of these factors can be addressed by
the PCP and the medical home team as soon as a mental health problem is
identified that would benefit from treatment (see Chapter 17 for further
discussion).

Table 34.4

Select Psychotherapy Engagement Elements

ELEMENT DEFINITION
Accessibility Any strategy used to make services convenient and accessible in order to proactively encourage
promotion and increase participation in treatment; e.g., hiring a co-located therapist or referring to a local
community-based therapist with whom the practice has an ongoing collaborative relationship
Psychoeducation Provision of information about services or the service delivery system; e.g., type of therapy
about services being recommended, information about the therapist, session frequency and duration
Appointment Providing information about the day, time, and location of the therapy office for the initial
reminders appointment via mail, text, phone, email, etc., to increase session attendance
Assessment of Discussion to elicit and identify barriers that hinder participation in treatment; e.g.
treatment transportation, scheduling, childcare, previous experiences with therapy, stigma
barriers
Assessment Measurement of the patient's strengths/needs through a variety of methods; e.g., mental health
screening instruments, interviews, recorded reviews during which the referring practitioner can
motivate treatment engagement
Modeling Vehicle to convey information about specific roles of the therapist; e.g., introductory video or
brochure
Expectation Instillation of hope regarding the efficacy of therapy and the patient's ability to participate
setting successfully in treatment
Homework Therapeutic tasks given to the patient to complete outside the therapy session to reinforce or
assignment facilitate knowledge or skills that are consistent with the treatment plan
Adapted from Lindsey MA, Brandt NE, Becker KD, et al: Identifying the common elements of
treatment engagement interventions in children's mental health services, Clin Child Fam Psychol
Rev 17:283–298, 2014; and Becker KD, Lee BR, Daleiden EL, et al: The common elements of
engagement in children's mental health services: which elements for which outcomes? J Clin
Child Adolesc Psychol 44(1):30–43, 2015.

Psychotherapy in the Medical Home

Recognizing that up to one half of visits to PCPs involve a mental health
problem, and that an estimated one fifth of pediatric patients have a functionally
impairing psychiatric disorder, in the context of limited access to specialty
CHAPTER 35

Somatic Symptom and Related

Disorders
Patricia I. Ibeziako, Heather J. Walter, David R. DeMaso

Pediatric psychosomatic medicine deals with the relation between physical and
psychological factors in the causation or maintenance of disease states. The
process whereby distress is experienced and expressed in physical symptoms is
referred to as somatization or psychosomatic illness . Even though present in
virtually every psychiatric disorder, physical symptoms are most prominent in
the various somatic symptom and related disorders.
In the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition
(DSM-5), illnesses previously referred to as “somatoform disorders” are
classified as somatic symptom and related disorders (SSRDs). In children and
adolescents, the SSRDs include somatic symptom disorder (Table 35.1 ),
conversion disorder (Table 35.2 ), factitious disorders (Table 35.3 ), illness
anxiety disorder (Table 35.4 ), and other specified/unspecified somatic
symptom disorders (Table 35.5 ), as well as psychological factors affecting
other medical conditions (Table 35.6 ).
Table 35.1
DSM-5 Diagnostic Criteria for Somatic
Symptom Disorder
A. One or more somatic symptoms that are distressing or result in significant
disruption of daily life.
B. Excessive thoughts, feelings, or behaviors related to the somatic symptoms
or associated health concerns, as manifested by at least one of the
following:
 1. Disproportionate and persistent thoughts about the seriousness of
one's symptoms.
2. Persistent high level of anxiety about health and symptoms.
3. Excessive time and energy devoted to these symptoms or health
concerns.
C. Although any one somatic symptom may not be continuously present, the
state of being symptomatic is persistent (typically >6 mo).
Specify if:
With predominant pain (previously known as “pain disorder” in
DSM IV-TR): for individuals whose somatic symptoms
predominantly involve pain.
Persistent: A persistent course is characterized by severe
symptoms, marked impairment, and long duration (>6 mo).

Adapted from the Diagnostic and Statistical Manual of Mental Disorders, Fifth
Edition, (Copyright 2013). American Psychiatric Association, p 311.
Table 35.2
DSM-5 Diagnostic Criteria for Conversion
Disorder or Functional Neurologic Symptom
Disorder

A. One or more symptoms of altered voluntary motor or sensory function.

B. Clinical findings provide evidence of incompatibility between the
symptom and recognized neurologic or medical conditions.
C. The symptom is not better explained by another medical or mental
disorder.
D. The symptom causes clinically significant distress or impairment in social,
occupational, or other important areas of functioning or warrants medical
evaluation.
Specify symptom type: weakness or paralysis, abnormal
movements, swallowing symptoms, speech symptom,
attacks/seizures, anesthesia/sensory loss, special sensory
symptom (e.g., visual, olfactory, hearing), or mixed symptoms.
Adapted from the Diagnostic and Statistical Manual of Mental Disorders, Fifth
Edition, (Copyright 2013). American Psychiatric Association, p 318.
Table 35.3
DSM-5 Diagnostic Criteria for Factitious
Disorders
Factitious Disorder Imposed on Self

A. Falsification of physical or psychological signs or symptoms, or induction

of injury or disease, associated with identified deception.
B. The individual presents himself or herself to others as ill, impaired, or
injured.
C. The deceptive behavior is evident even in the absence of obvious external
rewards.
D. The behavior is not better explained by another mental disorder, such as
delusional disorder or another psychotic disorder.
Specify if: single episode or recurrent episodes.

Factitious Disorder Imposed on Another (Previously “Factitious Disorder

by Proxy”)

A. Falsification of physical or psychological signs or symptoms, or induction

of injury or disease, in another, associated with identified deception.
B. The individual presents another individual (victim) to others as ill,
impaired, or injured.
C. The deceptive behavior is evident even in the absence of obvious external
rewards.
D. The behavior is not better explained by another mental disorder, such as
delusional disorder or another psychotic disorder.
Note : The perpetrator, not the victim, receives this diagnosis.
Specify if: single episode or recurrent episodes.

Adapted from the Diagnostic and Statistical Manual of Mental Disorders, Fifth
Edition, (Copyright 2013). American Psychiatric Association, p 324.
Table 35.4
DSM-5 Diagnostic Criteria for Illness Anxiety
Disorder

A. Preoccupation with having or acquiring a serious illness.

B. Somatic symptoms are not present, or, if present, are only mild in intensity.
If another medical condition is present or there is a high risk for developing
a medical condition (e.g., strong family history is present), the
preoccupation is clearly excessive or disproportionate.
C. There is a high level of anxiety about health, and the individual is easily
alarmed about personal health status.
D. The individual performs excessive health-related behaviors (e.g.,
repeatedly checks his or her body for signs of illness) or exhibits
maladaptive avoidance (e.g., avoids doctor appointments and hospitals).
E. Illness preoccupation has been present for at least 6 mo, but the specific
illness that is feared may change over that time.
F. The illness-related preoccupation is not better explained by another mental
disorder.
Specify whether: care-seeking type or care-avoidant type.

Adapted from the Diagnostic and Statistical Manual of Mental Disorders, Fifth
Edition, (Copyright 2013). American Psychiatric Association, p 315.
Table 35.5
DSM-5 Diagnostic Criteria for Other
Specified/Unspecified Somatic Symptom and
Related Disorders
Other Specified

This category applies to presentations in which symptoms characteristic of

a somatic symptom and related disorder that cause clinically significant
distress or impairment in social, occupational, or other important areas of
functioning predominate but do not meet full criteria for any of the
 disorders in the somatic symptom and related disorders diagnostic class.
Examples of presentations that can be specified using the “other specified”
designation include the following:
1. Brief somatic symptom disorder: duration of symptoms is <6
mo.
2. Brief illness anxiety disorder: duration of symptoms is <6 mo.
3. Illness anxiety disorder without excessive health-related
behaviors: Criterion D for illness anxiety disorder is not met
(see Table 35.4 ).
4. Pseudocyesis : a false belief of being pregnant that is associated
with objective signs and reported symptoms of pregnancy.

Unspecified

This category applies to presentations in which symptoms characteristic of

a somatic symptom and related disorder that cause clinically significant
distress or impairment in functioning predominate but do not meet
criteria for any of the other disorders in the somatic symptom and related
disorders diagnostic class.

Adapted from the Diagnostic and Statistical Manual of Mental Disorders, Fifth
Edition, (Copyright 2013). American Psychiatric Association, p 327.
Table 35.6
DSM-5 Diagnostic Criteria for Psychological
Factors Affecting Other Medical Conditions

A. A medical symptom or condition (other than a mental disorder) is present.

B. Psychological or behavioral factors adversely affect the medical condition
in one of the following ways:
1. The factors have influenced the course of the medical condition,
as shown by a close temporal association between the
psychological factors and the development or exacerbation of, or
delayed recovery from, the medical condition.
2. The factors interfere with the treatment of the medical condition
(e.g., poor adherence).
 3. The factors constitute additional well-established health risks for
the individual.
4. The factors influence the underlying pathophysiology,
precipitating or exacerbating symptoms or necessitating medical
attention.
C. The psychological and behavioral factors in Criterion B are not better
explained by another mental disorder (e.g., panic disorder, major depressive
disorder, posttraumatic stress disorder).
Specify if: mild, moderate, severe, or extreme.

Adapted from the Diagnostic and Statistical Manual of Mental Disorders, Fifth
Edition, (Copyright 2013). American Psychiatric Association, p 322.

With the exception of illness anxiety disorder, in which there is a high level of
anxiety about health in the absence of significant somatic symptoms, and
psychological factors affecting other medical conditions, in which psychological
and/or behavioral factors adversely affect a medical condition, SSRDs are
classified on the basis of physical symptoms associated with significant distress
and impairment, with or without the presence of a diagnosed medical condition.
The symptoms form a continuum that can range from pain to disabling
neurologic symptoms and generally interfere with school/home life and peer
relationships.
Most patients with SSRDs are seen by primary care practitioners or by
pediatric subspecialists, who may make specialty-specific diagnoses such as
visceral hyperalgesia, chronic fatigue syndrome, psychogenic syncope, or
noncardiac chest pain. Even within psychiatry, SSRDs are variously referred to
as functional or psychosomatic disorders or as medically unexplained
symptoms . The nosologic heterogeneity across the pediatric subspecialties
contributes to the varying diagnostic labels. There is a significant overlap in the
symptoms and presentation of patients with somatic symptoms who have
received different diagnoses from different specialties. Moreover, SSRDs share
similarities in etiology, pathophysiology, neurobiology, psychological
mechanisms, patient characteristics, and management and treatment response,
which is indicative of a single spectrum of somatic disorders.
It is helpful for healthcare providers to avoid the dichotomy of approaching
illness using a medical model in which diseases are considered physically or
motor and vocal tics at some point in the illness (although not necessarily
concurrently). The tic disorders are hierarchical in order (i.e., TD followed by
PTD followed by provisional tic disorder), such that once a tic disorder at one
level of the hierarchy is diagnosed, a lower-hierarchy diagnosis cannot be made.
Other specified/unspecified tic disorders are presentations in which symptoms
characteristic of a tic disorder that cause significant distress or impairment
predominate but do not meet the full criteria for a tic or other
neurodevelopmental disorder.
Table 37.1
DSM-5 Diagnostic Criteria for Tic Disorders
Note: A tic is a sudden, rapid, recurrent, nonrhythmic motor movement or
vocalization.

Tourette Disorder

A. Both multiple motor and one or more vocal tics have been present at some
time during the illness, although not necessarily concurrently.
B. The tics may wax and wane in frequency but have persisted for >1 yr since
first tic onset.
C. Onset is before age 18 yr.
D. The disturbance is not attributable to the physiologic effects of a substance
(e.g., cocaine) or another medical condition (e.g., Huntington disease,
postviral encephalitis).

Persistent (Chronic) Motor or Vocal Tic Disorder

A. Single or multiple motor or vocal tics have been present during the illness,
but not both motor and vocal.
B. The tics may wax and wane in frequency but have persisted for >1 yr since
first tic onset.
C. Onset is before age 18 yr.
D. The disturbance is not attributable to the physiologic effects of a substance
(e.g., cocaine) or another medical condition (e.g., Huntington disease,
 postviral encephalitis).
E. Criteria have never been met for Tourette disorder.
Specify if:
With motor tics only
With vocal tics only

Provisional Tic Disorder

A. Single or multiple motor and/or vocal tics.

B. The tics have been present for <1 yr since first tic onset.
C. Onset is before age 18 yr.
D. The disturbance is not attributable to the physiologic effects of a substance
(e.g., cocaine) or another medical condition (e.g., Huntington disease,
postviral encephalitis).
E. Criteria have never been met for Tourette disorder or persistent (chronic)
motor or vocal tic disorder.

Adapted from the Diagnostic and Statistical Manual of Mental Disorders, Fifth
Edition, (Copyright 2013). American Psychiatric Association, p. 81.

Description
Tics are sudden, rapid, recurrent, nonrhythmic motor movements or
vocalizations. Simple motor tics (e.g., eye blinking, neck jerking, shoulder
shrugging, extension of the extremities) are fast, brief movements involving one
or a few muscle groups. Complex motor tics involve sequentially and/or
simultaneously produced, relatively coordinated movements that can seem
purposeful (e.g., brushing back one's hair bangs, tapping the foot, imitating
someone else's movement [echopraxia ], or making a sexual or obscene gesture
[copropraxia ]). Simple vocal tics (e.g., throat clearing, sniffing, coughing) are
solitary, meaningless sounds and noises. Complex vocal tics involve
recognizable word or utterances (e.g., partial words [syllables], words out of
context, coprolalia [obscenities or slurs], palilalia [repeating one's own sounds
or words], or echolalia [repeating the last heard word or phrase]).
Sensory phenomena (premonitory urges) that precede and trigger the urge to
neuroacanthocytosis, Huntington syndrome, various frontal-subcortical brain
lesions), but it is rare for tics to be the only manifestation of these disorders.

Table 37.2

Repetitive Movements of Childhood

TYPICAL DISORDERS WHERE
MOVEMENT DESCRIPTION
PRESENT
Tics Sudden rapid, recurrent, nonrhythmic, stereotyped, Transient tics, Tourette disorder,
vocalization or motor movement persistent tic disorder
Dystonia Involuntary, sustained, or intermittent muscle contractions DYT1 gene, Wilson disease,
that cause twisting and repetitive movements, abnormal myoclonic dystonia, extrapyramidal
postures, or both symptoms caused by dopamine-
blocking agents
Chorea Involuntary, random, quick, jerking movements, most Sydenham chorea, Huntington
often of the proximal extremities, that flow from joint to chorea
joint. Movements are abrupt, nonrepetitive, and arrhythmic
and have variable frequency and intensity
Stereotypies Stereotyped, rhythmic, repetitive movements or patterns of Autism, stereotypic movement
speech, with lack of variation over time disorder, intellectual disability
Compulsions A repetitive, excessive, meaningless activity or mental Obsessive-compulsive disorder,
exercise that a person performs in an attempt to avoid anorexia, body dysmorphic disorder,
distress or worry trichotillomania, excoriation
disorder
Myoclonus Shock-like involuntary muscle jerk that may affect a single Hiccups, hypnic jerks, Lennox-
body region, one side of the body, or the entire body; may Gastaut syndrome, juvenile
occur as a single jerk or repetitive jerks myoclonic epilepsy, mitochondrial
encephalopathies, metabolic
disorders
Akathisia Unpleasant sensations of “inner” restlessness, often Extrapyramidal adverse effects from
prompting movements in an effort to reduce the sensations dopamine-blocking agents; anxiety
Volitional Behavior that may be impulsive or caused by boredom, Attention-deficit/hyperactivity
behaviors such as tapping peers or making sounds (animal noises) disorder, oppositional defiant
disorder, sensory integration
disorders
Adapted from Murphy TK, Lewin AB, Storch EA, et al: Practice parameter for the assessment and
treatment of children and adolescents with chronic tic disorders, J Am Acad Child Adolesc
Psychiatry 52(12):1341–1359, 2013.

Individuals presenting with tics in the context of declining motor or cognitive

function should be referred for neurologic assessment. Substances/medications
that are reported to worsen tics include selective serotonin reuptake inhibitors
(SSRIs), lamotrigine, and cocaine. If tics develop in close temporal relationship
to the use of a substance or medication and then remit when use of the substance
is discontinued, a causal relationship is possible. Although a long-standing
clinical concern, controlled studies show no evidence that stimulants commonly
increase tics.
effect size has been shown for behavioral therapy relative to comparison
conditions.
Table 37.3
Components of Habit Reversal Procedure
Increase Individual's Awareness of Habit

Response description—have individual describe behavior to therapist in

detail while reenacting the behavior and looking in a mirror.
Response detection—inform individual of each occurrence of the behavior
until each occurrence is detected without assistance.
Early warning—have individual practice identifying earliest signs of the
target behavior.
Situation awareness—have individual describe all situations in which the
target behavior is likely to occur.

Teach Competing Response to Habit

The competing response must result in isometric contraction of muscles

involved in the habit, be capable of being maintained for 3 min, and be
socially inconspicuous and compatible with normal ongoing activities but
incompatible with the habit (e.g., clenching one's fist, grasping and
clenching an object). For vocal tics and stuttering, deep relaxed breathing
with a slight exhale before speech has been used as the competing
response.

Sustain Compliance

Habit inconvenience review—have individual review in detail all problems

associated with target behavior.
Social support procedure—family members and friends provide high levels
of praise when a habit-free period is noted.
Public display—individual demonstrates to others that he or she can
control the target behavior in situations in which the behavior occurred in
the past.
Facilitate Generalization—Symbolic Rehearsal Procedure

For each situation identified in situation awareness procedure, individual

imagines himself or herself beginning the target behavior but stopping
and engaging in the competing response.

From Carey WB, Crocker AC, Coleman WL, et al, editors: Developmental-
behavioral pediatrics, ed 4, Philadelphia, 2009, Elsevier/Saunders, p 639.

Medications should be considered when the tics are causing severe

impairment in the quality of life, or when psychiatric comorbidities are present.
The only U.S. Food and Drug Administration (FDA)–approved medications to
treat TD in children and adolescents are 2 first-generation (typical)
antipsychotics (haloperidol, pimozide) and 1 second-generation (atypical)
antipsychotic (aripiprazole). Alpha-agonists (clonidine, guanfacine) are also a
consideration as first-line agents because of their more favorable side effect
profile than the first- or second-generation antipsychotics (see Chapter 33 ).
Both antipsychotic and α-adrenergic medications have significant benefit
compared with placebo for the pharmacologic treatment of youth with tic
disorders. There have been no significant differences between the first- and
second-generation antipsychotic agents tested.
Children with tic disorders may benefit from SSRIs for the treatment of
comorbid OCD, anxiety, or depressive disorders. Augmentation of SSRIs with
an atypical antipsychotic has been a consideration in patients with concurrent tic
disorders and OCD responding poorly to an SSRI alone. The presence of tics
does not preclude the use of stimulants to address comorbid ADHD. However,
close clinical monitoring is required for possible exacerbation of tics during
stimulant treatment. Anger and rage outbursts are not uncommon among youth
with tics (up to 80% in clinically referred samples). Behavioral therapies (CBT,
parent management training) that address anger management may be useful.
There are no controlled pharmacologic studies in youth with tic disorders with
anger outbursts. There also is no rigorous scientific evidence to support the use
of deep brain stimulation, repetitive magnetic stimulation, or dietary
supplements in the treatment of TD or PTD.
in adolescence are also a significant risk factor for experiencing later episodes of
major depression in adulthood. Anxiety and depressive disorder in adolescence
predict increased risk of anxiety and depressive symptoms (including suicide
attempts) in adulthood, underscoring the need to diagnose and treat these
underreported, yet prevalent, conditions early.
Because anxiety is both a normal phenomenon and, when highly activated,
strongly associated with impairment, the pediatrician must be able to
differentiate normal anxiety from abnormal anxiety across development (Fig.
38.1 and Table 38.1 ). Anxiety has an identifiable developmental progression for
most children; most infants exhibit stranger wariness or anxiety beginning at 7-9
mo of age. Behavioral inhibition to the unfamiliar (withdrawal or fearfulness to
novel stimuli associated with physiologic arousal) is evident in approximately
10–15% of the population at 12 mo of age and is moderately stable. Most
children who show behavioral inhibition do not develop impairing levels of
anxiety. A family history of anxiety disorders and maternal overinvolvement or
enmeshment predicts later clinically significant anxiety in behaviorally inhibited
infants. The infant who is excessively clingy and difficult to calm during
pediatric visits should be followed for signs of increasing levels of anxiety.

FIG. 38.1 Normative fears throughout childhood and adolescence. (From Craske MG,
Stein MB: Anxiety. Lancet 388:3048–3058, 2016.)

Table 38.1
Differential Diagnosis of Anxiety Disorders
 Shyness
Substance use
Substance use withdrawal
Hyperthyroidism
Arrhythmias
Pheochromocytoma
Mast cell disorders
Carcinoid syndrome
Anaphylaxis
Hereditary angioedema
Lupus
Autoimmune encephalitis
Body dysmorphic disorder
Autism spectrum disorder
Major depressive disorder
Delusional disorder
Oppositional defiant disorder
Embarrassing medical condition

Preschoolers typically have specific fears related to the dark, animals, and
imaginary situations, in addition to normative separation anxiety. Preoccupation
with orderliness and routines (just right phenomena) often takes on a quality of
anxiety for preschool children. Parents' reassurance is usually sufficient to help
the child through this period. Although most school-age children abandon the
imaginary fears of early childhood, some replace them with fears of bodily harm
or other worries (Table 38.2 ). In adolescence, general worrying about school
performance and worrying about social competence are common and remit as
the teen matures.
Table 38.2
DSM-5 Diagnostic Criteria for Specific
Phobia

A. Marked fear or anxiety about a specific object or situation (e.g., flying,

heights, animals, receiving an injection, seeing blood).
Note: In children, the fear or anxiety may be expressed by crying, tantrums,
 freezing, or clinging.
B. The phobic object or situation almost always provokes immediate fear or
anxiety.
C. The phobic object or situation is actively avoided or endured with intense
fear or anxiety.
D. The fear or anxiety is out of proportion to the actual danger posed by the
specific object or situation and to the sociocultural context.
E. The fear, anxiety, or avoidance is persistent, typically lasting for 6 mo or
more.
F. The fear, anxiety, or avoidance causes clinically significant distress or
impairment in social, occupational, or other important areas of functioning.
G. The disturbance is not better explained by the symptoms of another mental
disorder, including fear, anxiety and avoidance or situations associated with
panic-like symptoms or other incapacitating symptoms (as in agoraphobia);
objects or situations related to obsessions (as in obsessive-compulsive
disorder); remainders of traumatic events (as in posttraumatic stress
disorder); separation from home or attachment figures (as in separation
anxiety disorder); or social situations (as in social anxiety disorder).
Specify if:
Code based on the phobic stimulus:
Animal (e.g., spiders, insects, dogs).
Natural environment (e.g., heights, storms, water).
Blood-injection-injury (e.g., needles, invasive medical
procedures).
Situational (e.g., airplanes, elevators, enclosed places).
Other (e.g., situations that may lead to choking or vomiting; in
children, e.g., loud sounds or costumed characters).

From the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition,
(Copyright 2013). American Psychiatric Association, pp 197–198.

Genetic or temperamental factors contribute more to the development of some

anxiety disorders, whereas environmental factors are closely linked to the cause
of others. Specifically, behavioral inhibition appears to be a heritable tendency
and is linked with social phobia, generalized anxiety, and selective mutism. OCD
times more likely to develop PD in adolescence.
When a child reports recurring acute severe anxiety, antidepressant or
anxiolytic medication is often necessary. Controlled studies of tricyclic
antidepressants (TCAs, imipramine) and benzodiazepines (clonazepam) show
that these agents are not generally effective. Data support the use of cognitive-
behavioral therapy (CBT) and selective serotonin reuptake inhibitors (SSRIs)
(see Chapter 33 , Table 33.4 ). Adverse events with SSRI treatment, including
suicidal and homicidal ideation, are uncommon. CBT alone is associated with
less insomnia, fatigue, sedation, and restlessness than SSRIs. Combining SSRIs
with CBT may be the best approach to achieving a positive response; long-term
SSRI treatment can provide additional benefit.
Childhood-onset social phobia (social anxiety disorder) is characterized by
excessive anxiety in social settings (including the presence of unfamiliar peers,
or unfamiliar adults) or performance situations, leading to social isolation, and is
associated with social scrutiny and fear of doing something embarrassing (Table
38.3 ). Fear of social settings can also occur in other disorders, such as GAD.
Avoidance or escape from the situation usually dissipates anxiety in social
phobia (SP), unlike GAD, where worry persists.
Table 38.3
DSM-5 Diagnostic Criteria for Social Anxiety
Disorder (Social Phobia)

A. Marked fear or anxiety about 1 or more social situations in which the

individual is exposed to possible scrutiny by others. Examples include
social interactions (e.g., having a conversation, meeting unfamiliar people),
being observed (e.g., eating or drinking), and performing in front of others
(e.g., giving a speech).
B. The individual fears that he or she will act in a way or show anxiety
symptoms that will be negatively evaluated (i.e., will be humiliating or
embarrassing; will lead to rejection or offend others).
C. The social situations almost always provoke fear or anxiety.
Note: In children, the fear or anxiety may be expressed by crying, tantrums,
freezing, clinging, shrinking, or failing to speak in social situations.
D. The social situations are avoided or endured with intense fear or anxiety.
E. The fear or anxiety is out of proportion to the actual threat posed by the
 social situation and to the sociocultural context.
F. The fear, anxiety, or avoidance is persistent, typically lasting for 6 mo or
more.
G. The fear, anxiety, or avoidance causes clinically significant distress or
impairment in social, occupational, or other important areas of functioning.
H. The fear, anxiety, or avoidance is not attributable to the physiologic effects
of a substance (e.g., a drug of abuse, a medication) or another medical
condition.
I. The fear, anxiety, or avoidance is not better explained by the symptoms of
another mental disorder, such as panic disorder, body dysmorphic disorder,
or autism spectrum disorder.
J. If another medical condition (e.g., Parkinson disease, obesity, disfigurement
from burns or injury) is present, the anxiety or avoidance is clearly
unrelated or is excessive.
Specify if:
Performance only: If the fear is restricted to speaking or performing in
public.

From the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition,
(Copyright 2013). American Psychiatric Association, pp 202–203.

Children and adolescents with SP often maintain the desire for involvement
with family and familiar peers. When severe, the anxiety can manifest as a panic
attack. SP is associated with a decreased quality of life, with increased likelihood
of having failed at least 1 grade, and a 38% likelihood of not graduating from
high school. Its onset is typically during or before adolescence and is more
common in girls. A family history of SP or extreme shyness is common.
Approximately 70–80% of patients with SP have at least 1 comorbid psychiatric
disorder. Most shy patients do not have SP.
Social effectiveness therapy for children (SET-C), alone or with SSRIs, is
considered the treatment of choice for SP (see Table 33.4 ). SSRI and SET-C are
superior to placebo in reducing social distress and behavioral avoidance and
increasing general functioning. SET-C may be better than SSRI in reducing these
symptoms. SET-C, but not SSRI, may be superior to placebo in improving social
skills, decreasing anxiety in specific social interactions, and enhancing social
or discomfort in which patients experience abrupt onset of physical and
psychological symptoms called panic attacks (Table 38.4 ). Physical symptoms
can include palpitations, sweating, shaking, shortness of breath, dizziness, chest
pain, and nausea. Children can present with acute respiratory distress but without
fever, wheezing, or stridor, ruling out organic causes of the distress. The
associated psychological symptoms include fear of death, impending doom, loss
of control, persistent concerns about having future attacks, and avoidance of
settings where attacks have occurred (agoraphobia, Table 38.5 ).
Table 38.4
DSM-5 Diagnostic Criteria for Panic Disorder
A. Recurrent unexpected panic attacks. A panic attack is an abrupt surge of
intense fear or intense discomfort that reaches a peak within minutes, and
during which time 4 (or more) of the following symptoms occur:
Note: The abrupt surge can occur from a calm state or an anxious state.
1. Palpitations, pounding heart, or accelerated heart rate.
2. Sweating.
3. Trembling or shaking.
4. Sensations of shortness of breath or smothering.
5. Feelings of choking.
6. Chest pain or discomfort.
7. Nausea or abdominal distress.
8. Feeling dizzy, unsteady, light-headed, or faint.
9. Chills or heart sensations.
10. Paresthesias (numbness or tingling sensations).
11. Derealizations (feeling or unreality) or depersonalization (being
detached from one-self).
12. Fear of losing control or “going crazy.”
13. Fear of dying.
Note: Culture-specific symptoms (e.g., tinnitus, neck soreness, headache,
uncontrollable screaming or crying) may be seen. Such symptoms should
not count as 1 of the 4 required symptoms.
B. At least 1 of the attacks has been followed by 1 mo (or more) of 1 or both
of the following:
1. Persistent concern or worry about additional panic attacks or their
 consequences (e.g., losing control, having a heart attack, “going
crazy”).
2. A significant maladaptive change in behavior related to the
attacks (e.g., behaviors designed to avoid having panic attacks,
such as avoidance of exercise or unfamiliar situations).
C. The disturbance is not attributable to the physiologic effects of a substance
(e.g., a drug of abuse, a medication) or another medical condition (e.g.,
hyperthyroidism, cardiopulmonary disorders).
D. The disturbance is not better explained by another mental disorder (e.g.,
the panic attacks do not occur only in response to feared social situations,
as in social anxiety disorder; in response to circumscribed phobic objects or
situations, as in specific phobia; in response to obsessions, as in obsessive-
compulsive disorder; or in response to reminders of traumatic events, as in
posttraumatic stress disorder; or in response to separation from attachment
figures, as in separation anxiety disorder).

From the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition,
(Copyright 2013). American Psychiatric Association, pp 208–209.
Table 38.5
DSM-5 Diagnostic Criteria for Agoraphobia

A. Marked fear or anxiety about 2 (or more) if the following 5 situations:

1. Using public transportation (e.g., automobiles, buses, trains,
ships, planes).
2. Being in open spaces (e.g., parking lots, marketplaces, bridges).
3. Being in enclosed places (e.g., shops, theaters, cinemas).
4. Standing in line or being in a crowd.
5. Being outside of the home alone.
B. The individual fears or avoids these situations because of thoughts that
escape might be difficult or help might not be available in the event of a
developing panic-like symptoms or other incapacitating or embarrassing
symptoms (e.g., fear or falling in the elderly, fear of incontinence).
C. The agoraphobic situations almost always provoke fear or anxiety.
D. The agoraphobic situations are actively avoided, require the presence of a
companion, or are endured with intense fear or anxiety.
 E. The fear or anxiety is out of proportion to the actual danger posed by the
agoraphobic situations and to the sociocultural context.
F. The fear, anxiety, or avoidance is persistent, typically lasting for 6 mo or
more.
G. The fear, anxiety, or avoidance causes clinically significant distress or
impairment in social, occupational, or other important area of functioning.
H. If another medical condition (e.g., inflammatory bowel disease, Parkinson
disease) is present, the fear, anxiety, or avoidance is clearly excessive.
I. The fear, anxiety, or avoidance is not better explained by the symptoms or
another mental disorder—for example, the symptoms are not confined to
specific phobia, situational type; do not involve only social situations (as in
social anxiety disorder); and are not related exclusively to obsessions (as in
obsessive-compulsive disorder), reminders or traumatic events (as in
posttraumatic stress disorder), or fear of separation (as in separation anxiety
disorder).
Note: Agoraphobia is diagnosed irrespective of the presence of panic
disorder. If an individual's presentation meets criteria for panic disorder and
agoraphobia, both diagnoses should be assigned.

From the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition,
(Copyright 2013). American Psychiatric Association, pp 217–218.

PD is uncommon before adolescence, with the peak age of onset at 15-19 yr,
occurring more often in girls. The postadolescence prevalence of PD is 1–2%.
Early-onset PD and adult-onset PD do not differ in symptom severity or social
functioning. Early-onset PD is associated with greater comorbidity, which can
result from greater familial loading for anxiety disorders in the early-onset
subtype. Children of parents with PD are much more likely to develop PD. A
predisposition to react to autonomic arousal with anxiety may be a specific risk
factor leading to PD. Twin studies suggest that 30–40% of the variance is
attributed to genetics. The increasing rates of panic attack are also directly
related to earlier sexual maturity. Cued panic attacks can be present in other
anxiety disorders and differ from the uncued “out-of-the-blue” attacks in PD.
No randomized controlled trials (RCTs) have evaluated the effectiveness of
antidepressant medication in youth with PD. Open-label studies with SSRIs
appear to show effectiveness in the treatment of adolescents (see Table 33.4 ).
CBT may also be helpful. The recovery rate is approximately 70%.
Generalized anxiety disorder occurs in children who often experience
unrealistic worries about different events or activities for at least 6 mo with at
least 1 somatic complaint (Table 38.6 ). The diffuse nature of the anxiety
symptoms differentiates it from other anxiety disorders. Worries in children with
GAD usually center around concerns about competence and performance in
school and athletics. GAD often manifests with somatic symptoms, including
restlessness, fatigue, problems concentrating, irritability, muscle tension, and
sleep disturbance. Given the somatic symptoms characteristic of GAD, the
differential diagnosis must consider other medical causes. Excessive use of
caffeine or other stimulants in adolescence is common and should be determined
with a careful history. When the history or physical examination is suggestive,
the pediatrician should rule out hyperthyroidism, hypoglycemia, lupus,
pheochromocytoma, and other disorders (see Table 38.1 ; Fig. 38.2 ).
Table 38.6
DSM-5 Diagnostic Criteria for Generalized
Anxiety Disorder

A. Excessive anxiety and worry (apprehensive expectation), occurring more

days than not for at least 6 mo, about a number of events or activities (such
as work or school performance).
B. The individual finds it difficult to control the worry.
C. The anxiety and worry are associated with 3 (or more) of the following 6
symptoms (with at least some symptoms having been present for more days
than not for the past 6 mo):
Note: Only 1 item is required in children.
1. Restlessness or feeling keyed up or on edge.
2. Being easily fatigued.
3. Difficulty concentrating or mind going blank.
4. Irritability.
5. Muscle tension.
6. Sleep disturbance (difficulty falling or staying asleep, or restless,
unsatisfying sleep).
D. The anxiety, worry, or physical symptoms cause clinically significant
distress or impairment in social, occupational, or other important areas of
 functioning.
E. The disturbance is not attributable to the physiologic effects of a substance
(e.g., a drug of abuse, a medication) or other medical condition (e.g.,
hyperthyroidism).
F. The disturbance is not better explained by another mental disorder (e.g.,
anxiety or worry about having panic attacks in panic disorder, negative
evaluation in social anxiety disorder [social phobia], contamination or other
obsessions in obsessive-compulsive disorder, separation from attachment
figures in separation anxiety disorder, remainders of traumatic events in
posttraumatic stress disorder, gaining weight in anorexia nervosa, physical
complaints in somatic symptom disorder, perceived appearance flaws in
body dysmorphic disorder, having a serious illness in illness anxiety
disorder, or the content of delusional beliefs in schizophrenia or delusional
disorder).

From the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition,
(Copyright 2013). American Psychiatric Association, p 222.

FIG. 38.2 Evaluation of worry, fear, and panic. PANDAS , Pediatric autoimmune
neuropsychiatric disorders associated with Streptococcus pyogenes . (From Kliegman
RM, Lye PS, Bordini B, et al, editors: Nelson pediatric symptom-based diagnosis,
Philadelphia, 2018, Elsevier, p 429).

Children with GAD are extremely self-conscious and perfectionistic and

struggle with more intense distress than is evident to parents or others around
them. They often have other anxiety disorders, such as simple phobia and PD.
Onset may be gradual or sudden, although GAD seldom manifests until puberty.
Boys and girls are equally affected before puberty, when GAD becomes more
prevalent in girls. The prevalence of GAD ranges from 2.5–6% of children.
Hypermetabolism in frontal precortical area and increased blood flow in the
right dorsolateral prefrontal cortex may be present.
Children with GAD are good candidates for CBT, an SSRI, or their
combination (see Table 33.4 ). Buspirone may be used as an adjunct to SSRI
therapy. The combination of CBT and SSRI often results in a superior response
in pediatric patients with anxiety disorders, including GAD. The recovery rate is
approximately 80%.
It is important to distinguish children with GAD from those who present with
specific repetitive thoughts that invade consciousness (obsessions ) or repetitive
rituals or movements that are driven by anxiety (compulsions ). The most
common obsessions are concerned with bodily wastes and secretions, the fear
that something calamitous will happen, or the need for sameness. The most
common compulsions are handwashing, continual checking of locks, and
touching. At times of stress (bedtime, preparing for school), some children touch
certain objects, say certain words, or wash their hands repeatedly.
Obsessive-compulsive disorder is diagnosed when the thoughts or rituals
cause distress, consume time, or interfere with occupational or social functioning
(Table 38.7 ). In the DSM-5, OCD and related disorders, such as
trichotillomania, excoriation, body dysmorphic disorder, and hoarding, are listed
separately and are no longer included under anxiety disorders.
Table 38.7
DSM-5 Diagnostic Criteria for Obsessive-
Compulsive Disorder

A. Presence of obsessions, compulsions, or both:

Obsessions are defined by (1) and (2):
1. Recurrent and persistent thoughts, urges, or images that are
experienced, at some time during the disturbance, as intrusive and
unwanted, and that in most individuals cause marked anxiety or
distress.
 2. The individual attempts to ignore or suppress such thoughts,
urges, or images, or to neutralize them with some other thought
or action (i.e., by performing a compulsion).
Compulsions are defined by (1) and (2):
1. Repetitive behaviors (e.g., hand washing, ordering, checking) or
mental acts (e.g., praying, counting, repeating words silently) that
the individual feels driven to perform in response to an obsession
or according to rules that must be applied rigidly.
2. The behaviors or mental acts are aimed at preventing or reducing
anxiety or distress, or preventing some dreaded event or situation;
however, these behaviors or mental acts are not connected in a
realistic way with what they are designed to neutralize or prevent,
or are clearly excessive.
B. The obsessions or compulsions are time-consuming (e.g., take more than 1
hr per day) or cause clinically significant distress or impairment in social,
occupational, or other important areas of functioning.
C. The obsessive-compulsive symptoms are not attributable to the
physiologic effects of a substance (e.g., a drug of abuse, a medication) or
another medical condition.
D. The disturbance is not better explained by the symptoms of another mental
disorder (e.g., excessive worries, as in generalized anxiety disorder;
preoccupation with appearance, as in body dysmorphic disorder; difficulty
discarding or parting with possessions, as in hoarding disorder; hair pulling,
as in trichotillomania [hair-pulling disorder]; skin picking, as in excoriation
[skin-picking] disorder; stereotypies, as in stereotypic movement disorder;
ritualized eating disorder, as in eating disorders; preoccupation with
substances or gambling, as in substance-related and addictive disorders;
preoccupation with having an illness, as in illness anxiety disorder; sexual
urges or fantasies, as in paraphilic disorders; impulses, as in disruptive,
impulse-control, and conduct disorders; guilty ruminations, as in
schizophrenia spectrum and other psychotic disorders; or repetitive patterns
of behavior, as in autism spectrum disorder).
Specify if:
With good or fair insight: The individual recognizes that obsessive-
compulsive disorder beliefs are definitely or probably not true or that they
may or may not be true.
 With poor insight: The individual thinks obsessive-compulsive disorder
beliefs are probably true.
With absent insight/delusional beliefs: The individual is completely
convinced that obsessive-compulsive disorder beliefs are true.
Specify if:
Tic-related: The individual has a current or past history of a tic disorder.

From the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition,
(Copyright 2013). American Psychiatric Association, p 237.

OCD is a chronically disabling illness characterized by repetitive, ritualistic

behaviors over which the patient has little or no control. OCD has a lifetime
prevalence of 1–3% worldwide, and as many as 80% of all cases have their onset
in childhood and adolescence. Common obsessions include contamination (35%)
and thoughts of harming loved ones or oneself (30%). Washing and cleaning
compulsions are common in children (75%), as are checking (40%) and
straightening (35%). Many children are observed to have visuospatial
irregularities, memory problems, and attention deficits, causing academic
problems not explained by OCD symptoms alone.
The Children's Yale-Brown Obsessive-Compulsive Scale (C-YBOCS) and the
Anxiety Disorders Interview Schedule for Children (ADIS-C) are reliable and
valid methods for identifying children with OCD. The C-YBOCS is helpful in
following the progression of symptoms with treatment. The Leyton Obsessional
Inventory (LOI) is a self-report measure of OCD symptoms that is quite
sensitive. Patients with OCD have consistently identified abnormalities in the
frontostriatal-thalamic circuitry associated with severity of illness and treatment
response. Comorbidity is common in OCD, with 30% of patients having
comorbid tic disorders, 26% comorbid major depression, and 24% comorbid
developmental disorders.
Consensus guidelines recommend that children and adolescents with OCD
begin treatment with either CBT alone or CBT in combination with SSRI, when
symptoms are moderate to severe (YBOCS >21). In OCD patients with
comorbid tics, SSRIs are no more effective than placebo, and the combination of
CBT and SSRI is superior to CBT; CBT alone is superior to placebo. Pediatric
OCD patients with comorbid tics should begin treatment with CBT alone or
combined CBT and SSRI. Pediatric patients with OCD who have a family
anxiety or panic. Parents who become anxious themselves may reinforce their
children's anxiety, and the pediatrician can usefully interrupt this cycle by calmly
noting that phobias are not unusual and rarely cause impairment. The prevalence
of specific phobias in childhood is 0.5–2%.
Systematic desensitization is a form of behavior therapy that gradually
exposes the patient to the fear-inducing situation or object, while simultaneously
teaching relaxation techniques for anxiety management. Successful repeated
exposure leads to extinguishing anxiety for that stimulus. When phobias are
particularly severe, SSRIs can be used with behavioral intervention. Low-dose
SSRI treatment may be especially effective for some children with severe,
refractory choking phobia.
Posttraumatic stress disorder is typically precipitated by an extreme stressor
(see Chapter 14 ). PTSD is an anxiety disorder resulting from the long- and
short-term effects of trauma that cause behavioral and physiologic sequelae in
toddlers, children, and adolescents (Table 38.8 ). Another diagnostic category,
acute stress disorder , reflects that traumatic events often cause acute
symptoms that may or may not resolve. Previous trauma exposure, a history of
other psychopathology, and symptoms of PTSD in parents predict childhood-
onset PTSD. Many adolescent and adult psychopathologic conditions, such as
conduct disorder, depression, and some personality disorders, might relate to
previous trauma. PTSD is also linked to mood disorders and disruptive behavior.
Separation anxiety is common in children with PTSD. The lifetime prevalence of
PTSD by age 18 yr is approximately 6%. Up to 40% show symptoms, but do not
fulfill the diagnostic criteria.
Table 38.8
DSM-5 Diagnostic Criteria for Posttraumatic
Stress Disorder
Posttraumatic Stress Disorder

Note: The following criteria apply to adults, adolescents, and children older
than 6 yr. For children 6 yr and younger, see corresponding criteria below.
A. Exposure to actual or threatened death, serious injury, or sexual violence in
1 (or more) of the following ways:
1. Directly experiencing the traumatic event(s).
2. Witnessing, in person, the event(s) as it occurred to others.
 3. Learning that the traumatic event(s) occurred to a close family
member or close friend. In cases of actual or threatened death of a
family member or friend, the event(s) must have been violent or
accidental.
4. Experiencing repeated or extreme exposure to aversive details of
the traumatic event(s) (e.g., 1st responders collecting human
remains; police officers repeatedly exposed to details of child
abuse).
Note: Criterion A4 does not apply to exposure through electronic media,
television, movies, or pictures, unless this exposure is work related.
B. Presence of 1 (or more) of the following intrusion symptoms associated
with the traumatic event(s), beginning after the traumatic event(s) occurred:
1. Recurrent, involuntary, and intrusive distressing memories of the
traumatic event(s).
Note: In children older than 6 yr, repetitive play may occur in which themes
or aspects of the traumatic event(s) are expressed.
2. Recurrent distressing dreams in which the content and/or effect of
the dream are related to the traumatic event(s).
Note: In children, there may be frightening dreams without recognizable
content.
3. Dissociative reactions (e.g., flashbacks) in which the individual
feels or acts as if the traumatic event(s) were recurring. (Such
reactions may occur on a continuum, with the more extreme
expression being a complete loss or awareness of present
surroundings.)
Note: In children, trauma-specific reenactment may occur in play.
4. Intense or prolonged psychological distress at exposure to internal
or external cues that symbolize or resemble an aspect of the
traumatic event(s).
5. Marked physiologic reactions to internal or external cues that
symbolize or resemble an aspect of the traumatic event(s).
C. Persistent avoidance of stimuli associated with the traumatic event(s),
beginning after the traumatic event(s) occurred, as evidenced by 1 or both
of the following:
1. Avoidance of or efforts to avoid distressing memories, thoughts,
or feelings about or closely associated with the traumatic
 event(s).
2. Avoidance of or efforts to avoid external reminders (people,
places, conversations, activities, objects, situations) that arouse
distressing memories, thoughts, or feelings about or closely
associated with the traumatic event(s).
D. Negative alterations in cognitions and mood associated with the traumatic
event(s), beginning or worsening after the traumatic event(s) occurred, as
evidenced by 2 (or more) of the following:
1. Inability to remember an important aspect of the traumatic
event(s) (typically due to dissociative amnesia and not to other
factors such as head injury, alcohol, or drugs).
2. Persistent and exaggerated negative beliefs or expectations about
oneself, others, or the world (e.g., “I am bad,” “No one can be
trusted,” “The world is completely dangerous,” “My whole
nervous system is permanently ruined”).
3. Persistent, distorted cognitions about the cause or consequences
of the traumatic event(s) that lead the individual to blame
himself/herself or others.
4. Persistent negative emotional state (e.g., fear, horror, anger, guilt,
or shame).
5. Markedly diminished interest or participation in significant
activities.
6. Feelings of detachment or estrangement from others.
7. Persistent inability to experience positive emotions (e.g., inability
to experience happiness, satisfaction, or loving feelings).
E. Marked alterations in arousal and reactivity associated with the traumatic
event(s), beginning or worsening after the traumatic event(s) occurred, as
evidenced by 2 (or more) of the following:
1. Irritable behavior and angry outbursts (with little or no
provocation) typically expressed by verbal or physical aggression
toward people or objects.
2. Reckless or self-destructive behavior.
3. Hypervigilance.
4. Exaggerated startle response.
5. Problems with concentration.
6. Sleep disturbance (e.g., difficulty falling or staying asleep or
restless sleep).
 F. Duration of the disturbance (Criteria B, C, D, and E) is more than 1 mo.
G. The disturbance causes clinically significant distress or impairment in
social, occupational, or other important areas of functioning.
H. The disturbance is not attributable to the physiologic effects of a substance
(e.g., medication, alcohol) or another medical condition.
Specify whether:
With dissociative symptoms: The individual's symptoms meet the criteria
for posttraumatic stress disorder, and in addition, in response to the stressor,
the individual experiences persistent or recurrent symptoms of either of the
following:
1. Depersonalization: Persistent or recurrent experiences of feeling
detached from, and as if one were an outside observer of, one's
mental processes or body (e.g., feeling as though one were in a
dream; feeling a sense of unreality of self or body or of time
moving slowly).
2. Derealization: Persistent or recurrent experiences of unreality of
surroundings (e.g., the world around the individual is experienced
as unreal, dreamlike, distant, or distorted).
Note: To use this subtype, the dissociative symptoms must not be attributable
to the physiologic effects of a substance (e.g., blackouts, behavior during
alcohol intoxication) or another medical condition (e.g., complex partial
seizures).
Specify if:
With delayed expression: If the full diagnostic criteria are not met until at
least 6 mo after the event (although the onset and expression of some
symptoms may be immediate).

Posttraumatic Stress Disorder for Children 6 Yr and Younger

A. In children 6 yr and younger, exposure to actual or threatened death,

serious injury, or sexual violence in 1 (or more) of the following ways:
1. Directly experiencing the traumatic event(s).
2. Witnessing, in person, the event(s) as it occurred to others,
especially primary caregivers.
Note: Witnessing does not include events that are only in electronic media,
 television, movies, or pictures.
3. Learning that the traumatic event(s) occurred to a parent or
caregiving figure.
B. Presence of 1 (or more) of the following intrusion symptoms associated
with the traumatic event(s), beginning after the traumatic event(s) occurred:
1. Recurrent, involuntary, and intrusive distressing memories of the
traumatic event(s).
Note: Spontaneous and intrusive memories may not necessarily appear
distressing and may be expressed as play reenactment.
2. Recurrent distressing dreams in which the content and/or effect of
the dream is related to the traumatic event(s).
Note: It may not be possible to ascertain that the frightening content is related
to the traumatic event.
3. Dissociative reactions (e.g., flashbacks) in which the child feels
or acts as if the traumatic event(s) were recurring. (Such reactions
may occur on a continuum, with the most extreme expression
being a complete loss of awareness of present surroundings.)
Such trauma-specific reenactment may occur in play.
4. Intense or prolonged psychological distress at exposure to internal
or external cues that symbolize or resemble an aspect of the
traumatic event(s).
C. One (or more) of the following symptoms, representing either persistent
avoidance of stimuli associated with the traumatic event(s) or negative
alterations in cognitions and mood associated with the traumatic event(s),
must be present, beginning after the event(s) or worsening after the
event(s):
Persistent Avoidance of Stimuli
1. Avoidance of or efforts to avoid activities, places, or physical
reminders that arouse recollections or the traumatic event(s).
2. Avoidance of or efforts to avoid people, conversations, or
interpersonal situations that around recollections of the traumatic
event(s).
Negative Alterations in Cognitions
3. Substantially increased frequency of negative emotional states
(e.g., fear, guilt, sadness, shame, confusion).
4. Markedly diminished interest or participation in significant
 activities, including constriction of play.
5. Socially withdrawn behavior.
6. Persistent reduction in expression of positive emotions.
D. Alterations in arousal and reactivity associated with the traumatic event(s),
beginning or worsening after the traumatic event(s) occurred, as evidenced
by 2 (or more) of the following:
1. Irritable behavior and angry outbursts (with little or no
provocation), typically expressed as verbal and physical
aggression toward people or objects (including extreme temper
tantrums).
2. Hypervigilance.
3. Exaggerated startle response.
4. Problems with concentration.
5. Sleep disturbance (e.g., difficulty falling asleep or staying asleep
or restless sleep).
E. The duration of the disturbance is more than 1 mo.
F. The disturbance causes clinically significant distress or impairment in
relationships with parents, siblings, peers, or other caregivers or with
school behavior.
G. The disturbance is not attributable to the physiologic effects of a substance
(e.g., medication or alcohol) or another medical condition.
Specify whether:
With dissociative symptoms: The individual's symptoms meet the criteria
for posttraumatic stress disorder, and the individual experiences persistent
or recurrent symptoms of either of the following:
1. Depersonalization: Persistent or recurrent experiences of feeling
detached from, and as if one were an outside observer of, one's
mental processes or body (e.g., feeling as though one were in a
dream; feeling a sense of unreality of self or body or of time
moving slowly).
2. Derealization: Persistent or recurrent experiences of unreality of
surroundings (e.g., the world around the individual is experienced
as unreal, dreamlike, distant, or distorted).
Note: To use this subtype, the dissociative symptoms must not be attributable
to the physiologic effects of a substance (e.g., blackouts, behavior during
alcohol intoxication) or another medical condition (e.g., complex partial
 seizures).
Specify if:
With delayed expression: If the full diagnostic criteria are not met until at
least 6 mo after the event (although the onset and expression of some
symptoms may be immediate).

From the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition,
(Copyright 2013). American Psychiatric Association, pp 271–274.

Events that pose actual or threatened physical injury, harm, or death to the
child, child's caregiver, or others close to the child, and that produce
considerable stress, fear, or helplessness, are required to make the diagnosis of
PTSD. Three clusters of symptoms are also essential for diagnosis:
reexperiencing, avoidance, and hyperarousal. Persistent reexperiencing of the
stressor through intrusive recollections, nightmares, and reenactment in play are
typical responses in children. Persistent avoidance of reminders and numbing of
emotional responsiveness, such as isolation, amnesia, and avoidance, constitute
the 2nd cluster of behaviors. Symptoms of hyperarousal, such as
hypervigilance, poor concentration, extreme startle responses, agitation, and
sleep problems, complete the symptom profile of PTSD. Occasionally, children
regress in some of their developmental milestones after a traumatic event.
Avoidance symptoms are usually observable in younger children, whereas older
children may better describe reexperiencing and hyperarousal symptoms.
Repetitive play involving the event, psychosomatic symptoms, and nightmares
may also be observed.
Initial interventions after a trauma should focus on reunification with a parent
and attending to the child's physical needs in a safe place. Aggressive treatment
of pain, and facilitating a return to comforting routines, including regular sleep,
is indicated. Long-term treatment may include individual, group, school-based,
or family therapy, as well as pharmacotherapy, in selected cases. Individual
treatment involves transforming the child's concept of himself or herself as
victim to that of survivor and can occur through play therapy, psychodynamic
therapy, or CBT. Group work is also helpful for identifying which children might
need more intensive assistance. Goals of family work include helping the child
establish a sense of security, validating the child's emotions, and anticipating
situations when the child will need more support from the family.
 FIG. 39.1 Evaluation of mood disorders. (From Kliegman RM, Lye PS,
Bordini BJ, et al, editors: Nelson pediatric symptom-based diagnosis,
Philadelphia, 2018, Elsevier, p 426.)

Description
Major depressive disorder (MDD) is characterized by a distinct period of at
least 2 wk (an episode ) in which there is a depressed or irritable mood and/or
loss of interest or pleasure in almost all activities that is present for most of the
day, nearly every day (Table 39.1 ). Major depression is associated with
characteristic vegetative and cognitive symptoms, including disturbances in
appetite, sleep, energy, and activity level; impaired concentration; thoughts of
worthlessness or guilt; and suicidal thoughts or actions. Major depression is
considered mild if few or no symptoms in excess of those required to make the
diagnosis are present, and the symptoms are mildly distressing and manageable
and result in minor functional impairment. Major depression is considered severe
if symptoms substantially in excess of those required to make the diagnosis are
present, and the symptoms are highly distressing and unmanageable and
markedly impair function. Moderate major depression is intermediate in severity
between mild and severe.
Table 39.1
DSM-5 Diagnostic Criteria for Major
Depressive Episode
A. Five (or more) of the following symptoms have been present during the
same 2 wk period and represent a change from previous functioning; at
least 1 of the symptoms is either (1) depressed mood or (2) loss of interest
or pleasure.
1. Depressed most of the day, nearly every day, as indicated by
either subjective report (e.g., feels sad, empty, hopeless) or
observation made by others (e.g., appears tearful).
Note: In children and adolescents, can be irritable mood.
2. Markedly diminished interest or pleasure in all, or almost all,
activities most of the day, nearly every day (as indicated by either
subjective account or observation).
3. Significant weight loss when not dieting or weight gain (e.g., a
change of more than 5% of body weight in a month), or decrease
or increase in appetite nearly every day.
Note: In children, consider failure to make expected weight gain.
4. Insomnia or hypersomnia nearly every day.
5. Psychomotor agitation or retardation nearly every day
(observable by others, not merely subjective feelings of
restlessness or being slowed down).
6. Fatigue or loss of energy nearly every day.
7. Feelings of worthlessness or excessive or inappropriate guilt
(which may be delusional) nearly every day (not merely self-
reproach or guilt about being sick).
8. Diminished ability to think or concentrate, or indecisiveness,
nearly every day (either by subjective account or as observed by
others).
9. Recurrent thoughts of death (not just fear of dying), recurrent
suicidal ideation without a specific plan, or a suicide attempt or a
specific plan for committing suicide.
B. The symptoms cause clinically significant distress or impairment in social,
occupational, or other important areas of functioning.
C. The episode is not attributable to the physiologic effects of a substance or
to another medical condition.
Note: Criteria A-C represent a major depressive episode.
D. The occurrence of the major depressive episode is not better explained by
schizoaffective disorder, schizophrenia, schizophreniform disorder,
 delusional disorder, or other specified and unspecified schizophrenia
spectrum and other psychotic disorders.
E. There has never been a manic episode or a hypomanic episode.

From the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition,
(Copyright 2013). American Psychiatric Association, pp 125–126.

Persistent depressive disorder is characterized by depressed or irritable

mood for more days than not, for at least 1 yr (in children and adolescents). As
with major depression, this chronic form of depression is associated with
characteristic vegetative and cognitive symptoms; however, the cognitive
symptoms of persistent depression are less severe (e.g., low self-esteem rather
than worthlessness, hopelessness rather than suicidality). As with major
depression, persistent depressive disorder is characterized as mild, moderate, or
severe (Table 39.2 ).
Table 39.2
DSM-5 Diagnostic Criteria for Persistent
Depressive Disorder
A. Depressed mood for most of the day, for more days than not, as indicated
either by subjective account or observation by others, for at least 2 yr.
Note: In children and adolescents, mood can be irritable and duration must be
at least 1 yr.
B. Presence, while depressed, of 2 (or more) of the following:
1. Poor appetite or overeating.
2. Insomnia or hypersomnia.
3. Low energy or fatigue.
4. Low self-esteem.
5. Poor concentration or difficulty making decisions.
6. Feelings of hopelessness.
C. During the 2 yr period (1 yr for children or adolescents) of the disturbance,
the individual has never been without the symptoms in Criteria A and B for
more than 2 mo at a time.
D. Criteria for a major depressive disorder may be continuously present for 2
 yr.
E. There has never been a manic episode or a hypomanic episode, and criteria
have never been met for cyclothymic disorder.
F. The disturbance is not better explained by a persistent schizoaffective
disorder, schizophrenia, delusional disorder, or other specified or
unspecified schizophrenia spectrum and other psychotic disorder.
G. The symptoms are not attributable to the physiologic effects of a substance
(e.g., a drug of abuse, a medication) or another medical condition (e.g.,
hypothyroidism).
H. The symptoms cause clinically significant distress or impairment in social,
occupational, or other important areas of functioning.
Note: Because the criteria for a major depressive episode include 4 symptoms
that are absent from the symptom list for persistent depressive disorder
(dysthymia), a very limited number of individuals will have depressive
symptoms that have persisted longer than 2 yr but will not meet criteria for
persistent depressive disorder. If full criteria for a major depressive episode
have been met at some point during the current episode of illness, they
should be given a diagnosis of major depressive disorder. Otherwise, a
diagnosis of other specified depressive disorder or unspecified depressive
disorder is warranted.

From the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition,
(Copyright 2013). American Psychiatric Association, pp 168–169.

Overall, the clinical presentation of major and persistent depressive disorders

in children and adolescents is similar to that in adults. The prominence of the
symptoms can change with age: irritability and somatic complaints may be more
common in children, and energy, activity level, appetite, and sleep disturbances
may be more common in adolescents. Because of the cognitive and linguistic
immaturity of young children, symptoms of depression in that age-group may be
more likely to be observed than self-reported.
The core feature of disruptive mood dysregulation disorder (DMDD) is
severe, persistent irritability evident most of the day, nearly every day, for at
least 12 mo in multiple settings (at home, at school, with peers). The irritable
mood is interspersed with frequent (≥3 times/wk) and severe (verbal rages,
physical aggression) temper outbursts (Table 39.3 ). This diagnosis is intended to
characterize more accurately the extreme irritability that some investigators had
considered a developmental presentation of bipolar disorder, and to distinguish
extreme irritability from the milder presentations characteristic of oppositional
defiant disorder (ODD) and intermittent explosive disorder.
Table 39.3
DSM-5 Diagnostic Criteria for Disruptive
Mood Dysregulation Disorder

A. Severe recurrent temper outbursts manifested verbally (e.g., verbal rages)

and/or behaviorally (e.g., physical aggression toward people or property)
that are grossly out of proportion in intensity or duration to the situation or
provocation.
B. The temper outbursts are inconsistent with developmental level.
C. The temper outbursts occur, on average, 3 or more times per week.
D. The mood between temper outbursts is persistently irritable or angry most
of the day, nearly every day, and is observable by others (e.g., parents,
teachers, peers).
E. Criteria A-D have been present for 12 or more months. Throughout that
time, the individual has not had a period lasting 3 or more consecutive
months without all of the symptoms in Criteria A-D.
F. Criteria A and D are present in at least 2 of 3 settings (i.e., at home, at
school, with peers) and are severe in at least 1 of these.
G. The diagnosis should not be made for the first time before age 6 yr or after
age 18 yr.
H. By history or observation, the age at onset of Criteria A-E is before 10 yr.
I. There has never been a distinct period lasting more than 1 day during which
the full symptom criteria, except duration, for a manic or hypomanic
episode have been met.
Note: Developmentally appropriate mood elevation, such as occurs in the
context of a highly positive event or its anticipation, should not be
considered as a symptom of mania or hypomania.
J. The behaviors do not occur exclusively during an episode of major
depressive disorder and are not better explained by another mental disorder
(e.g., autism spectrum disorder, posttraumatic stress disorder, separation
 anxiety disorder, persistent depressive disorder [dysthymia]).
Note: The diagnosis cannot coexist with oppositional defiant disorder,
intermittent explosive disorder, or bipolar disorder, though it can coexist
with others, including major depressive disorder, attention-
deficit/hyperactivity disorder, conduct disorder, and substance use
disorders. Individuals whose symptoms meet criteria for both disruptive
mood dysregulation disorder and oppositional defiant disorder should only
be given the diagnosis of disruptive mood dysregulation disorder. If an
individual has ever experienced a manic or hypomanic episode, the
diagnosis of disruptive mood dysregulation disorder should not be
assigned.
K. The symptoms are not attributable to the physiologic effects of a substance
or to another medical or neurologic condition.

From the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition,
(Copyright 2013). American Psychiatric Association, p. 156.

Other specified/unspecified depressive disorder (subsyndromal depressive

disorder) applies to presentations in which symptoms characteristic of a
depressive disorder are present and cause clinically significant distress or
functional impairment, but do not meet the full criteria for any of the disorders in
this diagnostic class.

Epidemiology
The overall prevalence of parent-reported diagnosis of depressive disorder in the
United States (excluding DMDD) among 3-17 yr old children is approximately
2.1% (current) and 3.9% (ever); the prevalence rate increases to 12.8% (lifetime)
for 12-17 yr olds. The male:female ratio (excluding DMDD) is approximately 1 :
1 during childhood and beginning in early adolescence rises to 1 : 1.5-3.0 in
adulthood.
Based on rates of chronic and severe persistent irritability, which is the core
feature of DMDD, the overall 6 mo to 1 yr prevalence has been estimated in the
2–5% range. In 3 community samples, the 3 mo prevalence rate of DMDD
ranged from 0.8–3.3%, with the highest rates occurring in preschoolers
(although DSM-5 does not permit this diagnosis until age 6 yr). Approximately
pediatric practitioner can begin to assess the onset, duration, context, and
severity of the symptoms and associated dangerousness, distress, and functional
impairment. In the absence of acute dangerousness (e.g., suicidality, psychosis,
substance abuse) and significant distress or functional impairment, the pediatric
practitioner (or co-located behavioral health therapist) can schedule a follow-up
appointment within 1-2 wk to conduct a depression assessment. At this follow-
up visit, to assist with decision-making about appropriate level of care, a
depression-specific screening standardized rating scale can be administered to
assess symptom severity (Table 39.4 ), and additional risk factors can be
explored (see Etiology and Risk Factors earlier).

Table 39.4
Depression-Specific Rating Scales

NUMBER OF
NAME OF INSTRUMENT INFORMANT(S) AGE RANGE
ITEMS
Beck Depression Inventory Youth 13+ yr 21
Beck Depression Inventory for Youth Youth 7-14 yr 20
Center for Epidemiologic Studies-Depression- Youth 6-18 yr 20
Children
Children's Depression Rating Scale-Revised Youth, Parent, 6-18 yr 47
Clinician
Children's Depression Inventory, Second Edition Youth, Parent, 7-17 yr 28/17/12
Teacher
Depression Self-Rating Scale Youth 7-13 yr 18
Mood and Feelings Questionnaire Youth, Parent 7-18 yr 33-34
Patient Health Questionnaire-9 Youth 12/13+ yr 9
Preschool Feelings Checklist Parent 3-5.6 yr 20
PROMIS Emotional Distress-Depressive Youth, Parent Youth: 8-17 8/6
Symptoms yr
Parent: 5-17
yr
Reynolds Child Depression Scale Youth 8-13 yr 30
Reynolds Adolescent Depression Scale, Second Youth 11-20 yr 30
Edition

Treatment decisions should be guided by the understanding that depression in

youth is highly responsive to placebo (50–60%) or brief nonspecific intervention
(15–30%). The goal of treatment is remission, defined as a period of at least 2
wk with no or very few depressive symptoms, and ultimately recovery, defined
as a period of at least 2 mo with no or very few depressive symptoms.
Assessment of remission and recovery can be aided using the depression-specific
standardized rating scales, in which remission is defined as scores below the
39.2
Bipolar and Related Disorders
Heather J. Walter, David R. DeMaso

Description
The bipolar and related disorders include bipolar I, bipolar II, cyclothymic, and
other specified/unspecified bipolar and related disorders, as well as bipolar and
related disorder caused by another medical condition.
A manic episode is characterized by a distinct period of at least 1 wk in which
there is an abnormally and persistently elevated, expansive, or irritable mood
and abnormally and persistently increased goal-directed activity or energy that is
present for most of the day, nearly every day (or any duration if hospitalization is
necessary). The episode is associated with characteristic cognitive and
behavioral symptoms, including disturbances in self-regard, speech, attention,
thought, activity, impulsivity, and sleep (Table 39.5 ). To diagnose bipolar I
disorder , criteria must be met for at least 1 manic episode, and the episode must
not be better explained by a psychotic disorder. The manic episode may have
been preceded and may be followed by hypomanic or major depressive episodes.
Bipolar I disorder is rated as mild, moderate, or severe in the same way as the
depressive disorders (see Description section of Chapter 39.1 ).
Table 39.5
DSM-5 Diagnostic Criteria for a Manic
Episode

A. A distinct period of abnormally and persistently elevated, expansive, or

irritable mood and abnormally and persistently increased goal-directed
activity or energy, lasting at least 1 wk and present most of the day, nearly
every day (or any duration if hospitalization is necessary).
B. During the period of mood disturbance and increased energy or activity, 3
 (or more) of the following symptoms (4 if the mood is only irritable) are
present to a significant degree and represent a noticeable change from usual
behavior:
1. Inflated self-esteem or grandiosity.
2. Decreased need for sleep (e.g., feels rested after only 3 hr of
sleep).
3. More talkative than usual or pressure to keep talking.
4. Flight of ideas or subjective experience that thoughts are racing.
5. Distractibility (i.e., attention too easily drawn to unimportant or
irrelevant external stimuli), as reported or observed.
6. Increase in goal-directed activity (either socially, at work or
school, or sexually) or psychomotor agitation (i.e., purposeless
non-goal-directed activity).
7. Excessive involvement in activities that have a high potential for
painful consequences (e.g., engaging in unrestrained buying
sprees, sexual indiscretions, or foolish business investments).
C. The mood disturbance is sufficiently severe to cause marked impairment in
social or occupational functioning or to necessitate hospitalization to
prevent harm to self or others, or there are psychotic features.
D. The episode is not attributable to the physiologic effects of a substance
(e.g., a drug of abuse, a medication, other treatment) or to another medical
condition.
Note: A full manic episode that emerges during antidepressant treatment (e.g.,
medication, electroconvulsive therapy) but persists at a fully syndromal
level beyond the physiologic effect of that treatment is sufficient evidence
for a manic episode and, therefore, a bipolar I diagnosis.
Note: Criteria A-D constitute a manic episode. At least 1 lifetime manic
episode is required for the diagnosis of bipolar I disorder.

From the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition,
(Copyright 2013). American Psychiatric Association, p 124.

To diagnose bipolar II disorder , criteria must be met for at least 1

hypomanic episode and at least 1 major depressive episode. A hypomanic
episode is similar to a manic episode but is briefer (at least 4 days) and less
severe (causes less impairment in functioning, is not associated with psychosis,
and would not require hospitalization) (Table 39.6 ). In bipolar II disorder, there
must never have been a manic disorder, the episodes must not be better
explained by a psychotic disorder, and the symptoms of depression or the
unpredictability caused by frequent alternation between periods of depression
and hypomania must cause clinically significant distress or functional
impairment. Bipolar II disorder is also rated as mild, moderate, or severe.
Table 39.6
DSM-5 Diagnostic Criteria for a Hypomanic
Episode
A. A distinct period of abnormally and persistently elevated, expansive, or
irritable mood and abnormally and persistently increased goal-directed
activity or energy, lasting at least 4 consecutive days and present most of
the day, nearly every day.
B. During the period of mood disturbance and increased energy or activity, 3
(or more) of the following symptoms (4 if the mood is only irritable) have
persisted, represent a noticeable change from usual behavior, and have been
present to a significant degree:
1. Inflated self-esteem or grandiosity.
2. Decreased need for sleep (e.g., feels rested after only 3 hr of
sleep).
3. More talkative than usual or pressure to keep talking.
4. Flight of ideas or subjective experience that thoughts are racing.
5. Distractibility (i.e., attention too easily drawn to unimportant or
irrelevant external stimuli), as reported or observed.
6. Increase in goal-directed activity (either socially, at work or
school, or sexually) or psychomotor agitation (i.e., purposeless
non-goal-directed activity).
7. Excessive involvement in activities that have a high potential for
painful consequences (e.g., engaging in unrestrained buying
sprees, sexual indiscretions, or foolish business investments).
C. The episode is associated with an unequivocal change in functioning that is
uncharacteristic of the individual when not symptomatic.
D. The disturbance in mood and the change in functioning are observable by
others.
 E. The disturbance is not severe enough to cause marked impairment in social
or occupational functioning or to necessitate hospitalization. If there are
psychotic features, the episode is, by definition, manic.
F. The episode is not attributable to the physiologic effects of a substance
(e.g., a drug of abuse, a medication, other treatment) or to another medical
condition.
Note: A full hypomanic episode that emerges during antidepressant treatment
(e.g., medication, electroconvulsive therapy) but persists at a fully
syndromal level beyond the physiologic effect of that treatment is sufficient
evidence for a hypomanic episode diagnosis. However, caution is indicated
so that 1 or 2 symptoms (particularly increased irritability, edginess, or
agitation following antidepressant use) are not taken as sufficient for
diagnosis of a hypomanic episode, nor necessarily indicative of a bipolar
diathesis.
Note: Criteria A-F constitute a hypomanic episode. Hypomanic episodes are
common in bipolar I disorder but are not required for the diagnosis of
bipolar I disorder.

From the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition,
(Copyright 2013). American Psychiatric Association, p 124.

Cyclothymic disorder is characterized by a period of at least 1 yr (in children

and adolescents) in which there are numerous periods with hypomanic and
depressive symptoms that do not meet criteria for a hypomanic episode or a
major depressive episode, respectively.
Other specified/unspecified bipolar and related disorders (subsyndromal
bipolar disorder ) applies to presentations in which symptoms characteristic of
a bipolar and related disorder are present and cause distress or functional
impairment, but do not meet the full criteria for any of the disorders in this
diagnostic class. Although this diagnosis (formerly known as “bipolar disorder,
not otherwise specified”) had frequently been applied to children with severe
and chronic mood and behavioral dysregulation who did not precisely fit other
diagnostic categories, the empirical support for the validity of this practice has
been sparse. Children who formerly received this diagnosis may meet criteria for
DMDD (see Chapter 39.1 ).
In adolescents, the clinical manifestations of mania are similar to those in
suicidal ideation.
Pediatric practitioners should expect the mental health clinician to evaluate the
presence and degree of suicidality and underlying risk factors. The reliability and
validity of child interviewing are affected by children's level of cognitive
development as well as their understanding of the relationship between their
emotions and behavior. Confirmation of the youth's suicidal behavior can be
obtained from information gathered by interviewing others who know the child
or adolescent. A discrepancy between patient and parent reports is not unusual,
with both children and adolescents being more likely to disclose suicidal
ideation and suicidal actions than their parents.
In the mental health assessment, suicidal ideation can be assessed by explicit
questions posed in a nonjudgmental, noncondescending, matter-of-fact approach.
The Ask Suicide-Screening Questionnaire (ASQ) is a validated 4-item measure
shown in the ED setting to have high sensitivity and negative predictive value in
identifying youth at risk for suicide ideation and behavior: (1) “In the past few
weeks, have you felt that you or your family would be better off if you were
dead?” (2) “In the past few weeks, have you wished you were dead?” (3) “In the
past few weeks, have you been having thoughts about killing yourself?” and (4)
“Have you ever tried to kill yourself?” If a “yes” response is given to any of
these 4 questions, the patient is asked, (5) “Are you having thoughts of killing
yourself right now?” Another common screening test is the Columbia Suicide
Severity Rating Scale (C-SSRS) Screener (Table 40.1 ).
Table 40.1
Columbia Suicide Severity Rating Scale
Screener

1. Have you wished you were dead or wished you could go to sleep and not
wake up?
2. Have you actually had any thoughts about killing yourself?
If “Yes” to 2, answer questions 3, 4, 5, and 6.
If “No” to 2, go directly to question 6.
3. Have you thought about how you might do this?
4. Have you had any intention of acting on these thoughts of killing yourself,
as opposed to you having the thoughts but you definitely would not act
on them?
5. Have you started to work out or worked out the details of how to kill
 yourself? Do you intend to carry out this plan?
6. Have you done anything, started to do anything, or prepared to do
anything to end your life?

Response Protocol to Screening (based on last item answered “Yes”)

Item 1— Mental Health Referral at discharge

Item 2— Mental Health Referral at discharge
Item 3— Care Team Consultation (Psychiatric Nurse) and Patient Safety
Monitor/Procedures
Item 4— Psychiatric Consultation and Patient Safety Monitor/Procedures
Item 5— Psychiatric Consultation and Patient Safety Monitor/Procedures
Item 6— If over 3 months ago, Mental Health Referral at discharge
If 3 months ago or less, Psychiatric Consultation and Patient
Safety Monitor

From Posner K. Columbia Lighthouse Project. The Columbia-Suicide Severity

Rating Scale (C-SSRS) Screener–Recent.
http://www.cssrs.columbia.edu/scales_practice_cssrs.html .

The assessment of a suicidal attempt should include a detailed exploration of

the hours immediately preceding the attempt to identify precipitants as well as
the circumstances of the attempt itself, to understand fully the patient's intent and
potential lethality. The calculation of the level of suicide concern is complex,
requiring a determination across a spectrum of risk. At the low end of the risk
spectrum are youth with thoughts of death or wanting to die, but without suicidal
thoughts, intent, or plan. Those with highly specific suicide plans, preparatory
acts or suicide rehearsals, and clearly articulated intent are at the high end. A
suicidal history, presently impaired judgment (as seen in altered mental states
including depression, mania, anxiety, intoxication, substance abuse, psychosis,
trauma-reactive, hopelessness, rage, humiliation, impulsivity), as well as poor
social support, further exacerbates the heightened risk. Among adolescents who
consider self-harm, those who carry out (enactors ) self-injury are more likely to
have family or friends (or think that their peers) engaged in self-harm, and are
more impulsive than those who only have thoughts of self-harm (ideators ).
For youth who are an imminent danger to themselves (i.e, have active [“I want
challenging because most screening instruments have variable sensitivity and
specificity. In addition, the burden of follow-up mental health evaluations for
those who screen positive has been daunting. Although primary care–feasible
screening tools may be help to identify some adults at increased risk for suicide,
they have, to date, demonstrated limited ability to detect suicide risk in
adolescents.
Prevention strategies in the pediatric medical home include training staff to
recognize and respond to the warning signs of suicide (Table 40.2 ), screening
for and treating depression, educating patients/parents about warning signs for
suicide, and restricting access to modes of lethal self-harm. Young people have
increased rates of suicide attempts and completions if they live in homes where
firearms are present and available. When recommended by their primary care
providers, most parents restrict access of their children to guns and medications.
Pediatric practitioners should consider counseling parents to remove firearms
from the home entirely or securely lock guns and ammunition in separate
locations. Anecdotal evidence suggests youths frequently know where guns and
keys to gun cabinets are kept, even though parents may think they do not. The
same recommendation applies to restricting access to potentially lethal
prescription and nonprescription medications (e.g., containers of >25
acetaminophen tablets) and alcohol. These approaches emphasize the importance
of restriction of access to means for suicide to prevent self-harm.
Table 40.2
Warning Signs of Suicide
Seek help as soon as possible by contacting a mental health professional or by
calling the National Suicide Prevention Lifeline at 1-800-273-TALK if you or
someone you know exhibits any of the following signs:

• Threatening to hurt or kill oneself or talking about wanting to hurt or kill

oneself.
• Looking for ways to kill oneself by seeking access to firearms, available
pills, or other means.
• Talking or writing about death, dying, or suicide when these actions are out
of the ordinary for the person.
• Feeling hopeless.
• Feeling rage or uncontrolled anger or seeking revenge.
 • Acting reckless or engaging in risky activities, seemingly without thinking.
• Feeling trapped, “like there's no way out.”
• Increasing alcohol or drug use.
• Withdrawing from friends, family, and society.
• Feeling anxious, agitated, or unable to sleep, or sleeping all the time.
• Experiencing dramatic mood changes.
• Seeing no reason for living, or having no sense of purpose in life.

Developed by the US Department of Health and Human Services, Substance

Abuse and Mental Health Services Administration (SAMHSA).
https://www.nimh.nih.gov/health/topics/suicide-prevention/suicide-prevention-
studies/warning-signs-of-suicide.shtml .

Screening for suicide in schools is also fraught with problems related to low
specificity of the screening instrument and paucity of referral sites, as well as
poor acceptability among school administrators. Gatekeeper (e.g., student
support personnel) training appears effective in improving skills among school
personnel and is highly acceptable to administrators but has not been shown to
prevent suicide. School curricula (e.g., Signs of Suicide ) have shown some
preventive potential by teaching students to recognize the signs of depression
and suicide in themselves and others and providing them with specific action
steps necessary for responding to these signs. Peer helpers have not generally
been shown to be efficacious.

Bibliography
Barrocas AL, Hankin BL, Young JF, et al. Rates of nonsuicidal
self-injury in youth: age, sex, and behavioral methods in a
community sample. Pediatrics . 2012;130:39–45.
Björkenstam C, Kosidou K, Björkenstam E. Childhood
adversity and risk of suicide: cohort study of 548 721
adolescents and young adults in Sweden. BMJ .
2017;357:j1334.
Bohanna I, Wang X. Media guidelines for the responsible
CHAPTER 41

Eating Disorders
Richard E. Kreipe, Taylor B. Starr

Eating disorders (EDs) are characterized by body dissatisfaction related to

overvaluation of a thin body ideal, associated with dysfunctional patterns of
cognition and weight control behaviors that result in significant biologic,
psychological, and social complications. Although usually affecting white,
adolescent females, EDs also affect males and cross all racial, ethnic, and
cultural boundaries. Early intervention in EDs improves outcome.

Definitions
Anorexia nervosa (AN) involves significant overestimation of body size and
shape, with a relentless pursuit of thinness that, in the restrictive subtype,
typically combines excessive dieting and compulsive exercising. In the binge-
purge subtype, patients might intermittently overeat and then attempt to rid
themselves of calories by vomiting or taking laxatives, still with a strong drive
for thinness (Table 41.1 ).
Table 41.1
DSM-5 Diagnostic Criteria for Anorexia
Nervosa

A. Restriction of energy intake relative to requirements, leading to a

significantly low body weight in the context of age, sex, developmental
trajectory, and physical health. Significantly low weight is defined as a
weight that is less than minimally normal or, for children and adolescents,
less than that minimally expected.
B. Intense fear of gaining weight or of becoming fat, or persistent behavior
that interferes with weight gain, even though at a significantly low weight.
C. Disturbance in the way in which one's body weight or shape is
experienced, undue influence of body weight or shape on self-evaluation,
or persistent lack of recognition of the seriousness of the current low body
weight.

Specify whether:
Restricting type (ICD-10-CM code F50.01): During the last 3
mo, the individual has not engaged in recurrent episodes of
binge eating or purging behavior (i.e., self-induced vomiting or
the misuse of laxatives, diuretics, or enemas). This subtype
describes presentations in which weight loss is accomplished
primarily through dieting, fasting, and/or excessive exercise.
Binge-eating/purging type (ICD-10-CM code F50.02): During
the last 3 mo, the individual has engaged in recurrent episodes
of binge eating or purging behavior (i.e., self-induced vomiting
or the misuse of laxatives, diuretics, or enemas).
Specify if:
In partial remission : After full criteria for anorexia nervosa
were previously met, Criterion A (low body weight) has not
been met for a sustained period, but either Criterion B (intense
fear of gaining weight or becoming fat or behavior that
interferes with weight gain) or Criterion C (disturbances in self-
perception of weight and shape) is still met.
In full remission : After full criteria for anorexia nervosa were
previously met, none of the criteria has been met for a sustained
period of time.
Specify current severity:
The minimum level of severity is based, for adults, on current
body mass index (BMI) (see below) or, for children and
adolescents, on BMI percentile. The ranges below are derived
from World Health Organization categories for thinness in
adults; for children and adolescents, corresponding BMI
percentiles should be used. The level of severity may be
increased to reflect clinical symptoms, the degree of functional
disability, and the need for supervision.
 Mild : BMI ≥ 17 kg/m2
Moderate : BMI 16-16.99 kg/m2
Severe : BMI 15-15.99 kg/m2
Extreme : BMI < 15 kg/m2

From the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition,
(Copyright 2013). American Psychiatric Association, pp 338–339.

Bulimia nervosa (BN) is characterized by episodes of eating large amounts of

food in a brief period, followed by compensatory vomiting, laxative use,
exercise, or fasting to rid the body of the effects of overeating in an effort to
avoid obesity (Table 41.2 ).
Table 41.2
DSM-5 Diagnostic Criteria for Bulimia
Nervosa
A. Recurrent episodes of binge eating. An episode of binge eating is
characterized by both of the following:
1. Eating, in a discrete period of time (e.g., within any 2 hr period),
an amount of food that is definitely larger than what most
individuals would eat in a similar period of time under similar
circumstances.
2. A sense of lack of control over eating during the episode (e.g., a
feeling that one cannot stop eating or control what or how much
one is eating).
B. Recurrent inappropriate compensatory behaviors in order to prevent
weight gain, such as self-induced vomiting; misuse of laxatives, diuretics,
or other medications; fasting; or excessive exercise.
C. The binge eating and inappropriate compensatory behaviors both occur, on
average, at least once a week for 3 mo.
D. Self-evaluation is unduly influenced by body shape and weight.
E. The disturbance does not occur exclusively during episodes of anorexia
nervosa.
 Specify if:
In partial remission : After full criteria for bulimia nervosa were
previously met, some, but not all, of the criteria have been met for a
sustained period of time.
In full remission : After full criteria for bulimia nervosa were previously
met, none of the criteria has been met for a sustained period of time.
Specify current severity:
The minimum level of severity is based on the frequency of
inappropriate compensatory behaviors (see below). The level of
severity may be increased to reflect other symptoms and the
degree of functional disability.
Mild : An average of 1-3 episodes of inappropriate
compensatory behaviors per week.
Moderate : An average of 4-7 episodes of
inappropriate compensatory behaviors per week.
Severe : An average of 8-13 episodes of inappropriate
compensatory behaviors per week.
Extreme : An average of 14 or more episodes of
inappropriate compensatory behaviors per week.

From the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition,
(Copyright 2013). American Psychiatric Association, p 345.

Children and adolescents with EDs may not fulfill criteria for AN or BN in the
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5)
and may fall into a subcategory of atypical anorexia nervosa, or a more
appropriately defined category of avoidant/ restrictive food intake disorder
(ARFID). In these conditions, food intake is restricted or avoided because of
adverse feeding or eating experiences or the sensory qualities of food, resulting
in significant unintended weight loss or nutritional deficiencies and problems
with social interactions (Table 41.3 ).
Table 41.3
DSM-5 Diagnostic Criteria for
Avoidant/Restrictive Food Intake Disorder
 A. An eating or feeding disturbance (e.g., apparent lack of interest in eating or
food; avoidance based on the sensory characteristics of food; concern about
aversive consequences of eating) as manifested by persistent failure to meet
appropriate nutritional and/or energy needs associated with one (or more)
of the following:
1. Significant weight loss (or failure to achieve expected weight
gain or faltering growth in children).
2. Significant nutritional deficiency.
3. Dependence on enteral feeding or oral nutritional supplements.
4. Marked interference with psychosocial functioning.
B. The disturbance is not better explained by lack of available food or by an
associated culturally sanctioned practice.
C. The eating disturbance does not occur exclusively during the course of
anorexia nervosa or bulimia nervosa, and there is no evidence of a
disturbance in the way in which one's body weight or shape is experienced.
D. The eating disturbance is not attributable to a concurrent medical condition
or not better explained by another mental disorder. When the eating
disturbance occurs in the context of another condition or disorder, the
severity of the eating disturbance exceeds that routinely associated with the
condition or disorder and warrants additional clinical attention.

Specify if:
In remission : After full criteria for avoidant/restrictive food
intake disorder were previously met, the criteria have not been
met for a sustained period of time.

From the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition,
(Copyright 2013). American Psychiatric Association, p 334.

Binge eating disorder (BED) , in which binge eating is not followed

regularly by any compensatory behaviors (vomiting, laxatives), is a stand-alone
category in DSM-5 but shares many features with obesity (see Chapter 60 ).
Eating disorder–not otherwise specified (ED-NOS) , often called “disordered
eating,” can worsen into full syndrome EDs.
Clinical Manifestations
Except for ARFID, in which weight loss is unintentional, a central feature of
EDs is the overestimation of body size, shape, or parts (e.g., abdomen, thighs)
leading to intentional weight control practices to reduce weight (AN) or prevent
weight gain (BN). Associated practices include severe restriction of caloric
intake and behaviors intended to reduce the effect of calories ingested, such as
compulsive exercising or purging by inducing vomiting or taking laxatives.
Eating and weight loss habits commonly found in EDs can result in a wide range
of energy intake and output, the balance of which leads to a wide range in
weight, from extreme loss of weight in AN to fluctuation around a normal to
moderately high weight in BN. Reported eating and weight control habits thus
inform the initial primary care approach (Table 41.4 ).

Table 41.4
Eating and Weight Control Habits Commonly Found in
Children and Adolescents With an Eating Disorder (ED)

CLINICAL COMMENTS REGARDING ED

PROMINENT FEATURE
HABIT HABITS
Anorexia Nervosa Bulimia Nervosa Anorexia Nervosa Bulimia Nervosa
Overall Inadequate energy Variable, but Consistent inadequate caloric Inconsistent balance
intake (calories), although calories normal to intake leading to wasting of of intake, exercise
volume of food and high; intake in the body is an essential feature and vomiting, but
beverages may be high binges is often of diagnosis severe caloric
because of very low “forbidden” food or restriction is short-
caloric density of intake drink that differs lived
as a result of “diet” and from intake at
nonfat choices meals
Food Counts and limits Aware of Obsessive-compulsive Choices less
calories, especially calories and attention to nutritional data on structured, with more
from fat; emphasis fat, but less food labels and may have frequent diets
on “healthy food regimented in “logical” reasons for food
choices” with avoidance than choices in highly regimented
reduced caloric AN pattern, such as sports
density Frequent participation or family history
Monotonous, dieting of lipid disorder
limited “good” food interspersed
choices, often with
leading to overeating,
vegetarian or vegan often triggered
diet by depression,
Strong feelings of isolation, or
guilt after eating anger
more than planned
 leads to exercise
and renewed dieting
Beverages Water or other low- or Variable, diet soda Fluids often restricted to avoid Fluids ingested to aid
no-calorie drinks; nonfat common; may drink weight gain vomiting or replace
milk alcohol to excess losses
Meals Consistent schedule Meals less Rigid adherence to “rules” Elimination of a meal
and structure to regimented and governing eating leads to following a binge-
meal plan planned than in AN; sense of control, confidence, purge only reinforces
Reduced or more likely and mastery the drive for binge
eliminated caloric impulsive and later in the day
content, often unregulated, often
starting with eliminated
breakfast, then following a binge-
lunch, then dinner purge episode
Volume can
increase with fresh
fruits, vegetables,
and salads as
primary food
sources
Snacks Reduced or eliminated Often avoided in Snack foods removed early Snack “comfort
from meal plan meal plans, but then because “unhealthy” foods” can trigger a
impulsively eaten binge
Dieting Initial habit that Initial dieting gives Distinguishing between Dieting tends to be
becomes way to chaotic healthy meal planning with impulsive and short-
progressively eating, often reduced calories and dieting in lived, with “diets”
restrictive, although interpreted by the ED may be difficult often resulting in
often appearing patient as evidence unintended weight
superficially of being “weak” or gain
“healthy” “lazy”
Beliefs and “rules”
about the patient's
idiosyncratic
nutritional
requirements and
response to foods
are strongly held
Binge None in restrictive Essential Often “subjective” (more than Relieves emotional
eating subtype, but an essential feature, often planned but not large) distress, may be
feature in binge-purge secretive planned
subtype Shame and
guilt prominent
afterward
Exercise Characteristically Less May be difficult to distinguish Males often use
obsessive- predictable active thin vs ED exercise as means of
compulsive, May be “purging”
ritualistic, and athletic, or may
progressive avoid exercise
May excel in dance, entirely
long-distance
running
Vomiting Characteristic of Most common Physiologic and emotional Strongly “addictive”
binge-purge subtype habit intended instability prominent and self-punishing,
May chew, then spit to reduce but does not
out, rather than effects of eliminate calories
 swallow, food as a overeating ingested—many still
variant Can occur after absorbed
meal as well as
a binge
Laxatives If used, generally to Second most Physiologic and emotional Strongly “addictive,”
relieve constipation in common habit used instability prominent self-punishing, but
restrictive subtype, but to reduce or avoid ineffective means to
as a cathartic in binge- weight gain, often reduce weight
purge subtype used in increasing (calories are
doses for cathartic absorbed in small
effect intestine, but
laxatives work in
colon)
Diet pills Very rare, if used; more Used to either Use of diet pills implies Control over eating
common in binge-purge reduce appetite or inability to control eating may be sought by
subtype increase any means
metabolism
AN, Anorexia nervosa; BN, bulimia nervosa.

Although weight control patterns guide the initial pediatric approach, an

assessment of common symptoms and findings on physical examination is
essential to identify targets for intervention. When reported symptoms of
excessive weight loss (feeling tired and cold; lacking energy; orthostasis;
difficulty concentrating) are explicitly linked by the clinician to their associated
physical signs (hypothermia with acrocyanosis and slow capillary refill; loss of
muscle mass; bradycardia with orthostasis), it becomes more difficult for the
patient to deny that a problem exists. Furthermore, awareness that bothersome
symptoms can be eliminated by healthier eating and activity patterns can
increase a patient's motivation to engage in treatment. Tables 41.5 and 41.6
detail common symptoms and signs that should be addressed in a pediatric
assessment of a suspected ED.

Table 41.5
Symptoms Commonly Reported by Patients With an Eating
Disorder (ED)

DIAGNOSIS CLINICAL COMMENTS

SYMPTOMS REGARDING ED
Anorexia Nervosa Bulimia Nervosa SYMPTOMS
Body image Feels fat, even with extreme Variable body image Challenging patient's body
emaciation, often with specific body distortion and image is both ineffective and
distortions (e.g., stomach, thighs); dissatisfaction, but countertherapeutic clinically
strong drive for thinness, with self- drive for thinness is Accepting patient's expressed
efficacy closely tied to appraisal of less than desire to body image but noting its
body shape, size, and/or weight avoid gaining weight discrepancy with symptoms
and signs reinforces concept
 that patient can “feel” fat but
also “be” too thin and
unhealthy
Metabolism Hypometabolic symptoms Variable, depending Symptoms are evidence of
include feeling cold, tired, and on balance of intake body's “shutting down” in an
weak and lacking energy and output and attempt to conserve calories
May be both bothersome and hydration with an inadequate diet
reinforcing Emphasizing reversibility of
symptoms with healthy
eating and weight gain can
motivate patients to
cooperate with treatment
Skin Dry skin, delayed healing, easy No characteristic Skin lacks good blood flow
bruising, gooseflesh symptom; self- and ability to heal in low
Orange-yellow skin on hands injurious behavior weight
may be seen Carotenemia with large
intake of β-carotene foods;
reversible
Hair Lanugo-type hair growth on face No characteristic Body hair growth conserves
and upper body symptom energy
Slow growth and increased loss Scalp hair loss can worsen
of scalp hair during refeeding “telogen
effluvium” (resting hair is
replaced by growing hair)
Reversible with continued
healthy eating
Eyes No characteristic symptom Subconjunctival Caused by increased intrathoracic
hemorrhage pressure during vomiting
Teeth No characteristic symptom Erosion of Intraoral stomach acid resulting
dental enamel from vomiting etches dental
erosion enamel, exposing softer dental
Decay, fracture, elements
and loss of teeth
Salivary glands No characteristic symptom Enlargement (no to Caused by chronic binge eating
mild tenderness) and induced vomiting, with
parotid enlargement more
prominent than submandibular;
reversible
Heart Dizziness, fainting in restrictive Dizziness, fainting, Dizziness and fainting due to
subtype palpitations postural orthostatic
Palpitations more common in tachycardia and
binge-purge subtype dysregulation at
hypothalamic and cardiac
level with weight loss, as a
result of hypovolemia with
binge-purge
Palpitations and arrhythmias
often caused by electrolyte
disturbance
Symptoms reverse with
weight gain and/or cessation
of binge-purge

Abdomen Early fullness and discomfort Discomfort after Weight loss is associated
with eating a binge with reduced volume and
 Constipation Cramps and tone of GI tract musculature,
Perceives contour as “fat,” often diarrhea with especially the stomach
preferring well-defined laxative abuse Laxatives may be used to
abdominal musculature relieve constipation or as a
cathartic
Symptom reduction with
healthy eating can take
weeks to occur
Extremities and Cold, blue hands and feet No Energy-conserving low body
musculoskeletal characteristic temperature with slow blood
symptoms flow most notable
Self-cutting or peripherally
burning on Quickly reversed with
wrists or arms healthy eating
Nervous system No characteristic symptom No characteristic Neurologic symptoms suggest
symptom diagnosis other than ED
Mental status Depression, anxiety, obsessive- Depression; PTSD; Underlying mood
compulsive symptoms, alone or in borderline disturbances can worsen with
combination personality disorder dysfunctional weight control
traits practices and can improve
with healthy eating
AN patients might report
emotional “numbness” with
starvation preferable to
emotionality associated with
healthy eating
AN, Anorexia nervosa; BN, bulimia nervosa; ED, eating disorder; GI, gastrointestinal; PTSD,
posttraumatic stress disorder.

Table 41.6
Signs Commonly Found in Patients With Eating Disorder
(ED) Relative to Prominent Feature of Weight Control

PROMINENT FEATURE
PHYSICAL CLINICAL COMMENTS
SIGN Binge RELATED TO ED SIGNS
Restrictive Intake
Eating/Purging
General Thin to cachectic, depending on Thin to overweight, Examine in hospital gown
appearance balance of intake and output depending on the Weight loss more rapid with
Might wear bulky clothing to balance of intake reduced intake and excessive
hide thinness and might resist and output through exercise
being examined various means Binge eating can result in
large weight gain, regardless
of purging behavior
Appearance depends on
balance of intake and output
and overall weight control
habits
Weight Low and falling (if previously Highly Weigh in hospital gown with
overweight, may be normal or high); variable, no underwear, after voiding
may be falsely elevated if patient depending on (measure urine SG)
 drinks fluids or adds weights to body balance of Remain in gown until physical
before being weighed intake and exam completed to identify
output and state possible fluid loading (low
of hydration urine SG, palpable bladder) or
Falsification of adding weights to body
weight is
unusual
Metabolism Hypothermia: temp <35.5°C Variable, but Hypometabolism related to
(95.9°F), pulse <60 beats/min hypometabolic state disruption of hypothalamic
Slowed psychomotor response is less common than control mechanisms as a result
with very low core temperature in AN of weight loss
Signs of hypometabolism
(cold skin, slow capillary
refill, acrocyanosis) most
evident in hands and feet,
where energy conservation is
most active
Skin Dry Calluses over Carotenemia with large intake
Increased prominence of hair proximal knuckle of β-carotene foods
follicles joints of hand Russell's sign: maxillary
Orange or yellow hands (Russell's sign) incisors abrasion develops
into callus with chronic digital
pharyngeal stimulation,
usually on dominant hand
Hair Lanugo-type hair growth on face No characteristic Body hair growth conserves
and upper body sign energy
Scalp hair loss, especially Scalp hair loss “telogen
prominent in parietal region effluvium” can worsen weeks
after refeeding begins, as hair
in resting phase is replaced by
growing hair
Eyes No characteristic sign Subconjunctival Increased intrathoracic pressure
hemorrhage during vomiting
Teeth No characteristic sign Eroded dental Perimolysis, worse on lingual
enamel and surfaces of maxillary teeth, is
decayed, fractured, intensified by brushing teeth
missing teeth without preceding water rinse
Salivary glands No characteristic sign Enlargement, Parotid > submandibular
relatively nontender involvement with frequent and
chronic binge eating and induced
vomiting
Throat No characteristic sign Absent gag reflex Extinction of gag response with
repeated pharyngeal stimulation
Heart Bradycardia, hypotension, and Hypovolemia if Changes in AN resulting from
orthostatic pulse differential >25 dehydrated central hypothalamic and
beats/min intrinsic cardiac function
Orthostatic changes less
prominent if athletic, more
prominent if associated with
purging
Abdomen Scaphoid, organs may be palpable Increased bowel Presence of organomegaly
but not enlarged, stool-filled left sounds if recent requires investigation to
lower quadrant laxative use determine cause
Constipation prominent with
weight loss
 Extremities and Cold, acrocyanosis, slow No characteristic Signs of hypometabolism
musculoskeletal capillary refill sign, but may have (cold) and cardiovascular
system Edema of feet rebound edema after dysfunction (slow capillary
Loss of muscle, subcutaneous, stopping chronic refill and acrocyanosis) in
and fat tissue laxative use hands and feet
Edema, caused by capillary
fragility more than
hypoproteinemia in AN, can
worsen in early phase of
refeeding
Nervous system No characteristic sign No characteristic Water loading before weigh-ins
sign can cause acute hyponatremia
Mental status Anxiety about body image, Depression, Mental status often improves with
irritability, depressed mood, evidence of PTSD, healthier eating and weight; SSRIs
oppositional to change more likely suicidal only shown to be effective for BN
than AN
AN, Anorexia nervosa; BN, bulimia nervosa; PTSD, posttraumatic stress disorder; SG, specific
gravity; SSRIs, selective serotonin reuptake inhibitors.

Differential Diagnosis
In addition to identifying symptoms and signs that deserve targeted intervention
for patients who have an ED, a comprehensive history and physical examination
are required to rule out other conditions in the differential diagnosis. Weight loss
can occur in any condition with increased catabolism (e.g., hyperthyroidism,
malignancy, occult chronic infection) or malabsorption (e.g., inflammatory
bowel disease, celiac disease) or in other disorders (Addison disease, type 1
diabetes mellitus, stimulant abuse), but these illnesses are generally associated
with other findings and are not usually associated with decreased caloric intake.
Patients with inflammatory bowel disease can reduce intake to minimize
abdominal cramping; eating can cause abdominal discomfort and early satiety in
AN because of gastric atony associated with significant weight loss, not
malabsorption. Likewise, signs of weight loss in AN might include hypothermia,
acrocyanosis with slow capillary refill, and neutropenia similar to some features
of sepsis, but the overall picture in EDs is one of relative cardiovascular stability
compared with sepsis. Endocrinopathies are also in the differential of EDs.
With BN, voracious appetite in the face of weight loss might suggest diabetes
mellitus, but blood glucose levels are normal or low in EDs. Adrenal
insufficiency mimics many physical symptoms and signs found in restrictive AN
but is associated with elevated potassium levels and hyperpigmentation. Thyroid
disorders may be considered, because of changes in weight, but the overall
presentation of AN includes symptoms of both underactive and overactive
limiting foods that might trigger a binge.
When initiating treatment of an ED in a primary care setting, the clinician
should be aware of common cognitive patterns. Patients with AN typically have
all-or-none thinking (related to perfectionism) with a tendency to overgeneralize
and jump to catastrophic conclusions, while assuming that their body is
governed by rules that do not apply to others. These tendencies lead to the
dichotomization of foods into good or bad categories, having a day ruined
because of one unexpected event, or choosing foods based on rigid self-imposed
restrictions. These thoughts may be related to neurocircuitry and
neurotransmitter abnormalities associated with executive function and rewards.
Weight loss in the absence of body shape, size, or weight concerns should raise
suspicion about ARFID, because the emotional distress associated with “forced”
eating is not associated with gaining weight, but with the neurosensory
experience of eating.
A standard nutritional balance of 15–20% calories from protein, 50–55% from
carbohydrate, and 25–30% from fat is appropriate. The fat content may need to
be lowered to 15–20% early in the treatment of AN because of continued fat
phobia. With the risk of low BMD in patients with AN, calcium and vitamin D
supplements are often needed to attain the recommended 1,300 mg/day intake of
calcium. Refeeding can be accomplished with frequent small meals and snacks
consisting of a variety of foods and beverages (with minimal diet or fat-free
products), rather than fewer high-volume high-calorie meals. Some patients find
it easier to take in part of the additional nutrition as canned supplements
(medicine) rather than food. Regardless of the source of energy intake, the risk
for refeeding syndrome (see Complications earlier) increases with the degree of
weight loss and the rapidity of caloric increases. Therefore, if the weight has
fallen below 80% of expected weight for height, refeeding should proceed
carefully (not necessarily slowly) and possibly in the hospital (Table 41.7 ).
Table 41.7
Potential Indications for Inpatient Medical
Hospitalization of Patients With Anorexia
Nervosa
Physical and Laboratory

Heart rate <50 beats/min

 Other cardiac rhythm disturbances
Blood pressure <80/50 mm Hg
Postural hypotension resulting in >10 mm Hg decrease or >25 beats/min
increase
Hypokalemia
Hypophosphatemia
Hypoglycemia
Dehydration
Body temperature <36.1°C (97°F)
<80% healthy body weight
Hepatic, cardiac, or renal compromise

Psychiatric

Suicidal intent and plan

Very poor motivation to recover (in family and patient)
Preoccupation with ego-syntonic thoughts
Coexisting psychiatric disorders

Miscellaneous

Requires supervision after meals and while using the restroom

Failed day treatment

Patients with AN tend to have a highly structured day with restrictive intake,
in contrast to BN, which is characterized by a lack of structure, resulting in
chaotic eating patterns and binge-purge episodes. All patients with AN, BN, or
ED-NOS benefit from a daily structure for healthy eating that includes 3 meals
and at least 1 snack a day, distributed evenly over the day, based on balanced
meal planning. Breakfast deserves special emphasis because it is often the first
meal eliminated in AN and is often avoided the morning after a binge-purge
episode in BN. In addition to structuring meals and snacks, patients should plan
structure in their activities. Although overexercising is common in AN,
completely prohibiting exercise can lead to further restriction of intake or to
surreptitious exercise; inactivity should be limited to situations in which weight
loss is dramatic or there is physiologic instability. Also, healthy exercise (once a
CHAPTER 42

Disruptive, Impulse-Control, and

Conduct Disorders
Heather J. Walter, David R. DeMaso

The disruptive, impulse-control, and conduct disorders are interrelated sets of

psychiatric symptoms characterized by a core deficit in self-regulation of anger,
aggression, defiance, and antisocial behaviors. The disruptive, impulse-control,
and conduct disorders include oppositional defiant, intermittent explosive,
conduct, other specified/unspecified disruptive/impulse control/conduct, and
antisocial personality disorders, as well as pyromania and kleptomania.

Description
Oppositional defiant disorder (ODD) is characterized by a pattern lasting at
least 6 mo of angry, irritable mood, argumentative/defiant behavior, or
vindictiveness exhibited during interaction with at least 1 individual who is not a
sibling (Table 42.1 ). For preschool children, the behavior must occur on most
days, whereas in school-age children, the behavior must occur at least once a
week. The severity of the disorder is considered mild if symptoms are confined
to only 1 setting (e.g., at home, at school, at work, with peers), moderate if
symptoms are present in at least 2 settings, and severe if symptoms are present in
≥4 settings.
Table 42.1
DSM-5 Diagnostic Criteria for Oppositional
Defiant Disorder
A. A pattern of angry/irritable mood, argumentative/defiant behavior, or
 vindictiveness lasting at least 6 mo as evidenced by at least 4 symptoms
from any of the following categories, and exhibited during interaction with
at least 1 individual who is not a sibling:
Angry/Irritable Mood
1. Often loses temper.
2. Is often touchy or easily annoyed.
3. Is often angry and resentful.
Argumentative/Defiant Behavior
4. Often argues with authority figures or, for children
and adolescents, with adults.
5. Often actively defies or refuses to comply with
requests from authority figures or with rules.
6. Often deliberately annoys others.
7. Often blames others for his or her mistakes or
misbehavior.
Vindictiveness
8. Has been spiteful or vindictive at least twice within
the past 6 mo.
Note: The persistence and frequency of these
behaviors should be used to distinguish a behavior
that is within normal limits from a behavior that is
symptomatic. For children younger than 5 yr, the
behavior should occur on most days for a period of at
least 6 mo unless otherwise noted (Criterion A8). For
individuals 5 yr or older, the behavior should occur at
least once per week for at least 6 mo, unless
otherwise noted (Criterion A8). While these
frequency criteria provide guidance on a minimal
level of frequency to define symptoms, other factors
should be considered, such as whether the frequency
and intensity of the behaviors are outside a range that
is normative for the individual's developmental level,
gender, and culture.
B. The disturbance in behavior is associated with distress in the individual or
others in his or her immediate social context (e.g., family, peer group, work
colleagues), or it impacts negatively on social, educational, occupational, or
other important areas of functioning.
 C. The behaviors do not occur exclusively during the course of a psychotic,
substance use, depressive, or bipolar disorder. Also, the criteria are not met
for disruptive mood dysregulation disorder.

From the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition,
(Copyright 2013). American Psychiatric Association, pp 462–463.

Intermittent explosive disorder (IED) is characterized by recurrent verbal or

physical aggression that is grossly disproportionate to the provocation or to any
precipitating psychosocial stressors (Table 42.2 ). The outbursts, which are
impulsive and/or anger-based rather than premeditated and/or instrumental,
typically last <30 min and frequently occur in response to a minor provocation
by a close intimate.
Table 42.2
DSM-5 Diagnostic Criteria for Intermittent
Explosive Disorder
A. Recurrent behavioral outbursts representing a failure to control aggressive
impulses as manifested by either of the following:
1. Verbal aggression (e.g., temper tantrums, tirades, verbal
arguments or fights) or physical aggression toward property,
animals, or other individuals, occurring twice weekly, on average,
for a period of 3 mo. The physical aggression does not result in
damage or destruction of property and does not result in physical
injury to animals or other individuals.
2. Three behavioral outbursts involving damage or destruction of
property and/or physical assault involving physical injury against
animals or other individuals occurring with a 12 mo period.
B. The magnitude of aggressiveness expressed during the recurrent outbursts
is grossly out of proportion to the provocation or to any precipitating
psychosocial stressors.
C. The recurrent aggressive outbursts are not premeditated (i.e., they are
impulsive and/or anger-based) and are not committed to achieve some
tangible objective (e.g., money, power, intimidation).
D. The recurrent aggressive outbursts cause either marked distress in the
 individual or impairment in occupational or interpersonal functioning, or as
associated with financial or legal consequences.
E. Chronological age is at least 6 yr (or equivalent developmental level).
F. The recurrent aggressive outbursts are not better explained by another
mental disorder (e.g., major depressive disorder, bipolar disorder, disruptive
mood dysregulation disorder, a psychotic disorder, antisocial personality
disorder, borderline personality disorder) and are not attributable to another
medical condition (e.g., head trauma, Alzheimer disease) or to the
physiologic effects of a substance (e.g., a drug of abuse, a medication). For
children ages 6-18 yr, aggressive behavior that occurs as part of an
adjustment disorder should not be considered for this diagnosis.
Note: This diagnosis can be made in addition to the diagnosis of attention-
deficit/hyperactivity disorder, conduct disorder, oppositional defiant
disorder, or autism spectrum disorder when recurrent impulsive aggressive
outbursts are in excess of those usually seen in these disorders and warrant
clinical attention.

From the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition,
(Copyright 2013). American Psychiatric Association, p 466.

Conduct disorder (CD) is characterized by a repetitive and persistent pattern

over at least 12 mo of serious rule-violating behavior in which the basic rights of
others or major societal norms or rules are violated (Table 42.3 ). The symptoms
of CD are divided into 4 major categories: aggression to people and animals,
destruction of property, deceitfulness or theft, and serious rule violations (e.g.,
truancy, running away). Three subtypes of CD (which have different prognostic
significance) are based on the age of onset: childhood-onset type, adolescent-
onset type, and unspecified. A small proportion of individuals with CD exhibit
characteristics (lack of remorse/guilt, callous/lack of empathy, unconcerned
about performance, shallow/deficient affect) that qualify for the “with limited
prosocial emotions” specifier. CD is classified as mild when few if any
symptoms over those required for the diagnosis are present, and the symptoms
cause relatively minor harm to others. CD is classified as severe if many
symptoms over those required for the diagnosis are present, and the symptoms
cause considerable harm to others. Moderate severity is intermediate between
mild and severe.
Table 42.3
DSM-5 Diagnostic Criteria for Conduct
Disorder

A. A repetitive and persistent pattern of behavior in which the basic rights of

others or major age-appropriate societal norms or rules are violated, as
manifested by the presence of at least 3 of the following 15 criteria in the
past 12 mo from any of the categories below, with at least 1 criterion
present in the past 6 mo:
Aggression to People and Animals
1. Often bullies, threatens, or intimidates others.
2. Often initiates physical fights.
3. Has used a weapon that can cause serious physical
harm to others (e.g., a bat, brick, broken bottle, knife,
gun).
4. Has been physically cruel to people.
5. Has been physically cruel to animals.
6. Has stolen while confronting a victim (e.g., mugging,
purse snatching, extortion, armed robbery).
7. Has forced someone into sexual activity.
Destruction of Property
8. Has deliberately engaged in fire setting with the
intention of causing serious damage.
9. Has deliberately destroyed others' property (other than
by fire setting).
Deceitfulness or Theft
10. Has broken into someone else's house, building, or
car.
11. Often lies to obtain good or favors or to avoid
obligations (i.e., “cons” others).
12. Has stolen items of nontrivial value without
confronting a victim (e.g., shoplifting, but without
breaking and entering; forgery).
Serious Violations of Rules
13. Often stays out at night despite parental prohibitions,
beginning before age 13 yr.
 14. Has run away from home overnight at least twice
while living in the parental or parental surrogate home,
or once without returning for a lengthy period.
15. Is often truant from school, beginning before age 13
yr.
B. The disturbance in behavior causes clinically significant impairment in
social, academic, or occupational functioning.
C. If the individual is age 18 yr or older, criteria are not met for antisocial
personality disorder.

From the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition,
(Copyright 2013). American Psychiatric Association, pp 469–471.

Other specified/unspecified disruptive/impulse-control/CD (sub-

syndromal disorder) applies to presentations in which symptoms characteristic
of the disorders in this class are present and cause clinically significant distress
or functional impairment, but do not meet full diagnostic criteria for any of the
disorders in this class.

Epidemiology
The prevalence of ODD is approximately 3%, and in preadolescents is more
common in males than females (1.4 : 1). One-year prevalence rates for IED and
CD approximate 3% and 5%, respectively. For CD, prevalence rates rise from
childhood to adolescence and are higher among males than females. The
prevalence of these disorders has been shown to be higher in lower
socioeconomic classes. This class of disorders constitutes the most frequent
referral problem for youth, accounting for one third to one half of all cases seen
in mental health clinics. Racial/ethnic minority youth with these disorders utilize
specialty mental health services at lower rates than their white peers.

Clinical Course
Oppositional behavior can occur in all children and adolescents at times,
particularly during the toddler and early teenage periods when establishing
autonomy and independence are normative developmental tasks. Oppositional
Table 42.4
Anger/Aggression-Specific Screening Instruments

NAME OF INSTRUMENT INFORMANT(S) AGE RANGE NUMBER OF ITEMS

Children's Aggression Scale Parent, Teacher 5-18 yr 33 (P), 23 (T)
Eyberg Child Behavior Inventory Parent 2-16 yr 36
Outburst Monitoring Scale Parent 12-17 yr 20
Sutter-Eyberg Student Behavior Inventory–Revised Teacher 2-16 yr 38
Vanderbilt ADHD Diagnostic Rating Scales Parent, Teacher 6-12 yr 55 (P), 43 (T)

For mild symptoms (manageable by the parent and not functionally impairing)
and in the absence of major risk factors (homicidality, assaultiveness, psychosis,
substance use, child maltreatment, parental psychopathology, or severe family
dysfunction), guided self-help (anticipatory guidance) with watchful waiting
and scheduled follow-up may suffice. Guided self-help can include provision of
educational materials (pamphlets, books, videos, workbooks, internet sites) that
provide information to the youth about dealing with anger-provoking situations,
and advice to parents about strengthening the parent–child relationship, effective
parenting strategies, and the effects of adverse environmental exposures on the
development of behavior problems. In a Cochrane review, media-based
parenting interventions had a moderate positive effect on child behavior
problems, either alone or as an adjunct to medication. An example of a self-help
program for parents is the Positive Parenting Program (Triple P;
www.triplep.net ), online version, in which parents can purchase 4 modules of
instruction addressing techniques for positive parenting and strategies for
encouraging good behavior, teaching new emotional and behavioral skills, and
managing misbehavior (see Chapter 19 ).
If the problematic behavior is occurring predominantly at school, the parent
can be advised about the role of a special education evaluation in the assessment
and management of the child's misbehavior, including the development of a
behavioral intervention plan to prevent disciplinary actions that is formalized in
an individualized educational plan (IEP) or 504 plan.
If a mental health clinician has been co-located or integrated into the primary
care setting, all parents of young children (universal prevention), as well as the
parents of youth with mild behavior problems (indicated prevention), can be
provided with a brief version of parent training . Programs targeted at toddlers
through 12 yr olds have been found to be effective in improving parenting skills,
parental mental health, and child emotional and behavior problems. For
example, Incredible Years (http://www.incredibleyears.com ) has a 6-8 session
Description
The schizophrenia spectrum and other psychotic disorders are primarily
characterized by the active (or positive) symptoms of psychosis, specifically
delusions, hallucinations, disorganized speech, or grossly disorganized or
catatonic behavior. Brief psychotic disorder is characterized by the duration of
1 or more of these symptoms for at least 1 day but <1 mo followed by complete
resolution. Emergence of symptoms may or may not be preceded by an
identifiable stressor (Table 47.1 ). Although brief, the level of impairment in this
disorder may be severe enough that supervision is required to ensure that basic
needs are met and the individual is protected from the consequences of poor
judgment and cognitive impairment.
Table 47.1
DSM-5 Diagnostic Criteria for Brief Psychotic
Disorder

A. Presence of 1 (or more) of the following symptoms. At least 1 of these

must be (1), (2), or (3):
1. Delusions.
2. Hallucinations.
3. Disorganized speech (e.g., frequent derailment or incoherence).
4. Grossly disorganized or catatonic behavior.

Note: Do not include a symptom if it is a culturally sanctioned response.

B. Duration of an episode of the disturbance is at least 1 day but less than 1
mo, with eventual full return to premorbid level of functioning.
C. The disturbance is not better explained by major depressive or bipolar
disorder with psychotic features or another psychotic disorder such as
schizophrenia or catatonia, and is not attributable to the physiologic effects
of a substance (e.g., a drug of abuse, a medication) or another medical
condition.
Specify if:
With marked stressor(s) (brief reactive psychosis): If symptoms occur in
response to events that, singly or together, would be markedly stressful to
almost anyone in similar circumstances in the individual's culture.
 Without marked stressor(s) : If the symptoms do not occur in response to
events that, singly or together, would be would be markedly stressful to
almost anyone in similar circumstances in the individual's culture.
With postpartum onset : If onset is during pregnancy or within 4 wk
postpartum.

From the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition,
(Copyright 2013). American Psychiatric Association, p 94.

If 2 or more psychotic symptoms persist from 1 mo up to 6 mo, the condition

is called schizophreniform disorder (Table 47.2 ). To meet DSM-5 criteria for
schizophrenia , 2 or more psychotic symptoms must have been present for a
significant time during 1 mo (unless suppressed by treatment), and the level of
psychosocial functioning must be markedly below the level achieved before the
onset (or there is failure in children to achieve the expected level of functioning).
In addition, there must be continuous signs of the disturbance (prodromal, active,
or residual symptoms) for at least 6 mo (Table 47.3 ).
Table 47.2
DSM-5 Diagnostic Criteria for
Schizophreniform Disorder
A. Two (or more) of the following, each present for a significant portion of
time during a 1 mo period (or less if successfully treated). At least 1 of
these must be (1), (2), or (3):
1. Delusions.
2. Hallucinations.
3. Disorganized speech (e.g., frequent derailment or incoherence).
4. Grossly disorganized or catatonic behavior.
5. Negative symptoms (i.e., diminished emotional expression or
avolition).
B. An episode of the disorder lasts at least 1 mo but less than 6 mo. When the
diagnosis must be made without waiting for recovery, it should qualified as
“provisional.”
C. Schizoaffective disorder and depressive or bipolar disorder with psychotic
features have been ruled out because either (1) no major depressive or
 manic episodes have occurred concurrently with the active-phase
symptoms; or (2) if mood episodes have occurred during active-phase
symptoms, they have been present for a minority of the total duration of the
active and residual periods of the illness.
D. The disturbance is not attributable to the physiologic effects of a substance
(e.g., a drug of abuse, a medication) or another medical condition.
Specify if:
With good prognostic features : This specifier requires the presence of at
least 2 of the following features: onset of prominent psychotic symptoms
within 4 wk of the first noticeable change in usual behavior or functioning;
confusion or perplexity; good premorbid social and occupational
functioning; and absence of blunted or flat affect.
Without good prognostic features : This specifier is applied if 2 or more of
the above features have not been present.

From the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition,
(Copyright 2013). American Psychiatric Association, pp 96–97.
Table 47.3
DSM-5 Diagnostic Criteria for Schizophrenia

A. Two (or more) of the following, each present for a significant portion of
time during a 1 mo period (or less if successfully treated). At least 1 of
these must be (1), (2), or (3):
1. Delusions.
2. Hallucinations.
3. Disorganized speech (e.g., frequent derailment or incoherence).
4. Grossly disorganized or catatonic behavior.
5. Negative symptoms (i.e., diminished emotional expression or
avolition).
B. For a significant portion of the time since the onset of the disturbance,
level of functioning in 1 or more major areas, such as work, interpersonal
relations, or self-care, is markedly below the level achieved prior to the
onset (or when the onset is in childhood or adolescence, there is failure to
achieve expected level of interpersonal, academic, or occupational
functioning).
 C. Continuous signs of the disturbance persist for at least 6 mo. This 6 mo
period must include at least 1 mo of symptoms (or less if successfully
treated) that meet Criterion A (i.e., active-phase symptoms) and may
include periods of prodromal or residual symptoms. During these
prodromal or residual periods, the signs of the disturbance may be
manifested by only negative symptoms or by 2 or more symptoms listed in
Criterion A present in an attenuated form (e.g., odd beliefs, unusual
perceptual experiences).
D. Schizoaffective disorder and depressive or bipolar disorder with psychotic
features have been ruled out because either (1) no major depressive or
manic episodes have occurred concurrently with the active-phase
symptoms; or (2) if mood episodes have occurred during active-phase
symptoms, they have been present for a minority of the total duration of the
active and residual periods of the illness.
E. The disturbance is not attributable to the physiologic effects of a substance
(e.g., a drug of abuse, a medication) or another medical condition.
F. If there is a history of autism spectrum disorder or a communication
disorder of childhood onset, the additional diagnosis of schizophrenia is
made only if prominent delusions or hallucinations, in addition to the other
required symptoms of schizophrenia, are also present for at least a month
(or less if successfully treated).

From the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition,
(Copyright 2013). American Psychiatric Association, pp 99–100.

Individuals with schizophrenia can display inappropriate affect, dysphoric

mood, disturbed sleep patterns, and lack of interest in eating, or food refusal.
Depersonalization, derealization, somatic concerns, and anxiety and phobias are
common. Cognitive deficits are observed, including decrements in declarative
memory, working memory, language function, and other executive functions, as
well as slower processing speed. These individuals may have no insight or
awareness of their disorder, which is a predictor of nonadherence to treatment,
higher relapse rates, and poorer illness course. Hostility and aggression can be
associated with schizophrenia, although spontaneous or random assault is
uncommon. Aggression is more frequent for younger males and for individuals
with a past history of violence, non-adherence with treatment, substance abuse,
onset may be abrupt or insidious, but the majority of individuals manifest a slow
and gradual development of symptoms, with about half of individuals
complaining of depressive symptoms. The predictors of course and outcome are
largely unexplained. The course appears to be favorable in approximately 20%
of cases, and a small number of individuals are reported to recover completely.
However, many remain chronically ill, with exacerbations and remissions of
active symptoms, whereas others experience progressive deterioration. Most
individuals diagnosed with schizophrenia require daily living supports. Positive
symptoms tend to diminish over time, and negative symptoms are the most
persistent, along with cognitive deficits.

Differential Diagnosis
The differential diagnosis for the psychotic disorders is broad and includes
reactions to substances/medications (dextromethorphan, LSD, hallucinogenic
mushrooms, psilocybin, peyote, cannabis, stimulants, inhalants; corticosteroids,
anesthetics, anticholinergics, antihistamines, amphetamines); medical conditions
causing psychotic-like symptoms (Table 47.4 ); and other psychiatric disorders
(depressive, bipolar, obsessive-compulsive, factitious, body dysmorphic,
posttraumatic stress, autism spectrum, communication, personality). The
differential diagnosis can be difficult because many conditions that can be
mistaken for psychosis also increase the risk for it.

Table 47.4
Select Neurologic and Systemic Causes of Depression
and/or Psychosis

CATEGORY DISORDERS
Head trauma Traumatic brain injury
Subdural hematoma
Infectious Lyme disease
Prion diseases
Neurosyphilis
Viral infections/encephalitides (HIV infection/encephalopathy, herpes encephalitis,
cytomegalovirus. Epstein-Barr virus)
Whipple disease
Cerebral malaria
Systemic infection
Inflammatory Autoimmune encephalitis
Celiac disease
 Systemic lupus erythematosus
Sjögren syndrome
Temporal arteritis
Hashimoto encephalopathy
Sydenham chorea
Sarcoidosis
Neoplastic Primary or secondary cerebral neoplasm
Systemic neoplasm
Paraneoplastic encephalitis
Endocrine or acquired Hepatic encephalopathy
metabolic Uremic encephalopathy
Dialysis dementia
Hypo/hyperparathyroidism
Hypo/hyperthyroidism
Addison disease, Cushing disease
Postpartum
Vitamin deficiency: vitamin B12 , folate, niacin, vitamin C. thiamine
Gastric bypass–associated nutritional deficiencies
Hypoglycemia
Hyponatremia
Vascular Stroke
Cerebral autosomal dominant aneriopathy with subcortical infarcts and
leukoencephalopathy (CADASIL)
Degenerative Progressive supranuclear palsy
Huntington disease
Corticobasal ganglionic degeneration
Multisystem atrophy, striatonigral degeneration, olivopontocerebellar atrophy
Idiopathic basal ganglia calcifications, Fahr disease
Neuroacanthosis
Neurodegeneration with brain iron accumulation (NBIA)
Adrenoleukodystrophy
Metachromatic leukodystrophy
Demyelinating, Multiple sclerosis
dysmyelinating Acute disseminated encephalomyelitis
Adrenoleukodystrophy
Metachromatic leukodystrophy
Inherited metabolic Wilson disease
Posterior hom syndrome
Tay-Sachs disease
Neuronal ceroid lipofuscinosis
Niemann-Pick disease type C
Acute intermittent porphyria
Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS)
Cerebrotendinous xanthomatosis
Homocystinuria
Ornithine transcarbamylase deficiency
Syndromes Williams
Prader-Willi
Fragile X
Deletion 22q11.2
ROHHAD
Epilepsy Ictal
Interictal
Postictal
Forced normalization
 Postepilepsy surgery
Lafora progressive myoclonic epilepsy
Medications Analgesics
Androgens (anabolic steroids)
Antiarrhythmics
Anticonvulsants
Anticholinergics
Antibiotics
Antihypertensives
Antineoplastic agents
β-Blocking agents
Corticosteroids
Cyclosporin
Dopamine agonists
Oral contraceptives
Sedatives/hypnotics
Selective serotonin reuptake inhibitors (SSRIs) (serotonin syndrome)
Drugs of abuse Alcohol
Amphetamines
Cocaine
Hallucinogens
Marijuana and synthetic cannabinoids
Methylenedioxymethamphetamine (MDMA, Ecstasy)
Phencyclidine
Drug withdrawal Alcohol
syndromes Barbiturates
Benzodiazepines
Amphetamines
SSRIs
Toxins Heavy metals
Inhalants
Other Normal-pressure hydrocephalus
Ionizing radiation
Decompression sickness
ROHHAD, Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, autonomic
dysregulation.
Modified from Perez DL, Murray ED, Price BH: Depression and psychosis in neurological practice.
In Daroff RB, Jankovic J, Mazziotta JC, et al, editors: Bradley's neurology in clinical practice, 7th
ed, Philadelphia, 2015, Elsevier.

Autoimmune encephalitis caused by anti–N -methyl-D -aspartate (NMDA)

receptor or other autoantibodies may manifest with psychosis, anxiety,
depression, agitation, aggression, delusions, catatonia, visual or auditory
hallucinations, disorientation, and paranoia in combination with sleep
disturbances, autonomic dysfunction (hypoventilation), dyskinesias, movement
disorders, seizures, memory loss, and a depressed level of consciousness (Fig.
47.1 ). The electroencephalogram (EEG), cerebrospinal fluid (CSF), and MRI
are usually, but not always, abnormal. The constellation of psychosis and
encephalitic features should suggest the diagnosis, although at presentation,
behavioral problems may be the dominant feature (see Chapter 616.4 ).

FIG. 47.1 Clinical characteristics of patients with anti–NMDA receptor encephalitis.
(Modified from Wandinger KP, Saschenbrecker S, Stoecker W, Dalmau J: Anti-NMDA-
receptor encephalitis: a severe multistage, treatable disorder presenting with
psychosis, J Neuroimmunol 231:86-91, 2011, Fig 2.)

Determining when identifiable medical conditions are causing delirium with

prominent psychotic symptoms may be difficult (Table 47.5 and Table 47.6 ). In
general, delirium due to medical causes is often associated with abnormalities in
vital signs and the neurologic examination (including level of consciousness). A
positive family or prior personal history of serious psychiatric illness is less
likely. When psychotic symptoms are caused by identifiable medical conditions,
there are often impairments in attention, orientation, recent memory, and
intellectual function. Hallucinations may be caused by medical illness, but are
often tactile, visual, or olfactory, whereas auditory hallucinations are more
common in primary psychotic disorders. Patients whose hallucinations are
caused by medical illness are more likely than patients with primary psychotic
disorders to be aware that the hallucinations do not represent reality.

Table 47.5
Special Problems in the Differential Diagnosis of Delirium*

CLINICAL
DELIRIUM DEMENTIAS SCHIZOPHRENIA DEPRESSION
FEATURE
 Course Acute onset; hours, days, Insidious onset, Insidious onset, ≥6 Insidious onset,
or more months or years, mo, acute psychotic at least 2 wk,
progressive phases often months
Attention Markedly impaired Normal early; Normal to mild Mild
attention and arousal impairment later impairment impairment
Fluctuation Prominent in attention Prominent Absent Absent
arousal; disturbed fluctuations absent;
day/night cycle lesser disturbances in
day/night cycle
Perception Misperceptions; Perceptual Hallucinations, May have
hallucinations, usually abnormalities much auditory with mood-
visual, fleeting; less prominent; personal reference congruent
paramnesia paramnesia hallucinations
Speech and language Abnormal clarity, speed, Early anomia; empty Disorganized, with a Decreased
and coherence; disjointed speech; abnormal bizarre theme amount of
and dysarthric; comprehension speech
misnaming; characteristic
dysgraphia
Other cognition Disorientation to time, Disorientation to Disorientation to Mental
place; recent memory and time, place; multiple person; concrete slowing;
visuospatial abnormalities other higher interpretations indecisiveness;
cognitive deficits memory
retrieval
difficulty
Behavior Lethargy or delirium; Disinterested; Systematized Depressed
nonsystematized disengaged; delusions; paranoia; mood;
delusions; emotional disinhibited; bizarre behavior anhedonia; lack
lability delusions and other of energy; sleep
psychiatric and appetite
symptoms disturbances
Electroencephalogram Diffuse slowing; low- Normal early; mild Normal Normal
voltage fast activity; slowing later
specific patterns
* The characteristics listed are the usual ones and not exclusive.

From Mendez MF, Padilla CR: Delirium. In Daroff RB, Jankovic J, Mazziotta JC, et al, editors:
Bradley's neurology in clinical practice, 7th ed, Philadelphia, 2015, Elsevier.

Table 47.6
Features Suggesting Neurologic Disease in
Patients With Psychiatric Symptoms
Atypical Psychiatric Features

Late or very early age of onset

Acute or subacute onset
Lack of significant psychosocial stressors
Catatonia
 Diminished comportment
Cognitive decline
Intractability despite adequate therapy
Progressive symptoms

History of Present Illness

New or worsening headache

Inattention
Somnolence
Incontinence
Focal neurologic complaints such as weakness, sensory changes,
incoordination, or gait difficulty
Neuroendocrine changes
Anorexia/weight loss

Patient Medical History

Risk factors for cerebrovascular disease or central nervous system

infections
Malignancy
Immunocompromised status
Significant head trauma
Seizures
Movement disorder
Hepatobiliary disorders
Abdominal crises of unknown cause
Biologic relatives with similar diseases or complaints

Unexplained Diagnostic Abnormalities

Screening laboratory tests

Neuroimaging studies or possibly imaging of other systems
Electroencephalogram
Cerebrospinal fluid
From Perez DL Murray ED, Price BH: Depression and psychosis in neurological
practice. In Daroff RB, Jankovic J, Mazziotta JC, editors: Bradley's neurology in
clinical practice, 7th ed, Philadelphia, 2015, Elsevier.

The diagnosis of a psychotic disorder should be made only after other

explanations for the observed symptoms have been thoroughly considered.
Mistakenly diagnosing psychosis when it is not present can lead to inappropriate
use of antipsychotics with all their attendant risks, and mistakenly dismissing
psychotic symptoms as nonpsychotic manifestations of, for example, autism or
trauma can lead to long delays in treatment of the psychosis. The persistence,
frequency, and form of possible psychotic symptoms, as well the degree of
accompanying distress and functional regression, need to be considered in
determining the likelihood of an underlying psychotic pathophysiology.

Comorbidity
In a review of 35 studies of youth with schizophrenia, rates of comorbidity
approximated 34% for posttraumatic stress disorder, 34% for attention-
deficit/hyperactivity and/or disruptive behavior disorders, and 32% for substance
abuse/dependence.

Sequelae
Follow-up studies of early-onset schizophrenia suggest moderate to severe
impairment across the life span. Poor outcome is predicted by low premorbid
functioning, insidious onset, higher rates of negative symptoms, childhood onset,
and low intellectual functioning. When followed into adulthood, youth with
schizophrenia demonstrated greater social deficits, lower levels of employment,
and were less likely to live independently, relative to those with other childhood
psychotic disorders.
Approximately 5–6% of individuals with schizophrenia die by suicide,
approximately 20% attempt suicide on one or more occasions, and many more
have suicidal ideation. Life expectancy is reduced in individuals with
schizophrenia because of associated medical conditions; a shared vulnerability
for psychosis and medical disorders may explain some of the medical
comorbidity of schizophrenia.
Psychosis Associated With Epilepsy
Joseph Gonzalez-Heydrich, Heather J. Walter, David R. DeMaso

Schizophrenia spectrum and other psychotic disorders include psychotic disorder

due to another medical condition (Table 47.7 ). Psychosis associated with
epilepsy has been reported in children and adults. Also called schizophrenic-like
psychosis of epilepsy, the disorder manifests with delusions or hallucinations
associated with poor insight. The characterization is complicated by the fact that
anticonvulsant drugs can cause psychosis and antipsychotic drugs can lower the
seizure threshold, producing seizures.
Table 47.7
DSM-5 Diagnostic Criteria for Psychotic
Disorder Due to Another Medical Condition
A. Prominent hallucinations or delusions.
B. There is evidence from the history, physical examination, or laboratory
findings that the disturbance is the direct pathophysiologic consequence of
another medical condition.
C. The disturbance is not better explained by another mental disorder.
D. The disturbance does not occur exclusively during the course of a
delirium.
E. The disturbance causes clinically significant distress or impairment in
social, occupational, or other important areas of functioning.
Specify whether:
With delusions : If delusions are the predominant symptom.
With hallucinations : If hallucinations are the predominant symptom.

From the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition,
(Copyright 2013). American Psychiatric Association, pp 115–116.
47.3
Catatonia in Children and
Adolescents
Joseph Gonzalez-Heydrich, Heather J. Walter, David R. DeMaso

Catatonia is a poorly defined state presenting as an unusual manifestation of

decreased or increased muscle tone and decreased responsiveness (although
agitation may be present) occurring in association with a broad array of
conditions affecting children, adolescents, and adults. These conditions include
psychosis, autism spectrum disorder, developmental disorders, drug-induced
conditions, mood disorders, and a wide range of medical disorders (Table 47.8 ).
Not surprising given its ill-defined nature, the prevalence of catatonia in children
and adolescents is unknown, although it is generally believed to be significantly
underdiagnosed. Recognition of catatonia by a clinician is important because the
disorder is generally very responsive to treatment with benzodiazepines and/or
ECT.
Table 47.8
Conditions Associated With Catatonia

Psychotic disorders
Paranoid schizophrenia, catatonic schizophrenia, psychosis,
autism, Prader-Willi syndrome, intellectual impairment
Mood disorders
Bipolar disorder: manic or mixed episodes
Major depressive disorder
Medical conditions
Endocrine abnormalities, infections, electrolyte imbalances,
mutations in SCN2A gene
Neurologic conditions
Epilepsy, strokes, traumatic brain injury, multiple sclerosis,
 infectious and autoimmune encephalitis
Drugs
Withdrawal: benzodiazepines, L -dopa, gabapentin
Overdose: LSD, phencyclidine (PCP), cocaine, MDMA (Ecstasy),
disulfiram, levetiracetam

Adapted from Weder ND, Muralee S, Penland H, Tampi RR: Catatonia: a

review, Ann Clin Psychiatry 20(2):97–107, 2008, Table 2.

Diagnosis and Treatment

Catatonia is defined as 3 or more of the 12 symptoms listed in Table 47.9 . An
important next step is the evaluation (and possible elimination) of medications
being administered to the child for their potential to induce catatonic symptoms,
a not-infrequent side effect of many medical and psychiatric medications. Of
particular importance, antipsychotics should be discontinued because they have
been associated with an increased incidence of malignant catatonia or
neuroleptic malignant syndrome.
Table 47.9
DSM-5 Diagnostic Criteria for Catatonic
Disorder Due to Another Medical Condition
A. The clinical picture is dominated by 3 (or more) of the following
symptoms:
1. Stupor (i.e., no psychomotor activity; not actively relating to
environment).
2. Catalepsy (i.e., passive induction of a posture held against
gravity).
3. Waxy flexibility (i.e., slight, even resistance to positioning by
examiner).
4. Mutism (i.e., no, or very little, verbal response [Note: not
applicable if there is an established aphasia]).
5. Negativism (i.e., opposing or not responding to instructions or
external stimuli).
6. Posturing (i.e., spontaneous and active maintenance of a posture
 against gravity).
7. Mannerism (i.e., odd, circumstantial caricature of normal
actions).
8. Stereotypy (i.e., repetitive, abnormally frequent, non–goal-
directed movements).
9. Agitation, not influenced by external stimuli.
10. Grimacing.
11. Echolalia (i.e., mimicking another's speech).
12. Echopraxia (i.e., mimicking another's movements).
B. There is evidence from the history, physical examination, or laboratory
findings that the disturbance is the direct pathophysiologic consequence of
another medical condition.
C. The disturbance is not better explained by another mental disorder (e.g., a
manic episode).
D. The disturbance does not occur exclusively during the course of a
delirium.
E. The disturbance causes clinically significant distress or impairment in
social, occupational, or other areas of functioning.
Coding note: Include the name of the medical condition in the name of the
mental disorder (e.g., F06.1 catatonic disorder due to hepatic
encephalopathy). The other medical condition should be coded and listed
separately immediately before the catatonic disorder due to the medical
condition (e.g., K71.90 hepatic encephalopathy; F06.1 catatonic disorder
due to hepatic encephalopathy).

From the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition,
(Copyright 2013). American Psychiatric Association, pp 120–121.

Benzodiazepines (typically lorazepam) and ECT are effective in adults and

appear to be effective in children. Fig. 47.2 shows a treatment algorithm using a
lorazepam challenge test (oral, intravenous, or intramuscular lorazepam, 1-2
mg). If the challenge test does reverse symptoms, increasing doses of lorazepam
are indicated, with careful monitoring to avoid side effects. ECT may be
indicated alone (if no improvement with lorazepam) or in combination with
lorazepam if some but incomplete improvement is noted.
 FIG. 47.2 Evaluation, diagnosis, and treatment of catatonia in children and
adolescents. ECT, Electroconvulsive therapy; LZP, lorazepam. (From Dhossche DM,
Wilson C, Wachtel LE: Catatonia in childhood and adolescents: implications for the
DSM-5, Prim Psychiatry 17(4):23–26, 2010.)

The outlook for catatonia is greatly impacted by that of the associated

condition(s). The long-term outcome for patients treated with ECT is unknown,
but mortality rates in catatonic patients declined after the introduction of ECT in
treatment.

Bibliography
Consoli A, Benmiloud M, Wachtel L, et al. Electroconvulsive
therapy in adolescents with the catatonia syndrome: efficacy
and ethics. J ECT . 2010;26(4):259–265.
Cornic F, Consoli A, Cohen D. Catatonic syndrome in children
to challenges with behavior, emotional, and academic functioning and social
interaction (Table 48.1 ).

Table 48.1

Symptom Expression of Executive Dysfunction

EXECUTIVE FUNCTION
SYMPTOM EXPRESSION
DEFICIT
Disinhibition Impulsivity/poor behavioral regulation
Interrupts
“Blurts things out”
Shifting Problems with transitioning from one task/activity to another
Unable to adjust to unexpected change
Repeats unsuccessful problem-solving approaches
Initiation Difficulty independently beginning tasks/activities
Lacks initiative
Difficulty developing ideas or making decisions
Working memory Challenges following multistep instruction (e.g., only completes 1 of 3
steps)
Forgetfulness
Organization and planning Fails to plan ahead
Work is often disorganized
Procrastinates and does not complete tasks
“Messy” child
Self-monitoring Fails to recognize errors and check work
Does not appreciate impact of actions on others
Poor self-awareness
Affect control Experiences behavioral and emotional outbursts (e.g., tantrums)
Easily upset/frustrated
Frequent mood changes

Working memory (WM) can be defined as the ability to hold, manipulate,

and store information for short periods. This function is critical to be able to
complete multistep problems and more complex instructions and tasks. In its
simplest form, WM involves the interaction of short-term verbal and visual
processes (e.g., memory, phonologic, awareness, and spatial skills) with a
centralized control mechanism that is responsible for coordinating all the
cognitive processes involved (e.g., temporarily suspending information in
memory while working with it). Developmentally, WM capacity can double or
triple between the preschool years and adolescence. When doing math, a child
with WM dysfunction might carry a number and then forget what he intended to
do after carrying that number. WM is an equally important underlying function
for reading, where it enables the child to remember the beginning of a paragraph
when she arrives at the end of it. In writing, WM helps children remember what
they intend to express in written form while they are performing another task,
crayons/pencils, coloring, drawing) and social interaction may develop.
School-age children with neurodevelopmental and executive dysfunctions
can vary widely in clinical presentations. Their specific patterns of academic
performance and behavior represent final common pathways of
neurodevelopmental strengths and deficits interacting with environmental,
social, or cultural factors; temperament; educational experience; and intrinsic
resilience (Table 48.2 ). Children with language weaknesses might have
problems integrating and associating letters and sounds, decoding words,
deriving meaning, and being able to comprehend passages. Children with early
signs of a mathematics weakness might have difficulty with concepts of quantity
or with adding or subtracting without using concrete representation (e.g., their
fingers when calculating). Difficulty learning time concepts and confusion with
directions (right/left) might also be observed. Poor fine motor control and
coordination and poor planning can lead to writing problems. Attention and
behavioral regulation weaknesses observed earlier can continue, and together
with other executive functioning weaknesses (e.g., organization, initiation skills),
further complicate the child's ability to acquire and generalize new knowledge.
Children with weaknesses in WM may struggle to remember the steps necessary
to complete an activity or problem-solve. In social settings, these children often
have difficulty keeping up with more complex conversations.

Table 48.2

Neurodevelopmental Dysfunction Underlying Academic Disorders*

ACADEMIC DISORDER POTENTIAL UNDERLYING NEURODEVELOPMENTAL DYSFUNCTION
Reading Language
Phonologic processing
Verbal fluency
Syntactic and semantic skills
Memory
Working memory
Sequencing
Visual-spatial
Attention
Written expression, spelling Language
Phonologic processing
Syntactic and semantic skills
Graphomotor
Visual-spatial
Memory
Working memory
Sequencing
Attention
 Mathematics Visual-spatial
Memory
Working memory
Language
Sequencing
Graphomotor
Attention
* Isolated neurodevelopmental dysfunction can lead to a specific academic disorder, but more

often there is a combination of factors underlying weak academic performance. In addition to the
dysfunction in neurodevelopmental domains as listed in the table, the clinician must also consider
the possibility of limitations of intellectual and cognitive abilities or associated social and emotional
problems.

In middle school children the shift in cognitive, academic, and regulatory

demands can cause further difficulties for those with existing
neurodevelopmental and executive challenges. In reading and writing, middle
school children might present with transposition and sequencing errors; might
struggle with root words, prefixes, and suffixes; might have difficulty with
written expression; and might avoid reading and writing altogether. Challenges
completing word problems in math are common. Difficulty with recall of
information might also be experienced. Although observable in both lower and
more advanced grades, behavioral, emotional, and social difficulties tend to
become more salient in middle school children who experience cognitive or
academic problems.
High school students can present with deficient reading comprehension,
written expression, and slower processing efficiency. Difficulty in answering
open-ended questions, dealing with abstract information, and producing
executive control (e.g., self-monitoring, organization, planning, self-starting) is
often reported.

Academic Problems
Reading disorders (see Chapter 50 ) can stem from any number of
neurodevelopmental dysfunctions, as described earlier (see Table 48.2 ). Most
often, language and auditory processing weaknesses are present, as evidenced by
poor phonologic processing that results in deficiencies at the level of decoding
individual words and, consequently, a delay in automaticity (e.g., acquiring a
repertoire of words readers can identify instantly) that causes reading to be slow,
laborious, and frustrating. Deficits in other core neurodevelopmental domains
might also be present. Weak WM might make it difficult for a child to hold
sounds and symbols in mind while breaking down words into their component
than one EF simultaneously is encouraged as a means of scaffolding intervention
and building on previously mastered skills.

Table 48.3

Executive Function Categories: Presenting Symptoms, Suggested Dysfunction, and

Potential Interventions
SYMPTOM/PRESENTING SUSPECTED AREA
POSSIBLE “REAL WORLD” INTERVENTIONS
COMPLAINT OF DYSFUNCTION
Acts before thinking Disinhibition/impulsivity Increase structure in environment to set limits for
Interrupts inhibition problems.
Poor behavioral and/or Make behavior and work expectations clear and
emotional control explicit; review with child.
Post rules in view; point to them when child breaks
rule.
Teach response-delay techniques (e.g., counting to
10 before acting).
Cannot follow multistep Working memory Repeat instructions as needed.
instructions Keep instructions clear and concise.
Forgetful Provide concrete references.
Struggles starting Initiation Increase structure of tasks.
assignments/tasks Establish and rely on routine.
Lacks Break tasks into smaller, manageable steps.
initiative/motivation Place child with partner or group for modeling and
Has trouble developing cuing from peers.
ideas/strategies
Does not plan ahead Planning Practice with tasks with only a few steps first.
Uses trial-and-error Teach simple flow charting as a planning tool.
approach Practice with planning tasks (e.g., mazes).
Ask child to verbalize plan before beginning work.
Ask child to verbalize second plan if first does not
work.
Ask child to verbalize possible consequences of
actions before beginning.
Review incidents of poor planning/anticipation
with child.
Work/belongings is/are Organization Increase organization of classroom and activities to
“messy” serve as model, and help child grasp structure of
Random/haphazard new information.
problem solving Present framework of new information to be
Procrastinates/does not learned at the outset, and review again at the end of
complete tasks a lesson.
Begin with tasks with only few steps and increase
gradually.
Gets “stuck” Flexibility/shifting Increase routine to the day.
Trouble transitioning Make schedule clear and public.
Does not adapt to change Forewarn of any changes in schedule.
Give “2-minute warning” of time to change.
Make changes from one task to the next or one
topic to the next, clear and explicit.
Shifting may be a problem of inhibiting, so apply
 strategies for inhibition problems.

Developmental Therapy
Speech-language pathologists offer intervention for children with various forms
of language disability. Occupational therapists focus on sensorimotor skills,
including the motor skills of students with writing problems, and physical
therapists address gross motor incoordination.

Curriculum Modifications
Many children with neurodevelopmental dysfunctions require alterations in the
school curriculum to succeed, especially as they progress through secondary
school. Students with memory weaknesses might need to have their courses
selected for them so that they do not have an inordinate cumulative memory load
in any single semester. The timing of foreign language learning, the selection of
a mathematics curriculum, and the choice of science courses are critical issues
for many of these struggling adolescents.

Strengthening of Strengths
Affected children need to have their affinities, potentials, and talents identified
clearly and exploited widely. It is as important to augment strengths as it is to
attempt to remedy deficiencies. Athletic skills, artistic inclinations, creative
talents, and mechanical abilities are among the potential assets of certain
students who are underachieving academically. Parents and school personnel
need to create opportunities for such students to build on these assets and to
achieve respect and praise for their efforts. These well-developed personal assets
can ultimately have implications for the transition into young adulthood,
including career or college selection.

Individual and Family Counseling

When academic difficulties are complicated by family problems or identifiable
psychiatric disorders, psychotherapy may be indicated. Mental health
professionals may offer long-term or short-term therapy. Such intervention may
involve the child alone or the entire family. Cognitive-behavioral therapy is
CHAPTER 49

Attention-Deficit/Hyperactivity
Disorder
David K. Urion

Attention-deficit/hyperactivity disorder (ADHD) is the most common

neurobehavioral disorder of childhood, among the most prevalent chronic health
conditions affecting school-aged children, and one of the most extensively
studied neurodevelopmental disorders of childhood. ADHD is characterized by
inattention, including increased distractibility and difficulty sustaining attention;
poor impulse control and decreased self-inhibitory capacity; and motor
overactivity and motor restlessness (Table 49.1 and Fig. 49.1 ). Definitions vary
in different countries (Table 49.2 ). Affected children usually experience
academic underachievement, problems with interpersonal relationships with
family members and peers, and low self-esteem. ADHD often co-occurs with
other emotional, behavioral, language, and learning disorders (Table 49.3 ).
Evidence also suggests that for many people, the disorder continues with varying
manifestations across the life cycle, leading to significant under- and
unemployment, social dysfunction and increased risk of antisocial behaviors
(e.g., substance abuse), difficulty maintaining relationships, encounters with the
law, death from suicide, and, if untreated, accidents (Figs. 49.2 and 49.3 ).
Table 49.1
DSM-5 Diagnostic Criteria for Attention-
Deficit/Hyperactivity Disorder (ADHD)

A. A persistent pattern of inattention and/or hyperactivity/impulsivity that

interferes with functioning or development, as characterized by (1) and/or
(2):
1. Inattention: Six (or more) of the following symptoms of
inattention have persisted for ≥6 mo to a degree that is
inconsistent with development level and that negatively impacts
directly on social and academic/occupational activities:
a. Often fails to give close attention to details or makes
careless mistakes in schoolwork, at work, or during other
activities (e.g., overlooks or misses details, work is
inaccurate).
b. Often has difficulty sustaining attention in tasks or play
activities.
c. Often does not seem to listen when spoken to directly.
d. Often does not follow through on instructions and fails
to finish schoolwork, chores, or duties in the workplace
(not due to oppositional behavior or failure to understand
instructions).
e. Often has difficulty organizing tasks and activities.
f. Often avoids, dislikes, or is reluctant to engage in tasks
that require sustained mental effort (e.g., schoolwork,
homework).
g. Often loses things necessary for tasks or activities (e.g.,
toys, school assignments, pencils, books, tools).
h. Is often easily distracted by extraneous stimuli.
i. Is often forgetful in daily activities.
2. Hyperactivity/impulsivity: Six (or more) of the following
symptoms of inattention have persisted for ≥6 mo to a degree that
is inconsistent with development level and that negatively
impacts directly on social and academic/occupational activities.
a. Often fidgets with hands or feet or squirms in seat.
b. Often leaves seat in classroom or in other situations in
which remaining seated is expected.
c. Often runs about or climbs excessively in situations in
which it is inappropriate (in adolescents or adults, may
be limited to subjective feelings of restlessness).
d. Often has difficulty playing or engaging in leisure
activities quietly.
e. Is often “on the go” or often acts as if “driven by a
motor.”
 f. Often talks excessively.
Impulsivity.
g. Often blurts out answers before questions have been
completed.
h. Often has difficulty awaiting turn.
i. Often interrupts or intrudes on others (e.g., butts into
conversations or games).
B. Several inattentive or hyperactive/impulsive symptoms were present
before 12 yr of age.
C. Several inattentive or hyperactive/impulsive symptoms are present in 2 or
more settings (e.g., at school [or work] or at home) and is documented
independently.
D. There is clear evidence of clinically significant impairment in social,
academic, or occupational functioning.
E. Symptoms do not occur exclusively during the course of schizophrenia, or
another psychotic disorder, and are not better accounted for by another
mental disorder (e.g., mood disorder, anxiety disorder, dissociative
disorder, personality disorder, substance intoxication or withdrawal).

Code Based on Type

314.01 Attention-deficit/hyperactivity disorder, combined presentation: if

both Criteria A1 and A2 are met for the past 6 mo.
314.00 Attention-deficit/hyperactivity disorder, predominantly inattentive
presentation: if Criterion A1 is met but Criterion A2 is not met for the
past 6 mo.
314.01 Attention-deficit/hyperactivity disorder, predominantly hyperactive-
impulsive presentation: if Criterion A2 is met but Criterion A1 is not met
for the past 6 mo.
Specify if:
Mild: Few, if any, symptoms in excess of those required to make
the diagnosis are present, and if the symptoms result in no more
than minor impairments in social and occupational functioning.
Moderate: Symptoms or functional impairment between “mild”
and “severe” are present.
Severe: Many symptoms in excess of those required to make the
 diagnosis, or several symptoms that are particularly severe, are
present, or the symptoms result in marked impairment in social
or occupational functioning.

From the Diagnostic and Statistical Manual of Mental Disorders, Fourth

Edition, Text Revision, Washington, DC, 2000, and Fifth Edition, (Copyright
2013). American Psychiatric Association.

FIG. 49.1 How to assess children for attention-deficit/hyperactivity

disorder. (From Verkuijl N, Perkins M, Fazel M: Childhood attention-
deficit/hyperactivity disorder, BMJ 350:h2168, 2015, Fig 2, p 146.)

Table 49.2
Differences Between U.S. and European Criteria for ADHD
or HKD

DSM-5 ADHD ICD-10 HKD

SYMPTOMS
Either or both of the following: All of the following:
At least 6 of 9 inattentive symptoms At least 6 of 8 inattentive symptoms
At least 6 of 9 hyperactive or impulsive symptoms At least 3 of 5 hyperactive symptoms
At least 1 of 4 impulsive symptoms
 PERVASIVENESS
Some impairment from symptoms is present in >1 setting Criteria are met for >1 setting
ADHD, Attention-deficit/hyperactivity disorder; HKD, hyperkinetic disorder; DSM-5, Diagnostic and
Statistical Manual of Mental Disorders, Fifth Edition ; ICD-10, International Classification of
Diseases, Tenth Edition .
From Biederman J, Faraone S: Attention-deficit hyperactivity disorder, Lancet 366:237–248, 2005.

Table 49.3
Differential Diagnosis of Attention-
Deficit/Hyperactivity Disorder (ADHD)
Psychosocial Factors

Response to physical or sexual abuse

Response to inappropriate parenting practices
Response to parental psychopathology
Response to acculturation
Response to inappropriate classroom setting

Diagnoses Associated With ADHD Behaviors

Fragile X syndrome
Fetal alcohol syndrome
Pervasive developmental disorders
Obsessive-compulsive disorder
Gilles de la Tourette syndrome
Attachment disorder with mixed emotions and conduct

Medical and Neurologic Conditions

Thyroid disorders (including general resistance to thyroid hormone)

Heavy metal poisoning (including lead)
Adverse effects of medications
Effects of abused substances
Sensory deficits (hearing and vision)
Auditory and visual processing disorders
Neurodegenerative disorder, especially leukodystrophies
 Posttraumatic head injury
Postencephalitic disorder

Note: Coexisting conditions with possible ADHD presentation include

oppositional defiant disorder, anxiety disorders, conduct disorder, depressive
disorders, learning disorders, and language disorders. Presence of one or more
of the symptoms of these disorders can fall within the spectrum of normal
behavior, whereas a range of these symptoms may be problematic but fall short
of meeting the full criteria for the disorder.

From Reiff MI, Stein MT: Attention-deficit/hyperactivity disorder evaluation

and diagnosis: a practical approach in office practice, Pediatr Clin North Am
50:1019–1048, 2003. Adapted from Reiff MI: Attention-deficit/hyperactivity
disorders. In Bergman AB, editor: 20 Common problems in pediatrics, New
York, 2001, McGraw-Hill, p 273.

FIG. 49.2 Possible developmental impacts of attention-deficit/hyperactivity

disorder. (From Verkuijl N, Perkins M, Fazel M: Childhood attention-
deficit/hyperactivity disorder, BMJ 350:h2168, 2015, Fig 1, p 145.)
number in the 10s column when borrowing: “64 − 39 = 35.” For both adding and
subtracting, there is a lack of understanding of the commutative property of
numbers and a tendency to use repeated addition rather than fact retrieval. It is
not that children with a MLD do not develop these skills, it is that they develop
them much later than their peers, thereby making the transition to complicated
math concepts much more challenging.

Memory for Math Facts

Committing math facts to or retrieving facts from memory have consistently
been found to be problematic for children with MLD. Weak fact encoding or
retrieval alone do not determine a MLD diagnosis. Many math curricula in the
United States do not include development of math facts as a part of the
instructional process, resulting in children not knowing basic facts.
Unlike dyslexia, in which deficits have been isolated and identified as causal
(see Chapter 50 ), factors involved in the development of a MLD are much more
heterogeneous. Alone, none of the processes previously outlined fully accounts
for MLD, although all have been implicated as problematic for those struggling
with math.

Treatment and Interventions

The most effective interventions for MLD are those that include explicit
instruction on solving specific types of problems and that take place over several
weeks to several months. Skill-based instruction is a critical component; general
math problem solving will not carry over across various math skills, unless the
skill is part of a more complex math concept. Clear, comprehensive guidelines
for effective interventions for students struggling with math have been provided
by the U.S. Department of Education in the form of a Practice Guide released
through the What Works Clearinghouse. This document gives excellent direction
in the identification and treatment of children with math difficulties in the
educational system. Although not intended for medical personnel or parents, the
guide is available free of charge and can be helpful for parents when talking to
teachers about their child's learning. Table 51.1 lists additional resources for
parents concerned about their young child's development of math facts.
Table 51.1
Parent Resources for the Child With Math
Learning Disability
Let's Talk About Math . Available from:
http://www.zerotothree.org/parenting-resources/early-math-video-series .
Accessed January 2, 2017.
Mixing in Math . Available from:
https://mixinginmath.terc.edu/aboutMiM/what_isMiM.php . Accessed
January 2, 2017.
PBS Parents. Math resources available to parents through the Public
Broadcasting Service website. Accessed January 28, 2017:
http://www.pbs.org/parents/earlymath/index.html
http://www.pbs.org/parents/education/math/
US Department of Education: Helping your child learn mathematics .
Available from:
https://www2.ed.gov/parents/academic/help/math/index.html . Accessed
January 28, 2017.

Awareness that most public school systems have implemented some form of a
RtI to identify learning disabilities allows the primary care physician to
encourage parents to return to the school seeking an intervention to address their
child's concern. Receiving special education services in the form of an IEP may
be necessary for some children. However, the current approach to identifying
children with a learning disability allows school systems to intervene earlier,
when problems arise, and potentially avoid the need for an IEP. Pediatricians
with patients whose parents have received feedback from school with any of the
risk factors outlined in Table 51.2 should encourage the parents to discuss an
intervention plan with the child's teacher.
Table 51.2
Risk Factors for a Specific Learning
Disability Involving Mathematics
The child is at or below the 20th percentile in any math area, as reflected
by standardized testing or ongoing measures of progress monitoring.
The teacher expresses concerns about the child's ability to “take the next
step” in math.
 There is a positive family history for math learning disability (this alone
will not initiate an intervention).
Parents think they have to “reteach” math concepts to their child.

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learning difficulties: fragile X, Turner and 22q deletion
Oral language is a complex process that typically develops in the absence of
formal instruction. In contrast, written language requires instruction in
acquisition (word reading), understanding (reading comprehension), and
expression (spelling and composition). Unfortunately, despite reasonable
pedagogy, a subset of children struggle with development in one or several of
these areas. The disordered output of written language is currently referred to
within the Diagnostic and Statistical Manual for Mental Disorders, Fifth Edition
(DSM-5) as a specific learning disorder with impairment in written
expression (Table 51.3 ).
Table 51.3
DSM-5 Diagnostic Criteria for Specific
Learning Disability With Impairment in
Written Expression
A. Difficulties learning and using academic skills that have persisted for at
least 6 mo, despite the provision of interventions that target those
difficulties.
Difficulties with written expression (e.g., makes multiple
grammatical or punctuation errors within sentences; employs
poor paragraph organization; written expression of ideas lacks
clarity).
B. The affected academic skills are substantially and quantifiably below those
expected for the individual's chronological age, and cause significant
interference with academic or occupational performance, or with activities
of daily living, as confirmed by individually administered standardized
achievement measures and comprehensive clinical assessment. For
individuals age 17 yr and older, a documented history of impairing learning
difficulties may be substituted for the standardized assessment.
C. The learning difficulties begin during school-age years but may not
become fully manifest until the demands for those affected academic skills
exceed the individual's limited capacities (e.g., as in timed tests, reading or
writing lengthy complex reports for a tight deadline, excessively heavy
academic loads).
D. The learning difficulties are not better accounted for by intellectual
disabilities, uncorrected visual or auditory acuity, other mental or
 neurologic disorders, psychosocial adversity, lack of proficiency in the
language of academic instruction, or inadequate educational instruction.

315.2 (F81.81) With impairment in written expression:

Spelling accuracy
Grammar and punctuation accuracy
Clarity or organization of written expression
Specify current severity:
Mild: Some difficulties learning skills in 1 or 2 academic domains, but of
mild enough severity that the individual may be able to compensate or
function well when provided with appropriate accommodations or
support services, especially during the school years.
Moderate: Marked difficulties learning skills in ≥1 academic domain(s),
so that the individual is unlikely to become proficient without some
intervals of intensive and specialized teaching during the school years.
Some accommodations or supportive services at least part of the day at
school, in the workplace, or at home may be needed to complete activities
accurately and efficiently.
Severe: Severe difficulties learning skills, affecting several academic
domains, so that the individual is unlikely to learn those skills without
ongoing intensive individualized and specialized teaching for most of the
school years. Even with an array of appropriate accommodations or
services at home, at school, or in the workplace, the individual may not
be able to complete all activities efficiently.

Adapted from the Diagnostic and Statistical Manual of Mental Disorders, Fifth
Edition, (Copyright 2013). American Psychiatric Association, pp 66–67.

Various terminology has been used when referring to individuals with writing
deficits; this subchapter uses the term impairment in written expression (IWE)
rather than “writing disorder” or “disorder of written expression.” Dysgraphia is
often used when referring to children with writing problems, sometimes
synonymously with IWE, although the two are related but distinct conditions.
Dysgraphia is primarily a deficit in motor output (paper/pencil skills), and IWE
is a conceptual weakness in developing, organizing, and elaborating on ideas in
writing.
Table 52.1
Normal Language Milestones: Birth to 5 Years

HEARING AND UNDERSTANDING TALKING

BIRTH TO 3 MONTHS
Startles to loud sounds Makes pleasure sounds (cooing, gooing)
Quiets or smiles when spoken to Cries differently for different needs
Seems to recognize your voice and quiets if crying Smiles when sees you
Increases or decreases sucking behavior in response to
sound
4-6 MONTHS
Moves eyes in direction of sounds Babbling sounds more speech-like, with
Responds to changes in tone of your voice many different sounds, including p, b, and m
Notices toys that make sounds Vocalizes excitement and displeasure
Pays attention to music Makes gurgling sounds when left alone and
when playing with you
7 MONTHS TO 1 YEAR
Enjoys games such as peek-a-boo and pat-a-cake Babbling has both long and short groups of
Turns and looks in direction of sounds sounds, such as tata upup bibibibi.
Listens when spoken to Uses speech or noncrying sounds to get and
Recognizes words for common items, such as cup, shoe, keep attention
and juice Imitates different speech sounds
Begins to respond to requests (Come here; Want more?) Has 1 or 2 words (bye-bye, dada, mama),
although they might not be clear
1-2 YEARS
Points to a few body parts when asked Says more words every month
Follows simple commands and understands simple Uses some 1-2 word questions (Where kitty?
questions (Roll the ball; Kiss the baby; Where's your Go bye-bye? What's that?)
shoe?) Puts 2 words together (more cookie, no
Listens to simple stories, songs, and rhymes juice, mommy book)
Points to pictures in a book when named Uses many different consonant sounds at the
beginning of words
2-3 YEARS
Understands differences in meaning (e.g., go–stop, in–on, Has a word for almost everything
big–little, up–down) Uses 2-3 word “sentences” to talk about and
Follows 2-step requests (Get the book and put it on the ask for things
table.) Speech is understood by familiar listeners
most of the time
Often asks for or directs attention to objects
by naming them
3-4 YEARS
Hears you when you call from another room Talks about activities at school or at friends'
Hears television or radio at the same loudness level as homes
other family members Usually understood by people outside the
Understands simple who, what, where, why questions family
Uses a lot of sentences that have ≥4 words
Usually talks easily without repeating
syllables or words
4-5 YEARS
Pays attention to a short story and answers simple Voice sounds as clear as other children's
questions about it Uses sentences that include details (I like to
Hears and understands most of what is said at home and in read my books)
 school Tells stories that stick to a topic
Communicates easily with other children
and adults
Says most sounds correctly except a few,
such as l, s, r, v, z, ch, sh, and th
Uses the same grammar as the rest of the
family
Adapted from American Speech-Language-Hearing Association, 2005.
http://www.asha.org/public/speech/development/chart.htm .

Receptive Language Development

The peripheral auditory system is mature by 26 wk gestation, and the fetus
responds to and discriminates speech sounds. Anatomic asymmetry in the
planum temporale , the structural brain region specialized for language
processing, is present by 31 wk gestation. At birth, the full-term newborn
appears to have functionally organized neural networks that are sensitive to
different properties of language input. The normal newborn demonstrates
preferential response to human voices over inanimate sound and recognizes the
mother's voice, reacting stronger to it than to a stranger's voice. Even more
remarkable is the ability of the newborn to discriminate sentences in their
“native” (mother's) language from sentences in a “foreign” language. In research
settings, infants of monolingual mothers showed a preference for only that
language, whereas infants of bilingual mothers showed a preference for both
exposed languages over any other language.
Between 4 and 6 mo, infants visually search for the source of sounds, again
showing a preference for the human voice over other environmental sounds. By
6 mo, infants can passively follow the adult's line of visual regard, resulting in a
“joint reference” to the same objects and events in the environment. The ability
to share the same experience is critical to the development of further language,
social, and cognitive skills as the infant “maps” specific meanings onto his or her
experiences. By 8-9 mo, the infant can actively show, give, and point to objects.
Comprehension of words often becomes apparent by 9 mo, when the infant
selectively responds to his or her name and appears to comprehend the word
“no.” Social games, such as “peek-a-boo,” “so big,” and waving “bye-bye” can
be elicited by simply mentioning the words. At 12 mo, many children can follow
a simple, 1-step request without a gesture (e.g., “Give it to me”).
Between 1 and 2 yr, comprehension of language accelerates rapidly. Toddlers
can point to body parts on command, identify pictures in books when named,
palate), and neuromotor conditions affecting oral motor coordination (e.g.,
dysarthria from cerebral palsy or other neuromuscular disorders).

Classification
Each professional discipline has adopted a somewhat different classification
system, based on cluster patterns of symptoms. The American Psychiatric
Association (APA) Diagnostic and Statistical Manual of Mental Disorders, Fifth
Edition (DSM-5) organized communication disorders into: (1) language disorder
(which combines expressive and mixed receptive-expressive language
disorders), speech sound disorder (phonologic disorder), and childhood-onset
fluency disorder (stuttering); and (2) social (pragmatic) communication disorder,
which is characterized by persistent difficulties in the social uses of verbal and
nonverbal communication (Table 52.2 ). In clinical practice, childhood speech
and language disorders occur as a number of distinct entities.
Table 52.2
DSM-5 Diagnostic Criteria for
Communication Disorders
Language Disorder

A Persistent difficulties in the acquisition and use of language across

modalities (i.e., spoken, written, sign language, or other) due to deficits in
comprehension or production that include the following:
1. Reduced vocabulary (word knowledge and use).
2. Limited sentence structure (ability to put words and word endings
together to form sentences based on the rules of grammar and
morphology).
3. Impairments in discourse (ability to use vocabulary and connect
sentences to explain or describe a topic or series of events or have
a conversation).
B. Language abilities are substantially and quantifiably below those expected
for age, resulting in functional limitations in effective communication,
social participation, academic achievement, or occupational performance,
individually or in any combination.
C. Onset of symptoms is in the early developmental period.
D. The difficulties are not attributable to hearing or other sensory impairment,
 motor dysfunction, or another medical or neurologic condition and are not
better explained by intellectual disability (intellectual developmental
disorder) or global developmental delay.

Speech Sound Disorder

A. Persistent difficulty with speech sound production that interferes with

speech intelligibility or prevents verbal communication of messages.
B. The disturbance causes limitations in effective communication that
interfere with social participation, academic achievement, or occupational
performance, individually or in any combination.
C. Onset of symptoms is in the early developmental period.
D. The difficulties are not attributable to congenital or acquired conditions,
such as cerebral palsy, cleft palate, deafness or hearing loss, traumatic brain
injury, or other medical or neurologic conditions.

Social (Pragmatic) Communication Disorder

A. Persistent difficulties in the social use of verbal and nonverbal

communication as manifested by all of the following:
1. Deficits in using communication for social purposes, such as
greeting and sharing information, in a manner that is appropriate
for the social context.
2. Impairment of the ability to change communication to match
context or the needs of the listener, such as speaking differently
in a classroom than on a playground, talking differently to a child
than to an adult, and avoiding use of overly formal language.
3. Difficulties following rules for conversation and storytelling, such
as taking turns in conversation, rephrasing when misunderstood,
and knowing how to use verbal and nonverbal signals to regulate
interaction.
4. Difficulties understanding what is not explicitly stated (e.g.,
making inferences) and nonliteral or ambiguous meanings of
language (e.g., idioms, humor, metaphors, multiple meanings that
depend on the context for interpretation).
B. The deficits result in functional limitations in effective communication,
 social participation, social relationships, academic achievement, or
occupational performance, individually or in combination.
C. The onset of the symptoms is in the early developmental period (but
deficits may not become fully manifest until social communication
demands exceed limited capacities).
D. The symptoms are not attributable to another medical or neurologic
condition or to low abilities in the domains of word structure and grammar,
and are not better explained by autism spectrum disorder, intellectual
disability (intellectual developmental disorder), global developmental
delay, or another mental disorder.

From the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition,
(Copyright 2013). American Psychiatric Association, pp 42, 44, 47–48.

Language Disorder or Specific Language Impairment

The condition DSM-5 refers to as language disorder is also referred to as
specific language impairment (SLI) , developmental dysphasia , or
developmental language disorder . SLI is characterized by a significant
discrepancy between the child's overall cognitive level (typically nonverbal
measures of intelligence) and functional language level. These children also
follow an atypical pattern of language acquisition and use. Closer examination of
the child's skills might reveal deficits in understanding and use of word meaning
(semantics) and grammar (syntax). Often, children are delayed in starting to talk.
Most significantly, they usually have difficulty understanding spoken language.
The problem may stem from insufficient understanding of single words or from
the inability to deconstruct and analyze the meaning of sentences. Many affected
children show a holistic pattern of language development, repeating memorized
phrases or dialog from movies or stories (echolalia). In contrast to their difficulty
with spoken language, children with SLI appear to learn visually and
demonstrate their ability on nonverbal tests of intelligence.
After children with SLI become fluent talkers, they are generally less
proficient at producing oral narratives than their peers. Their stories tend to be
shorter and include fewer propositions, main story ideas, or story grammar
elements. Older children include fewer mental state descriptions (e.g., references
to what their characters think and how they feel). Their narratives contain fewer
cohesive devices, and the story line may be difficult to follow.
Screening
Developmental surveillance at each well child visit should include specific
questions about normal language developmental milestones and observations of
the child's behavior. Clinical judgment, defined as eliciting and responding to
parents' concerns, can detect the majority of children with speech and language
problems. The AAP recommends clinicians employ standardized developmental
screening questionnaires and observation checklists at select well child visits.
(see Chapter 28 ).
In 2015 the U.S. Preventive Services Task Force reviewed screening for SLI
in young children in primary care settings and found inadequate evidence to
support screening in the absence of parental or clinician concern about children's
speech, language, hearing, or development. When either parents or physicians
are concerned about speech or language development for reasons such as
highlighted in Table 52.3 , the child should be referred for further evaluation and
intervention (see Diagnostic Evaluation ).

Table 52.3
Speech and Language Screening
REFER FOR SPEECH–LANGUAGE EVALUATION IF:
AT RECEPTIVE EXPRESSIVE
AGE
15 Does not look/point at 5-10 objects Is not using 3 words
mo
18 Does not follow simple directions (“get Is not using Mama, Dada, or other names
mo your shoes”)
24 Does not point to pictures or body parts Is not using 25 words
mo when they are named
30 Does not verbally respond or nod/shake Is not using unique 2-word phrases, including noun–verb
mo head to questions combinations
36 Does not understand prepositions or Has a vocabulary of <200 words; does not ask for things;
mo action words; does not follow 2-step echolalia to questions; language regression after attaining 2-
directions word phrases

Noncauses of Language Delay

Twinning, birth order, “laziness,” exposure to multiple languages (bilingualism),
tongue-tie (ankyloglossia), or otitis media are not adequate explanations for
significant language delay. Normal twins learn to talk at the same age as normal
 childhood-onset fluency disorder
cluttering
physical concomitants
stammering, stuttering

Developmental stuttering is a childhood speech disorder that is not associated

with stroke, traumatic brain injury, or other possible medical conditions and that
interrupts the normal flow of speech through repeated or prolonged sounds,
syllables, or single-syllable words. (Table 52.4 lists definitions of terminology.)
All speakers experience speech dysfluencies . During the toddler and preschool
years, children often make repetitions of sounds, syllables, or words, particularly
at the beginning of sentences (normal dysfluencies). However, dysfluencies
found in individuals who stutter are distinct from those experienced by typically
developing speakers. Specifically, children who stutter show greater part-word
repetition (“b-b-b-b-but”), single-syllable word repetition (“My, my, my”), and
sound prolongation (“MMMMMM-an”), and the frequency of their stuttering is
much greater than found in normal dysfluencies. Other types of dysfluency that
are not exclusive to children who stutter include interjections (“well, uhh,
umm”), revisions (“I thought…I mean”), and phrase repetitions (“Did you say–
Did you say”). The perspective of the speaker also characterizes differences
between those children who stutter and a typical dysfluency. Children who
stutter have decided on a word to use but are unable to “get the word out,” while
a typically developing child may struggle to express herself because she is
unable to retrieve the word, changes thought, or is distracted.

Table 52.4

Terminology Related to Childhood-Onset Fluency Disorder

TERM DEFINITION
Stuttering A speech disorder manifested through abnormal speech patterns referred to as
dysfluencies
Childhood-onset Term used in DSM-5 that is synonymous with stuttering
fluency disorder
Stammering The clinical term used in the United Kingdom rather than stuttering; stammering also
used informally to describe halting speech
Cluttering A speech disorder characterized by excessively rapid and irregular rate of speech
Dysfluency Speech disruptions that can occur in normal or disordered speech

Multiple nonspeech features can accompany stuttering. Physical

concomitants that occur at the onset and as the condition persists include
movements of the head (head turning or jerking), face (eye blinking/squinting,
grimacing, opening or tightly closing the jaw), and neck (tightening) and
irregular inhalations and exhalations. Fear and anxiety about speaking in a large-
group setting, such as in front of a class or in interpersonal social interactions,
are emotional symptoms associated with stuttering. As with all social beings,
children closely monitor the reactions of those with whom they associate,
especially as they get older. It is not difficult to imagine the impact a single or
series of negative interactions or comments could have on a child's future
attempts to interact verbally with another or in a large social setting. Consider
also the potential social challenges associated with entering a classroom for the
first time, transitioning to middle/high school/college, beginning a job, dating,
and so on. Not surprisingly, avoidance is a common way of coping with the
anxiety created by the fear of stuttering.
In the Diagnostic and Statistical Manual for Mental Disorders, Fifth Edition
(DSM-5), the term stuttering has been removed from the diagnostic
classification, and the disorder is referred to as childhood-onset fluency
disorder (Table 52.5 ). Note that impact on functional behavior is a component
of the psychiatric diagnosis of this condition. In contrast, communication
disorder specialists would consider possible anxiety and avoidance of various
activities and situations a common concomitant of childhood-onset fluency
disorder (stuttering) and not necessarily a requirement for the diagnosis to be
made.
Table 52.5
DSM-5 Diagnostic Criteria for Childhood-
Onset Fluency Disorder (Stuttering)

A. Disturbances in the normal fluency and time patterning of speech that are
inappropriate for the individual's age and language skills, persist over time,
and are characterized by frequent and marked occurrences of one (or more)
of the following:
1. Sound and syllable repetitions.
2. Sound prolongations of consonants as well as vowels.
3. Broken words (e.g., pauses within a word).
4. Audible or silent blocking (filled or unfilled pauses in speech).
5. Circumlocutions (word substitutions to avoid problematic words).
6. Words produced with an excess of physical tension.
 7. Monosyllabic whole-word repetitions (e.g., “I-I-I-I see him”).
B. The disturbance causes anxiety about speaking or limitations in effective
communication, social participation, or academic or occupational
performance, individually or in any combination.
C. The onset of symptoms is in the early developmental period.
Note: Later-onset cases are diagnosed as 307.0 [F98.5] adult-onset fluency
disorder.
D. The disturbance is not attributable to a speech-motor or sensory deficit,
dysfluency associated with neurologic insult (e.g., stroke, tumor, trauma),
or another medical condition and is not better explained by another mental
disorder.

From the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition,
(Copyright 2013). American Psychiatric Association, pp 45–46.)

Stuttering is distinct from other disordered speech output conditions such as

cluttering in several ways. Unlike stuttering, for which distinct episodes can be
identified and even counted, cluttering affects the entire speech output. In
addition to elevated repetitions of partial words (as in stuttering), whole words,
and phrases, those who clutter show speech bursts that are often choppy, and
articulation can be slurred and imprecise. The level of awareness of how their
speech affects those listening, unlike children who stutter, is minimal for those
who clutter. Stammering and stuttering are terms used interchangeably,
although the former is used in the United Kingdom and the latter in the United
States. “Stammer” is also used informally to describe when an individual is
struggling to express himself and may speak in a halting or “bumbling” manner.

Epidemiology
Although prevalence studies have produced a range of estimates for
developmental stuttering, it appears that 0.75–1% of the population is
experiencing this condition at any one time. Incidence rates are considerably
higher: Estimates to date suggest an incidence rate of approximately 5%, with
rates considerably higher among young children than older children or
adolescents. Seldom does a child begin stuttering before 2 yr of age or after 12
yr; in fact, the mean age of onset is 2-4 yr, and most children stop stuttering
abnormalities may be mendelian (autosomal dominant de novo, autosomal
recessive, X-linked) or nonmendelian (imprinting, methylation, mitochondrial
defects; see Chapter 97 ). De novo mutations may also cause other phenotypic
features such as seizures or autism; the presence of these features suggests more
pleotropic manifestations of genetic mutations. Consistent with the finding that
disorders altering early embryogenesis are the most common and severe, the
earlier the problem occurs in development, the more severe its consequences
tend to be.

Table 53.1

Identification of Cause in Children With Significant Intellectual Disability

% OF
CAUSE EXAMPLES
TOTAL
Chromosomal disorder Trisomies 21, 18, 13 ~20
Deletions 1p36, 4p, 5p, 11p, 12q, 17p
Microdeletions; 47,XXX
Klinefelter and Turner syndromes
Genetic syndrome Fragile X, Prader-Willi, Angelman, and Rett syndromes ~20
Nonsyndromic autosomal Variations in copy number; de novo mutations in SYNGAP1 , GRIK2 , ~10
mutations TUSC3, oligosaccharyl transferase, and others
Developmental brain Hydrocephalus ± meningomyelocele; schizencephaly, lissencephaly ~8
abnormality
Inborn errors of metabolism or Phenylketonuria, Tay-Sachs disease, various storage diseases ~7
neurodegenerative disorder
Congenital infections HIV, toxoplasmosis, rubella, cytomegalovirus, syphilis, herpes simplex ~3
Familial intellectual disability Environment, syndromic, or genetic ~5
Perinatal causes Hypoxic-ischemic encephalopathy, meningitis, intraventricular 4
hemorrhage, periventricular leukomalacia, fetal alcohol syndrome
Postnatal causes Trauma (abuse), meningitis, hypothyroidism ~4
Unknown 20
Adapted from Stromme P, Hayberg G: Aetiology in severe and mild mental retardation: a
population based study of Norwegian children, Dev Med Child Neurol 42:76–86, 2000.

Etiologic workup is recommended in all cases of GDD or ID. Although there

are only about 80 disorders (all of which are metabolic in nature) for which
treatment may ameliorate the core symptoms of ID, several reasons beyond
disease modification should prompt providers to seek etiologic answers in
patients with ID. These include insight into possible associated medical or
behavioral comorbidities; information on prognosis and life expectancy;
estimation of recurrence risk for family planning counseling, potential
validation, and closure for the family; increased access to services or specific
supports; and better understanding of underlying pathology with the hope of new
which to develop targeted therapies to bypass or correct newly identified defects.
For example, use of histone deacetylase (HDAC) inhibitors has been shown to
rescue structural and functional neural deficits in mouse models of Kabuki
syndrome, a disorder of histone methylation that leads to variable levels of ID
and characteristic facial features (see Chapter 100 ).

Clinical Manifestations
Early diagnosis of ID facilitates earlier intervention, identification of abilities,
realistic goal setting, easing of parental anxiety, and greater acceptance of the
child in the community. Most children with ID first come to the pediatrician's
attention in infancy because of dysmorphisms, associated developmental
disabilities, or failure to meet age-appropriate developmental milestones (Tables
53.2 and 53.3 ). There are no specific physical characteristics of ID, but
dysmorphisms may be the earliest signs that bring children to the attention of the
pediatrician. They might fall within a genetic syndrome such as Down syndrome
or might be isolated, as in microcephaly or failure to thrive. Associated
developmental disabilities include seizure disorders, cerebral palsy, and ASD.

Table 53.2
Physical Examination of a Child With Suspected
Developmental Disabilities

ITEM POSSIBLE SIGNIFICANCE

General appearance May indicate significant delay in development or obvious syndrome
Stature
Short stature Malnutrition, many genetic syndromes are associated with short stature
(e.g., Turner, Noonan)
Obesity Prader-Willi syndrome
Large stature Sotos syndrome
Head
Macrocephaly Alexander syndrome, Canavan disease, Sotos syndrome,
gangliosidosis, hydrocephalus, mucopolysaccharidosis, subdural
effusion
Microcephaly Virtually any condition that can restrict brain growth (e.g., malnutrition,
Angelman syndrome, Cornelia de Lange syndrome, fetal alcohol
effects)
Face
Coarse, triangular, round, or flat face; Specific measurements may provide clues to inherited, metabolic, or
hypotelorism or hypertelorism; slanted other diseases such as fetal alcohol syndrome, cri du chat (5p−)
or short palpebral fissure; unusual nose, syndrome, or Williams syndrome.
maxilla, and mandible
Eyes
Prominent Crouzon, Seckel, and fragile X syndromes
Cataract Galactosemia, Lowe syndrome, prenatal rubella, hypothyroidism
Cherry-red spot in macula Gangliosidosis (GM1 ), metachromatic leukodystrophy, mucolipidosis,
Tay-Sachs disease, Niemann-Pick disease, Farber lipogranulomatosis,
sialidosis type III
Chorioretinitis Congenital infection with cytomegalovirus, toxoplasmosis, Zika virus,
or rubella
Corneal cloudiness Mucopolysaccharidosis types I and II, Lowe syndrome, congenital
syphilis
Ears
Low-set or malformed pinnae Trisomies such as Down syndrome, Rubinstein-Taybi syndrome,
CHARGE syndrome, cerebrooculofacioskeletal syndrome, fetal
phenytoin effects
Hearing Loss of acuity in mucopolysaccharidosis; hyperacusis in many
encephalopathies
Heart
Structural anomaly or hypertrophy CHARGE syndrome, velocardiofacial syndrome, glycogenosis type II,
fetal alcohol effects, mucopolysaccharidosis type I; chromosomal
anomalies such as Down syndrome; maternal PKU; chronic cyanosis
may impair cognitive development.
Liver
Hepatomegaly Fructose intolerance, galactosemia, glycogenosis types I-IV,
mucopolysaccharidosis types I and II, Niemann-Pick disease, Tay-
Sachs disease, Zellweger syndrome, Gaucher disease, ceroid
lipofuscinosis, gangliosidosis
Genitalia
Macroorchidism Fragile X syndrome
Hypogenitalism Prader-Willi, Klinefelter, and CHARGE syndromes
Extremities
Hands, feet; dermatoglyphics, creases May indicate a specific entity such as Rubinstein-Taybi syndrome or
may be associated with chromosomal anomaly
Joint contractures Signs of muscle imbalance around the joints; e.g., with
meningomyelocele, cerebral palsy, arthrogryposis, muscular dystrophy;
also occurs with cartilaginous problems such as mucopolysaccharidosis
Skin
Café au lait spots Neurofibromatosis, tuberous sclerosis, chromosomal aneuploidy,
ataxia-telangiectasia, multiple endocrine neoplasia type 2b
Fanconi anemia, Gaucher disease
Syndromes: basal cell nevus, McCune-Albright, Silver-Russell,
Bloom, Chediak-Higashi, Hunter, Bannayan-Riley-Ruvalcaba,
Maffucci
Seborrheic or eczematoid rash PKU, histiocytosis
Hemangiomas and telangiectasia Sturge-Weber syndrome, Bloom syndrome, ataxia-telangiectasia
Hypopigmented macules, streaks, Tuberous sclerosis, hypomelanosis of Ito
adenoma sebaceum
Hair
Hirsutism De Lange syndrome, mucopolysaccharidosis, fetal phenytoin effects,
cerebrooculofacioskeletal syndrome, trisomy 18, Wiedemann-Steiner
syndrome (hypertrichosis cubiti)
Neurologic
Asymmetry of strength and tone Focal lesion, hemiplegic cerebral palsy
Hypotonia Prader-Willi, Down, and Angelman syndromes; gangliosidosis; early
cerebral palsy; muscle disorders (dystrophy or myopathy)
 Hypertonia Neurodegenerative conditions involving white matter, cerebral palsy,
trisomy 18
Ataxia Ataxia-telangiectasia, metachromatic leukodystrophy, Angelman
syndrome
CHARGE, Coloboma, heart defects, atresia choanae, retarded growth, genital anomalies, ear
anomalies (deafness); CATCH-22, cardiac defects, abnormal face, thymic hypoplasia, cleft palate,
hypocalcemia—defects on chromosome 22; PKU, phenylketonuria.
From Simms M: Intellectual and developmental disability. In Kliegman RM, Lye PS, Bordini BJ, et
al, editors: Nelson pediatric symptom-based diagnosis, Philadelphia, 2018, Elsevier, Table 24.11,
p 376.

Table 53.3

Examples of Minor Anomalies and Associated Syndromes* †

AREA ANOMALY/SYNDROME
Head Flat occiput: Down syndrome, Zellweger syndrome; prominent occiput: trisomy 18
Delayed closure of sutures: hypothyroidism, hydrocephalus
Craniosynostosis: Crouzon syndrome, Pfeiffer syndrome
Delayed fontanel closure: hypothyroidism, Down syndrome, hydrocephalus, skeletal dysplasias
Face Midface hypoplasia: fetal alcohol syndrome, Down syndrome
Triangular facies: Russell-Silver syndrome, Turner syndrome
Coarse facies: mucopolysaccharidoses, Sotos syndrome
Prominent nose and chin: fragile X syndrome
Flat facies: Apert syndrome, Stickler syndrome
Round facies: Prader-Willi syndrome
Eyes Hypertelorism: fetal hydantoin syndrome, Waardenburg syndrome
Hypotelorism: holoprosencephaly sequence, maternal phenylketonuria effect
Inner canthal folds/Brushfield spots: Down syndrome; slanted palpebral fissures: trisomies
Prominent eyes: Apert syndrome, Beckwith-Wiedemann syndrome
Lisch nodules: neurofibromatosis
Blue sclera: osteogenesis imperfecta, Turner syndrome, hereditary connective tissue disorders
Ears Large pinnae/simple helices: fragile X syndrome
Malformed pinnae/atretic canal: Treacher Collins syndrome, CHARGE syndrome
Low-set ears: Treacher Collins syndrome, trisomies, multiple disorders
Nose Anteverted nares/synophrys: Cornelia de Lange syndrome; broad nasal bridge: fetal drug effects,
fragile X syndrome
Low nasal bridge: achondroplasia, Down syndrome
Prominent nose: Coffin-Lowry syndrome, Smith-Lemli-Opitz syndrome
Mouth Long philtrum/thin vermilion border: fetal alcohol effects
Cleft lip and palate: isolated or part of a syndrome
Micrognathia: Pierre Robin sequence, trisomies, Stickler syndrome
Macroglossia: hypothyroidism, Beckwith-Wiedemann syndrome
Teeth Anodontia: ectodermal dysplasia
Notched incisors: congenital syphilis
Late dental eruption: Hunter syndrome, hypothyroidism
Talon cusps: Rubinstein-Taybi syndrome
Wide-spaced teeth: Cornelia de Lange syndrome, Angelman syndrome
Hair Hirsutism: Hurler syndrome
Low hairline: Klippel-Feil sequence, Turner syndrome
Sparse hair: Menkes disease, argininosuccinic acidemia
 Abnormal hair whorls/posterior whorl: chromosomal aneuploidy (e.g., Down syndrome)
Abnormal eyebrow patterning: Cornelia de Lange syndrome
Neck Webbed neck/low posterior hairline: Turner syndrome, Noonan syndrome
Chest Shield-shaped chest: Turner syndrome
Genitalia Macroorchidism: fragile X syndrome
Hypogonadism: Prader-Willi syndrome
Extremities Short limbs: achondroplasia, rhizomelic chondrodysplasia
Small hands: Prader-Willi syndrome
Clinodactyly: trisomies, including Down syndrome
Polydactyly: trisomy 13, ciliopathies
Broad thumb: Rubinstein-Taybi syndrome
Syndactyly: de Lange syndrome
Transverse palmar crease: Down syndrome
Joint laxity: Down syndrome, fragile X syndrome, Ehlers-Danlos syndrome
Phocomelia: Cornelia de Lange syndrome
Spine Sacral dimple/hairy patch: spina bifida
Skin Hypopigmented macules/adenoma sebaceum: tuberous sclerosis
Café au lait spots and neurofibromas: neurofibromatosis
Linear depigmented nevi: hypomelanosis of Ito
Facial port-wine hemangioma: Sturge-Weber syndrome
Nail hypoplasia or dysplasia: fetal alcohol syndrome, trisomies
*
Increased incidence of minor anomalies have been reported in cerebral palsy, intellectual
disability, learning disabilities, and autism.
† The presence of 3 or more minor anomalies implies a greater chance that the child has a major
anomaly and a diagnosis of a specific syndrome.
CHARGE, Coloboma, heart defects, atresia choanae, retarded growth, genital anomalies, ear
anomalies (deafness).
Modified from Levy SE, Hyman SL. Pediatric assessment of the child with developmental delay,
Pediatr Clin North Am 40:465-477, 1993.

Most children with ID do not keep up with their peers' developmental skills.
In early infancy, failure to meet age-appropriate expectations can include a lack
of visual or auditory responsiveness, unusual muscle tone (hypo- or hypertonia)
or posture, and feeding difficulties. Between 6 and 18 mo of age, gross motor
delay (lack of sitting, crawling, walking) is the most common complaint.
Language delay and behavior problems are common concerns after 18 mo (Table
53.4 ). For some children with mild ID, the diagnosis remains uncertain during
the early school years. It is only after the demands of the school setting increase
over the years, changing from “learning to read” to “reading to learn,” that the
child's limitations are clarified. Adolescents with mild ID are typically up to date
on current trends and are conversant as to “who,” “what,” and “where.” It is not
until the “why” and “how” questions are asked that their limitations become
apparent. If allowed to interact at a superficial level, their mild ID might not be
appreciated, even by professionals, who may be their special education teachers
or healthcare providers. Because of the stigma associated with ID, adolescents
may use euphemisms to avoid being thought of as “stupid” or “retarded” and
may refer to themselves as learning disabled, dyslexic, language disordered, or
slow learners. Some people with ID emulate their social milieu to be accepted.
They may be social chameleons and assume the morals of the group to whom
they are attached. Some would rather be thought “bad” than “incompetent.”

Table 53.4

Common Presentations of Intellectual Disability by Age

AGE AREA OF CONCERN
Newborn Dysmorphic syndromes, (multiple congenital anomalies), microcephaly
Major organ system dysfunction (e.g., feeding, breathing)
Early infancy (2-4 mo) Failure to interact with the environment
Concerns about vision and hearing impairments
Later infancy (6-18 mo) Gross motor delay
Toddlers (2-3 yr) Language delays or difficulties
Preschool (3-5 yr) Language difficulties or delays
Behavior difficulties, including play
Delays in fine motor skills: cutting, coloring, drawing
School age (>5 yr) Academic underachievement
Behavior difficulties (e.g., attention, anxiety, mood, conduct)

Children with ID have a nonprogressive disorder; loss of developmental

milestones or progressive symptoms suggest another disorder (see Chapter 53.1
).

Diagnostic Evaluation
Intellectual disability is one of the most frequent reasons for referral to pediatric
genetic providers, with separate but similar diagnostic evaluation guidelines put
forth by the American College of Medical Genetics, the American Academy of
Neurology, the American Academy of Pediatrics (AAP), and the American
Academy of Child and Adolescent Psychiatry. ID is a diagnosis of great clinical
heterogeneity, with only a subset of syndromic etiologies identifiable through
classic dysmorphology. If diagnosis is not made after conducting an appropriate
history and physical examination, chromosomal microarray is the recommended
first step in the diagnostic evaluation of ID. Next-generation sequencing
represents the new diagnostic frontier, with extensive gene panels (exome or
whole genome) that increase the diagnostic yield and usefulness of genetic
testing in ID. Other commonly used medical diagnostic testing for children with
ID includes neuroimaging, metabolic testing, and electroencephalography (Fig.
53.1 ).

FIG. 53.1 Algorithm for the evaluation of the child with unexplained global
developmental delay (GDD) or intellectual disability (ID). AA, amino acids; ASD, autistic
spectrum disorder; CK, creatine kinase; CSF, cerebrospinal fluid; FBC, full blood count;
GAA, guanidinoacetic acid; GAG, glycosaminoglycans; LFT, liver function test; OA,
organic acids; TFT, thyroid function tests; TSC, tuberous sclerosis complex; U&E, urea
and electrolytes; VLCFA, very long chain fatty acids; WES, whole exome sequencing;
WGS, whole genome sequencing; X-linked intellectual disability genes.

Decisions to pursue an etiologic diagnosis should be based on the medical and

family history, physical examination, and the family's wishes. Table 53.5
summarizes clinical practice guidelines and the yields of testing to assist in
decisions about evaluating the child with GDD or ID. Yield of testing tends
increase with worsening severity of delays.

Table 53.5

Suggested Evaluation of the Child With Intellectual Disability (ID) or Global

Developmental Delay (GDD)
TEST COMMENT
In-depth Includes pre-, peri-, and postnatal events (including seizures); developmental attainments; and 3-
history generation pedigree in family history (focusing on neurologic or developmental abnormalities,
miscarriages, consanguinity, etc.)
 Physical Particular attention to minor or subtle dysmorphisms; growth issues; neurocutaneous
examination findings; eye and skull abnormalities; hepatosplenomegaly; and neurologic examination for
focality
Behavioral phenotype
Vision and Essential to detect and treat; can mask as developmental delay
hearing
evaluation
Gene A 15% yield overall
microarray Better resolution than with karyotype; may identify up to twice as many abnormalities as
analysis karyotyping
Karyotype Yield of 4% in ID/GDD (18.6% if syndromic features, 3% excluding trisomy 21)
Best for inversions and balanced insertions, reciprocal translocations, and polyploidy
Fragile X Combined yield of 2%
screen Preselection on clinical grounds can increase yield to 7.6%
Next- Detects inherited and de novo point mutations, especially in nonsyndromic severe intellectual
generation disability
gene Whole exome sequencing (WES, introduced in 2010) gives an additional yield of about 30–
sequencing 40%.
Although not yet used clinically, pilot studies of whole genome sequencing (WGS) reveal
additional yield of about 15%.
Neuroimaging MRI preferred; positive findings increased by abnormalities of skull contour or microcephaly
and macrocephaly, or focal neurologic examination (30–40% if indicated, 10–14% if
screening).
Identification of specific etiologies is rare; most conditions that are found do not alter the
treatment plan; need to weigh risk of sedation against possible yield.
Thyroid (T4 , Near 0% in settings with universal newborn screening program
TSH)
Serum lead If there are identifiable risk factors for excessive environmental lead exposure (e.g., low
socioeconomic status, home built before 1950)
Metabolic Yield of 0.2–4.6% based on clinical indicators and tests performed
testing Urine organic acids, plasma amino acids, ammonia, lactate, and capillary blood gas
Focused testing based on clinical findings is warranted if lack of newborn screen results or
suggestive history/exam (e.g., regression, consanguinity, hepatosplenomegaly, course facies).
Tandem mass spectrometry newborn screening has allowed for identification of many
disorders in perinatal period and have decreased yield in older children; other disorders have
emerged, such as congenital disorders of glycosylation (yield 1.4%) and disorders of creatine
synthesis and transport (yield 2.8%).
MECP2 for 1.5% of females with criteria suggestive of Rett (e.g., acquired microcephaly, loss of skills)
Rett 0.5% of males
syndrome
EEG May be deferred in absence of history of seizures
Repeated Can give time for maturation of physical and behavioral phenotype; new technology may be
history and available for evaluation.
physical
examination

EEG, Electroencephalogram; CGH, comparative genomic hybridization; MECP2, methyl CpG–

binding protein 2; T4 , thyroxine; TSH, thyroid-stimulating hormone.
Data from Michelson DJ et al: Evidence report. Genetic and metabolic testing on children with
global developmental delay: report of the Quality Standards Subcommittee of the American
Academy of Neurology and the Practice Committee of Child Neurology, Neurology 77:1629-35,
2011; Curry CJ et al: Evaluation of mental retardation: recommendations of a Consensus
Conference: American College of Medical Genetics, Am J Med Genet 12:72:468-477, 1997;
 FIG. 53.2 Summary of treatable inherent errors of metabolism (IEM) that
can be detected by metabolic tests in affected children, each of which is
affordable and accessible and has the potential to identify at least 2 IEM
(and up to 22). Each bar represents the yield of the specific screening test
and lists the number and types of treatable IEM it can identify. PAA, Plasma
amino acids; tHcy, total homocysteine; ACP, plasma acylcarnitine profile;
UOA, urine organic acids. (From van Karnebeek CD, Stockler S: Treatable
inborn errors of metabolism causing intellectual disability: a systematic
literature review, Mol Genet Metab 105:368–381, 2012, Fig 1, p 374.)

Table 53.6
Treatable Intellectual Disability Endeavor
(TIDE) Diagnostic Protocol
Tier 1: Nontargeted Metabolic Screening to Identify 54 (60%) Treatable
IEM

Blood
Plasma amino acids
Plasma total homocysteine
Acylcarnitine profile
Copper, ceruloplasmin
Urine
Organic acids
 Purines and pyrimidines
Creatine metabolites
Oligosaccharides
Glycosaminoglycans
Amino acids (when indicated)

Tier 2: Current Practice Adhering to International Guidelines* (1 or more

of:)

Audiology
Ophthalmology
Cytogenetic testing (array CGH)
Thyroid studies
Complete blood count (CBC)
Lead
Metabolic testing
Brain MRI and 1H spectroscopy (where available)
Fragile X
Targeted gene sequencing/molecular panel
Other

Tier 3: Targeted Workup to Identify 35 (40%) Treatable IEM Requiring

Specific Testing

According to patient's symptomatology and clinician's expertise

Utilization of digital tools (www.treatable-id.org )
Specific biochemical/gene test
Whole blood manganese
Plasma cholestanol
Plasma 7-dehydroxycholesterol:cholesterol ratio
Plasma pipecolic acid and urine α-amino adipic semialdehyde (AASA)
Plasma very-long-chain fatty acids
Plasma vitamin B12 and folate
Serum and CSF lactate to pyruvate ratio
Enzyme activities (leukocytes): arylsulfatase A, biotinidase,
glucocerebrosidase, fatty aldehyde dehydrogenase
 Urine deoxypyridinoline
CSF amino acids
CSF neurotransmitters
CSF-to-plasma glucose ratio
CoQ measurement: fibroblasts
Molecular analysis: CA5A, NPC1, NPC2, SC4MOL, SLC18A2, SLC19A3,
SLC30A10, SLC52A2, SLC52A3, PDHA1, DLAT, PDHX, SPR, TH genes

IEM, Inborn errors of metabolism; CSF, cerebrospinal fluid; CGH,

comparative genomic hybridization; CoQ, coenzyme Q (ubiquinone).

* Low threshold for ordering tests.

Adapted from Van Karnebeek CD, Stockler-Ipsiroglu S. Early identification of

treatable inborn errors of metabolism in children with intellectual disability: The
Treatable Intellectual Disability Endeavor protocol in British Columbia,
Paediatr Child Health 19(9):469–471, 2014.

Some children with subtle physical or neurologic findings can also have
determinable biologic causes of their ID (see Tables 53.2 and 53.3 ). How
intensively one investigates the cause of a child's ID is based on the following
factors:

◆ What is the degree of delay, and what is the age of

the child? If milder or less pervasive delays are
present, especially in a younger child, etiologic yield
is likely to be lower.
◆ Is the medical history, family history, or physical
exam suggestive of a specific disorder, increasing the
likelihood that a diagnosis will be made? Are the
parents planning on having additional children, and
does the patient have siblings? If so, one may be more
Mild ID might not always be a lifelong disorder. Children might meet criteria for
GDD at an early age, but later the disability can evolve into a more specific
developmental disorder (communication disorder, autism, specific learning
disability, or borderline normal intelligence). Others with a diagnosis of mild ID
during their school years may develop sufficient adaptive behavior skills that
they no longer fit the diagnosis as adolescents or young adults, or the effects of
maturation and plasticity may result in children moving from one diagnostic
category to another (from moderate to mild ID). Conversely, some children who
have a diagnosis of a specific learning disability or communication disorder
might not maintain their rate of cognitive growth and may fall into the range of
ID over time.
The apparent higher prevalence of ID in low- and middle-income countries is
of concern given the limitations in available resources. Community-based
rehabilitation (CBR) is an effort promoted by WHO over the past 4 decades as
a means of making use of existing community resources for persons with
disabilities in low-income countries with the goal of increasing inclusion and
participation within the community. CBR is now being implemented in >90
countries, although the efficacy of such programs has not been established.
The long-term outcome of persons with ID depends on the underlying cause,
degree of cognitive and adaptive deficits, presence of associated medical and
developmental impairments, capabilities of the families, and school and
community supports, services, and training provided to the child and family
(Table 53.7 ). As adults, many persons with mild ID are capable of gaining
economic and social independence with functional literacy, but they may need
periodic supervision (especially when under social or economic stress). Most
live successfully in the community, either independently or in supervised
settings.

Table 53.7

Severity of Intellectual Disability and Adult-Age Functioning

MENTAL
LEVEL AGE AS ADULT ADAPTATION
ADULT
Mild 9-11 yr Reads at 4th-5th grade level; simple multiplication and division; writes simple letter, lists;
completes job application; basic independent job skills (arrive on time, stay at task, interact
with coworkers); uses public transportation, might qualify for driver's license; keeps house,
cooks using recipes
Moderate 6-8 yr Sight-word reading; copies information (e.g., address from card to job application);
 matches written number to number of items; recognizes time on clock; communicates;
some independence in self-care; housekeeping with supervision or cue cards; meal
preparation, can follow picture recipe cards; job skills learned with much repetition; uses
public transportation with some supervision
Severe 3-5 yr Needs continuous support and supervision; might communicate wants and needs,
sometimes with augmentative communication techniques
Profound <3 yr Limitations of self-care, continence, communication, and mobility; might need complete
custodial or nursing care
Data from World Health Organization: International Statistical Classification of Diseases and
Related Health Problems, 10th revision, Geneva, 2011, WHO.

For persons with moderate ID, the goals of education are to enhance adaptive
abilities and “survival” academic and vocational skills so they are better able to
live and function in the adult world (Table 53.7 ). The concept of supported
employment has been very beneficial to these individuals; the person is trained
by a coach to do a specific job in the setting where the person is to work,
bypassing the need for a “sheltered workshop” experience and resulting in
successful work adaptation in the community. These persons generally live at
home or in a supervised setting in the community.
As adults, people with severe to profound ID usually require extensive to
pervasive supports (Table 53.7 ). These individuals may have associated
impairments, such as cerebral palsy, behavioral disorders, epilepsy, or sensory
impairments, that further limit their adaptive functioning. They can perform
simple tasks in supervised settings. Most people with this level of ID can live in
the community with appropriate supports.
The life expectancy of people with mild ID is similar to the general
population, with a mean age at death in the early 70s. However, persons with
severe and profound ID have a decreased life expectancy at all ages, presumably
from associated serious neurologic or medical disorders, with a mean age at
death in the mid-50s. Given that persons with ID are living longer and have high
rates of comorbid health conditions in adulthood (e.g., obesity, hypertension,
diabetes), ID is now one of the costliest ICD-10 diagnoses, with an average
lifetime cost of 1-2 million dollars per person. Thus the priorities for
pediatricians are to improve healthcare delivery systems during childhood,
facilitate the transition of care to adult providers, and ensure high-quality,
integrated community-based services for all persons with ID.

53.1
Intellectual Disability With
Regression
Bruce K. Shapiro, Meghan E. O'Neill

The patients discussed in Chapter 53 with intellectual disability (ID) usually

have a static and nonprogressive disease course. They may acquire new
developmental milestones, although at a slower rate than unaffected children, or
they may remain fixed at a particular developmental stage. Regression of
milestones in these children may be caused by increasing spasticity or
contractures, new-onset seizures or a movement disorder, or the progression of
hydrocephalus.
Nonetheless, regression or loss of milestones should suggest a progressive
encephalopathy caused by an inborn error of metabolism, including disorders
of energy metabolism and storage disorders, or a neurodegenerative disorder,
including disorders of the whole brain (diffuse encephalopathies), white matter
(leukodystrophies), cerebral cortex, and basal ganglia as well as spinocerebellar
disorders (Table 53.8 ) (see Chapters 616 and 617 ).
Table 53.8
Causes of Progressive Encephalopathy
Onset Before Age 2 Years
Acquired Immunodeficiency Syndrome Encephalopathy *
Disorders of Amino Acid Metabolism

Guanidinoacetate methyltransferase deficiency*

Homocystinuria (21q22)*
Maple syrup urine disease (intermediate and thiamine response forms)*
Phenylketonuria
Guanidinoacetate methyltransferase deficiency*
Hyperammonemic disorders
Disorders of Lysosomal Enzymes

Ganglioside storage disorders

GM1 gangliosidosis
GM2 gangliosidosis (Tay-Sachs disease, Sandhoff disease)
Gaucher disease type II (glucosylceramide lipidosis)*
Globoid cell leukodystrophy (Krabbe disease)
Glycoprotein degradation disorders
I-cell disease
Mucopolysaccharidoses*
Type I (Hurler Syndrome)*
Type III (Sanfilippo disease)
Niemann-Pick disease type A (sphingomyelin lipidosis)
Sulfatase deficiency disorders
Metachromatic leukodystrophy (sulfatide lipidoses)
Multiple sulfatase deficiency

Carbohydrate-Deficient Glycoprotein Syndromes

Hypothyroidism *
Mitochondrial Disorders

Alexander disease
Mitochondrial myopathy, encephalopathy, lactic acidosis, stroke
Progressive infantile poliodystrophy (Alpers disease)
Subacute necrotizing encephalomyelopathy (Leigh disease)
Trichopoliodystrophy (Menkes disease)

Neurocutaneous Syndromes

Chediak-Higashi syndrome
Neurofibromatosis*
Tuberous sclerosis*

Other Disorders of Gray Matter

 Infantile ceroid lipofuscinosis (Santavuori-Haltia disease)
Infantile neuroaxonal dystrophy
Lesch-Nyhan disease*
Progressive neuronal degeneration with liver disease
Rett syndrome

Progressive Hydrocephalus *
Other Disorders of White Matter

Aspartoacylase deficiency (Canavan disease)

Galactosemia: Transferase deficiency*
Neonatal adrenoleukodystrophy
Pelizaeus-Merzbacher disease
Progressive cavitating leukoencephalopathy

Onset After Age 2 Years

Disorders of Lysosomal Enzymes

Gaucher disease type III (glucosylceramide lipidosis)

Globoid cell leukodystrophy (late-onset Krabbe disease)
Glycoprotein degradation disorders
Aspartylglycosaminuria
Mannosidosis type II
GM2 gangliosidosis (juvenile Tay-Sachs disease)
Metachromatic leukodystrophy (late-onset sulfatide lipidoses)
Mucopolysaccharidoses types II and VII
Niemann-Pick type C (sphingomyelin lipidosis)

Infectious Disease

Acquired immunodeficiency syndrome encephalopathy*

Congenital syphilis*
Subacute sclerosing panencephalitis

Other Disorders of Gray Matter

 Ceroid lipofuscinosis
Juvenile
Late infantile (Bielschowsky-Jansky disease)
Huntington disease
Mitochondrial disorders
Late-onset poliodystrophy
Myoclonic epilepsy and ragged-red fibers
Progressive neuronal degeneration with liver disease
Xeroderma pigmentosum

Other Disorders of White Matter

Adrenoleukodystrophy
Alexander disease
Cerebrotendinous xanthomatosis
Progressive cavitating leukoencephalopathy

Other Diseases

Wilson disease
Friedreich ataxia
Pantothenate kinase neurodegeneration
Neurodegeneration with brain iron accumulation

* Denotes the most common conditions and those with disease-modifying

treatment.

From Pina-Garza JE: Fenichel's clinical pediatric neurology, ed 7, Philadelphia,

2013, Elsevier, Boxes 5-2 and 5-5, pp 114, 121.

Bibliography
American Academy of Pediatrics, Committee on Children with
Disabilities. Pediatrician's role in the development and
CHAPTER 54

Autism Spectrum Disorder

Carolyn F. Bridgemohan

Definition
Autism spectrum disorder (ASD) is a neurobiologic disorder with onset in
early childhood. The key features are impairment in social communication and
social interaction accompanied by restricted and repetitive behaviors. The
presentation of ASD can vary significantly from one individual to another, as
well as over the course of development for a particular child. There is currently
no diagnostic biomarker for ASD. Accurate diagnosis therefore requires careful
review of the history and direct observation of the child's behavior.

Diagnostic Criteria and Symptoms

The diagnostic criteria in the Diagnostic and Statistical Manual, Fifth Edition
(DSM-5) focus on symptoms in two primary domains (Table 54.1 ). To meet
criteria for ASD, the symptoms need to have been present since the early
developmental period, significantly impact functioning, and not be better
explained by the diagnoses of intellectual disability (ID) or global developmental
delay (GDD; Chapter 53 ). Table 54.2 provides associated features not included
in DSM-5 criteria.
Table 54.1
DSM-5 Diagnostic Criteria for Autism
Spectrum Disorder
A. Persistent deficits in social communication and social interaction across
 multiple contexts, as manifested by the following, currently or by history:
1. Deficits in social-emotional reciprocity.
2. Deficits in nonverbal communicative behaviors used for social
interaction.
3. Deficits in developing, maintaining, and understanding
relationships.
B. Restricted, repetitive patterns of behavior, interests, or activities, as
manifested by at least 2 of the following, currently or by history:
1. Stereotyped or repetitive motor movements, use of objects, or
speech.
2. Insistence on sameness, inflexible adherence to routines, or
ritualized patterns of verbal or nonverbal behavior.
3. Highly restricted, fixated interests that are abnormal in intensity
or focus.
4. Hyper- or hyporeactivity to sensory input or unusual interest in
sensory aspects of the environment.
C. Symptoms must be present in the early developmental period (may not
become fully manifest until social demands exceed limited capacities, or
may be masked by learned strategies in later life).
D. Symptoms cause clinically significant impairment in social, occupational,
or other important areas of current functioning.
E. These disturbances are not better explained by intellectual disability
(intellectual developmental disorder) or global developmental delay.

From the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition,
(Copyright 2013). American Psychiatric Association, pp 50–51.
Table 54.2
Associated Features of Autism Not in DSM-5
Criteria

Atypical language development and abilities

Age <6 yr: frequently disordered and delayed in comprehension;
two-thirds have difficulty with expressive phonology and
grammar
Age ≥6 yr: disordered pragmatics, semantics, and morphology,
 with relatively intact articulation and syntax (i.e., early
difficulties are resolved)
Motor abnormalities: motor delay; hypotonia; catatonia; deficits in
coordination, movement preparation and planning, praxis, gait, and
balance

For version with full references, see Diagnostic and Statistical Manual of Mental
Disorders, Fifth Edition, Washington DC, 2013, American Psychiatric
Association. Adapted from Lai MC, Lombardo MV, Baron-Cohen S: Autism,
Lancet 383:896–910, 2014.

Previously, ASD was grouped under the heading of pervasive developmental

disorders (PDDs) and included a variety of subdiagnoses, including autistic
disorder, PDD not otherwise specified (PDD-NOS), and Asperger disorder .
Research did not support these as distinct conditions; in the current diagnostic
framework, any individual previously diagnosed with 1 of these conditions
should be diagnosed with ASD.
Symptoms can present early in infancy, with reduced response to name and
unusual use of objects being strong predictors for risk of ASD. However,
symptoms before age 12 mo are not as reliably predictive of later diagnosis.
Individuals with milder severity may not present until preschool or school age,
when the social demands for peer interaction and group participation are higher.

Social Communication and Social Interaction

Individuals with ASD have difficulty understanding and engaging in social
relationships. The problems are pervasive and impact 3 major areas: reciprocal
social interactions (social-emotional reciprocity), nonverbal communication, and
understanding of social relationships. The presentation can vary with severity
and developmental functioning. Diagnosis of ASD requires the presence of
symptoms from all 3 categories (Table 54.3 ).
Table 54.3
Signs and Symptoms of Possible Autism in
Preschool Children (or Equivalent Mental
Age)
Social Interaction and Reciprocal Communication Behaviors
Spoken Language

Language delay (in babbling or using words; e.g., using <10 words by age
2 yr).
Regression in, or loss of, use of speech.
Spoken language (if present) may include unusual features, such as
vocalizations that are not speech-like; odd or flat intonation; frequent
repetition of set words and phrases (echolalia); reference to self by name
or “you” or “she” or “he” beyond age 3 yr.
Reduced and/or infrequent use of language for communication; e.g., use of
single words, although able to speak in sentences.

Responding to Others

Absent or delayed response to name being called, despite normal hearing.

Reduced or absent responsive social smiling.
Reduced or absent responsiveness to other people's facial expressions or
feelings.
Unusually negative response to the requests of others (“demand avoidance”
behavior).
Rejection of cuddles initiated by parent or caregiver, although the child
may initiate cuddles.

Interacting With Others

Reduced or absent awareness of personal space, or unusually intolerant of

people entering their personal space.
Reduced or absent social interest in others, including children of own age
—may reject others; if interested in others, child may approach others
inappropriately, seeming to be aggressive or disruptive.
Reduced or absent imitation of others' actions.
Reduced or absent initiation of social play with others; plays alone.
Reduced or absent enjoyment of situations that most children like; e.g.,
birthday parties.
Reduced or absent sharing of enjoyment.
Eye Contact, Pointing, and Other Gestures

Reduced or absent use of gestures and facial expressions to communicate

(although may place an adult's hand on objects).
Reduced and poorly integrated gestures, facial expressions, body
orientation, eye contact (looking at people's eyes when speaking), and
speech used in social communication.
Reduced or absent social use of eye contact (assuming adequate vision).
Reduced or absent “joint attention” (when 1 person alerts another to
something by means of gazing, finger pointing, or other verbal or
nonverbal indication for the purpose of sharing interest). This would be
evident in the child from lack of:
Gaze switching
Following a point (looking where the other person points to—may
look at hand)
Using pointing at or showing objects to share interest

Ideas and Imagination

Reduced or absent imagination and variety of pretend play.

Unusual or Restricted Interests and/or Rigid and Repetitive Behaviors

Repetitive “stereotypic” movements such as hand flapping, body rocking

while standing, spinning, and finger flicking.
Repetitive or stereotyped play; e.g., opening and closing doors.
Over focused or unusual interests.
Excessive insistence on following own agenda.
Extremes of emotional reactivity to change or new situations; insistence on
things being “the same.”
Overreaction or underreaction to sensory stimuli, such as textures, sounds,
or smells.
Excessive reaction to the taste, smell, texture, or appearance of food, or
having extreme food fads.

Adapted from Baird G, Douglas HR, Murphy MS: Recognizing and diagnosing
autism in children and young people: summary of NICE guidance. BMJ
343:d6360, 2011, Box 1, p 901.

Social-Emotional Reciprocity
Reduced social interactions in ASD may range from active avoidance or reduced
social response to having an interest in, but lacking ability to initiate or sustain,
an interaction with peers or adults. A young child with ASD may not respond
when his name is called, may exhibit limited showing and sharing behaviors, and
may prefer solitary play. In addition, the child may avoid attempts by others to
play and may not participate in activities that require taking turns, such as peek-
a-boo and ball play. An older child with ASD may have an interest in peers but
may not know how to initiate or join in play. The child may have trouble with
the rules of conversation and may either talk at length about an area of interest or
abruptly exit the interaction. Younger children often have limited capacity for
imaginative or pretend play skills. Older children may engage in play but lack
flexibility and may be highly directive to peers. Some children with ASD
interact well with adults but struggle to interact with same-age peers.

Nonverbal Communicative Behavior

Difficulties with nonverbal communication may manifest as reduced use of eye
contact and gestures such as pointing. Children may also show reduced
awareness or response to the eye gaze or pointing of others. They may use eye
contact only when communicating a highly preferred request or may have
difficulty coordinating the use of nonverbal with verbal communication.
Children with ASD may have limited range of facial expression or expressed
emotion.

Developing, Maintaining, and Understanding

Relationships
Children with ASD have limited insight regarding social relationships. They
have difficulty understanding the difference between a true friend and a casual
acquaintance. They have trouble picking up on the nuances of social interactions
and understanding social expectations for polite behavior. They may have
reduced understanding of personal boundaries and may stand too close to others.
In addition, they can have trouble understanding and inferring others' emotions
child may only want to talk about her area of interest or may insist that peers act
out a particular story in a rigid and inflexible manner.

Hypo- or Hyperreactivity to Sensory Input

Children with ASD may be overly sensitive to sensory input, such as noise,
smells, or texture. Children may scream when they hear a siren or vacuum and
may gag and choke with certain foods or odors. They may refuse to wear certain
clothing or may become very distressed with bathing or with cutting nails and
hair. Conversely, some affected children seem to crave sensory input. They may
engage in repetitive jumping or hugging and may smell or lick objects or people.
Young children may inappropriately touch the face or hair of others.
Diagnosing ASD with DSM-5 criteria can be challenging in very young
children because of reduced expression of repetitive behaviors, particularly
stereotyped behavior and intense interests. Studies monitoring development in
high-risk young children who have an older sibling with ASD indicate these
additional symptoms may emerge over time. This creates a dilemma for
specialty clinicians evaluating very young children for ASD, because they may
not be able to endorse sufficient symptoms to make an early diagnosis and
access specialized intervention services.

Severity Levels Defined in DSM-5

Severity level in ASD is based on the level of support the individual requires in
each of the major domains impacted—social communication and restricted and
repetitive behavior. Levels range from –“needing support” (level 1), to
–“needing substantial support” (level 2), to –“needing very substantial support”
(level 3) (Table 54.4 ).

Table 54.4

DSM-5 Severity Levels for Autism Spectrum Disorder

SEVERITY RESTRICTED, REPETITIVE
SOCIAL COMMUNICATION
LEVEL BEHAVIORS
Level 3 Severe deficits in verbal and nonverbal social communication Inflexibility of behavior,
“Requiring skills cause severe impairments in functioning, very limited extreme difficulty coping with
very initiation of social interactions, and minimal response to social change, or other
substantial overtures from others. For example, a person with few words restricted/repetitive behaviors
support” of intelligible speech who rarely initiates interaction and, markedly interfere with
when he or she does, makes unusual approaches to meet needs functioning in all spheres. Great
 only and responds to only very direct social approaches distress/difficulty changing
focus or action.
Level 2 Marked deficits in verbal and nonverbal social communication Inflexibility of behavior,
“Requiring skills; social impairments apparent even with supports in difficulty coping with change, or
substantial place; limited initiation of social interactions; and reduced or other restricted/repetitive
support” abnormal responses to social overtures from others. For behaviors appear frequently
example, a person who speaks simple sentences, whose enough to be obvious to the
interaction is limited to narrow special interests, and who has casual observer and interfere
markedly odd nonverbal communication with functioning in a variety of
contexts. Distress and/or
difficulty changing focus or
action.
Level 1 Without supports in place, deficits in social communication Inflexibility of behavior causes
“Requiring cause noticeable impairments. Difficulty initiating social significant interference with
support” interactions, and clear examples of atypical or unsuccessful functioning in one or more
responses to social overtures of others. May appear to have contexts. Difficulty switching
decreased interest in social interactions. For example, a person between activities. Problems of
who is able to speak in full sentences and engages in organization and planning
communication but whose to-and-fro conversation with others hamper independence.
fails, and whose attempts to make friends are odd and
typically unsuccessful
From the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, (Copyright 2013).
American Psychiatric Association, p 52.

Specifiers Defined in DSM-5

Formal diagnosis of ASD also includes documenting associated conditions
including whether the individual has cognitive and/or language impairment, any
related medical, genetic or environmental factors and any other
neurodevelopmental or behavioral health conditions, including catatonia (Table
54.5 ). This process helps to better characterize the presentation in an individual
child and ensures that the diagnosis has been made by considering the symptoms
in the context of the child's current cognitive and language abilities.

Table 54.5
Common Co-occurring Conditions in Autism Spectrum
Disorder (ASD)

INDIVIDUALS
WITH
COMORBIDITY COMMENTS
AUTISM
AFFECTED
DEVELOPMENTAL DISORDERS
Intellectual ~45% Prevalence estimate is affected by the diagnostic boundary and
disability definition of intelligence (e.g., whether verbal ability is used as a
criterion).
 In individuals, discrepant performance between subtests is common.
Language disorders Variable In DSM-IV, language delay was a defining feature of autism (autistic
disorder), but is no longer included in DSM-5.
An autism-specific language profile (separate from language
disorders) exists, but with substantial interindividual variability.
Attention- 28–44% In DSM-IV, not diagnosed when occurring in individuals with autism, but
deficit/hyperactivity no longer so in DSM-5.
disorder
Tic disorders 14–38% ~6⋅5% have Tourette syndrome.
Motor abnormality ≤79% See Table 54.2 .
GENERAL MEDICAL DISORDERS
Epilepsy 8–35% Increased frequency in individuals with intellectual disability or
genetic syndromes.
Two peaks of onset: early childhood and adolescence.
Increases risk of poor outcome.
Gastrointestinal 9–70% Common symptoms include chronic constipation, abdominal pain,
problems chronic diarrhea, and gastroesophageal reflux.
Associated disorders include gastritis, esophagitis, gastroesophageal
reflux disease, inflammatory bowel disease, celiac disease, Crohn
disease, and colitis.
Immune ≤38% Associated with allergic and autoimmune disorders.
dysregulation
Genetic disorders 10–20% Collectively called syndromic autism.
Examples include fragile X syndrome (21–50% of individuals
affected have autism), Rett syndrome (most have autistic features but
with profiles different from idiopathic autism), tuberous sclerosis
complex (24–60%), Down syndrome (5–39%), phenylketonuria (5–
20%), CHARGE syndrome* (15–50%), Angelman syndrome (50–
81%), Timothy syndrome (60–70%), and Joubert syndrome (~40%).
Sleep disorders 50–80% Insomnia is the most common.
PSYCHIATRIC DISORDERS
Anxiety ~40% Common across all age-groups.
Most common are social anxiety disorder (13–29% of individuals
with autism) and generalized anxiety disorder (13–22%).
High-functioning individuals are more susceptible (or symptoms are
more detectable).
Depression 12–70% Common in adults, less common in children.
High-functioning adults who are less socially impaired are more
susceptible (or symptoms are more detectable).
Obsessive- 7–24% Shares the repetitive behavior domain with autism that could cut
compulsive disorder across nosologic categories.
(OCD) Important to distinguish between repetitive behaviors that do not
involve intrusive, anxiety-causing thoughts or obsessions (part of
autism) and those that do (and are part of OCD).
Psychotic disorders 12–17% Mainly in adults.
Most commonly recurrent hallucinosis.
High frequency of autism-like features (even a diagnosis of ASD)
preceding adult-onset (52%) and childhood-onset schizophrenia (30–
50%).
Substance use ≤16% Potentially because individual is using substances as self-medication to
disorders relieve anxiety.
Oppositional 16–28% Oppositional behaviors could be a manifestation of anxiety, resistance to
defiant disorder change, stubborn belief in the correctness of own point of view, difficulty
seeing another's point of view, poor awareness of the effect of own
behavior on others, or no interest in social compliance.
 Eating disorders 4–5% Could be a misdiagnosis of autism, particularly in females, because both
involve rigid behavior, inflexible cognition, self-focus, and focus on
details.
PERSONALITY DISORDERS †
Paranoid 0–19% Could be secondary to difficulty understanding others' intentions and
personality disorder negative interpersonal experiences.
Schizoid 21–26% Partly overlapping diagnostic criteria.
personality disorder
Schizotypal 2–13% Some overlapping criteria, especially those shared with schizoid
personality disorder personality disorder.
Borderline 0–9% Could have similarity in behaviors (e.g., difficulties in interpersonal
personality disorder relationships, misattributing hostile intentions, problems with affect
regulation), which requires careful differential diagnosis.
Could be a misdiagnosis of autism, particularly in females.
Obsessive- 19–32% Partly overlapping diagnostic criteria.
compulsive
personality disorder
Avoidant 13–25% Could be secondary to repeated failure in social experiences.
personality disorder
BEHAVIORAL DISORDERS
Aggressive ≤68% Often directed toward caregivers rather than noncaregivers.
behaviors Could be a result of empathy difficulties, anxiety, sensory overload,
disruption of routines, and difficulties with communication.
Self-injurious ≤50% Associated with impulsivity and hyperactivity, negative affect, and
behaviors lower levels of ability and speech.
Could signal frustration in individuals with reduced communication,
as well as anxiety, sensory overload, or disruption of routines.
Could also become a repetitive habit.
Could cause tissue damage and need for restraint.
Pica ~36% More likely in individuals with intellectual disability.
Could be a result of a lack of social conformity to cultural categories
of what is deemed edible, or sensory exploration, or both.
Suicidal ideation or 11–14% Risks increase with concurrent depression and behavioral problems, and
attempt after being teased or bullied.
* Coloboma of the eye; heart defects; atresia of the choanae; retardation of growth and

development, or both; genital and urinary abnormalities, or both; and ear abnormalities and
deafness.
† Particularly in high-functioning adults.

DSM-IV, Diagnostic and Statistical Manual of Mental Disorders, 4th edition ; DSM-5, Diagnostic
and Statistical Manual of Mental Disorders, Fifth edition.
Adapted from Lai MC, Lombardo MV, Baron-Cohen S: Autism, Lancet 383:896–910, 2014.

Epidemiology
The prevalence of ASD is estimated at 1 in 59 persons by the U.S. Centers for
Disease Control and Prevention (CDC). The prevalence increased significantly
over the past 25 years, primarily because of improved diagnosis and case finding
the child's age and the presenting concerns.
Assessment of ASD includes direct observation of the child to evaluate social
skills and behavior. Informal observation can be supplemented with structured
diagnostic tools such as the Autism Diagnostic Observation Schedule, Second
Edition (ADOS-2) and Autism Diagnostic Observation Schedule, Toddler
module (ADOS-T). These structured play-based assessments provide social
prompts and opportunities to evaluate the frequency and quality of a child's
social responsiveness to, initiation, and maintenance of social interactions; the
capacity for joint attention and shared enjoyment; the child's behavioral
flexibility; and presence of repetitive patterns of behavior. The ADOS-2 and
ADOS-T are not required for accurate diagnosis and do not stand alone, but
rather can be used to augment a careful history and observation. The Childhood
Autism Rating Scale, Second Edition (CARS-2) is a 15-item direct clinical
observation instrument that can assist clinicians in the diagnosis of ASD. The
Autism Diagnostic Interview-Revised (ADI-R) is a lengthy clinical interview tool
that is used primarily in research settings since it takes several hours to
administer. Other tools include standardized rating scales that parents and
teachers can complete to report on the child's social skills and behaviors.
Medical evaluation should include a thorough history and detailed physical
examination of the child, including direct behavioral observations of
communication and play. In addition, the examination should include
measurement of head circumference, careful evaluation for dysmorphic features,
and screening for tuberous sclerosis with Wood lamp exam. Children with ASD
should have genetic testing (described later), an audiology examination to rule
out hearing loss, and in children with pica, a lead test (Table 54.6 ).
Table 54.6
Medical and Genetic Evaluation of Children
With Autism Spectrum Disorder
Physical Examination

Dysmorphic physical features

Muscle tone and reflexes
Head circumference
Wood lamp examination for tuberous sclerosis
Diagnostic Testing

Chromosomal microarray (CMA) in all individuals

Fragile X DNA test in males
Audiology evaluation
Lead test in children with pica

Additional Targeted Genetic Testing

Fragile X DNA test in females with symptoms suggestive of fragile X,

family history of X-linked intellectual disability, tremor, ataxia, or
premature ovarian failure
MeCP2 sequencing in females
PTEN mutation testing if head circumference >2.5 SD above the mean
MeCP2 deletion/duplication testing in males with significant
developmental regression, drooling, respiratory infections, and hypotonia
Karyotype if unable to obtain CMA or if balanced translocation suspected

Additional Targeted Diagnostic Testing

EEG in children with seizures, staring spells, or developmental regression

Brain MRI in children with microcephaly, focal neurologic findings, or
developmental regression
Metabolic testing in children with developmental regression, hypotonia,
seizures, food intolerance, hearing loss, ataxia, or course facial features

Data from Schaefer GB, Mendelsohn NJ: Clinical genetics evaluation in

identifying the etiology of autism spectrum disorders: 2013 guideline revisions,
Genet Med 15(5):399–407, 2013.

There are currently several specialty-specific clinical guidelines for genetic

evaluation of children diagnosed with ASD. Genetic testing is shown to impact
clinical decision-making, but no studies have evaluated the impact of genetic
testing on the outcome for the child. The American College of Medical Genetics
recommends a tiered approach to genetic testing.
Treatment and Management
Educational
The primary treatment for ASD is done outside the medical setting and includes
developmental and educational programming. Numerous resources have been
developed that can help families in the complex process of treatment planning
(Table 54.7 ). Intensive behavioral therapies have the strongest evidence to date.
Earlier age at initiation of treatment and higher intensity of treatment are
associated with better outcomes. Programming must be individualized, and no
approach is successful for all children. In addition, research treatments are often
conducted with a high level of intensity and fidelity that are difficult to scale up
or reproduce in community settings. Higher cognitive, play, and joint attention
skills and lower symptom severity at baseline are predictors for better outcomes
in core symptoms, intellectual function, and language function.
Table 54.7
Autism Resources for Families

Autism Speaks First 100 Days kit

https://www.autismspeaks.org/family-services/tool-kits/100-day-
kit
Autism Speaks Toolkits–dental, transition, guardianship
https://www.autismspeaks.org/family-services/tool-kits
AACAP Autism Spectrum Disorder Parent's Medication Guide
https://www.aacap.org/App_Themes/AACAP/Docs/resource_centers/autism/Au
Sexuality information for individuals with developmental disability
http://vkc.mc.vanderbilt.edu/healthybodies/

Behavioral approaches based on the principles of applied behavioral

analysis (ABA) involve direct incremental teaching of skills within a traditional
behavioral framework using reinforcement of desired behavior, careful data
collection, and analysis and adjustment of the treatment program based on
review of data. Comprehensive models integrating behavioral and
developmental approaches that build on key foundational skills, such as joint
attention, shared enjoyment, and reciprocal communication, show strong
evidence of efficacy for young children, particularly toddlers, with ASD.
Pharmacology
There are currently no medications that treat the core symptoms of ASD.
Medications can be used to target specific co-occurring conditions or symptoms
(Table 54.8 ; see also Table 54.5 ). Families should be cautioned, however, that
the effect size may be lower and the rate of medication side effects higher in
children with ASD.

Table 54.8
Common Pharmacologic Treatments in Autism Spectrum
Disorder (ASD)

TARGET MEDICATION
EFFECTS SIDE EFFECTS MONITORING
SYMPTOM CLASS*
Hyperactivity Stimulants Decreased Activation, irritability, emotional Height, weight, BP,
and/or hyperactivity, lability, lethargy/social HR
Inattention impulsivity, improved withdrawal, stomach ache,
attention reduced appetite, insomnia,
increased stereotypy
α2 -Agonists Decreased Drowsiness, irritability, enuresis, Height, weight, BP,
hyperactivity, decreased appetite, dry mouth, HR
impulsivity, improved hypotension
attention
Selective Decreased Irritability, decreased appetite, Height, weight, BP,
norepinephrine hyperactivity, fatigue, stomach ache, nausea, HR
reuptake impulsivity, improved vomiting, racing heart rate
inhibitor attention
Anxiety Selective Decreased anxiety Activation, hyperactivity, Weight, BP, HR
serotonin inattention, sedation, change
reuptake in appetite, insomnia,
inhibitors stomach ache, diarrhea
Citalopram: prolonged QTc
interval
Irritability Atypical Decreased irritability, Somnolence, weight gain, Weight, BP, HR
antipsychotics aggression, self- extrapyramidal movements, Monitor CBC,
(risperidone, injurious behavior, drooling, tremor, dizziness, cholesterol,
aripiprazole) repetitive behavior, vomiting, gynecomastia ALT, AST,
hyperactivity prolactin,
glucose or
hemoglobin
A1c
Insomnia Melatonin Shortened sleep onset Nightmares, enuresis —
* Specific medications names are provided in parentheses when there is a FDA-approved
indication for the use of the medication to treat the symptom in children with ASD. Further
information about these medications is available in Chapter 33 .
BP, Blood pressure; HR, heart rate; CBC, complete blood count; ALT, alanine transaminase; AST,
aspartate transaminase.
inability to provide adequate energy substrate. Excess energy intakes can
increase the risk for obesity. Adequacy of energy intake in adults is associated
with maintenance of a healthy weight. The three components of energy
expenditure in adults are the basal metabolic rate (BMR), thermal effect of food
(e.g., energy required for digestion and absorption), and energy for physical
activity. In children, additional energy intake is required to support growth and
development.
Estimated energy requirement (EER) is the average dietary energy intake
predicted to maintain energy balance in a healthy individual and takes into
account age, gender, weight, stature, and level of physical activity (Table 55.1 ).
The 2015–2020 Dietary Guidelines for Americans refer to the 2008 Physical
Activity Guidelines for Americans. These guidelines recommend ≥60 min of
moderate- or vigorous-intensity aerobic physical daily for children and
adolescents. This activity should include vigorous intensity physical activity at
least 3 days per week. In addition, as part of their ≥60 min of daily physical
activity, children and adolescents are advised to incorporate muscle- and bone-
strengthening activity for ≥3 days a week, to maintain a healthy weight and to
prevent or delay progression of chronic noncommunicable diseases such as
obesity and CV disease.

Table 55.1
Equations to Estimate Energy Requirement
INFANTS AND YOUNG CHILDREN: EER (kcal/day) = TEE + ED
0-3 mo EER = (89 × weight [kg] − 100) + 175
4-6 mo EER = (89 × weight [kg] − 100) + 56
7-12 mo EER = (89 × weight [kg] − 100) + 22
13-36 mo EER = (89 × weight [kg] − 100) + 20
CHILDREN AND ADOLESCENTS 3-18 yr: EER (kcal/day) = TEE + ED
Boys
3-8 yr EER = 88.5 − (61.9 × age [yr] + PA × [(26.7 × weight [kg] + (903 × height [m])] + 20
9-18 yr EER = 88.5 − (61.9 × age [yr] + PA × [(26.7 × weight [kg] + (903 × height [m])] + 25
Girls
3-8 yr EER = 135.3 − (30.8 × age [yr] + PA [(10 × weight [kg] + (934 × height [m])] + 20
9-18 yr EER = 135.3 − (30.8 × age [yr] + PA [(10 × weight [kg] + (934 × height [m])] + 25
EER, Estimated energy requirement; TEE, total energy expenditure; ED, energy deposition
(energy required for growth /new tissue accretion).
PA indicates the physical activity coefficient:
For boys:
PA = 1.00 (sedentary, estimated physical activity level 1.0-1.4)
PA = 1.13 (low active, estimated physical activity level 1.4-1.6)
PA = 1.26 (active, estimated physical activity level 1.6-1.9)
PA = 1.42 (very active, estimated physical activity level 1.9-2.5)
For girls:
PA = 1.00 (sedentary, estimated physical activity level 1.0-1.4)
PA = 1.16 (low active, estimated physical activity level 1.4-1.6)
PA = 1.31 (active, estimated physical activity level 1.6-1.9)
PA = 1.56 (very active, estimated physical activity level 1.9-2.5)
Adapted from Kleinman RE, editor: Pediatric nutrition handbook, ed 7, Elk Grove Village, IL, 2013,
American Academy of Pediatrics.

The EER was determined based on empirical research in healthy persons at

different levels of physical activity, including levels different from recommended
levels. They do not necessarily apply to children with acute or chronic diseases.
EER is estimated by equations that account for total energy expenditure (TEE)
and energy deposition (ED) for healthy growth. EERs for infants, relative to
body weight, are approximately twice those for adults because of the increased
metabolic rate and requirements for weight maintenance and tissue accretion
(growth).
Dietary nutrients that provide energy include fats (approximately 9 kcal/g),
carbohydrates (4 kcal/g), and protein (4 kcal/g). These nutrients are called
macronutrients . If alcohol is consumed, it also contributes to energy intake (7
kcal/g). The EER does not specify the relative energy contributions of
macronutrients. Once the minimal intake of each macronutrient is attained (e.g.,
sufficient protein intake to meet specific amino acid requirements, sufficient fat
intake to meet linoleic acid and α-linolenic acid needs for brain development),
the remainder of the intake is used to meet energy requirements, with some
degree of freedom and interchangeability among fat, carbohydrate, and protein.
This argument forms the basis for the acceptable macronutrient distribution
ranges (AMDRs) , expressed as a function of total energy intake (Table 55.2 ).

Table 55.2
Acceptable Macronutrient Distribution Ranges

AMDA (% OF ENERGY)
Macronutrient Age 1-3 yr Age 4-18 yr
Fat 30-40 25-35
ω6 PUFAs (linoleic acid) 5-10 5-10
 ω3 PUFAs (α-linolenic acid) 0.6-1.2 0.6-1.2
Carbohydrate 45-65 45-65
Protein 5-20 10-30
PUFAs, Polyunsaturated fatty acids.
Adapted from Otten JJ, Hellwig JP, Meyers LD, editors; Institute of Medicine: Dietary reference
intakes: the essential guide to nutrient requirements , Washington, DC, 2006, National Academies
Press.

Fat
Fat is the most calorically dense macronutrient, providing approximately 9
kcal/g. For infants, human milk and formula are the main dietary sources of fat,
whereas older children obtain fat from animal products, vegetable oils, and
margarine. The AMDR for fats is 30–40% of total energy intake for children 1-3
yr and 25–35% for children 4-18 yr of age. In addition to being energy dense,
fats provide essential fatty acids that have body structural and functional roles
(e.g., cholesterol moieties are precursors for cell membranes, hormones, and bile
acids). Fat intake facilitates absorption of fat-soluble vitamins (vitamins A, D, E,
and K). Both roles are relevant to neurologic and ocular development (Table
55.3 ).

Table 55.3
Dietary Reference Intakes: Macronutrients

LIFE
RDA OR AI* SELECTED FOOD ADVERSE EFFECTS OF
FUNCTION STAGE
(g/day) SOURCES EXCESSIVE CONSUMPTION
GROUP
TOTAL DIGESTIBLE CARBOHYDRATE
RDA based on its Infants Major types: No defined intake level for
role as the primary 0-6 mo 60* starches and potential adverse effects of
energy source for 7-12 mo 95* sugars, grains, total digestible carbohydrate is
the brain Children and vegetables identified, but the upper end of
AMDR based on >1 yr 130 (corn, pasta, rice, the AMDR was based on
its role as a source Pregnancy potatoes, and decreasing risk of chronic
of kcal to maintain ≤18 yr 175 breads) are disease and providing adequate
body weight 19-30 yr 175 sources of starch. intake of other nutrients.
Natural sugars are It is suggested that the maximal
found in fruits intake of added sugars be
and juices. limited to providing no more
Sources of added than 10% of energy.
sugars: soft
drinks, candy,
fruit drinks,
 desserts, syrups,
and sweeteners †
TOTAL FIBER
Improves laxation, Infants Includes dietary fiber Dietary fiber can have variable
reduces risk of 0-6 mo ND naturally present in compositions; therefore it is
coronary artery (heart) 7-12 mo ND grains (e.g., oats, difficult to link a specific
disease, assists in Children wheat, unmilled rice) source of fiber with a particular
maintaining normal 1-3 yr 190* and functional fiber adverse effect, especially when
blood glucose levels 4-8 yr 25* synthesized or isolated phytate is also present in the
Males from plants or animals natural fiber source.
9-13 yr 31* and shown to be of As part of an overall healthy
benefit to health diet, a high intake of dietary
14-18 yr 38*
fiber will not produce
19-21 yr 38* deleterious effects in healthy
Females persons.
9-13 yr 26* Occasional adverse GI
14-18 yr 26* symptoms are observed when
19-21 yr 25* consuming some isolated or
Pregnancy synthetic fibers, but serious
≤18 yr 28* chronic adverse effects have
19-21 yr 28* not been observed because of
the bulky nature of fibers.
Excess consumption is likely to
be self-limiting; therefore, UL
was not set for individual
functional fibers.
TOTAL FAT
Energy source Infants Infants: Human UL is not set because there is
When found in 0-6 mo 31* milk or infant no defined intake of fat at
foods, is a source 7- 30* formula which adverse effects occur.
of ω3 and ω6 12 Insufficient Older children: High fat intake will lead to
PUFAs mo evidence to Butter, margarine, obesity. Upper end of AMDR
Facilitates 1- determine vegetable oils, is also based on reducing risk
absorption of fat- 18 AI or whole milk, of chronic disease and
soluble vitamins yr EAR; see visible fat on providing adequate intake of
AMDR, meat and poultry other nutrients. †
Table 55.2 products, invisible Low fat intake (with high
. fat in fish, carbohydrate) has been shown
shellfish, some to increase plasma
plant products triacylglycerol concentrations
such as seeds and and decrease HDL cholesterol.
nuts, bakery
products
ω6 POLYUNSATURATED FATTY ACIDS
Essential Infants Nuts, seeds; vegetable There is no defined intake of
component of 0-6 mo 4.4* oils such as soybean, ω6 level at which adverse
structural 7-12 mo 4.6* safflower, corn oil effects occur.
membrane lipids, Children Upper end of AMDR is based
involved with cell 1-3 yr 7* on the lack of evidence that
signaling 4-8 yr 10* demonstrates long-term safety
Precursor of Males and human in vitro studies that
eicosanoids show increased free radical
9-13 yr 12*
Required for formation and lipid
normal skin 14-18 yr 16* peroxidation with higher
function 19-21 yr 17* amounts of ω6 fatty acids.
 Females Lipid peroxidation is thought to
9-13 yr 10* be a component of
14-18 yr 11* atherosclerotic plaques.
19-21 yr 12*
Pregnancy
≤18 yr 13*
19-21 yr 13*
Lactation
≤18 yr 13*
19-21 yr 13*
ω3 POLYUNSATURATED FATTY ACIDS
Involved with Infants Vegetable oils, e.g., No defined intake levels for
neurologic 0-6 mo 0.5* soybean, canola, flax potential adverse effects of ω3
development and 7-12 mo 0.5* seed oil; fish oils, fatty PUFAs are identified.
growth Children fish, walnuts; † smaller Upper end of AMDR is based
Precursor of 1-3 yr 0.7* amounts in meats and on maintaining appropriate
eicosanoids 4-8 yr 0.9* eggs balance with ω6 fatty acids and
Males the lack of evidence that
9-13 yr 1.2* demonstrates long-term safety,
along with human in vitro
14-18 yr 1.6*
studies that show increased free
19-21 yr 1.6*
radical formation and lipid
Females peroxidation with higher
9-13 yr 1.0* amounts of PUFAs.
14-18 yr 1.1* Because the longer-chain n -3
19-21 yr 1.1* fatty acids, eicosapentaenoic
Pregnancy acid (EPA) and
≤18 yr 1.4* docosahexaenoic acid (DHA),
19-21 yr 1.4* are biologically more potent
Lactation than their precursor, linolenic
≤18 yr 1.3* acid, much of the work on
19-21 yr 1.3* adverse effects of this group of
fatty acids has been on DHA
and EPA.
Lipid peroxidation is thought to
be a component in the
development of atherosclerotic
plaques.
SATURATED AND TRANS FATTY ACIDS
The body can No dietary Saturated fatty There is an incremental increase in
synthesize its needs for requirement acids are present plasma total and LDL cholesterol
saturated fatty acids in animal fats concentrations with increased intake
from other sources. (meat fats and of saturated or trans fatty acids;
butter fat), and therefore, saturated fat intake
coconut and palm should be limited to <10% with no
kernel oils. trans fat. † ‡
Trans fat: stick
margarines, foods
containing
hydrogenated or
partially
hydrogenated
vegetable
shortenings
CHOLESTEROL
 No dietary Sources: liver, eggs,
requirement foods that contain
eggs, e.g., cheesecake,
custard pie
PROTEIN AND AMINO ACIDS ‡
Major structural Infants Proteins from No defined intake levels for
component of all 0-6 mo 9.1* animal sources, potential adverse effects of
cells in the body 7-12 mo 11.0 e.g., meat, protein are identified.
Functions as Children poultry, fish, Upper end of AMDR was
enzymes, in 1-3 yr 13 eggs, milk, based on complementing
membranes, as 4-8 yr 19 cheese, yogurt, AMDR for carbohydrate and
transport carriers, Males provide all 9 fat for the various age-groups.
and as some indispensable Lower end of AMDR is set at
9-13 yr 34
hormones amino acids in approximately the RDA.
14-18 yr 52
During digestion adequate amounts
≥19 yr 56
and absorption, and are
dietary protein is Females considered
broken down to 9-13 yr 34 “complete
amino acids, which ≥14 yr 46 protein.”
become the ≤18 yr Protein from
building blocks of 19-21 yr 71 plants, legumes,
these structural and grains, nuts,
functional seeds, and
compounds. vegetables tend to
Nine indispensable be deficient in ≥1
amino acids must of the
be provided in the indispensable
diet; the body can amino acids and
make the other are called
amino acids “incomplete
needed to protein.”
synthesize specific Vegan diets
structures from adequate in total
other amino acids. protein content
can be “complete”
by combining
sources of
incomplete
protein, which
lack different
indispensable
amino acids.
* Adequate intake.

† 2015–2020 Dietary Guidelines for Americans. US Department of Health and Human Services.
https://health.gov/dietaryguidelines/2015/ .
‡ Based on 1.5 g/kg/day for infants, 1.1 g/kg/day for 1-3 yr, 0.95 g/kg/day for 4-13 yr, 0.85
g/kg/day for 14-18 yr, 0.8 g/kg/day for adults, and 1.1 g/kg/day for pregnant (using pre-pregnancy
weight) and lactating women.
Note: Starred (*) numbers are AI; bold numbers are RDA. RDAs and AIs may both be used as
goals for individual intake. RDAs are set to meet the needs of 97-98% of members in a group. For
healthy breastfed infants, the AI is the mean intake. The AI for other life stage and gender groups
is believed to cover the needs of all members of the group, but lack of data prevents specifying
critical illnesses, burn injuries, compensated liver disease, and bariatric surgery
(e.g., laparoscopic sleeve gastrectomy and Roux-en-Y gastric bypass). Intake of
protein or specific amino acids needs to be limited in some health conditions,
such as renal disease and decompensated liver disease, and metabolic diseases
such as phenylketonuria and maple syrup urine disease, in which specific amino
acids can be toxic.
The amino acid content of dietary protein is also important. Certain amino
acids are indispensable , and humans depend on dietary sources to meet
adequacy and prevent deficiency. Certain amino acids are termed conditional
essential/indispensable , meaning they become essential in patients affected by
some diseases or during a certain life stage, such as with cysteine, tyrosine, and
arginine in newborns because of enzyme immaturity (Table 55.4 ). Human milk
contains both the indispensable and conditionally indispensable amino acids and
therefore meets the protein requirements for infants. Breast milk is considered
the optimal protein source for infants and is the reference amino acid
composition by which biologic quality is determined for infants. If a single
amino acid in a food protein source is low or absent but is required to support
normal metabolism, that specific amino acid becomes the limiting nutrient in
that food. For soy-based infant formula, supplementing the formula with the
limiting amino acid (methionine) is necessary. Certain amino acid–like
substances, such as creatinine, are used by some athletes and may enhance
performance. Such supplementation should be monitored for potential side
effects.

Table 55.4
Indispensable, Dispensable, and Conditionally
Indispensable Amino Acids in the Human Diet

CONDITIONALLY PRECURSORS OF CONDITIONALLY

INDISPENSABLE DISPENSABLE
INDISPENSABLE* INDISPENSABLE
Histidine† Alanine Arginine Glutamine/glutamate, aspartate
Isoleucine Aspartic Cysteine Methionine, serine
Leucine acid Glutamine Glutamic acid/ammonia
Lysine Asparagine Glycine Serine, choline
Methionine Glutamic Proline Glutamate
Phenylalanine acid Tyrosine Phenylalanine
Threonine Serine
Tryptophan
Valine
* Conditionally indispensable is defined as requiring a dietary source when endogenous synthesis
tapioca, flax, corn, rice, sorghum, and quinoa.

Micronutrients
(See Chapters 61-67 .)
Vitamins and trace minerals, the dietary micronutrients , are essential for
growth and development and contribute to a host of physiologic functions. Many
U.S. children have suboptimal intake of iron, zinc, potassium, calcium, vitamin
D, and vitamin K, and excess intake of sodium. Dietary recommendations for
micronutrients were originally established to prevent deficiency and currently
also include the impact of micronutrients on long-term health outcomes (Table
55.5 ). Food fortification is an effective strategy to prevent some nutrient
deficiencies and has been successfully implemented to prevent iodine and folate
deficiency.

Table 55.5
Dietary Reference Intakes for Vitamins

ADVERSE
LIFE- RDA SELECTED
EFFECTS OF SPECIAL
NUTRIENT FUNCTION STAGE OR UL FOOD
EXCESSIVE CONSIDERATIONS
GROUP AI SOURCES
CONSUMPTION
Biotin (vitamin B7 Coenzyme in Infants (µg/day) Liver No adverse None
) synthesis of fat, 0-6 mo 5* ND Smaller effects of
glycogen, and 7-12 mo 6* ND amounts biotin in
amino acids Children (µg/day) in fruits humans or
1-3 yr 8* ND and animals have
4-8 yr 12* ND meats been found;
Males (µg/day) this does not
9-13 yr 20* ND mean there is
no potential
14-18 yr 25* ND
for adverse
19-21 yr 30* ND effects
Females (µg/day) resulting from
9-13 yr 20* ND high intakes.
14-18 yr 25* ND Because data
19-21 yr 30* ND on the adverse
Pregnancy (µg/day) effects of
≤18 yr 30* ND biotin are
19-21 yr 30* ND limited,
Lactation (µg/day) caution may
≤18 yr 35* ND be warranted.
19-21 yr 35* ND
Choline Precursor for Infants (mg/day) Milk, liver, Fishy body odor, Patients with
acetylcholine, eggs, sweating, trimethylaminuria,
 phospholipids, 0-6 mo 125* ND peanuts salivation, renal disease, liver
and betaine 7-12 mo 150* ND hypotension, disease,
Children (mg/day) hepatotoxicity depression, and
1-3 yr 200* 1,000 Parkinson disease
4-8 yr 250* 1,000 may be at risk for
Males (mg/day) adverse effects
9-13 yr 375* 2,000 with choline
14-18 yr 550* 3,000 intakes at the UL.
AIs have been set
19-21 yr 550* 3,500
for choline, but
Females (mg/day)
there are little data
9-13 yr 375* 2,000 to assess whether
14-18 yr 400* 3,000 a dietary supply of
19-21 yr 425* 3,500 choline is needed
Pregnancy (mg/day) at all stages of the
≤18 yr 450* 3,000 life cycle, and the
19-21 yr 450* 3,500 choline
Lactation (mg/day) requirement might
≤18 yr 550* 3,000 be met by
19-21 yr 550* 3,500 endogenous
synthesis at some
of these stages.

Folate (folic Coenzyme in Infants (µg/day) Enriched Masks In view of evidence

acid, vitamin metabolism 0-6 mo 65* ND cereal, neurologic linking poor folate
B9 , folacin); of nucleic 7-12 mo 80* ND grains, dark complications intake with neural tube
pteroyl- and amino Children (µg/day) leafy in people with defects, all women
polyglutamates acids 1-3 yr 150 300 vegetables, vitamin B12 who can become
given as Prevents enriched and deficiency pregnant should
4-8 yr 200 400
dietary folate megaloblastic whole-grain No adverse consume 400 µg/day
Males (µg/day)
equivalents anemia breads and effects from supplements or
9-13 yr 300 600
(DFEs) bread associated fortified foods in
14-18 yr 400 800 products, addition to intake of
1 DFE = 1 µg with folate
19-21 yr 400 1,000 fortified food folate from a
food folate = from food or
0.6 µg folate Females (µg/day) ready-to-eat supplements varied diet.
from fortified 9-13 yr 300 600 cereals have been
food, or as 14-18 yr 400 800 reported; this
supplement 19-21 yr 400 1,000 does not mean
consumed with Pregnancy (µg/day) that there is
food = 0.5 µg ≤18 yr 600 800 no potential
of supplement 19-21 yr 600 1,000 for adverse
taken on Lactation (µg/day) effects
empty stomach ≤18 yr 500 800 resulting from
19-21 yr 500 1,000 high intakes.
Because data
on adverse
effects of
folate are
limited,
caution may
be warranted.
UL for folate
applies to
synthetic
forms
obtained from
 supplements
and/or
fortified
foods.
Niacin Coenzyme or Infants (mg/day) Meat, fish, No evidence Extra niacin may be
(vitamin B3 ) cosubstrate in 0-6 mo 2* ND poultry, of adverse required by persons
Includes many biologic 7-12 mo 4* ND enriched and effects from treated with
nicotinic acid reduction and Children (mg/day) whole-grain consuming hemodialysis or
amide, oxidation 1-3 yr 6 10 breads and naturally peritoneal dialysis or
nicotinic acid reactions, thus 4-8 yr 8 15 bread occurring those with
(pyridine-3 required for Males (mg/day) products, niacin in food malabsorption
carboxylic energy fortified Adverse syndrome.
9-13 yr 12 20
acid), and metabolism ready-to-eat effects from
14-18 yr 16 30
derivatives cereals niacin-
19-21 yr 16 35 containing
that exhibit
Females (mg/day) supplements
biologic
activity of 9-13 yr 12 20 can include
nicotinamide 14-18 yr 14 30 flushing and
Given as 19-21 yr 14 35 GI distress.
niacin Pregnancy (mg/day) UL for niacin
equivalents ≤18 yr 18 30 applies to
(NE) 19-21 yr 18 35 synthetic
1 mg niacin = Lactation (mg/day) forms
60 mg ≤18 yr 17 30 obtained from
tryptophan 19-21 yr 17 35 supplements,
Age 0-6 mo: fortified food,
preformed or a
niacin (not combination
NE). of these.
Pantothenic acid Coenzyme in fatty Infants (mg/day) Chicken, No adverse None
(vitamin B5 ) acid metabolism 0-6 mo 1.7* ND beef, effects
7-12 mo 1.8* ND potatoes, associated
Children (mg/day) oats, cereals, with
1-3 yr 2* ND tomato pantothenic
4-8 yr 3* ND products, acid from
Males (mg/day) liver, kidney, food or
yeast, egg supplements
9-13 yr 4* ND
yolk, have been
14-18 yr 5* ND
broccoli, reported; this
19-21 yr 5* ND whole grains does not mean
Females (mg/day) there is no
9-13 yr 4* ND potential for
14-18 yr 5* ND adverse
19-21 yr 5* ND effects
Pregnancy (mg/day) resulting from
≤18 yr 6* ND high intakes.
19-21 yr 6* ND Because data
Lactation (mg/day) on adverse
≤18 yr 7* ND effects of
19-21 yr 7* ND pantothenic
acid are
limited,
caution may
be warranted.
Riboflavin (vitamin Coenzyme in Infants (mg/day) Organ meats, No adverse None
B2 ) numerous redox 0-6 mo 0.3* ND milk, bread effects
reactions 7-12 mo 0.4* ND products, associated
Children (mg/day) fortified with vitamin
1-3 yr 0.5 ND cereals B2
4-8 yr 0.6 ND consumption
Males (mg/day) from food or
9-13 yr 0.9 ND supplements
14-18 yr 1.3 ND have been
19-21 yr 1.3 ND reported; this
does not mean
Females (mg/day)
there is no
9-13 yr 0.9 ND
potential for
14-18 yr 1.0 ND adverse
19-21 yr 1.1 ND effects
Pregnancy (mg/day) resulting from
≤18 yr 1.4 ND high intake.
19-21 yr 1.4 ND Because data
Lactation (mg/day) on adverse
≤18 yr 1.6 ND effects of
19-21 yr 1.6 ND vitamin B2 are
limited,
caution may
be warranted.
Thiamin (vitamin Coenzyme in Infants (mg/day) Enriched, No adverse Persons who might
B1 , aneurin) metabolism of 0-6 mo 0.2* ND fortified, or effects have increased need
carbohydrates and 7-12 mo 0.3* ND whole-grain associated for vitamin B
branched-chain Children (mg/day) products, with vitamin those being treated
amino acids 1-3 yr 0.5 ND bread and B1 with hemodialysis or
4-8 yr 0.6 ND bread consumption persons with a
Males (mg/day) products, from food or malabsorption
mixed foods supplements syndrome.
9-13 yr 0.9 ND
whose main have been
14-18 yr 1.2 ND
ingredient is reported; this
19-21 yr 1.2 ND grain, ready- does not mean
Females (mg/day) to-eat cereals there is no
9-13 yr 0.9 ND
potential for
14-18 yr 1.0 ND adverse
19-21 yr 1.1 ND effects
Pregnancy (mg/day) resulting from
≤18 yr 1.4 ND high intake.
19-21 yr 1.4 ND Because data
Lactation (mg/day) on adverse
≤18 yr 1.4 ND effects of
19-21 yr 1.4 ND vitamin B1 are
limited,
caution may
be warranted.
Vitamin A Required for Infants (µg/day) Liver, dairy Teratologic Persons with high
Includes normal vision, products, effects, liver alcohol intake,
provitamin A gene expression, 0-6 mo 400* 600 fish, dark- toxicity (from preexisting liver
carotenoids reproduction, 7-12 mo 500* 600 colored fruit, preformed vitamin disease,
that are dietary embryonic Children (µg/day) leafy A only) hyperlipidemia, or
precursors of development, and 1-3 yr 300 600 vegetable severe protein
retinol immune function 4-8 yr 400 900 malnutrition may
Given as Males (µg/day) be distinctly
 retinol activity 9-13 yr 600 1,700 susceptible to the
equivalents 14-18 yr 900 2,800 adverse effects of
(RAEs) 19-21 yr 900 3,000 excess preformed
1 RAE = 1 µg Females (µg/day) vitamin A intake.
retinol, 12 µg 9-13 yr 600 1,700 β-Carotene
β-carotene, 24 14-18 yr 700 2,800 supplements are
µg α-carotene, 19-21 yr 700 3,000 advised only to
or 24 µg β- Pregnancy (µg/day) serve as a
cryptoxanthin provitamin A
≤18 yr 750 2,800
To calculate source for persons
19-21 yr 770 3,000
RAEs from at risk for vitamin
REs of Lactation (µg/day) A deficiency.
provitamin A ≤18 yr 1,200 2,800
carotenoids in 19-21 yr 1,300 3,000
food, divide
REs by 2.
For preformed
vitamin A in
food or
supplements
and for
provitamin A
carotenoids in
supplements, 1
RE = 1 RAE
Pyridoxine Coenzyme in Infants (mg/day) Fortified No adverse None
(vitamin B6 ) metabolism of 0-6 mo 0.1* ND cereals, effects
Comprises a amino acids, 7-12 mo 0.3* ND organ meats, associated
group of 6 glycogen, and Children (mg/day) fortified soy- with vitamin
related sphingoid bases 1-3 yr 0.5 30 based meat B6 from food
compounds: 4-8 yr 0.6 40 substitutes have been
pyridoxal, Males (mg/day) reported; this
pyridoxine, 9-13 yr 1.0 60 does not mean
pyridoxamine, 14-18 yr 1.3 80 there is no
and 5′- potential for
19-21 yr 1.3 100
phosphates adverse
Females (mg/day)
(PLP, PNP, effects
9-13 yr 1.0 60
PMP) resulting from
14-18 yr 1.2 80 high intake.
19-21 yr 1.3 100 Because data
Pregnancy (mg/day) on adverse
≤18 yr 1.9 80 effects of
19-21 yr 1.9 100 vitamin B6 are
Lactation (mg/day) limited,
≤18 yr 2.0 80 caution may
19-21 yr 2.0 100 be warranted.
Sensory
neuropathy
has occurred
from high
intakes of
supplemental
forms.
Cobalamin Coenzyme in Infants (µg/day) Fortified No adverse Because 10–30% of
(vitamin B12 ) nucleic acid cereals, effects have older people
 metabolism 0-6 mo 0.4* ND meat, fish, been malabsorb food-bound
Prevents 7-12 mo 0.5* ND poultry associated vitamin B12 , those
megaloblastic Children (µg/day) with >50 yr are advised to
anemia 1-3 yr 0.9 ND consumption meet their RDA
4-8 yr 1.2 ND of the mainly by consuming
Males (µg/day) amounts of foods fortified with
9-13 yr 1.8 ND vitamin B12 vitamin B12 or a
14-18 yr 2.4 ND normally supplement containing
19-21 yr 2.4 ND found in food vitamin B12 .
Females (µg/day) or
supplements;
9-13 yr 1.8 ND
this does not
14-18 yr 2.4 ND
mean there is
19-21 yr 2.4 ND no potential
Pregnancy (µg/day) for adverse
≤18 yr 2.6 ND effects
19-21 yr 2.6 ND resulting from
Lactation (µg/day) high intake.
≤18 yr 2.8 ND Because data
19-21 yr 2.8 ND on adverse
effects of
vitamin B12
are limited,
caution may
be warranted.

Vitamin C Cofactor for Infants (mg/day) Citrus fruit, GI disturbances, Smokers require
(ascorbic acid, reactions 0-6 mo 40* ND tomatoes, kidney stones, additional 35
dehydroascorbic requiring reduced 7-12 mo 50* ND tomato juice, excess iron mg/day of vitamin
acid) copper or iron Children (mg/day) potatoes, absorption C over that
metalloenzyme 1-3 yr 15 400 Brussels needed by
and as a 4-8 yr 25 650 sprouts, nonsmokers.
protective Males (mg/day) cauliflower, Nonsmokers
antioxidant 9-13 yr 45 1,200 broccoli, regularly exposed
strawberries, to tobacco smoke
14-18 yr 75 1,800
cabbage, should ensure
19-21 yr 90 2,000
spinach they meet the
Females (mg/day) RDA for vitamin
9-13 yr 45 1,200 C.
14-18 yr 65 1,800
19-21 yr 75 2,000
Pregnancy (mg/day)
≤18 yr 80 1,800
19-21 yr 85 2,000
Lactation (mg/day)
≤18 yr 115 1,800
19-21 yr 120 2,000
Vitamin E (α- A metabolic Infants (mg/day) Vegetable No evidence Patients receiving
tocopherol function has oil, of adverse anticoagulant therapy
α-Tocopherol not yet been 0-6 mo 4* ND unprocessed effects from should be monitored
includes RRR- identified. 7-12 mo 5* ND cereal grains, consuming when taking vitamin E
α- tocopherol, Vitamin E's Children (mg/day) nuts, fruit, vitamin E supplements.
the only form major 1-3 yr 6 200 vegetables, naturally
of α- function 4-8 yr 7 300 meat occurring in
tocopherol that appears to be Males (mg/day) food
 occurs as a 9-13 yr 11 600 Adverse
naturally in nonspecific 14-18 yr 15 800 effects from
foods, and the chain- 19-21 yr 15 1,000 vitamin E–
2R - breaking Females (mg/day) containing
stereoisomeric antioxidant. 9-13 yr 11 600 supplements
forms of α- 14-18 yr 15 800 may include
tocopherol 19-21 yr 15 1,000 hemorrhagic
(RRR- , RSR- , Pregnancy (mg/day) toxicity.
RRS-, and UL for
≤18 yr 15 800
RSS- α- vitamin E
19-21 yr 15 1,000
tocopherol) applies to any
that occur in Lactation (mg/day) form of α-
fortified foods ≤18 yr 19 800 tocopherol
and 19-21 yr 19 1,000 obtained from
supplements supplements,
It does not fortified
include the 2S foods, or a
- combination
stereoisomeric of these.
forms of α-
tocopherol
(SRR-, SSR-,
SRS-, and SSS-
α-tocopherol),
also found in
fortified foods
and
supplements
Vitamin K Coenzyme during Infants (µg/day) Green No adverse Patients receiving
synthesis of many 0-6 mo 2.0* ND vegetables effects anticoagulant therapy
proteins involved 7-12 mo 2.5* ND (collards, associated should monitor
in blood clotting Children (µg/day) spinach, with vitamin vitamin K intake.
and bone 1-3 yr 30* ND salad greens, K
metabolism 4-8 yr 55* ND broccoli), consumption
Males (µg/day) Brussels from food or
9-13 yr 60* ND sprouts, supplements
cabbage, have been
14-18 yr 75* ND
plant oil, reported in
19-21 yr 120* ND margarine humans or
Females (µg/day) animals; this
9-13 yr 60* ND does not mean
14-18 yr 75* ND there is no
19-21 yr 90* ND potential for
Pregnancy (µg/day) adverse
≤18 yr 75* ND effects
19-21 yr 90* ND resulting from
Lactation (µg/day) high intake.
≤18 yr 75* ND Because data
19-21 yr 90* ND on adverse
effects of
vitamin K are
limited,
caution may
be warranted.
determined to be low.

Table 55.6
Dietary Reference Intakes for Select Micronutrients and
Water

ADVERSE
LIFE- SELECTED
AI UL EFFECTS OF SPECIAL
NUTRIENT FUNCTION STAGE FOOD
(mg/day) (mg/day) EXCESSIVE CONSIDERATIONS
GROUP SOURCES
CONSUMPTION
Sodium Maintains fluid Infants Processed Hypertension AI is set based on
volume outside 0-6 mo 120 ND foods with Increased risk ability to obtain a
of cells and thus 7-12 mo 370 ND added of nutritionally
normal cell Children sodium cardiovascular adequate diet for
function 1-3 yr 1,000 1,500 chloride disease and other nutrients
4-8 yr 1,200 1,900 (salt), stroke and to meet the
Males benzoate, needs for sweat
9-13 yr 1,500 2,200 phosphate; losses for persons
salted engaged in
14-21 yr 1,500 2,300
meats, recommended
Females
bread, nuts, levels of physical
9-13 yr 1,500 2,200 cold cuts; activity.
13-21 yr 1,500 2,300 margarine; Persons engaged
Pregnancy and Lactation butter; salt in activity at
≥14 yr 1,500 2,300 added to higher levels or in
foods in humid climates
cooking or resulting in
at the table excessive sweat
Salt is about might need more
40% than the AI.
sodium by UL applies to
weight. apparently
healthy persons
without
hypertension; it
thus may be too
high for persons
who already have
hypertension or
who are under the
care of a health
professional.
Chloride With sodium, Infants Processed In concert with Chloride is lost,
maintains fluid foods with sodium, results in usually with
volume outside 0-6 mo 180 ND added hypertension sodium, in sweat,
of cells and thus 7-12 mo 570 ND sodium as well as in
normal cell Children chloride vomiting and
function 1-3 yr 1,500 2,300 (salt), diarrhea.
4-8 yr 1,900 2,900 benzoate, AI and UL are
Males phosphate; equimolar in
9-13 yr 2,300 3,400 salted amount to sodium
 14-21 yr 2,300 3,600 meats, nuts, because most of
Females cold cuts; sodium in diet
9-13 yr 2,300 3,400 margarine; comes as sodium
13-21 yr 2,300 3,600 butter; salt chloride (salt).
Pregnancy and Lactation added to
≥14 yr 2,300 3,600 foods in
cooking or
at the table
Salt is about
60%
chloride by
weight.
Potassium Maintains fluid Infants Fruits and None documented Persons taking drugs
volume 0-6 mo 400 None set vegetables, dried from food alone, but for cardiovascular
inside/outside of 7-12 mo 700 peas, dairy potassium from disease such as ACE
cells and thus Children products, meats, supplements or salt inhibitors, ARBs, or
normal cell 1-3 yr 3,000 No UL nuts substitutes can potassium-sparing
function; acts to 4-8 yr 3,800 result in diuretics should be
blunt the rise of Males hyperkalemia and careful not to
blood pressure 9-13 yr 4,500 possibly sudden consume supplements
in response to death if excess is containing potassium
14-21 yr 4,700
excess sodium consumed by and might need to
Females
intake, and persons with consume less than the
decrease 9-13 yr 4,500 chronic renal AI.
markers of bone 13-21 yr 4,700 insufficiency
turnover and Pregnancy (kidney disease) or
recurrence of ≥14 yr 4,700 diabetes.
kidney stones Lactation
≥14 yr 5,100
Vitamin D Maintains serum Infants (µg/day) * Fish liver oils, Elevated plasma Patients receiving
(calciferol) calcium and 0-6 mo 10 25 flesh of fatty 25(OH)D glucocorticoid therapy
1 µg phosphorus 7-12 mo 10 38 fish, liver and concentration might require
calciferol concentrations Children (µg/day) * fat from seals causing additional vitamin D.
= 40 IU 1-3 yr 15 63 and polar bears, hypercalcemia
vitamin D 4-8 yr 15 75 eggs from hens
DRI Males (µg/day) * that have been
values are fed vitamin D,
9-21 yr 15 100
based on fortified milk
Females (µg/day) *
absence of products,
9-21 yr 15 100
adequate fortified cereals
exposure Pregnancy (µg/day) *
to ≤18 yr 15 100
sunlight. Lactation (µg/day)
≤18 yr 15 100
19-21 yr 15 100
Calcium Essential role in Infants Milk, cheese, Kidney stones, Amenorrheic women
blood clotting, 0-6 mo 200 1,000 yogurt, corn hypercalcemia, milk (exercise or anorexia
muscle 7-12 mo 260 1,500 tortillas, alkali syndrome, nervosa induced) have
contraction, Children calcium-set tofu, renal insufficiency reduced net calcium
nerve 1-3 yr 700 2,500 Chinese absorption.
transmission, 4-8 yr 1,000 2,500 cabbage, kale,
and bone and Males broccoli
tooth formation
9-18 yr 1,300 3,000
19-21 yr 1,000 2,500
Females
 9-18 yr 1,300 3,000
19-21 yr
Pregnancy
≤18 yr 1,300 3,000
19-21 yr 1,000 2,500
Lactation
≤18 yr 1,300 3,000
19-21 yr 1,000 2,500
Iron Critical Infants Heme GI distress Persons with
component of 0-6 mo 0.27 40 sources: decreased gastric
enzymes, 7-12 mo 11 40 meat, acidity may be at
cytochromes, Children poultry, fish increased risk for
myoglobin, and 1-3 yr 7 40 Nonheme deficiency.
hemoglobin 4-8 yr 10 40 sources: Cow's milk is a
Males dairy, eggs, poor source of
9-13 yr 8 40 plant-based bioavailable iron
foods, and is not
14-18 yr 11 45
breads, recommended for
19-21 yr 8 45
cereals, children <1 yr
Females breakfast old.
9-13 yr 8 40 foods Neurocognitive
14-18 yr 15 45 deficits have been
19-21 yr 18 45 reported in
Pregnancy infants with iron
≤18 yr 27 45 deficiency.
19-21 yr 27 45 RDA for females
Lactation increases with
≤18 yr 10 45 menarche related
19-21 yr 9 45 to increased
losses during
menstruation.
Vegans and
vegetarians might
require iron
supplementation
or intake of iron-
fortified foods.
GI parasites can
increase iron
losses via GI
bleeds.
Iron supplements
can interfere with
zinc absorption,
and vice versa; if
supplements are
being used, the
doses should be
staggered.
Zinc Essential for Infants Meats, shellfish, Acutely, zinc Zinc supplements
proper growth legumes, supplements cause interfere with
and 0-6 mo 2 4 fortified cereals, GI irritation and iron absorption,
development; 7-12 mo 3 5 whole grains headache; chronic and vice versa;
important Children effects of zinc therefore, if
catalyst for 100 1-3 yr 3 7 supplementation supplements are
 specific 4-8 yr 5 12 include impaired being used, the
enzymes Males immune function, doses should be
9-13 yr 8 23 changes in staggered.
14-18 yr 11 34 lipoprotein and Zinc deficiency
19-21 yr 11 40 cholesterol levels, can be associated
Females and reduced copper with stunting or
9-13 yr 8 23 status. impaired linear
14-18 yr 9 34 growth.
19-21 yr 8 40
Pregnancy
≤18 yr 12 34
19-21 yr 11 40
Lactation
≤18 yr 13 34
19-21 yr 12 40
Water Maintains Infants (L/day) All No UL because Recommended
homeostasis 0-6 mo 0.7 None set beverages, normally intakes for water
in the body 7-12 mo 0.8 including functioning are based on
Allows Children water kidneys can median intakes of
transport of 1-3 yr 1.3 Moisture in handle >0.7 L generally healthy
nutrients to 4-8 yr 1.7 foods (24 oz) of fluid persons who are
cells and Males (L/day) High- per hour adequately
removal 9-13 yr 2.4 moisture Symptoms of hydrated.
and foods water Persons can be
14-18 yr 3.3
excretion of include intoxication adequately
≥19 yr 3.7
waste watermelon, include hydrated at levels
products of Females (L/day) meats, and hyponatremia, above or below
metabolism 9-13 yr 2.1 soups which can the AIs provided;
14-18 yr 2.3 result in heart AIs provided are
≥19 yr 2.7 failure, and for total water in
Pregnancy (L/day) rhabdomyolysis temperate
≥14 yr 3.0 (skeletal climates.
Lactation (L/day) muscle tissue All sources can
≥14 yr 3.8 injury), which contribute to total
can lead to water needs:
kidney failure. beverages (tea,
coffee, juice,
soda, drinking
water) and
moisture found in
foods.
Moisture in food
accounts for
about 20% of
total water intake.
Thirst and
consumption of
beverages at
meals are
adequate to
maintain
hydration.
* Vitamin D RDA in IU/day: 40 if <1 yr, 600 if >1 yr of age or pregnant or lactating.
also describe growth of adequately nourished healthy children under best-care
practices.
In the clinical setting, the 2.3rd and 97.7th percentiles on the WHO growth
charts are used to identify insufficient and excessive growth from birth to 2 yr,
respectively. In contrast, the 5th and 95th percentiles are recommended for the
equivalent identification in the CDC growth charts from 2-20 yr (Table 55.7 ).
Note that length, weight, and weight-for-length are used in the WHO growth
charts from birth to 2 yr. Body mass index (BMI) can be calculated but is not
recommended for use in children <2 yr. Stature, weight, and BMI are used in the
CDC 2000 growth charts from 2-20 yr of age. These charts can be used to
categorize children 2-20 yr as underweight (<5th BMI percentile), normal
weight (5–85th), overweight (85–95th), and obese (≥95th BMI percentile).
Severe obesity is defined as BMI ≥120% of the 95th percentile, or BMI ≥35
kg/m2 (whichever is lower). This assessment corresponds to approximately the
99th percentile or a BMI z score ≥2.33. Severe obesity that exceeds the 99th
percentile is tracked on a specialized percentile curve for obesity. Furthermore,
adult classification is used for BMI ≥27 kg/m2 in adolescents over age 18 for
consideration of medication and bariatric surgery.

Table 55.7
Growth Chart Comparisons for Measuring Growth from
Birth to 20 Years

INSUFFICIENT EXCESSIVE
GROWTH AGE GROWTH BMI STATUS
GROWTH GROWTH
CHART RANGE METRICS PERCENTILE
PERCENTILE PERCENTILE
World Health Birth to Weight, length, <2.3rd >97.7th —
Organization, 2006 2 yr weight-for-length,
and head
circumference
US Centers for 2-20 yr Weight, height, body <5th >95th Under (<5th)
Disease Control and mass index (BMI) Normal (5–
Prevention, 2000 85th)
Over (85–95th)
Obese (>95th)
Severe Obesity
(≥120% of
95th, or ≥35
kg/m2 )
Table 56.1
Selected Beneficial Properties of Human Milk Compared
With Infant Formula

FACTOR ACTION
ANTIBACTERIAL FACTORS
Secretory IgA Specific antigen-targeted antiinfective action
Lactoferrin Immunomodulation, iron chelation, antimicrobial action, antiadhesive,
trophic for intestinal growth
κ-Casein Antiadhesive, bacterial flora
Oligosaccharides Prevention of bacterial attachment
Cytokines Antiinflammatory, epithelial barrier function
GROWTH FACTORS
Epidermal growth factor Luminal surveillance, repair of intestine
Transforming growth factor (TGF) Promotes epithelial cell growth (TGF-β)
Suppresses lymphocyte function (TGF-β)
Nerve growth factor Promotes neural growth
ENZYMES
Platelet-activating factor (PAF)– Blocks action of PAF
acetylhydrolase
Glutathione peroxidase Prevents lipid oxidation
Nucleotides Enhance antibody responses, bacterial flora
Adapted from Hamosh M: Bioactive factors in human milk, Pediatr Clin North Am 48:69–86, 2001.

Table 56.2

Absolute and Relative Contraindications to Breastfeeding Because of Maternal

Health Conditions
MATERNAL
HEALTH DEGREE OF RISK
CONDITION
HIV and HTLV In the United States, breastfeeding is contraindicated.
infection In other settings, health risks of not breastfeeding must be weighed against the risk of
transmitting virus to the infant.
Tuberculosis infection Breastfeeding is contraindicated until completion of approximately 2 wk of appropriate
maternal therapy.
Varicella-zoster Infant should not have direct contact to active lesions.
infection Infant should receive immune globulin.
Herpes simplex Breastfeeding is contraindicated with active herpetic lesions of the breast.
infection
CMV infection May be found in milk of mothers who are CMV seropositive.
Transmission through human milk causing symptomatic illness in term infants is
uncommon.
Hepatitis B infection Infants routinely receive hepatitis B immune globulin and hepatitis B vaccine if
mother is HBsAg positive.
No delay in initiation of breastfeeding is required.
Hepatitis C infection Breastfeeding is not contraindicated.
 Alcohol intake Limit maternal alcohol intake to <0.5 g/kg/day (for a woman of average weight, this is
the equivalent of 2 cans of beer, 2 glasses of wine, or 2 oz of liquor).
Cigarette smoking Discourage cigarette smoking, but smoking is not a contraindication to breastfeeding.
Chemotherapy, Breastfeeding is generally contraindicated.
radiopharmaceuticals
CMV, Cytomegalovirus; HBsAg, hepatitis B surface antigen; HIV, human immunodeficiency virus;
HTLV, human T-lymphotropic virus.
Data from Schanler RJ, Krebs NF, Mass SB, editors: Breastfeeding handbook for physicians , ed
2, Elk Grove Village, IL, 2014, American Academy of Pediatrics, pp 223–226.

Table 56.3
Conditions for Which Human Milk May Have
a Protective Effect

Diarrhea
Otitis media
Urinary tract infection
Necrotizing enterocolitis
Septicemia
Infant botulism
Insulin-dependent diabetes mellitus
Celiac disease
Crohn disease
Childhood cancer
Lymphoma
Leukemia
Recurrent otitis media
Allergy
Hospitalizations
Infant mortality

Table 56.4
Ten Hospital Practices to Encourage and Support
Breastfeeding* ‡
1. Have a written breastfeeding policy that is routinely communicated to all health care staff.
2. Train all health care staff in the skills necessary to implement this policy.
3. Inform all pregnant women about the benefits and management of breastfeeding.
 4. Help women initiate breastfeeding within 1 hour of birth.
5. Show women how to breastfeed and how to maintain lactation, even if they are separated from their newborns.
6. Give newborns no food or drink other than breast milk unless medically indicated.
7. Practice rooming-in; allow mothers and newborns to remain together 24 hours a day.
8. Encourage breastfeeding on demand.
9. Give no pacifiers or artificial nipples to breastfeeding infants. †
10. Foster the establishment of breastfeeding support groups and refer to them on discharge from the hospital or
birth center.
COMPONENTS OF SAFE POSITIONING FOR THE NEWBORN WHILE SKIN-TO-SKIN **
1. Infant's face can be seen.
2. Infant's head is in “sniffing” position.
3. Infant's nose and mouth are not covered.
4. Infant's head is turned to one side.
5. Infant's neck is straight, not bent.
6. Infant's shoulders and chest face mother.
7. Infant's legs are flexed.
8. Infant's back is covered with blankets.
9. Mother-infant dyad is monitored continuously by staff in the delivery environment and regularly on the
postpartum unit.
10. When mother wants to sleep, infant is placed in bassinet or with another support person who is awake and alert.
* The 1994 report of the Healthy Mothers, Health Babies National Coalition Expert Work Group
recommend that the UNICEF-WHO Baby Friendly Hospital Initiative be adapted for use in the
United States as the United States Breastfeeding Health Initiative, using the adapted ten hospital
practices above.
† The American Academy of Pediatrics endorsed the UNICEF-WHO Ten Steps to Successful
Breastfeeding, but does not support a categorical ban on pacifiers because of their role in
reducing the risk of sudden infant death syndrome and their analgesic benefit during painful
procedures when breastfeeding cannot provide the analgesia.
‡ Data from Baby-Friendly USA. Guidelines and evaluation criteria for facilities seeking baby-
friendly designation. Sandwich (MA): Baby Friendly USA, 2010. Available at
https://www.babyfriendlyusa.org/for-facilities/practice-guidelines/. Accessed 10 December 2018.
From ACOG Committee Opinion: Optimizing support for breastfeeding as part of obstetric
practice. Obstet Gynecol 132(4):e187-e195, 2018 (Box 1, p. e191 and Box 2, p. e192).
** Data from Ludington-Hoe SM, Morgan K. Infant assessment and reduction of sudden
unexpected postnatal collapse risk during skin-to-skin contact. Newborn Infant Nurs Rev
2014;14:28-33.

Table 56.5
Recommendations on Breastfeeding
Management for Healthy Term Infants
1. Exclusive breastfeeding for about 6 months
• Breastfeeding preferred; alternatively expressed mother's milk, or
donor breast milk
 • To continue for at least the first year and beyond as long as
mutually desired by mother and child
• Complementary foods rich in iron and other micronutrients should
be introduced at about 6 mo of age
2. Peripartum policies and practices that optimize breastfeeding initiation
and maintenance should be compatible with the AAP and Academy of
Breastfeeding Medicine Model Hospital Policy and include the
following:
• Direct skin-to-skin contact with mothers immediately after delivery
until the first feeding is accomplished and encouraged throughout
the postpartum period
• Delay in routine procedures (weighing, measuring, bathing, blood
tests, vaccines, and eye prophylaxis) until after the first feeding is
completed
• Delay in administration of intramuscular vitamin K until after the
first feeding is completed but within 6 hr of birth
• Ensure 8-12 feedings at the breast every 24 hr
• Ensure formal evaluation and documentation of breastfeeding by
trained caregivers (including position, latch, milk transfer,
examination) at least once for each nursing shift
• Give no supplements (water, glucose water, commercial infant
formula, or other fluids) to breastfeeding newborn infants unless
medically indicated using standard evidence-based guidelines for
the management of hyperbilirubinemia and hypoglycemia
• Avoid routine pacifier use in the postpartum period
• Begin daily oral vitamin D drops (400 IU) at hospital discharge
3. All breastfeeding infants should be seen by a pediatrician within 48 to 72
hr after discharge from the hospital
• Evaluate hydration and elimination patterns
• Evaluate body weight gain (body weight loss no more than 7%
from birth and no further weight loss by day 5: assess feeding and
consider more frequent follow-up)
• Discuss maternal/infant issues
• Observe feeding
4. Mother and infant should sleep in proximity to each other to facilitate
breastfeeding
5. Pacifier should be offered, while placing infant in back-to-sleep-position,
 no earlier than 3 to 4 weeks of age and after breastfeeding has been
established

From American Academy of Pediatrics (AAP): Breast-feeding and the use of

human milk, Pediatrics 129:e827–e841, 2012.

Feedings should be initiated soon after birth unless medical conditions

preclude them. Mothers should be encouraged to nurse at each breast at each
feeding starting with the breast offered second at the last feeding. It is not
unusual for an infant to fall asleep after the 1st breast and refuse the 2nd. It is
preferable to empty the 1st breast before offering the 2nd to allow complete
emptying of both breasts and therefore better milk production. Table 56.6
summarizes patterns of milk supply in the 1st week.

Table 56.6

Patterns of Milk Supply

DAY OF LIFE MILK SUPPLY
Day 1 Some milk (~5 mL) may be expressed.
Days 2-4 Lactogenesis; milk production increases.
Day 5 Milk present; fullness and leaking are felt.
Day 6 onward Breasts should feel “empty” after feeding.
Adapted from Neifert MR: Clinical aspects of lactation: promoting breastfeeding success, Clin
Perinatol 26:281–306, 1999.

New mothers should be instructed about infant hunger cues, correct nipple
latch, positioning of the infant on the breast, and feeding frequency. It is also
suggested that someone trained in lactation observe a feeding to evaluate
positioning, latch, milk transfer, maternal responses, and infant satiety. Attention
to these issues during the birth hospitalization allows dialog with the mother and
family and can prevent problems that could occur with improper technique or
knowledge of breastfeeding. As part of the discharge teaching process, issues on
infant feeding, elimination patterns, breast engorgement, breast care, and
maternal nutrition should be discussed. A follow-up appointment is
recommended within 24-48 hr after hospital discharge.

Nipple Pain
Nipple pain is one of the most common complaints of breastfeeding mothers in
Important Principles for Weaning

Begin at 6 mo of age.
At the proper age, encourage a cup rather than a bottle.
Introduce 1 new food at a time.
Energy density should exceed that of breast milk.
Iron-containing foods (meat, iron-supplemented cereals) are required.
Zinc intake should be encouraged with foods such as meat, dairy products,
wheat, and rice.
Phytate intake should be low to enhance mineral absorption.
Breast milk should continue to 12 mo of age; formula or cow's milk is then
substituted.
Give no more than 24 oz/day of cow's milk.
Fluids other than breast milk, formula, and water should be discouraged.
Give no more than 4-6 oz/day of 100% fruit juice; no sugar-sweetened
beverages.

Adapted from American Academy of Pediatrics: Pediatric nutrition handbook ,

ed 6, Elk Grove Village, IL, 2008, American Academy of Pediatrics.

Some foods are more nutritionally appropriate than others to complement

breast milk or infant formula. The food consumption patterns of U.S. infants and
toddlers demonstrate that almost all infants ≤12 mo consumed some form of
milk every day; infants >4 mo consumed more formula than human milk, and by
9-11 mo, 20% consumed whole cow's milk and 25% consumed nonfat or
reduced-fat milk.
The most common complementary foods between 4 and 11 mo of age are
infant cereals. Almost 45% of infants between 9 and 11 mo of age consumed
noninfant cereals. Infant eating patterns also vary, with up to 61% of infants 4-11
mo of age consuming no vegetables. French fries were the most frequently
consumed vegetables in toddlers. Positive changes in the last decade include
increased duration of breastfeeding, delayed introduction of complementary
foods, and decreased juice consumption. Continuing concerns include lack of
fruits and vegetables; diets low in iron, essential fatty acids, fiber, and whole
grains; and diets high in saturated fat and sodium. Table 56.7 summarizes the
AAP recommendations for initiating complementary foods.
Table 56.8

Feeding Skills Birth to 36 Months

AGE (mo) FEEDING/ORAL SENSORIMOTOR SKILLS
Birth to 4-6 Nipple feeding, breast or bottle
Hand on bottle during feeding (2-4 mo)
Maintains semiflexed posture during feeding
Promotion of infant–parent interaction
6-9 (transition feeding) Feeding more in upright position
Spoon feeding thin, pureed foods
Both hands to hold bottle
Finger feeding introduced
Vertical munching of easily dissolvable solids
Preference for parents to feed
9-12 Cup drinking
Eats lumpy, mashed food
Finger feeding for easily dissolvable solids
Chewing includes rotary jaw action
12-18 Self-feeding; grasps spoon with whole hand
Holds cup with 2 hands
Drinking with 4-5 consecutive swallows
Holding and tipping bottle
>18-24 Swallowing with lip closure
Self-feeding predominates
Chewing broad range of food
Up-down tongue movements
24-36 Circulatory jaw rotations
Chewing with lips closed
One-handed cup holding and open cup drinking with no spilling
Using fingers to fill spoon
Eating wide range of solid food
Total self-feeding, using fork
Adapted from Arvedson JC: Swallowing and feeding in infants and young children. GI Motility
online, 2006. doi:10.1038/gimo17.

Juices should not be given before 12 mo of age. The volume of juices should
be limited to 4 oz/day in children 1-3 yr old, to 4-6 oz/day for 4-6 yr olds, and to
8 oz/day for 7-18 yr olds. Children taking medications metabolized by CYP3A4
must avoid grapefruit juices.
In the 2nd year of life, self-feeding becomes a norm and provides the
opportunity for the family to eat together with less stress. Self-feeding allows the
child to limit her intake. Child feeding is an interactive process. Children receive
cues regarding appropriate feeding behaviors from parents. Parents should praise
positive and ignore negative eating behaviors unless the behavior jeopardizes the
health and safety of the child. In addition, parents should eat with their toddlers
and not simply feed them, in order to model positive eating behaviors.
The 2 yr old child should progress from small pieces of soft food to prepared
setting. Another parenting challenge is to control the excess appetite of some
children and adolescents. Children should be supported to eat at a slower pace
and to chew their food properly. Conversation at the dinner table should be
encouraged to prolong eating to at least 15 min. Offering vegetables while
children are hungry at the beginning of the meal has been shown to increase
vegetable consumption. Useful strategies, when the child is still hungry after a
meal, include a 15-20 min pause (allow child to engage in another activity)
before a 2nd serving or offering foods that are insufficiently consumed, such as
vegetables, whole grains, or fruits.

Eating at School
The National School Lunch Program and the School Breakfast Program
provide low-cost meals to more than 5 billion children nationwide. Guidelines
for meals are taken from the Dietary Guidelines for Americans and the 2005
Dietary Reference. Recommendations include the use of age-grade portion sizes
and the amounts of vegetables and fruits, grains, and fats (Table 56.9 ). The
training and equipment for school food service staff, school community
engagement, parent education, and food industry involvement are among the
necessary components. The target year is 2020 for achieving recommendations
for sodium. In the meantime, while schools are working on implementing
changes, parents should be encouraged to examine the weekly menu with their
child and assist with their choices. If children bring their lunch from home,
recommendations for what constitutes a healthful lunch should be provided by
the pediatrician. Parents can be directed to www.choosemyplate.org for healthful
lunch ideas. In addition, parties within classrooms should be limited to once a
month.
Table 56.9
Revised National School Lunch Program and
School Breakfast Program Recommendations

• Portion sizes of food are to be based on age-grade groups.

• School lunches and breakfasts will have a minimum and maximum calorie
level, maximum saturated fat content, and a maximum sodium content.
• Foods must contain zero grams of trans fat per serving.
 • The inclusion of unsaturated vegetable oils is encouraged within calorie
limits.
• Vegetables and fruits are not interchangeable.
• Vegetable offerings at lunch must include cup equivalent of the
following: dark-green vegetables, bright-orange vegetables, and legumes.
• No more than half of fruit servings may be in the form of juice.
• At least one half of bread/grain offered must be whole grain.
• Milk must be fat free if flavored and either fat free or 1% fat if plain.
• Students must select a fruit option at breakfast with their meal, and either a
fruit or a vegetable at lunch, for the meal to be reimbursable.

Adapted from the National Academies of Engineering, Science and Medicine:

School meals: building blocks for healthy children, Washington, DC, 2010,
National Academies Press.

Eating Out
The number of meals eaten outside the home or brought home from takeout
restaurants has increased in all age-groups of the U.S. population. The increased
convenience of this meal pattern is undermined by the generally lower
nutritional value of the meals, compared to home-cooked meals. Typically, meals
consumed or purchased in fast-food or casual restaurants are of large portion
size, are dense in calories, and contain large amounts of saturated fat, salt, and
sugar and low amounts of whole grains, fruits, and vegetables. Although still a
problem currently, trans fat is being phased out of most commercial restaurants
and prepared foods. Although an increasing number of restaurants offer healthier
alternatives, the vast majority of what is consumed at restaurants does not fit
MyPlate recommendations.
With increasing age, an increasing number of meals and snacks are also
consumed during peer social gatherings at friends' houses and parties. When a
large part of a child's or adolescent's diet is consumed on these occasions, the
diet quality can suffer, because food offerings are typically of low nutritional
value. Parents and pediatricians need to guide teens in navigating these
occasions while maintaining a healthful diet and enjoying meaningful social
interactions. These occasions often are also opportunities for teens to consume
alcohol; consequently, adult supervision is important.
developing regions except sub-Saharan Africa achieved the target to halve the
proportion of people living in extreme poverty, with the proportion falling from
47% in 1990 to 14% in 2015. Reductions in hunger were broadly consistent with
those of poverty reduction, and rates of undernourishment in developing regions
fell from 23% in 1990 to 13% in 2015. The prevalence of underweight children
(another MDG indicator of “hunger”) fell from 29% in 1990 to 15% in 2015 for
the developing regions combined. Rural children are almost twice as likely to be
underweight as urban children, and the poorest quintile is almost 3 times as
likely to be underweight as the richest quintile.
Eradicating poverty and hunger continue to be core targets of the Sustainable
Development Goals , as agreed by 193 countries of the United Nations General
Assembly in September 2015, and are to be achieved by 2030. In addition, in
2012 the World Health Assembly agreed to 6 global nutrition targets to be
reached by 2025, measured against a 2010 baseline, and the United Nations
Secretary-General launched the Zero Hunger Challenge with 5 objectives that
“would boost economic growth, reduce poverty and safeguard the environment”
and “would foster peace and stability” (Table 57.1 ).

Table 57.1
Global Food Security and Nutrition Targets

WORLD HEALTH ASSEMBLY GLOBAL

ZERO HUNGER CHALLENGE OBJECTIVES
NUTRITION TARGETS FOR 2025
1. Access to an adequate and stable food supply for all 1. A 40% reduction in the number of stunted
2. Elimination of stunting in children <2 yr, and no children <5 yr
malnutrition in pregnancy and early childhood 2. A 50% reduction in anemia in women of
3. Sustainable food systems reproductive age
4. Doubling of smallholder productivity and income, 3. A 30% reduction in low birthweight
particularly for women 4. No increase in childhood overweight
5. No loss or waste of food, and responsible consumption 5. Increase exclusive breastfeeding rates to at least
50% in the 1st 6 mo
6. Reduce and maintain childhood wasting to <5%

Future Food Security

Between now and 2050 the world's population is expected to exceed 9 billion,
and an increase in food supply of 70–100% will be needed to feed this larger,
more urban, and more affluent populace. Over this same period, the world's food
supply is expected to diminish unless action is taken. Accelerating the decline in
fertility rates and reducing overconsumption are basic but difficult actions to
deficiency, which increases the risk of birth defects, this particular window is
before conception.

Measurement of Undernutrition
The term malnutrition encompasses both ends of the nutrition spectrum, from
undernutrition to overweight. Many poor nutritional outcomes begin in utero and
are manifest as low birthweight (LBW, <2,500 g). Preterm delivery and fetal
growth restriction are the 2 main causes of LBW, with prematurity relatively
more common in richer countries and fetal growth restriction relatively more
common in poorer countries.
Nutritional status is often assessed in terms of anthropometry (Table 57.2 ).
International standards of normal child growth under optimum conditions from
birth to 5 yr have been established by the World Health Organization (WHO). To
compile the standards, longitudinal data from birth to 24 mo of healthy,
breastfed, term infants were combined with cross-sectional measurements of
children ages 18-71 mo. The standards allow normalization of anthropometric
measures in terms of z scores (standard deviation [SD] scores). A z-score is the
child's height (weight) minus the median height (weight) for the child's age and
sex divided by the relevant SD. The standards are applicable to all children
everywhere, having been derived from a large, multicountry study reflecting
diverse ethnic backgrounds and cultural settings.

Table 57.2
Classification of Undernutrition
CLASSIFICATION INDEX GRADING
Gomez (underweight) 90–75% of median weight-for-age Grade 1 (mild)
75-60% Grade 2 (moderate)
<60% Grade 3 (severe)
Waterlow (wasting) 90–80% of median weight-for-height Mild
80–70% Moderate
<70% Severe
Waterlow (stunting) 95–90% of median height-for-age Mild
90–85% Moderate
<85% Severe
WHO (wasting) < −2 to > −3 SD weight-for-height Moderate
< −3 Severe
WHO (stunting) < −2 to > −3 SD height-for-age Moderate
<−3 Severe
WHO (wasting) (for age-group 6-59 mo) 115-125 mm mid-upper arm circumference Moderate
 <115 mm Severe
SD, Standard deviation; WHO, World Health Organization.

Height-for-age (or length-for-age for children <2 yr) is a measure of linear

growth, and a deficit represents the cumulative impact of adverse events, usually
in the first 1000 days from conception, that result in stunting, or chronic
malnutrition. A low height-for-age typically reflects socioeconomic
disadvantage. A low weight-for-height , or wasting , usually indicates acute
malnutrition. Conversely, a high weight-for-height indicates overweight .
Weight-for-age is the most commonly used index of nutritional status, although
a low value has limited clinical significance because it does not differentiate
between wasting and stunting. Weight-for-age has the advantage of being
somewhat easier to measure than indices that require height measurements. In
humanitarian emergencies and some community or outpatient settings, mid-
upper arm circumference is used for screening wasted children (Fig. 57.4 ).

FIG. 57.4 Measuring mid-upper arm circumference. (Courtesy of Nyani
Quarmyne/Panos Pictures.)

Body mass index (BMI) is calculated by dividing weight in kilograms by the

square of height in meters. For children, BMI is age and gender specific. BMI-
for-age can be used from birth to 20 yr and is a screening tool for thinness (less
than −2 SD), overweight (between +1 SD and +2 SD), and obesity (greater than
+2 SD). To diagnose obesity, additional measures of adiposity are desirable
because a high BMI can result from high muscularity, and not only from excess
Table 57.3
Global Deaths in Children <5 yr Attributed to Nutritional
Conditions

CONDITION ATTRIBUTABLE DEATHS % OF TOTAL DEATHS <5 YR

(a) Fetal growth restriction (<1 mo) 817,000 11.8
(b) Stunting (1-59 mo) 1,017,000 14.7
(c) Wasting (1-59 mo) 875,000 12.6
(d) Zinc deficiency (12-59 mo) 116,000 1.7
(e) Vitamin A deficiency (6-59 mo) 157,000 2.3
(f) Suboptimal breastfeeding (0-23 mo) 804,000 11.6
Joint effects of (a) + (f) 1,348,000 19.4
Joint effects of all 6 factors 3,097,000 44.7
From Black RE, Victora CG, Walker SP, et al: Maternal and child undernutrition and overweight in
low- and middle-income countries, Lancet 382:427–451, 2013.

The risk of child death from infectious diseases increases even with mild
undernutrition, and as the severity of undernutrition increases, the risk increases
exponentially (Table 57.4 ). Undernutrition impairs immune function and other
host defenses; consequently, childhood infections are more severe and longer-
lasting in undernourished children and more likely to be fatal than the same
illnesses in well-nourished children. Infections can adversely affect nutritional
status, and young children can quickly enter a cycle of repeated infections and
ever-worsening malnutrition. Even for the survivors, physical and cognitive
damage as a result of undernutrition can impact their future health and economic
well-being. For girls, the cycle of undernutrition is passed on to the next
generation when undernourished women give birth to LBW babies.

Table 57.4
Hazard Ratios for All-Cause and Cause-Specific Deaths
Associated With Stunting, Wasting, and Underweight in
Children <5 yr

DEATHS
STANDARD DEVIATION (SD) SCORE
All Pneumonia Diarrhea Measles Other Infections
Height/length-for-age
< −3 5.5 6.4 6.3 6.0 3.0
−3 to < −2 2.3 2.2 2.4 2.8 1.9
−2 to < −1 1.5 1.6 1.7 1.3 0.9
≥ −1 1.0 1.0 1.0 1.0 1.0
Weight-for-length
 < −3 11.6 9.7 12.3 9.6 11.2
−3 to < −2 3.4 4.7 3.4 2.6 2.7
−2 to < −1 1.6 1.9 1.6 1.0 1.7
≥ −1 1.0 1.0 1.0 1.0 1.0
Weight-for-age
< −3 9.4 10.1 11.6 7.7 8.3
−3 to < −2 2.6 3.1 2.9 3.1 1.6
−2 to < −1 1.5 1.9 1.7 1.0 1.5
≥ −1 1.0 1.0 1.0 1.0 1.0
From Black RE, Victora CG, Walker SP, et al: Maternal and child undernutrition and overweight in
low- and middle-income countries, Lancet 382:427–451, 2013.

Fetal growth restriction and early childhood undernutrition have consequences

for adult chronic illness. LBW is associated with an increased risk of
hypertension, stroke, and type 2 diabetes in adults. The increased risk is thought
to reflect “fetal programming,” a process by which fetal undernutrition leads to
permanent changes in the structure and metabolism of organs and systems that
manifest as disease in later life. The risk is exacerbated by low weight gain
during the first 2 yr of life. The increased risk of adult chronic disease from
undernutrition early in life is a particular challenge to low-income countries with
rapid economic growth.
Stunting before age 3 yr is associated with poorer motor and cognitive
development and altered behavior in later years. The effect is 6-13 DQ
(developmental quotient) points. Iodine and iron deficiencies also lead to loss of
cognitive potential. Indications are that children living in areas of chronic iodine
deficiency have an average reduction in IQ (intelligence quotient) of 12-13.5
points compared with children in iodine-sufficient areas. Iron deficiency has a
detrimental effect on the motor development of children <4 yr and on cognition
of school-age children. The estimated deficit is 1.73 IQ points for each 10 g/L
decrease in hemoglobin concentration.
Undernutrition can have substantial economic consequences for survivors and
their families. The consequences can be quantified in 5 categories: (1) increased
costs of healthcare, either neonatal care for LBW babies or treatment of illness
for infants and young children; (2) productivity losses (and thus reduced
earnings) associated with smaller stature and muscle mass; (3) productivity
losses from reduced cognitive ability and poorer school performance; (4)
increased costs of chronic diseases associated with fetal and early child
malnutrition; and (5) consequences of maternal undernutrition on future
generations. The impact of nutrition on earnings appears to be independent of
the effects of childhood deprivation.
Key Interventions
Interventions to address child undernutrition can be divided into those that
address immediate causes (nutrition-specific interventions ) and those that
address underlying causes (nutrition-sensitive interventions ) (Table 57.5 ). In
the short-term, nutrition-specific interventions (e.g., salt iodization) can have
substantial impact even in the absence of economic growth, and micronutrient
interventions (supplementation and fortification) are consistently ranked as the
most cost-effective investment. There is increased attention to nutrition-sensitive
interventions as the best means of sustainably eliminating malnutrition, and to
multisectoral policies that harness the synergism between the two types of
intervention (e.g., cross-sectoral linkages among agriculture, nutrition, and
health).

Table 57.5
Examples of Nutrition-Specific and Nutrition-Sensitive
Interventions

NUTRITION-SPECIFIC INTERVENTIONS NUTRITION-SENSITIVE INTERVENTIONS

• Promotion and support for exclusive breastfeeding for • Increased access to affordable, nutritious food;
6 mo, and continued breastfeeding for at least 2 yr smallholder agriculture; credit and microfinance
• Promotion of adequate, timely, and safe • Postharvest food processing and preservation
complementary feeding from 6 mo • Vaccination against neonatal and childhood illness;
• Increased micronutrient intake through dietary access to healthcare
diversity • Improved water/sanitation and hygiene (e.g.,
• Micronutrient supplements for pregnant women handwashing with soap)
(iron/folate) and young children (vitamin A, iron, • Education; women's empowerment; gender equality
zinc) in deficient areas • Social protection (e.g., cash transfers)
• Zinc supplements to children during and after diarrhea • Malaria prevention (vector control/bednets);
(10-20 mg/day for 2 wk) intermittent preventive treatment during pregnancy
• Prevention and treatment of severe acute malnutrition and in children 3-59 mo
• Crop biofortification, food fortification, salt iodization • Birth spacing; delaying pregnancy until after 18 yr of
• Reduced heavy physical activity in pregnancy age

To reduce the adverse consequences of undernutrition on mortality, morbidity,

and cognitive development, interventions must encompass both fetal and
postnatal periods. Preventing LBW is essential, with emphasis on prevention of
low maternal BMI and anemia, and in the longer term, prevention of low
maternal stature. Other measures include smoking cessation, birth spacing,
delaying pregnancy until after 18 yr of age, and intermittent preventive treatment
of malaria. In the postnatal period, promotion and support of exclusive
breastfeeding is a high priority. Although the Baby Friendly Hospital Initiative
(glutathione, vitamins A, C, and E, and essential fatty acids) or cofactors (zinc,
copper, selenium).

Clinical Manifestations of Severe Acute

Malnutrition (Table 57.6 )
Severe wasting is most visible on the thighs, buttocks, and upper arms, as well
as over the ribs and scapulae, where loss of fat and skeletal muscle is greatest
(Fig. 57.5 ). Wasting is preceded by failure to gain weight and then by weight
loss. The skin loses turgor and becomes loose as subcutaneous tissues are broken
down to provide energy. The face may retain a relatively normal appearance, but
eventually becomes wasted and wizened. The eyes may be sunken from loss of
retroorbital fat, and lacrimal and salivary glands may atrophy, leading to lack of
tears and a dry mouth. Weakened abdominal muscles and gas from bacterial
overgrowth of the upper gut may lead to a distended abdomen. Severely wasted
children are often fretful and irritable.

Table 57.6

Clinical Signs of Malnutrition

SITE SIGNS
Face Moon face (kwashiorkor), simian facies (marasmus)
Eye Dry eyes, pale conjunctiva, Bitot spots (vitamin A), periorbital edema
Mouth Angular stomatitis, cheilitis, glossitis, spongy bleeding gums (vitamin C), parotid enlargement
Teeth Enamel mottling, delayed eruption
Hair Dull, sparse, brittle hair; hypopigmentation; flag sign (alternating bands of light and normal
color); broomstick eyelashes; alopecia
Skin Loose and wrinkled (marasmus); shiny and edematous (kwashiorkor); dry, follicular
hyperkeratosis; patchy hyper- and hypopigmentation (“crazy paving” or “flaky paint”
dermatoses); erosions; poor wound healing
Nails Koilonychia; thin and soft nail plates, fissures, or ridges
Musculature Muscle wasting, particularly buttocks and thighs; Chvostek or Trousseau sign (hypocalcemia)
Skeletal Deformities, usually as a result of calcium, vitamin D, or vitamin C deficiencies
Abdomen Distended: hepatomegaly with fatty liver; ascites may be present
Cardiovascular Bradycardia, hypotension, reduced cardiac output, small vessel vasculopathy
Neurologic Global developmental delay, loss of knee and ankle reflexes, impaired memory
Hematologic Pallor, petechiae, bleeding diathesis
Behavior Lethargic, apathetic, irritable on handling
From Grover Z, Ee LC: Protein energy malnutrition, Pediatr Clin North Am 56:1055–1068, 2009.
fluid overload, they must be monitored closely.

Table 57.7
Emergency Treatment in Severe Malnutrition

CONDITION IMMEDIATE ACTION

Shock 1. Give oxygen.
• Lethargic or 2. Give sterile 10% glucose (5 mL/kg) rapidly by IV injection.
unconscious and3. Give IV fluid at 15 mL/kg over 1 hr, using:
• Cold hands • Ringer lactate with 5% dextrose or
Plus either: • Half-normal saline* with 5% dextrose or
• Slow capillary • Half-strength Darrow solution with 5% dextrose
refill (>3 sec) or • If all the above are unavailable, Ringer lactate
• Weak fast pulse4. Measure and record pulse and respirations at the start and every 10 min.
If there are signs of improvement (pulse and respiration rates fall) repeat IV drip, 15 mL/kg
for 1 more hr. Then switch to oral or nasogastric rehydration with ReSoMal, 5-10 mL/kg in
alternate hr (see Table 57.8 step 3).
If there are no signs of improvement, assume septic shock and:
1. Give maintenance fluid IV (4 mL/kg/hr) while waiting for blood.
2. Order 10 mL/kg fresh whole blood and transfuse slowly over 3 hr. If signs of heart
failure, give 5-7 mL/kg packed cells rather than whole blood.
3. Give furosemide, 1 mL/kg IV at start of transfusion.
Hypoglycemia See Table 57.8 step 1 for treatment.
Blood glucose
<3 mmol/L
Severe Do not give IV fluids except in shock.
dehydration See Table 57.8 step 3 for treatment.
Very severe If very severe anemia (or Hgb 4-6 g/dL and respiratory distress):
anemia 1. Give whole blood 10 mL/kg slowly over 3 hr. If signs of heart failure, give 5-7 mL/kg
Hgb <4 g/dL packed cells rather than whole blood.
2. Give furosemide 1 mL/kg IV at the start of the transfusion.
Emergency If corneal ulceration:
eye care 1. Give vitamin A immediately (age <6 mo: 50,000 IU; 6-12 mo: 100,000 IU; >12 mo:
Corneal 200,000 IU)
ulceration 2. Instill 1 drop atropine (1%) into affected eye to relax the eye and prevent the lens from
pushing out.
* Some would recommend 5% dextrose in normal saline.

Hgb, Hemoglobin; IV, intravenous(ly).

Stabilization
Table 57.8 summarizes the therapeutic directives for stabilization steps 1-7 (Fig.
57.7 ). Giving broad-spectrum antibiotics (Table 57.9 ) and feeding frequent
small amounts of F75 (a specially formulated low-lactose milk with 75 kcal and
0.9 g protein per 100 mL to which potassium, magnesium, and micronutrients
are added), will reestablish metabolic control, treat edema, and restore appetite.
The parenteral route should be avoided; children who lack appetite should be fed
by nasogastric tube, because nutrients delivered within the gut lumen help in its
repair. Table 57.10 provides recipes for preparing the special feeds and their
nutrient composition. Of the 2 recipes for F75, one requires no cooking, and the
other is cereal based and has a lower osmolality, which may benefit children
with persistent diarrhea. F75 is also available commercially; maltodextrins
replace some of the sugar, and potassium, magnesium, minerals, and vitamins
are already added.

Table 57.8
Therapeutic Directives for Stabilization of Malnourished
Children
STEP PREVENTION TREATMENT
1. Prevent/treat Avoid long gaps without food If conscious:
hypoglycemia and minimize need for 1. Give 10% glucose (50 mL), or a feed (see step 7), or
blood glucose <3 glucose: 1 tsp sugar under tongue, whichever is quickest.
mmol/L. 1. Feed immediately.
2. Feed every 2 hr for at least 1st day. Initially give
2. Feed every 3 hr day and
of feed every 30 min.
night (2 hr if ill).
3. Keep warm.
3. Feed on time.
4. Start broad-spectrum antibiotics.
4. Keep warm.
If unconscious:
5. Treat infections (they
1. Immediately give sterile 10% glucose (5 mL/kg)
compete for glucose).
rapidly by IV.
Note: Hypoglycemia and
hypothermia often coexist and 2. Feed every 2 hr for at least 1st day. Initially give
are signs of severe infection. of feed every 30 min. Use nasogastric (NG) tube if
unable to drink.
3. Keep warm.
4. Start broad-spectrum antibiotics.
2. Prevent/treat Keep warm and dry and feed Actively rewarm.
hypothermia frequently. 1. Feed.
axillary <35°C 1. Avoid exposure. 2. Skin-to-skin contact with caregiver (“kangaroo
(95°F); rectal 2. Dress warmly, including technique”) or dress in warmed clothes, cover
<35.5°C (95.9°F). head and cover with head, wrap in warmed blanket and provide indirect
blanket. heat (e.g., heater; transwarmer mattress;
3. Keep room hot; avoid incandescent lamp).
drafts. 3. Monitor temperature hourly (or every 30 min if
4. Change wet clothes and using heater).
bedding. 4. Stop rewarming when rectal temperature is 36.5°C
5. Do not bathe if very ill. (97.7°F).
6. Feed frequently day and
night.
7. Treat infections.
3. Prevent/treat Replace stool losses. Do not give IV fluids unless the child is in shock.
dehydration. 1. Give ReSoMal after each 1. Give ReSoMal 5 mL/kg every 30 min for 1st 2 hr
watery stool. ReSoMal orally or NG tube.
(37.5 mmol Na/L) is a low- 2. Then give 5-10 mL/kg in alternate hours for up to
 sodium rehydration solution 10 hr. Amount depends on stool loss and eagerness
for malnutrition. to drink. Feed in the other alternate hour.
3. Monitor hourly and stop if signs of overload
develop (pulse rate increases by 25 beats/min and
respiratory rate by 5 breaths/min; increasing
edema; engorged jugular veins).
4. Stop when rehydrated (≥3 signs of hydration: less
thirsty, passing urine, skin pinch less slow, eyes
less sunken, moist mouth, tears, less lethargic,
improved pulse and respiratory rate).
4. Correct electrolyte 1. Give extra potassium (4 mmol/kg/day) and
imbalance—deficit magnesium (0.6 mmol/kg/day) for at least 2 wk (see
of potassium and Table 57.12 ).
magnesium, excess Note: Potassium and magnesium are already added
sodium. in Nutriset F75 and F100 packets.
5. Prevent/treat Minimize risk of cross-infection. Infections are often silent. Starting on 1st day, give
infections. 1. Avoid overcrowding. broad-spectrum antibiotics to all children.
2. Wash hands. 1. For antibiotic choices/schedule, see Table 57.9 .
3. Give measles vaccine to 2. Ensure all doses are given, and given on time.
unimmunized children age 3. Cover skin lesions so that they do not become
>6 mo. infected.
Note: Avoid steroids because they depress immune
function.
6. Correct Note: Folic acid, multivitamins, Do not give iron in the stabilization phase.
micronutrient zinc, copper, and other trace 1. Give vitamin A on day 1 (<6 mo 50,000 units; 6-
deficiencies. minerals are already added in 12 mo 100,000 units; >12 mo 200,000 units) if
Nutriset F75 and F100 packets. child has any eye signs of vitamin A deficiency or
has had recent measles. Repeat this dose on days 2
and 14.
2. Give folic acid, 1 mg (5 mg on day 1).
3. Give zinc (2 mg/kg/day) and copper (0.3
mg/kg/day). These are in the electrolyte/mineral
solution and Combined Mineral Vitamin mix
(CMV) and can be added to feeds and ReSoMal.
4. Give multivitamin syrup or CMV.
7. Start cautious 1. Give 8-12 small feeds of F75 to provide 130
feeding. mL/kg/day, 100 kcal/kg/day, and 1-1.5 g
protein/kg/day.
2. If gross edema, reduce volume to 100 mL/kg/day.
3. Keep a 24-hr intake chart. Measure feeds carefully.
Record leftovers.
4. If child has poor appetite, coax and encourage to
finish the feed. If unfinished, reoffer later. Use NG
tube if eating ≤80% of the amount offered.
5. If breastfed, encourage continued breastfeeding but
also give F75.
6. Transfer to F100 when appetite returns (usually
within 1 wk) and edema has been lost or is reduced.
7. Weigh daily and plot weight.

Table 57.9

Recommended Antibiotics for Malnourished Children*

 GIVE
If no complications Amoxicillin, 25 mg/kg PO twice daily for 5 days
If complications (shock, hypoglycemia, hypothermia, Gentamicin, 7.5 mg/kg IV or IM once daily for 7
skin lesions, respiratory or urinary tract infections, or days
lethargy/sickly) and
Ampicillin, 50 mg/kg IV or IM every 6 hr for 2
days, then amoxicillin, 25-40 mg/kg PO every 8
hr for 5 days
*
Local resistance patterns may require these to be adjusted: Ensure that there is Gram-negative
cover.
If specific infections are identified, add appropriate antibiotics.
For persistent diarrhea or small bowel overgrowth, add metronidazole, 7.5 mg/kg PO every 8 hr
for 7 days.
PO, Orally; IM, intramuscularly; IV, intravenously.

Table 57.10
Recipes for Milk Formulas F75 and F100

F75 c
F75 b F100 d
(STARTER)
(STARTER) (CATCH-UP)
(CEREAL-BASED)
Dried skimmed milk (g) 25 25 80
Sugar (g) 100 70 50
Cereal flour (g) — 35 —
Vegetable oil (g) 30 30 60
Electrolyte/mineral solution (mL) a 20 20 20
Water: make up to (mL) 1000 1000 1000
Content/100 mL
Energy (kcal) 75 75 100
Protein (g) 0.9 1.1 2.9
Lactose (g) 1.3 1.3 4.2
Potassium (mmol) 4.0 4.2 6.3
Sodium (mmol) 0.6 0.6 1.9
Magnesium (mmol) 0.43 0.46 0.73
Zinc (mg) 2.0 2.0 2.3
Copper (mg) 0.25 0.25 0.25
% Energy from protein 5 6 12
% Energy from fat 32 32 53
Osmolality (mOsm/L) 413 334 419
a See Table 57.12 for recipe, or use commercially available therapeutic Combined Mineral Vitamin
mix (CMV).
b A comparable F75 can be made from 35 g dried whole milk, 100 g sugar, 20 g oil, 20 mL
electrolyte/mineral solution, and water to 1000 mL; or from 300 mL full-cream cow's milk, 100 g
sugar, 20 g oil, 20 mL electrolyte/mineral solution, and water to 1000 mL.
c This lower-osmolality formula may be helpful for children with dysentery or persistent diarrhea.

Cook for 4 min.

d A comparable F100 can be made from 110 g dried whole milk, 50 g sugar, 30 g oil, 20 mL

electrolyte/mineral solution, and water to 1000 mL; or from 880 mL full-cream cow's milk, 75 g
sugar, 20 g oil, 20 mL electrolyte/mineral solution, and water to 1000 mL.
Whisk at high speed to prevent oil from separating out.

Dehydration status is easily misdiagnosed in severely wasted children,

because the usual signs (e.g., slow skin pinch, sunken eyes) may be present even
without dehydration. Rehydration must therefore be closely monitored for signs
of fluid overload. Serum electrolyte levels can be misleading because of sodium
leaking from the blood into cells and potassium leaking out of cells. Keeping the
intake of electrolytes and nutrients constant (see Table 57.8 ) allows systems to
stabilize more quickly than adjusting intake in response to laboratory results.
Table 57.11 provides a recipe for the special rehydration solution used in
severe malnutrition (ReSoMal). Therapeutic Combined Mineral Vitamin mix
(CMV) contains electrolytes, minerals, and vitamins and is added to ReSoMal
and feeds. If unavailable, potassium, magnesium, zinc, and copper can be added
as an electrolyte/mineral stock solution (Table 57.12 provides a recipe), and a
multivitamin supplement can be given separately.

Table 57.11

Recipe for Rehydration Solution for Malnutrition (ReSoMal)

INGREDIENT AMOUNT
Water 2 L
WHO ORS One 1-L sachet*
Sucrose 50 g
Electrolyte/mineral solution † 40 mL
* Sachet contains 2.6 g sodium chloride, 2.9 g trisodium citrate dihydrate, 1.5 g potassium
chloride, and 13.5 g glucose.
† See Table 57.12 for recipe, or use commercially available therapeutic Combined Mineral Vitamin
mix (CMV).
ReSoMal contains 37.5 mmol sodium and 40 mmol potassium/L.
WHO ORS, World Health Organization Oral Rehydration Solution.

Table 57.12

Recipe for Concentrated Electrolyte/Mineral Solution*

 INGREDIENT g mol/20 mL
Potassium chloride: KCl 224.0 24 mmol
Tripotassium citrate 81.0 2 mmol
Magnesium chloride: MgCl2 •6H2 O 76.0 3 mmol
Zinc acetate: Zn acetate•2H2 O 8.2 300 µmol
Copper (cupric) sulfate: CuSO4 •5H2 O 1.4 45 µmol
Water: make up to 2500 mL
* Make fresh each month. Use cooled boiled water.

Add 20 mL when preparing 1 L of feed or ReSoMal.

Rehabilitation
The signals for entry to the rehabilitation phase are reduced or minimal edema
and return of appetite.
A controlled transition over 3 days is recommended to prevent refeeding
syndrome (see Chapter 58 ). After the transition, unlimited amounts should be
given of a high-energy, high-protein milk formula such as F100 (100 kcal and 3
g protein per 100 mL), or a ready-to-use therapeutic food (RUTF) , or family
foods modified to have comparable energy and protein contents.
To make the transition, for 2 days replace F75 with an equal volume of F100,
then increase each successive feed by 10 mL until some feed remains uneaten
(usually at about 200 mL/kg/day). After this transition, give 150-220 kcal/kg/day
and 4-6 g protein/kg/day, and continue to give potassium, magnesium, and
micronutrients. Add iron (3 mg/kg/day). If breastfed, encourage continued
breastfeeding. Children with severe malnutrition have developmental delays, so
loving care, structured play, and sensory stimulation during and after treatment
are essential to aid recovery of brain function.

Community-Based Treatment
Many children with severe acute malnutrition can be identified in their
communities before medical complications arise. If these children have a good
appetite and are clinically well, they can be rehabilitated at home through
community-based therapeutic care, which has the added benefit of reducing their
exposure to nosocomial infections and providing continuity of care after
recovery. It also reduces the time caregivers spend away from home and their
opportunity costs and can be cost-effective for health services.
Fig. 57.8 shows the criteria for inpatient and outpatient care. To maximize
coverage and compliance, community-based therapeutic care has 4 main
CHAPTER 58

Refeeding Syndrome
Robert M. Kliegman

The refeeding syndrome may occur if high-energy feeding is started too soon or
too vigorously, and it may lead to sudden death with signs of heart failure. Early
accounts of the syndrome were among starved survivors of wartime sieges and
concentration camps and among prisoners of war when given sudden access to
unlimited food. The refeeding syndrome occurs in malnourished individuals as a
result of untimely, overzealous oral, enteral, or parenteral (highest risk) feeding,
and the risk is not widely recognized. Refeeding syndrome has also been seen
among malnourished patients with anorexia nervosa with a body mass index
(BMI) <70% median values. Onset is usually 24-48 hr after the start of high-
energy feeding and is characterized by breathlessness, rapid pulse, increased
venous pressure, rapid enlargement of the liver, and watery diarrhea. Other
features are noted in Table 58.1 .

Table 58.1
Clinical Signs and Symptoms of Refeeding Syndrome

VITAMIN/THIAMINE SODIUM
HYPOPHOSPHATEMIA HYPOKALEMIA HYPOMAGNESEMIA
DEFICIENCY RETENTION
Cardiac Cardiac Cardiac Encephalopathy Fluid overload
Hypotension Arrhythmias Arrhythmias Lactic acidosis Pulmonary
Decreased stroke volume Respiratory Neurologic Death edema
Respiratory Failure Weakness Cardiac
Impaired diaphragm Neurologic Tremor compromise
contractility Weakness Tetany
Dyspnea Paralysis Seizures
Respiratory failure Gastrointestinal Altered mental status
Neurologic Nausea Coma
Paresthesia Vomiting Gastrointestinal
Weakness Constipation Nausea
Confusion Muscular Vomiting
Disorientation Rhabdomyolysis Diarrhea
 Lethargy Muscle necrosis Other
Areflexic paralysis Other Refractory hypokalemia
Seizures Death and hypocalcemia
Coma Death
Hematologic
Leukocyte dysfunction
Hemolysis
Thrombocytopenia
Other
Death
Data from Kraft MD, Btaiche IF, Sacks GS: Review of RFS, Nutr Clin Pract 20:625–633, 2005.
From Fuentebella J, Kerner JA: Refeeding syndrome, Pediatr Clin North Am 56:1201–1210, 2009.

An increase in the supply of energy (usually carbohydrates) is accompanied

by an increase in sodium pump activity, and too sudden a supply risks causing a
rapid release of accumulated sodium from cells, causing expansion of
extracellular and plasma volumes. At the same time there is increased uptake by
cells of glucose, potassium, magnesium, and phosphate. A sudden lowering of
serum potassium, magnesium, and phosphate concentrations is an important
feature of the refeeding syndrome.
The key to preventing the syndrome is to minimize the risk of its occurrence.
It can be avoided by following the World Health Organization (WHO) guidelines
for the treatment of malnutrition (see Chapter 57 ). Of particular relevance to
minimizing the risk is the initial stabilization phase , which includes providing
maintenance amounts of energy and protein and correcting electrolyte
imbalances and micronutrient deficiencies, followed by a controlled transition to
high-energy feeding. Milk-based diets are desirable because milk is a good
source of phosphate. No or minimal edema and return of appetite are signs of
readiness for the transition. Monitoring for sudden increases in pulse and
respiration rates during the transition to high-energy feeding is advisable to
detect these early warning signs. Should refeeding syndrome occur, prompt
treatment with a single parenteral dose of digoxin and furosemide has been
useful.

Bibliography
Friedli N, Stanga Z, Sobotka L, et al. Revisiting the refeeding
syndrome: results of a systematic review. Nutrition .
2017;31:151–160.
Pulani CD, Zettle S, Srinath A. Refeed syndrome. Pediatr Rev .
(WHO) charts for children up to 2 yr of age who are measured supine for length.
The CDC 2000 growth charts are recommended for children and adolescents
(age 2-20 yr) when measured with a standing height. The severity of
malnutrition (mild, moderate, or severe) may be determined by plotting the z
score (standard deviation [SD] from the mean) for each of these anthropometric
values (Table 59.1 ).

Table 59.1
Comprehensive Malnutrition Indicators
SEVERE MODERATE MILD
INDICATORS*
MALNUTRITION MALNUTRITION MALNUTRITION
Weight-for-length z score ≥ −3 z score or worse −2.0 to 2.99 z score −1.0 to −1.99 z score †
BMI-for-age z score ≥ −3 z score or worse −2.0 to 2.99 z score −1.0 to −1.99 z score †
Weight-for-length/height z score ≥ −3 z score or worse No data available No data available
Mid-upper arm circumference ≥ −3 z score or worse −2.0 to 2.99 z score −1.0 to −1.99 z score
(<5 yr of age)
Weight gain velocity (≤2 yr of ≤25% of norm 26–50% of norm 51–75% of the norm
age)
Weight loss (2-20 yr of age) >10% of UBW >7.5% UBW >5% UBW
Deceleration in weight-for- Deceleration across 3 z Deceleration across 2 z Deceleration across 1 z
length/height or BMI-for-age score lines score lines score line
Inadequate nutrient intake ≤25% of estimated 26–50% of estimated 51–75% of estimated
energy − protein need energy − protein need energy − protein need
* It is recommended that when a child meets more than one malnutrition acuity level, the provider
should document the severity of the malnutrition at the highest acuity level to ensure that an
appropriate treatment plan and appropriate intervention, monitoring, and evaluation are provided.
† Needs additional positive diagnostic criteria to make a malnutrition diagnosis.

BMI, Body mass index; UBW, usual body weight.

Use clinical judgment when applying these diagnostic criteria.
Adapted from Becker PJ, Carney LN, Corkins MR, et al: Consensus Statement of the Academy of
Nutrition and Dietetics/American Society for Parenteral and Enteral Nutrition: Indicators
recommended for the identification and documentation of pediatric malnutrition (undernutrition). J
Acad Nutr Diet 114(12):1988-2000, 2014.

Etiology and Diagnosis

The most common mechanisms for illness-related causes of insufficient growth
include (1) failure to ingest sufficient calories, or starvation (e.g., cardiac failure,
fluid restriction), (2) increased nutrient losses (e.g., protein-losing enteropathy,
complete blood count, and urinalysis represent a reasonable initial screen.

Table 59.2

Approach to Malnutrition Based on Signs and Symptoms

HISTORY/PHYSICAL
DIAGNOSTIC CONSIDERATION
EXAMINATION
Spitting, vomiting, food Gastroesophageal reflux, chronic tonsillitis, food allergies, eosinophilic esophagitis
refusal
Diarrhea, fatty stools Malabsorption, intestinal parasites, milk protein intolerance, pancreatic insufficiency,
celiac disease, immunodeficiency, inflammatory bowel disease
Snoring, mouth Adenoid hypertrophy, obstructive sleep apnea
breathing, enlarged
tonsils
Recurrent wheezing, Asthma, aspiration, food allergy, cystic fibrosis, immunodeficiency
pulmonary infections
Recurrent infections HIV or congenital primary immunodeficiency diseases, anatomic defects
Travel to/from Parasitic or bacterial infections of gastrointestinal tract
developing countries

Table 59.3
Findings in Failure to Thrive in Infancy

SYSTEM-
APPROXIMATE
SYSTEM-SPECIFIC PHYSICAL SPECIFIC
CAUSE PERCENTAGE HISTORY
FINDINGS LABORATORY
OF ALL CASES
STUDIES
Psychosocial Up to 50% or Vague, None, may have soft neurologic signs None
more inconsistent
feeding history,
history of bottle
propping
CNS 13% Poor feeding, Grossly abnormal neurologic findings Frequent gross
gross abnormalities on
developmental EEG and MRI
delay, vomiting scan or grossly
abnormal tests of
neuromuscular
function
Gastrointestinal 10% Chronic Often negative, may have abdominal Abnormal
vomiting and/or distention barium, pH
diarrhea, probe, or
abnormal stools, endoscopic
crying with study; abnormal
feedings, stool findings
nocturnal (pH, reducing
cough/snoring substances, fat
stain, Wright
 stain)
Cardiac 9% Slow feeding, Often cyanotic or have signs of Abnormal
dyspnea and congestive heart failure echocardiogram,
diaphoresis with ECG,
feeding, catheterization
restlessness and findings
diaphoresis
during sleep
Genetic 8% May have Often have facies typical of a May have typical
positive family syndrome, skeletal abnormalities, radiographic
history or a neurologic abnormalities, or findings,
history of visceromegaly chromosomal
developmental abnormalities,
delay abnormal
metabolic
screens
Pulmonary 3.5% Chronic or Grossly abnormal chest examination Abnormal chest
recurrent findings radiographs
dyspnea with
feedings,
tachypnea
Renal 3.5% May be Often negative, may have flank masses Abnormal
negative or may urinalysis,
have history of frequently
polyuria elevated BUN
and creatinine,
signs of renal
osteodystrophy
on radiographs
Endocrine 3.5% With With hypothyroidism, no wasting but Decreased T4 ,
hypothyroidism, mottling, umbilical hernia, often open increased TSH;
constipation and posterior fontanelle. With diabetes, glucosuria and
decreased often without specific abnormality, but hyperglycemia;
activity level; may have signs of dehydration, ketotic abnormal
with diabetes, breath, and hyperpnea. With pituitary function
polyuria, hypopituitarism and isolated growth study results
polydipsia hormone deficiency, growth normal
until 9 mo or later, then plateaus, but
normal weight for height; delayed tooth
eruption
BUN, Blood urea nitrogen; CNS, central nervous system; CT, computed tomography; ECG,
electrocardiogram; EEG, electroencephalogram; T4 , thyroxine; TSH, thyroid-stimulating hormone.
From Carrasco MM, Wolford JE: Child abuse and neglect. In Zitelli BJ, McIntire SC, Nowalk AJ,
editors: Atlas of pediatric physical diagnosis, ed 7, Philadelphia, 2018, Elsevier, Table 6.6.

Additional measurements that are useful for following the progress of the
acutely malnourished child are mid-upper arm circumference (MUAC) and
hand-grip strength. MUAC is a particularly useful anthropometric measure when
weight may be distorted by use of corticosteroids or fluid status (e.g., ascites,
edema).
For children 6 yr and older, hand-grip strength may be a more acute
proopiomelanocortin (POMC) deficiency, a prohormone precursor of
adrenocorticotropic hormone (ACTH) and melanocyte-stimulating hormone
(MSH), resulting in adrenal insufficiency, light skin, hyperphagia, and obesity.

Table 60.1
Endocrine and Genetic Causes of Obesity

DISEASE SYMPTOMS LABORATORY

ENDOCRINE
Cushing syndrome Central obesity, hirsutism, moon face, hypertension Dexamethasone
suppression test
GH deficiency Short stature, slow linear growth Evoked GH
response, IGF-1
Hyperinsulinism Nesidioblastosis, pancreatic adenoma, hypoglycemia, Mauriac Insulin level
syndrome
Hypothyroidism Short stature, weight gain, fatigue, constipation, cold TSH, FT4
intolerance, myxedema
Pseudohypoparathyroidism Short metacarpals, subcutaneous calcifications, dysmorphic Urine cAMP after
facies, mental retardation, short stature, hypocalcemia, synthetic PTH
hyperphosphatemia infusion
GENETIC
Albright hereditary Short stature, skeletal defects, PTH resistance GNAS gene
osteodystrophy
Alström syndrome Cognitive impairment, retinitis pigmentosa, diabetes mellitus, ALMS1 gene
hearing loss, hypogonadism, cardiomyopathy
Bardet-Biedl syndrome Retinitis pigmentosa, renal abnormalities, polydactyly, BBS1 gene
syndactyly, hypogonadism
BDNF/TrkB deficiency Hyperactivity, impaired concentration, limited attention span, BDNF/TrkB gene
impaired short-term memory and pain sensation
Biemond syndrome Cognitive impairment, iris coloboma, hypogonadism,
polydactyly
Carpenter syndrome Polydactyly, syndactyly, cranial synostosis, mental retardation Mutations in
RAB23 gene,
located on
chromosome 6 in
humans
Cohen syndrome Mid-childhood-onset obesity, short stature, prominent maxillary Mutations in
incisors, hypotonia, mental retardation, microcephaly, decreased VPS13B gene
visual activity (often called
COH1 ) at locus
8q22
Deletion 9q34 Early-onset obesity, mental retardation, brachycephaly, Deletion 9q34
synophrys, prognathism, behavior and sleep disturbances
Down syndrome Short stature, dysmorphic facies, mental retardation Trisomy 21
ENPP1 gene mutations Insulin resistance, childhood obesity Gene mutation on
chromosome 6q
Fröhlich syndrome Hypothalamic tumor
FTO gene polymorphism, Dysregulation of orexigenic hormone acyl-ghrelin, poor Homozygous for
plus upstream regulatory postprandial appetite suppression FTO AA allele
and downstream activation
 genes
KSR2 deficiency Mild hyperphagia and reduced basal metabolic rate, insulin KSR2 gene
resistance often with acanthosis nigricans, irregular menses,
early development of type 2 diabetes mellitus
Leptin or leptin receptor Early-onset severe obesity, infertility (hypogonadotropic Leptin
gene deficiency hypogonadism), hyperphagia, infections
Melanocortin 4 receptor Early-onset severe obesity, increased linear growth, MC4R mutation
gene mutation hyperphagia, hyperinsulinemia
Most common known genetic cause of obesity
Homozygous worse than heterozygous
PCSK1 deficiency Small bowel enteropathy, hypoglycemia, hypothyroidism, PCSK1 gene
ACTH deficiency, diabetes insipidus
Prader-Willi syndrome Neonatal hypotonia, slow infant growth, small hands and feet, Partial deletion of
mental retardation, hypogonadism, hyperphagia leading to chromosome 15 or
severe obesity, paradoxically elevated ghrelin loss of paternally
expressed genes
Proopiomelanocortin Obesity, red hair, adrenal insufficiency due to ACTH deficiency, Loss-of-function
(POMC) deficiency hyperproinsulinemia, hyperphagia, pale skin, cholestatic mutations of
jaundice POMC gene
Rapid-onset obesity with Often confused with congenital central hypoventilation Unknown
hypothalamic dysfunction, syndrome (CCHS); presentation ≥1.5 yr with weight gain, genes
hypoventilation, and hyperphagia, hypoventilation, cardiac arrest, central diabetes May be a
autonomic dysregulation insipidus, hypothyroidism, GH deficiency, pain insensitivity, paraneoplastic
(ROHHAD) hypothermia, precocious puberty, neural crest tumors disorder
SH2B1 deficiency Hyperphagia, disproportionate hyperinsulinemia, early speech SH2B1 gene
and language delay that often resolves, behavioral problems
including aggression
SIM1 deficiency Hyperphagia with autonomic dysfunction (characterized by low SIM1 gene
systolic blood pressure), speech and language delay,
neurobehavioral abnormalities including autistic-type behaviors
TUB deficiency Retinal dystrophy, deafness TUB gene
Turner syndrome Ovarian dysgenesis, lymphedema, web neck, short stature, XO chromosome
cognitive impairment
ACTH, Adrenocorticotropic hormone; cAMP, cyclic adenosine monophosphate; FT4 , free
thyroxine; GH, growth hormone; IGF, insulin-like growth factor; PTH, parathyroid hormone; TSH,
thyroid-stimulating hormone.

In addition, evidence suggests that appetitive traits are moderately heritable.

For example, some genes associated with appetite also relate to weight, and vice-
versa. In addition, there are genetic conditions associated with obesity, such as
Prader-Willi syndrome, which results from absence of paternally expressed
imprinted genes in the 15q11.2–q13 region. Prader-Willi syndrome is
characterized by insatiable appetite and food seeking. In the era of genomic
medicine, it will be increasingly possible to identify risks according to specific
genes and consider gene-environment interactions. Epigenetic environmental
modification of genes may have a role in the development of obesity, especially
during fetal and early life.
restore PYY levels in children, even though this does not happen in adults. In
addition, patients homozygous for the FTO obesity-risk allele demonstrate poor
regulation of the orexigenic hormone acyl-ghrelin and have poor postprandial
appetite suppression.

Comorbidities
Complications of pediatric obesity occur during childhood and adolescence and
persist into adulthood. An important reason to prevent and treat pediatric obesity
is the increased risk for morbidity and mortality later in life. The Harvard
Growth Study found that boys who were overweight during adolescence were
twice as likely to die from CV disease as those who had normal weight. More
immediate comorbidities include type 2 diabetes, hypertension, hyperlipidemia,
and nonalcoholic fatty liver disease (NAFLD) (Table 60.2 ). Insulin resistance
increases with increasing adiposity and independently affects lipid metabolism
and CV health. The metabolic syndrome (central obesity, hypertension, glucose
intolerance, and hyperlipidemia) increases risk for CV morbidity and mortality.
NAFLD has been reported in 34% of patients treated in pediatric obesity clinic.
NAFLD is now the most common chronic liver disease in U.S. children and
adolescents. It can present with advanced fibrosis or nonalcoholic steatohepatitis
and may result in cirrhosis and hepatocellular carcinoma. Insulin resistance is
often associated. Furthermore, NAFLD is independently associated with
increased risk of CV disease.

Table 60.2
Obesity-Associated Comorbidities

DISEASE POSSIBLE SYMPTOMS LABORATORY CRITERIA

CARDIOVASCULAR
Dyslipidemia HDL <40, LDL >130, total cholesterol Fasting total cholesterol, HDL, LDL, triglycerides
>200 mg/dL
Hypertension SBP >95% for sex, age, height Serial testing, urinalysis, electrolytes, blood urea
nitrogen, creatinine
ENDOCRINE
Type 2 diabetes Acanthosis nigrans, polyuria, polydipsia Fasting blood glucose >110, hemoglobin A1c , insulin
mellitus level, C-peptide, oral glucose tolerance test
Metabolic Central adiposity, insulin resistance, Fasting glucose, LDL and HDL cholesterol
syndrome dyslipidemia, hypertension, glucose
intolerance
Polycystic Irregular menses, hirsutism, acne, Pelvic ultrasound, free testosterone, LH, FSH
 ovary syndrome insulin resistance, hyperandrogenemia
GASTROINTESTINAL
Gallbladder Abdominal pain, vomiting, jaundice Ultrasound
disease
Nonalcoholic Hepatomegaly, abdominal pain, AST, ALT, ultrasound, CT, or MRI
fatty liver dependent edema, ↑ transaminases
disease Can progress to fibrosis, cirrhosis
(NAFLD)
NEUROLOGIC
Pseudotumor Headaches, vision changes, papilledema Cerebrospinal fluid opening pressure, CT, MRI
cerebri
Migraines Hemicrania, headaches None
ORTHOPEDIC
Blount disease Severe bowing of tibia, knee pain, limp Knee radiographs
(tibia vara)
Musculoskeletal Back pain, joint pain, frequent strains or Radiographs
problems sprains, limp, hip pain, groin pain, leg
bowing
Slipped capital Hip pain, knee pain, limp, decreased Hip radiographs
femoral mobility of hip
epiphysis
PSYCHOLOGIC
Behavioral Anxiety, depression, low self-esteem, Child Behavior Checklist, Children's Depression
complications disordered eating, signs of depression, Inventory, Peds QL, Eating Disorder Inventory 2,
worsening school performance, social subjective ratings of stress and depression, Behavior
isolation, problems with bullying or Assessment System for Children, Pediatric Symptom
being bullied Checklist
PULMONARY
Asthma Shortness of breath, wheezing, Pulmonary function tests, peak flow
coughing, exercise intolerance
Obstructive Snoring, apnea, restless sleep, Polysomnography, hypoxia, electrolytes (respiratory
sleep apnea behavioral problems acidosis with metabolic alkalosis)
ALT, Alanine transaminase; AST, aspartate transaminase; CT, computed tomography; FSH,
follicle-stimulating hormone; HDL, high-density lipoprotein; LDL, low-density lipoprotein; LH,
luteinizing hormone; MRI, magnetic resonance imaging; Peds QL, Pediatric Quality of Life
Inventory; SBP, systolic blood pressure.

Obesity may also be associated with chronic inflammation. Adiponectin, a

peptide with antiinflammatory properties, occurs in reduced levels in obese
patients compared to insulin-sensitive, lean persons. Low adiponectin levels
correlate with elevated levels of free fatty acids and plasma triglycerides as well
as a high BMI, and high adiponectin levels correlate with peripheral insulin
sensitivity. Adipocytes secrete peptides and cytokines into the circulation, and
proinflammatory peptides such interleukin (IL)-6 and tumor necrosis factor
(TNF)-α occur in higher levels in obese patients. Specifically, IL-6 stimulates
production of C-reactive protein (CRP) in the liver. CRP is a marker of
inflammation and might link obesity, coronary disease, and subclinical
inflammation.
likely to have developed comorbid conditions than those who are obese (BMI
≥95th percentile). Those with a BMI ≥99th percentile are more likely to have
coexisting medical problems. Once obesity severity is determined, the BMI
trajectory is examined to elucidate when the child became obese. Several periods
during childhood are considered sensitive periods, or times of increased risk for
developing obesity, including infancy, adiposity rebound (when body fat is
lowest at approximately age 5.5 yr), and adolescence. An abrupt change in BMI
might signal the onset of a medical problem or a period of family or personal
stress for the child. Examination of the weight trajectory can further reveal how
the problem developed. A young child might exhibit high weight and high height
because linear growth can increase early in childhood if a child consumes excess
energy. At some point the weight percentile exceeds the height percentile, and
the child's BMI climbs into the obese range. Another example is a child whose
weight rapidly increases when she reduces her activity level and consumes more
meals away from home. Examination of the height trajectory can reveal
endocrine problems, which often occur with slowing of linear growth.
Consideration of possible medical causes of obesity is essential, even though
endocrine and genetic causes are rare (see Table 60.1 ). Growth hormone
deficiency, hypothyroidism, and Cushing syndrome are examples of endocrine
disorders that can lead to obesity. In general, these disorders manifest with slow
linear growth. Because children who consume excessive amounts of calories
tend to experience accelerated linear growth, short stature warrants further
evaluation. Genetic disorders associated with obesity may manifest extreme
hyperphagia, or they can have coexisting dysmorphic features, cognitive
impairment, vision and hearing abnormalities, or short stature. In some children
with congenital disorders such as myelodysplasia or muscular dystrophy, lower
levels of PA can lead to secondary obesity. Some medications, such as atypical
antipsychotics, can cause excessive appetite and hyperphagia, resulting in
obesity (Table 60.3 ). Rapid weight gain in a child or adolescent taking one of
these medications might require its discontinuation. Poor linear growth and rapid
changes in weight gain are indications for evaluation of possible medical causes.
Table 60.3
Medications Associated With Obesity

Prednisone and other glucocorticoids

Thioridazine
 Olanzapine
Clozapine
Quetiapine
Risperidone
Lithium
Amitriptyline and other tricyclic antidepressants
Paroxetine
Valproate
Carbamazepine
Gabapentin
Cyproheptadine
Propranolol and other β-blockers

Exploration of family eating, nutritional, and activity patterns begins with a

description of regular meal and snack times and family habits for walking,
bicycle riding, active recreation, and screen time (TV, computer, video games).
It is useful to request a 24-hr dietary recall with special attention to intake of
fruits, vegetables, and water, as well as high-calorie foods and high-carbohydrate
beverages. When possible, evaluation by a nutritionist is extremely helpful. This
information will form the basis for incremental changes in eating behavior,
caloric intake, and PA during the intervention.
Initial assessment of the overweight or obese child includes a complete review
of bodily systems focusing on the possibility of comorbid conditions (see Table
60.2 ). Developmental delay and visual and hearing impairment can be
associated with genetic disorders. Difficulty sleeping, snoring, or daytime
sleepiness suggests sleep apnea. Abdominal pain might suggest NAFLD.
Symptoms of polyuria, nocturia, or polydipsia may be the result of type 2
diabetes. Hip or knee pain can be caused by secondary orthopedic problems,
including Blount disease and slipped capital femoral epiphysis. Irregular menses
may be associated with polycystic ovary syndrome. Acanthosis nigricans can
suggest insulin resistance and type 2 diabetes (Fig. 60.4 ).
guided by history or physical examination findings. Fig. 60.5 provides a
recommended approach to categorization, evaluation, and treatment.

Table 60.4

Normal Laboratory Values for Recommended Tests

LABORATORY TEST NORMAL VALUE
Glucose <110 mg/dL
Insulin <15 mU/L
Hemoglobin A1c <5.7%
AST (age 2-8 yr) <58 U/L
AST (age 9-15 yr) <46 U/L
AST (age 15-18 yr) <35 U/L
ALT <35 U/L
Total cholesterol <170 mg/dL
LDL <110 mg/dL
HDL >45 mg/dL
Triglycerides (age 0-9 yr) <75 mg/dL
Triglycerides (age 10-19 yr) <90 mg/dL
AST, Aspartate transaminase; ALT, alanine transaminase; LDL, low-density lipoprotein; HDL, high-
density lipoprotein.
From Children's Hospital of Wisconsin: The NEW (nutrition, exercise and weight management)
kids program (PDF file). http://www.chw.org/display/displayFile.asp?
docid=33672&filename=/Groups/NEWKids/NewKidsReferral.PDF .
 FIG. 60.5 Diagnosis and management flow chart. *Measure insulin and proinsulin in
patients with clinical features of PCSK1 deficiency. BMI, Body mass index; CNS, central
nervous system. (From Farooqi SOR, O'Rahilly S: Genetic obesity syndromes. In Grant
S, editor: The genetics of obesity, New York, 2014, Springer, pp 23–32; originally
adapted from August GP, Caprio S, Fennoy I, et al: Prevention and treatment of
pediatric obesity: an Endocrine Society clinical practice guideline based on expert
opinion, J Clin Endocrinol Metab 93:4576–4599, 2008.)

Intervention
Evidence shows that some interventions result in modest but significant and
sustained improvement in body mass. Based on behavior change theories,
treatment includes specifying target behaviors , self-monitoring , goal setting ,
stimulus control , and promotion of self-efficacy and self-management skills.
Behavior changes associated with improving BMI include drinking lower
quantities of sugar-sweetened beverages, consuming higher-quality diets,
increasing exercise, decreasing screen time, and self-weighing. Most successful
interventions have been family based and consider the child's developmental age.
“Parent-only” treatment can be as effective as “parent–child” treatment. Because
obesity is multifactorial, not all children and adolescents will respond to the
same approach. For example, loss-of-control eating, associated with weight gain
and obesity, predicts poor outcome in response to family-based treatment.
Furthermore, clinical treatment programs are expensive and not widely
available. Therefore, interest has grown in novel approaches such as internet-
based treatments and guided self-help.
It is important to begin with clear recommendations about appropriate
caloric intake for the obese child (Table 60.5 ). Working with a dietitian is
essential. Meals should be based on fruits, vegetables, whole grains, lean meat,
fish, and poultry. Prepared foods should be chosen for their nutritional value,
with attention to calories and fat. Foods that provide excessive calories and low
nutritional value should be reserved for infrequent treats.

Table 60.5
Recommended Caloric Intake Designated by Age and
Gender

LIFE-STAGE AGE RELATIVELY SEDENTARY LEVEL MODERATE LEVEL OF ACTIVE

 GROUP (yr) OF ACTIVITY (kcal) ACTIVITY (kcal) (kcal)
Child 2-3 1,000 1,000-1,400 1,000-
1,400
Female 4-8 1,200 1,400-1,600 1,400-
1,800
9-13 1,600 1,600-2,000 1,800-
2,200
14-18 1,800 2,000 2,400
Male 4-8 1,400 1,400-1,600 1,600-
2,000
9-13 1,800 1,800-2,200 2,000-
2,600
14-18 2,200 2,400-2,800 2,800-
3,200
Adapted from U.S. Department of Agriculture: Dietary guidelines for Americans , 2005.
http://www.health.gov/DIETARYGUIDELINES/dga2005/document/html/chapter2.htm .

Weight reduction diets in adults generally do not lead to sustained weight loss.
Therefore the focus should be on changes that can be maintained for life.
Attention to eating patterns is helpful. Families should be encouraged to plan
family meals, including breakfast. It is almost impossible for a child to make
changes in nutritional intake and eating patterns if other family members do not
make the same changes. Dietary needs also change developmentally; adolescents
require greatly increased calories during their growth spurts, and adults who lead
inactive lives need fewer calories than active, growing children.
Psychologic strategies are helpful. The “traffic light” diet groups foods into
those that can be consumed without any limitations (green), in moderation
(yellow), or reserved for infrequent treats (red) (Table 60.6 ). The concrete
categories are very helpful to children and families. This approach can be
adapted to any ethnic group or regional cuisine. Motivational interviewing
begins with assessing how ready the patient is to make important behavioral
changes. The professional then engages the patient in developing a strategy to
take the next step toward the ultimate goal of healthy nutritional intake. This
method allows the professional to take the role of a coach, helping the child and
family reach their goals. Other behavioral approaches include family rules about
where food may be consumed (e.g., “not in the bedroom”).

Table 60.6
“Traffic Light” Diet Plan

YELLOW LIGHT
FEATURE GREEN LIGHT FOODS RED LIGHT FOODS
FOODS
 Quality Low-calorie, high-fiber, low- Nutrient-dense, but higher in High in calories, sugar, and fat
fat, nutrient-dense calories and fat
Types of Fruits, vegetables Lean meats, dairy, starches, Fatty meats, sugar, sugar-sweetened
food grains beverages, fried foods
Quantity Unlimited Limited Infrequent or avoided

Increasing PA without decreasing caloric intake is unlikely to result in weight

loss. However, aerobic exercise training has been shown to improve metabolic
profiles in obese children and adolescents. Furthermore, it can increase aerobic
fitness and decrease percent body fat even without weight loss. Therefore,
increasing PA can decrease risk for CV disease, improve well-being, and
contribute to weight loss. Increased PA can be accomplished by walking to
school, engaging in PA during leisure time with family and friends, or enrolling
in organized sports. Children are more likely to be active if their parents are
active. As with family meals, family PA is recommended. When adults lose
significant weight, they may regain that weight despite eating fewer calories.
The body may adapt to weight loss by reducing the basal metabolic rate (BMR),
thus requiring fewer calories. One approach to this phenomenon is to increase
PA.
Active pursuits can replace more sedentary activities. The American Academy
of Pediatrics recommends that screen time be restricted to no more than 2 hr/day
for children >2 yr old and that children <2 yr old not watch television. TV
watching is often associated with eating, and many highly caloric food products
are marketed directly to children during child-oriented television programs.
Pediatric healthcare providers should assist families to develop goals to
change nutritional intake and PA. They can also provide the child and family
with needed information. The family should not expect immediate lowering of
BMI percentile related to behavioral changes, but can instead count on a gradual
decrease in the rate of BMI percentile increase until it stabilizes, followed by a
gradual decrease. Referral to multidisciplinary, comprehensive pediatric weight
management programs is ideal for obese children whenever possible.
Pharmacotherapy for weight loss in the pediatric population is understudied.
Randomized controlled trials (RCTs) have evaluated many medications,
including metformin, orlistat, sibutramine, and exanatide (Table 60.7 ). Available
medications result in modest weight loss or BMI improvement, even when
combined with behavioral interventions. Various classes of drugs are of interest,
including those that decrease energy intake or act centrally as anorexiants ,
those that affect the availability of nutrients through intestinal or renal tubular
reabsorption, and those that affect metabolism. The only U.S. Food and Drug
Administration (FDA)–approved medication for obesity in children <16 yr old is
orlistat, which decreases absorption of fat, resulting in modest weight loss.
Complications include flatulence, oily stools, and spotting. This agent offers
little benefit to severely obese adolescents. Because multiple redundant neural
mechanisms act to protect body weight, promoting weight loss is extremely
difficult. Thus there is considerable interest in combining therapies that
simultaneously target multiple weight-regulating pathways. One example,
approved for adults, combines phentermine, a noradrenergic agent, with
topiramate, a γ-aminobutyric acid (GABA)–ergic medication. This combination
resulted in a mean 10.2-kg weight loss vs 1.4 kg in the placebo group. Side
effects are common and include dry mouth, constipation, paresthesias, insomnia,
and cognitive dysfunction. Another promising example is the combination of
amylin (decreases food intake and slows gastric emptying) with leptin, which
has no anorexigenic effects when given alone. This combination requires
injection and is in clinical trials in adults. Another FDA-approved drug for adults
is lorcaserin, a selective serotonin 2C receptor agonist. Establishing long-term
safety and tolerability in children is a challenge because medications of interest
have CNS effects or interfere with absorption of nutrients. Teratologic effects
must be considered for use in adolescent girls.

Table 60.7
Medications for Weight Management With Mechanism of
Action, Availability, and Dosing

AVAILABLE MEAN
FOR PERCENTAGE
MECHANISM CHRONIC USE WEIGHT LOSS
MEDICATION ADVANTAGES DISADVANTAGES
OF ACTION
European
USA Placebo Drug
Union
Phentermine, 15-30 mg Sympathomimetic For No Not Not stated Inexpensive Side effect profile;
PO short- stated in in label no long-term data
term label
use
Orlistat, 120 mg PO tid Pancreatic lipase Yes Yes −2.6% † −6.1% † Not absorbed; Modest weight loss;
before meals inhibitor long-term data* side effect profile
Lorcaserin, 10 mg PO 5-HT2c serotonin Yes No −2.5% −5.8% Mild side Expensive; modest
bid agonist with little effects; long- weight loss
affinity for other term data*
serotonergic
receptors
Phentermine/topiramate Sympathomimetic Yes No −1.2% −7.8% Robust weight Expensive; teratogen
ER, 7.5 mg/46 mg or anticonvulsant (mid- loss; long-term
 15 mg/92 mg PO (GABA receptor dose) data*
indicated as rescue modulation, −9.8%
(requires titration) carbonic (full
anhydrase dose)
inhibition,
glutamate
antagonism)
Naltrexone Opioid receptor Yes Yes −1.3% −5.4% Reduces food Moderately
SR/bupropion SR, 32 antagonist; craving; long- expensive; side
mg/360 mg PO dopamine and term data* effect profile
(requires titration) noradrenaline
reuptake inhibitor
Liraglutide, 3.0 mg GLP-1 receptor Yes Yes −3% −7.4% Side effect Expensive;
injection (requires agonist (full dose) profile; long- injectable
titration) term data*
* Data from randomized controlled trials lasting >52 wk.

†
Assuming the average patient in the orlistat and placebo groups weighed 100 kg at baseline.
Information is from U.S. product labels, except where noted. The data supporting these tables are
derived from the prescribing information labeling approved by the US Food and Drug
Administration.
ER, Extended release; SR, sustained release; PO, orally; bid, twice daily; tid, 3 times daily.
Adapted from Bray GA, Frühbeck G, Ryan DH, Wilding JPH: Management of obesity, Lancet
387:1947–1965, 2016, p 1950.

Hormone replacement therapy is available for patients with leptin

deficiency and may become available for patients with POMC deficiency.
Setmelanotide binds to and activates MC4R and may be useful for patients with
POMC deficiency–associated obesity.
In some cases it is reasonable to refer adolescents for bariatric surgery
evaluation. The American Pediatric Surgical Association guidelines recommends
that surgery be considered only in children with complete or near-complete
skeletal maturity, a BMI ≥40, and a medical complication resulting from obesity,
after they have failed 6 mo of a multidisciplinary weight management program.
Surgical approaches include the Roux-en-Y and the adjustable gastric band (Fig.
60.6 ). In obese adults, bariatric surgery reduces the risk of developing type 2
diabetes mellitus. In obese adult patients with existing type 2 diabetes, bariatric
surgery improves diabetic control. Nutritional complications of bariatric surgery
include malabsorption and vitamin (A, B1 , B2 , B6 , B12 , D, E, K) and mineral
(copper, iron) deficiencies that require supplementation.
Infant, and Children Supplemental Food Program (WIC), and school lunch
programs, to meet the needs of today's children.
Table 60.8
Proposed Suggestions for Preventing Obesity
Pregnancy

Normalize body mass index (BMI) before pregnancy.

Do not smoke.
Maintain moderate exercise as tolerated.
In women with gestational diabetes, provide meticulous glucose control.
Monitor gestational weight gain within Institute of Medicine (IOM)
recommendations.

Postpartum and Infancy

Breastfeeding: exclusive for 4-6 mo; continue with other foods for 12 mo.
Postpone introduction of baby foods to 4-6 mo and juices to 12 mo.

Families

Eat meals as a family in a fixed place and time.

Do not skip meals, especially breakfast.
Do not allow television during meals.
Use small plates, and keep serving dishes away from the table.
Avoid unnecessary sweet or fatty foods and sugar-sweetened drinks.
Remove televisions from children's bedrooms; restrict times for TV
viewing and video games.
Do not use food as a reward.

Schools

Eliminate candy and cookie sales as fundraisers.

Review the contents of vending machines, and replace with healthier
choices; eliminate sodas.
 Avoid financial support for sports teams from beverage and food industries.
Install water fountains and hydration stations.
Educate teachers, especially physical education and science faculty, about
basic nutrition and the benefits of physical activity (PA).
Educate children from preschool through high school on appropriate diet
and lifestyle.
Mandate minimum standards for physical education, including 60 min of
strenuous exercise 5 times weekly.
Encourage “the walking school bus”: groups of children walking to school
with adult supervision.

Communities

Increase family-friendly exercise and safe play facilities for children of all
ages.
Develop more mixed residential-commercial developments for walkable
and bicyclable communities.
Discourage the use of elevators and moving walkways.
Provide information on how to shop and prepare healthier versions of
culture-specific foods.

Healthcare Providers

Explain the biologic and genetic contributions to obesity.

Give age-appropriate expectations for body weight in children.
Work toward classifying obesity as a disease to promote recognition,
reimbursement for care, and willingness and ability to provide treatment.

Industry

Mandate age-appropriate nutrition labeling for products aimed at children

(e.g., “red light/green light” foods, with portion sizes).
Encourage marketing of interactive video games in which children must
exercise to play.
Use celebrity advertising directed at children for healthful foods to promote
breakfast and regular meals.
 Reduce portion size (drinks and meals).

Government and Regulatory Agencies

Classify childhood obesity as a legitimate disease.

Find novel ways to fund healthy lifestyle programs (e.g., with revenues
from food and drink taxes).
Subsidize government-sponsored programs to promote the consumption of
fresh fruits and vegetables.
Provide financial incentives to industry to develop more healthful products
and to educate the consumer on product content.
Provide financial incentives to schools that initiate innovative PA and
nutrition programs.
Allow tax deductions for the cost of weight loss and exercise programs.
Provide urban planners with funding to establish bicycle, jogging, and
walking paths.
Ban advertising of fast foods, non-nutritious foods, and sugar-sweetened
beverages directed at preschool children, and restrict advertising to
school-age children.
Ban toys as gifts to children for purchasing fast foods.

Adapted from Speiser PW, Rudolf MCJ, Anhalt H, et al: Consensus statement:
childhood obesity, J Clin Endocrinol Metab 90:1871–1887, 2005.
Table 60.9
Anticipatory Guidance: Establishing Healthy
Eating Habits in Children

Do not punish a child during mealtimes with regard to eating. The

emotional atmosphere of a meal is very important. Interactions during
meals should be pleasant and happy.
Do not use foods as rewards.
Parents, siblings, and peers should model healthy eating, tasting new foods,
and eating a well-balanced meal.
Children should be exposed to a wide range of foods, tastes, and textures.
New foods should be offered multiple times. Repeated exposure leads to
 acceptance and liking.
Forcing a child to eat a certain food will decrease the child's preference for
that food. Children's wariness of new foods is normal and should be
expected. Offering a variety of foods with low-energy density helps
children balance energy intake.
Parents should control what foods are in the home. Restricting access to
foods in the home will increase rather than decrease a child's desire for
that food.
Children tend to be more aware of satiety than adults, so allow children to
respond to satiety, and stop eating. Do not force children to “clean their
plate.”

Adapted from Benton D: Role of parents in the determination of food

preferences of children and the development of obesity, Int J Obes Relat Metab
Disord 28:858–869, 2004. Copyright 2004. Reprinted by permission from
Macmillan Publishers Ltd.

Pediatric prevention efforts begin with careful monitoring of weight and BMI
percentiles at healthcare maintenance visits. Attention to changes in BMI
percentiles can alert the pediatric provider to increasing adiposity before the
child becomes overweight or obese. All families should be counseled about
healthy nutrition for their children, because the current prevalence of overweight
and obesity in adults is 65%. Therefore, approximately two thirds of all children
can be considered at risk for becoming overweight or obese at some time in their
lives. Those who have an obese parent are at increased risk. Prevention efforts
begin with promotion of exclusive breastfeeding for 6 mo and total breastfeeding
for 12 mo. Introduction of infant foods at 6 mo should focus on cereals, fruits,
and vegetables. Lean meats, poultry, and fish may be introduced later in the 1st
year of life. Parents should be specifically counseled to avoid introducing highly
sugared beverages and foods in the 1st year of life. Instead, they should expose
their infants and young children to a rich variety of fruits, vegetables, grains,
lean meats, poultry, and fish to facilitate acceptance of a diverse and healthy diet.
Parenting matters, and authoritative parents are more likely to have children
with a healthy weight than those who are authoritarian or permissive. Families
who eat regularly scheduled meals together are less likely to have overweight or
obese children. Child health professionals can address a child's nutritional status
and provide expertise in child growth and development.
physiologic processes are sensitive to a deficiency or excess of vitamin A or RA,
including reproduction, growth, bone development, and the functions of the
respiratory, gastrointestinal, hematopoietic, and immune systems. Vitamin A,
presumably by enhancing immune function and host defense, is particularly
important in developing countries; studies show that vitamin A supplementation
or therapy reduces morbidity and mortality from various infectious diseases,
including measles (see Chapter 273 ).
Vitamin A plays a critical role in vision, mediated by 11-cis retinal. The
human retina contains 2 distinct photoreceptor systems: the rods, in which
rhodopsin senses light of low-intensity, and the cones, in which iodopsins detect
different colors; 11-cis -retinal is the prosthetic group on both these visual
proteins. The mechanism of vitamin A action is similar for rods and cones, based
on photoisomerization of 11-cis to all-trans retinal (change shape when exposed
to light), which initiates signal transduction via the optic nerve to the brain,
resulting in visual sensation. After isomerization (also known as
photobleaching), a series of reactions serves to regenerate the 11-cis retinal for
resynthesis of rhodopsin and iodopsin; accessory cells, including retinal pigment
epithelium and Müller cells, are involved in this recycling process.

Vitamin A Deficiency
If the growing child has a well-balanced diet and obtains vitamin A from foods
rich in vitamin A or provitamin A (Table 61.1 ), the risk of vitamin A deficiency
is small. However, even subclinical vitamin A deficiency can have serious
consequences.

Table 61.1
Vitamin A Characteristics

NAMES AND BIOCHEMICAL EFFECTS OF EFFECTS OF

CHARACTERISTICS SOURCES
SYNONYMS ACTION DEFICIENCY EXCESS
Retinol Fat-soluble; heat- In vision, as Nyctalopia Anorexia, Liver, fish
(vitamin A1 ); stable; destroyed retinal, for Photophobia, slow growth, liver oils
1 µg retinol = by oxidation, synthesis of xerophthalmia, drying and Dairy
3.3 IU drying the visual Bitôt spots, cracking of products,
vitamin A = 1 Bile necessary for pigments conjunctivitis, skin, except skim
RAE absorption rhodopsin keratomalacia enlargement milk
Provitamins Stored in liver and iodopsin leading to of liver and Egg yolk,
A: the plant Protected by In growth, blindness spleen, fortified
pigments α-, vitamin E reproduction, Faulty swelling and margarine,
 β-, and γ- embryonic epiphyseal pain of long fortified
carotenes and and fetal bone bones, bone skim milk
cryptoxanthin development, formation fragility, Carotenoids
have partial bone growth, Defective increased from
retinol immune and tooth enamel intracranial plants:
activity: 12 epithelial Keratinization pressure, green
µg β- functions, via of mucous alopecia, vegetables,
carotene, or retinoic acid membranes carotenemia yellow
24 µg other as a ligand and skin Fetal fruits, and
provitamin A for specific Retarded abnormalities vegetables
carotenoids = nuclear growth
1 µg retinol transcription Impaired
factors, resistance to
regulating infection,
genes anemia,
involved in reproductive
many failure, fetal
fundamental abnormalities
cellular
processes
RAE, Retinol activity equivalent.

Deficiency states in developed countries are rare, except in some

impoverished populations (see Chapter 57 ), or after mistakes in food
preparation or with fad diets, but are common in many developing countries and
often associated with global malnutrition. In the clinical setting, vitamin
deficiencies can also occur as complications in children with various chronic
disorders or diseases. Information obtained in the medical history related to
dietary habits can be important in identifying the risk of such nutritional
problems. Except for vitamin A, toxicity from excess intake of vitamins is rare.
Table 61.1 summarizes the food sources, functions, and deficiency and excess
symptoms of the vitamins.

Clinical Manifestations of Vitamin A Deficiency

The most obvious symptoms of vitamin A deficiency are associated with
changes in epithelial cell morphology and functions. In the intestines, mucus-
secreting goblet cells are affected, and loss of an effective barrier against
pathogens can cause diarrhea or impairment of epithelial barrier function.
Similarly, mucus secretion by the epithelium is essential in the respiratory tract
for the disposal of inhaled pathogens and toxicants. Characteristic epithelial
changes result from vitamin A deficiency, including proliferation of basal cells,
hyperkeratosis, and formation of stratified cornified squamous epithelium.
Squamous metaplasia of the renal pelves, ureters, vaginal epithelium, and the
Table 61.2
Dietary Reference Intakes for Vitamin A in Children

UPPER LEVEL
RECOMMENDED DIETARY
AGE (UL) (µg retinol
ALLOWANCE (RDA) (µg COMMENTS
RANGE equivalents per
retinol equivalents per day)
day)
0-6 mo 400 600 The recommended intake for infants is an
7-12 mo 500 600 adequate intake, based on the amount of
vitamin A normally present in breast milk.
1-3 yr 300 600 The UL applies only to preformed vitamin A
4-8 yr 400 900 (retinol).
9-13 yr 600 1,700
14-18 yr 900, male; 700, female 2,800

It is noteworthy that, especially for young children, the UL is only about 2

times higher than the RDA. This suggests that for children whose diet is good,
care should be taken not to overuse dietary supplements (vitamin-mineral
supplements) containing preformed vitamin A, and/or to avoid excessive
consumption of foods that are very rich in vitamin A, such as liver.

Vitamin A for Treatment of Deficiency

A daily supplement of 1,500 µg of vitamin A is sufficient for treating latent
vitamin A deficiency, after which intake at the RDA level should be the goal. In
children without overt signs of vitamin A deficiency but suspected low reserves
of vitamin A, rates of morbidity and mortality, as from viral infections such as
measles, have been reduced by a weekly doses of vitamin A at the RDA level.
More often, higher doses of 30-60 mg of retinol (100,000-200,000 IU/child) are
given once or twice, under careful monitoring to avoid toxicity associated with
excess vitamin A. Xerophthalmia is treated by giving 1,500 µg/kg body weight
orally for 5 days, followed by intramuscular injection of 7,500 µg of vitamin A
in oil, until recovery. In neonatal rats, vitamin A given as a supplemental dose
only transiently increased retinol levels in most tissues, although liver vitamin A
remained higher more persistently.
Vitamin A is also used in preterm infants to improve respiratory function and
prevent development of chronic lung disease. An analysis of 9 randomized
controlled trials found that vitamin A appears to be beneficial in reducing death
or oxygen requirement with no difference in neurodevelopmental outcomes.

FIG. 62.2 Glossitis as seen in riboflavin deficiency. (From Zappe HA, Nuss
S, Becker K, et al: Riboflavin deficiency in Baltistan . http://www.rzuser.uni-
heidelberg.de/%7Ecn6/baltista/ribofl_e.htm .)

Diagnosis
Most often, the diagnosis is based on the clinical features of angular cheilosis in
a malnourished child, who responds promptly to riboflavin supplementation. A
functional test of riboflavin status is done by measuring the activity of
erythrocyte glutathione reductase (EGR), with and without the addition of FAD.
An EGR activity coefficient (ratio of EGR activity with added FAD to EGR
activity without FAD) of >1.4 is used as an indicator of deficiency. Urinary
excretion of riboflavin <30 µg/24 hr also suggests low intakes.

Prevention
Table 62.1 lists the recommended daily allowance of riboflavin for infants,
children, and adolescents. Adequate consumption of milk, milk products, and
eggs prevents riboflavin deficiency. Fortification of cereal products is helpful for
those who follow vegan diets or who are consuming inadequate amounts of milk
products for other reasons.

Table 62.1
Water-Soluble Vitamins
NAMES TREATMENT
EFFECTS OF CAUSES OF DIETARY
AND BIOCHEMICAL ACTION OF
DEFICIENCY DEFICIENCY SOURCES
SYNONYMS DEFICIENCY
Thiamine Coenzyme in Neurologic 3-5 mg/day PO Polished rice– Meat,
(vitamin B1 ) carbohydrate metabolism (dry beriberi): thiamine for 6 based diets especially
Nucleic acid synthesis irritability, wk Malabsorptive pork; fish;
Neurotransmitter peripheral states liver
synthesis neuritis, Severe Rice
muscle malnutrition (unmilled),
tenderness, Malignancies wheat
ataxia Alcoholism germ;
Cardiac (wet enriched
beriberi): cereals;
tachycardia, legumes
edema,
cardiomegaly,
cardiac failure

Riboflavin Constituent of flavoprotein Glossitis, 3-10 mg/day Severe Milk, milk

(vitamin B2 ) enzymes important in redox photophobia, PO riboflavin malnutrition products, eggs,
reactions: amino acid, fatty lacrimation, Malabsorptive fortified
acid, and carbohydrate corneal states cereals, green
metabolism and cellular vascularization, Prolonged vegetables
respiration poor growth, treatment with
cheilosis phenothiazines,
probenecid, or
OCPs

Niacin Constituent of NAD and Pellagra 50-300 mg/day Predominantly Meat, fish,
(vitamin B3 ) NADP, important in manifesting as PO niacin maize-based poultry
respiratory chain, fatty acid diarrhea, diets Cereals,
synthesis, cell differentiation, symmetric scaly Anorexia legumes,
and DNA processing dermatitis in sun- nervosa green
exposed areas, and Carcinoid vegetables
 neurologic syndrome
symptoms of
disorientation and
delirium

Pyridoxine Constituent of coenzymes for Irritability, 5-25 Prolonged Fortified ready-

(vitamin B6 ) amino acid and glycogen convulsions, mg/day PO treatment with INH, to-eat cereals,
metabolism, heme synthesis, hypochromic for penicillamine, meat, fish,
steroid action, anemia deficiency OCPs poultry, liver,
neurotransmitter synthesis Failure to states bananas, rice,
thrive 100 mg IM potatoes
Oxaluria or IV for
pyridoxine-
dependent
seizures

Biotin Cofactor for carboxylases, Scaly periorificial 1-10 mg/day Consumption Liver, organ
important in gluconeogenesis, dermatitis, PO biotin of raw eggs for meats, fruits
fatty acid and amino acid conjunctivitis, prolonged
metabolism alopecia, lethargy, periods
hypotonia, and Parenteral
withdrawn nutrition with
behavior infusates
lacking biotin
Valproate
therapy
Pantothenic Component of coenzyme A Experimentally Isolated deficiency Beef, organ
acid (vitamin and acyl carrier protein produced extremely rare in meats,
B5 ) involved in fatty acid deficiency in humans poultry,
metabolism humans: seafood,
irritability, fatigue, egg yolk
numbness, Yeast,
paresthesias soybeans,
(burning feet mushrooms
syndrome),
muscle cramps

Folic acid Coenzymes in amino acid and Megaloblastic 0.5-1 mg/day Malnutrition Enriched
nucleotide metabolism as an anemia PO folic acid Malabsorptive cereals, beans,
acceptor and donor of 1- Growth states leafy
carbon units retardation, Malignancies vegetables,
glossitis Hemolytic citrus fruits,
Neural tube anemias papaya
defects in Anticonvulsant
progeny therapy

Cobalamin As Megaloblastic 1,000 µg IM Vegan diets Organ meats,

(vitamin B12 ) deoxyadenosylcobalamin, anemia, vitamin B12 Malabsorptive sea foods
acts as cofactor for lipid irritability, states poultry, egg
and carbohydrate developmental Crohn disease yolk, milk,
metabolism delay, Intrinsic factor fortified ready-
As methylcobalamin, developmental deficiency to-eat cereals
important for conversion regression, (pernicious
of homocysteine to involuntary anemia)
methionine and folic acid movements,
metabolism hyperpigmentation
 Ascorbic acid Important for collagen Scurvy 100-200 Predominantly Citrus fruits and
(vitamin C) synthesis, metabolism of manifesting as mg/day PO milk-based fruit juices,
cholesterol and irritability, ascorbic acid (non–human peppers,
neurotransmitters tenderness and for up to 3 mo milk) diets berries, melons,
Antioxidant functions and swelling of legs, Severe tomatoes,
nonheme iron absorption bleeding gums, malnutrition cauliflower,
petechiae, leafy green
ecchymoses, vegetables
follicular
hyperkeratosis,
and poor wound
healing

*
For healthy breastfed infants, the values represent adequate intakes, that is, the mean intake of
apparently “normal” infants.
PO, Orally, IM, intramuscularly; IV, intravenously; INH, isoniazid; NAD, nicotinamide adenine
dinucleotide; NADP, nicotinamide adenine dinucleotide phosphate; OCP, oral contraceptive pill;
RDA, recommended dietary allowance.
From Dietary reference intakes (DRIs): Recommended dietary allowances and adequate intakes,
vitamins, Food and Nutrition Board, Institute of Medicine, National Academies.
http://www.nationalacademies.org/hmd/~/media/Files/Activity%20Files/Nutrition/DRI-
Tables/2_%20RDA%20and%20AI%20Values_Vitamin%20and%20Elements.pdf?la=en .

Treatment
Treatment includes oral administration of 3-10 mg/day of riboflavin, often as an
ingredient of a vitamin B–complex mix. The child should also be given a well-
balanced diet, including milk and milk products.

Riboflavin Toxicity
No adverse effects associated with riboflavin intakes from food or supplements
have been reported, and the upper safe limit for consumption has not been
established. Although the photosensitizing property of vitamin B2 suggests some
potential risks, limited absorption in high-intake situations precludes such
CHAPTER 64

Vitamin D Deficiency (Rickets) and

Excess
Larry A. Greenbaum

Rickets
Bone consists of a protein matrix called osteoid and a mineral phase, principally
composed of calcium and phosphate, mostly in the form of hydroxyapatite .
Osteomalacia occurs with inadequate mineralization of bone osteoid in children
and adults. Rickets is a disease of growing bone caused by unmineralized matrix
at the growth plates in children only before fusion of the epiphyses. Because
growth plate cartilage and osteoid continue to expand but mineralization is
inadequate, the growth plate thickens. Circumference of the growth plate and
metaphysis is also greater, increasing bone width at the growth plates and
causing classic clinical manifestations, such as widening of the wrists and
ankles. The general softening of the bones causes them to bend easily when
subject to forces such as weight bearing or muscle pull. This softening leads to a
variety of bone deformities.
Rickets is principally caused by vitamin D deficiency and was rampant in
northern Europe and the United States during the early years of the 20th century.
Although largely corrected through public health measures that provided
children with adequate vitamin D, rickets remains a persistent problem in
developed countries, with many cases still secondary to preventable nutritional
vitamin D deficiency. It remains a significant problem in developing countries
and may be secondary to nutritional vitamin D deficiency and inadequate intake
of calcium (Table 64.1 ).

Table 64.1
Physical and Metabolic Properties and Food Sources of
Vitamins D, E, and K
NAMES AND BIOCHEMICAL EFFECTS OF EFFECTS OF
CHARACTERISTICS SOURCES
SYNONYMS ACTION DEFICIENCY EXCESS
VITAMIN D
Vitamin D3 (3- Fat-soluble, stable to Necessary for GI Rickets in Hypercalcemia, Exposure to
cholecalciferol), heat, acid, alkali, and absorption of growing which can sunlight
which is oxidation; bile calcium; also children; cause emesis, (UV light);
synthesized in the necessary for increases osteomalacia; anorexia, fish oils,
skin, and vitamin absorption; absorption of hypocalcemia pancreatitis, fatty fish,
D2 (from plants or hydroxylation in the phosphate; direct can cause hypertension, egg yolks,
yeast) are liver and kidney actions on bone, tetany and arrhythmias, and vitamin
biologically necessary for biologic including seizures CNS effects, D–fortified
equivalent; 1 µg = activity mediating polyuria, formula,
40 IU vitamin D. resorption nephrolithiasis, milk,
renal failure cereals,
bread
VITAMIN E
Group of related Fat-soluble; readily Antioxidant; Red cell Unknown Vegetable
compounds with oxidized by oxygen, protection of cell hemolysis in oils, seeds,
similar biologic iron, rancid fats; bile membranes from premature nuts, green
activities; α- acids necessary for lipid peroxidation infants; leafy
tocopherol is the absorption and formation of posterior vegetables,
most potent and free radicals column and margarine
most common form cerebellar
dysfunction;
pigmentary
retinopathy
VITAMIN K
Group of Natural compounds are Vitamin K– Hemorrhagic Not Green leafy
naphthoquinones fat-soluble; stable to dependent manifestations; established; vegetables,
with similar heat and reducing proteins include long-term bone analogs (no liver,
biologic activities; agents; labile to coagulation and vascular longer used) certain
K1 (phylloquinone) oxidizing agent, strong factors II, VII, IX, health caused legumes
from diet; K2 acids, alkali, light; bile and X; proteins C, hemolytic and plant
(menaquinones) salts necessary for S, Z; matrix Gla anemia, oils; widely
from intestinal intestinal absorption protein, jaundice, distributed
bacteria osteocalcin kernicterus,
death
CNS, Central nervous system; GI, gastrointestinal; UV, ultraviolet.

Etiology
There are many causes of rickets, including vitamin D disorders, calcium
deficiency, phosphorus deficiency, and distal renal tubular acidosis (Table 64.2 ).
Table 64.2
Causes of Rickets
Vitamin D Disorders

Nutritional vitamin D deficiency

Congenital vitamin D deficiency
Secondary vitamin D deficiency
Malabsorption
Increased degradation
Decreased liver 25-hydroxylase
Vitamin D–dependent rickets types 1A and 1B
Vitamin D–dependent rickets types 2A and 2B
Chronic kidney disease

Calcium Deficiency

Low intake
Diet
Premature infants (rickets of prematurity)
Malabsorption
Primary disease
Dietary inhibitors of calcium absorption

Phosphorus Deficiency

Inadequate intake
Premature infants (rickets of prematurity)
Aluminum-containing antacids

Renal Losses

X-linked hypophosphatemic rickets*

Autosomal dominant hypophosphatemic rickets*
Autosomal recessive hypophosphatemic rickets types 1 and 2*
Hereditary hypophosphatemic rickets with hypercalciuria
 Overproduction of fibroblast growth factor-23
Tumor-induced rickets*
McCune-Albright syndrome*
Epidermal nevus syndrome*
Neurofibromatosis*
Fanconi syndrome
Dent disease
Distal renal tubular acidosis

* Disorders secondary to excess fibroblast growth factor-23.

Clinical Manifestations
Most manifestations of rickets are a result of skeletal changes (Table 64.3 ).
Craniotabes is a softening of the cranial bones and can be detected by applying
pressure at the occiput or over the parietal bones. The sensation is similar to the
feel of pressing into a Ping-Pong ball and then releasing. Craniotabes may also
be secondary to osteogenesis imperfecta, hydrocephalus, and syphilis. It is a
normal finding in many newborns, especially near the suture lines, but typically
disappears within a few months of birth. Widening of the costochondral
junctions results in a rachitic “rosary ,” which feels like the beads of a rosary as
the examiner's fingers move along the costochondral junctions from rib to rib
(Fig. 64.1 ). Growth plate widening is also responsible for the enlargement at the
wrists and ankles (Fig. 64.2 ). The horizontal depression along the lower anterior
chest known as Harrison groove occurs from pulling of the softened ribs by the
diaphragm during inspiration. Softening of the ribs also impairs air movement
and predisposes patients to atelectasis and pneumonia. Valgus or varus
deformities of the legs are common; windswept deformity occurs when one leg
is in extreme valgus and the other is in extreme varus (Fig. 64.3 ).
Table 64.3
Clinical Features of Rickets
General

Failure to thrive (malnutrition)

 Listlessness
Protruding abdomen
Muscle weakness (especially proximal)
Hypocalcemic dilated cardiomyopathy
Fractures (pathologic, minimal trauma)
Increased intracranial pressure

Head

Craniotabes
Frontal bossing
Delayed fontanel closure (usually closed by 2 yr)
Delayed dentition
No incisors by age 10 mo
No molars by age 18 mo
Caries
Craniosynostosis

Chest

Rachitic rosary
Harrison groove
Respiratory infections and atelectasis*

Back

Scoliosis
Kyphosis
Lordosis

Extremities

Enlargement of wrists and ankles

Valgus or varus deformities
Windswept deformity (valgus deformity of one leg with varus deformity of
 other leg)
Anterior bowing of tibia and femur
Coxa vara
Leg pain

Hypocalcemic Symptoms †

Tetany
Seizures
Stridor caused by laryngeal spasm

* These features are most frequently associated with the vitamin D deficiency

disorders.
† These symptoms develop only in children with disorders that produce

hypocalcemia (see Table 64.4 ).

FIG. 64.1 Rachitic “rosary” in a child with rickets. (Courtesy of Dr. Thomas
D. Thacher, Rochester, MN.)

FIG. 64.5 Radiographs of the knees in 7 yr old girl with distal renal tubular acidosis
and rickets. A, At initial presentation, there is widening of the growth plate and
metaphyseal fraying. B, Dramatic improvement after 4 mo of therapy with alkali.

Diagnosis
The diagnosis of rickets is based on the presence of classic radiographic
abnormalities. It is supported by physical examination findings, history, and
laboratory results consistent with a specific etiology (Table 64.4 ).

Table 64.4
Laboratory Findings in Various Disorders Causing Rickets

Disorder Ca Pi PTH 25-(OH)D 1,25-(OH)2 D ALP URINE Ca URINE Pi

Vitamin D deficiency N, ↓ ↓ ↑ ↓ ↓, N, ↑ ↑ ↓ ↑
VDDR, type 1A N, ↓ ↓ ↑ N ↓ ↑ ↓ ↑
VDDR, type 1B N, ↓ ↓ ↑ ↓ N ↑ ↓ ↑
 VDDR, type 2A N, ↓ ↓ ↑ N ↑↑ ↑ ↓ ↑
VDDR, type 2B N, ↓ ↓ ↑ N ↑↑ ↑ ↓ ↑
Chronic kidney disease N, ↓ ↑ ↑ N ↓ ↑ N, ↓ ↓
Dietary Pi deficiency N ↓ N, ↓ N ↑ ↑ ↑ ↓
XLH* N ↓ N, ↑ N RD ↑ ↓ ↑
ADHR* N ↓ N N RD ↑ ↓ ↑
HHRH N ↓ N, ↓ N ↑ ↑ ↑ ↑
ARHR, type 1 or type 2* N ↓ N N RD ↑ ↓ ↑
Tumor-induced rickets † N ↓ N N RD ↑ ↓ ↑
Fanconi syndrome N ↓ N N RD or ↑ ↑ ↓ or ↑ ↑
Dent's disease N ↓ N N N ↑ ↑ ↑
Dietary Ca deficiency N, ↓ ↓ ↑ N ↑ ↑ ↓ ↑
* Elevated fibroblast growth factor-23 (FGF-23).

† FGF-23 elevated in some patients.

ADHR, Autosomal dominant hypophosphatemic rickets; ALP, alkaline phosphatase; ARHR,

autosomal recessive hypophosphatemic rickets; Ca, calcium; HHRH, hereditary
hypophosphatemic rickets with hypercalciuria; N, normal; Pi, inorganic phosphorus; PTH,
parathyroid hormone; RD, relatively decreased (because it should be increased given the
concurrent hypophosphatemia); VDDR, vitamin D–dependent rickets; XLH, X-linked
hypophosphatemic rickets; 1,25-(OH)2 D, 1,25-dihydroxyvitamin D; 25-OHD, 25-hydroxyvitamin
D; ↓, decreased; ↑, increased; ↑↑, extremely increased.

Clinical Evaluation
Because the majority of children with rickets have a nutritional deficiency, the
initial evaluation should focus on a dietary history, emphasizing intake of both
vitamin D and calcium. Most children in industrialized nations receive vitamin D
from formula, fortified milk, or vitamin supplements. Along with the amount,
the exact composition of the formula or milk is pertinent, because rickets has
occurred in children given products that are called “milk” (e.g., soy milk) but are
deficient in vitamin D and minerals.
Cutaneous synthesis mediated by sunlight exposure is an important source of
vitamin D. It is important to ask about time spent outside, sunscreen use, and
clothing, especially if there may be a cultural reason for increased covering of
the skin. Because winter sunlight is ineffective at stimulating cutaneous
synthesis of vitamin D, the season is an additional consideration. Children with
increased skin pigmentation are at increased risk for vitamin D deficiency
because of decreased cutaneous synthesis.
The presence of maternal risk factors for nutritional vitamin D deficiency,
including diet and sun exposure, is an important consideration when a neonate or
young infant has rachitic findings, especially if the infant is breastfed (Table 64.5
). Determining a child's intake of dairy products, the main dietary source of
calcium, provides a general sense of calcium intake. High dietary fiber can
interfere with calcium absorption.
Table 64.5
Risk Factors for Nutritional Rickets and
Osteomalacia and Their Prevention
Maternal Factors

Vitamin D deficiency
Dark skin pigmentation
Full body clothing cover
High latitude during winter/spring season
Other causes of restricted sun (UVB) exposure, e.g., predominant
indoor living, disability, pollution, cloud cover
Low–vitamin D diet
Low-calcium diet
Poverty, malnutrition, special diets

Infant/Childhood Factors

Neonatal vitamin D deficiency secondary to maternal deficiency/vitamin D

deficiency
Lack of infant supplementation with vitamin D
Prolonged breastfeeding without appropriate complementary
feeding from 6 mo
High latitude during winter/spring season
Dark skin pigmentation and/or restricted sun (UVB) exposure,
e.g., predominant indoor living, disability, pollution, cloud
cover
Low–vitamin D diet
Low-calcium diet
Poverty, malnutrition, special diets

Preventive Measures
 Sun exposure (UVB content of sunlight depends on latitude and season)
Vitamin D supplementation
Strategic fortification of the habitual food supply
Normal calcium intake

Adapted from Munns CF, Shaw N, Kiely M, et al: Global consensus

recommendations on prevention and management of nutritional rickets, J Clin
Endocrinol Metab 101:394-415, 2016, p 401.

The child's medication use is relevant, because certain medications, such as

the anticonvulsants phenobarbital and phenytoin, increase degradation of
vitamin D, and phosphate binders or aluminum-containing antacids interfere
with the absorption of phosphate.
Malabsorption of vitamin D is suggested by a history of liver or intestinal
disease. Undiagnosed liver or intestinal disease should be suspected if the child
has gastrointestinal (GI) symptoms, although occasionally rickets is the
presenting complaint. Fat malabsorption is often associated with diarrhea or oily
stools, and there may be signs or symptoms suggesting deficiencies of other fat-
soluble vitamins (A, E, and K; see Chapters 61 , 65 , and 66 ).
A history of renal disease (proteinuria, hematuria, urinary tract infections) is
an additional significant consideration, given the importance of chronic kidney
disease as a cause of rickets. Polyuria can occur in children with chronic kidney
disease or Fanconi syndrome.
Children with rickets might have a history of dental caries, poor growth,
delayed walking, waddling gait, pneumonia, and hypocalcemic symptoms.
The family history is critical, given the large number of genetic causes of
rickets, although most of these causes are rare. Along with bone disease, it is
important to inquire about leg deformities, difficulties with walking, or
unexplained short stature, because some parents may be unaware of their
diagnosis. Undiagnosed disease in the mother is not unusual in X-linked
hypophosphatemia. A history of an unexplained sibling death during infancy
may be present in the child with cystinosis, the most common cause of Fanconi
syndrome in children.
The physical examination focuses on detecting manifestations of rickets (see
Table 64.3 ). It is important to observe the child's gait, auscultate the lungs to
detect atelectasis or pneumonia, and plot the patient's growth. Alopecia suggests
vitamin D–dependent rickets type 2.
CHAPTER 67

Micronutrient Mineral Deficiencies

Larry A. Greenbaum

Micronutrients include vitamins (see Chapters 61-66 ) and trace elements. By

definition, a trace element is <0.01% of the body weight. Trace elements have a
variety of essential functions (Table 67.1 ). With the exception of iron deficiency,
trace element deficiency is uncommon in developed countries, but some
deficiencies (iodine, zinc, selenium) are important public health problems in a
number of developing countries. Because of low nutritional requirements and
plentiful supply, deficiencies of some of the trace elements are extremely rare in
humans and typically occur in patients receiving unusual diets or prolonged total
parenteral nutrition (TPN) without adequate delivery of a specific trace element.
Trace element deficiencies can also occur in children with short bowel syndrome
or malabsorption. Excess intake of trace elements is uncommon but can result
from environmental exposure or overuse of supplements (Table 67.1 ).

Table 67.1
Trace Elements

EFFECTS OF DIETARY
ELEMENT PHYSIOLOGY EFFECTS OF EXCESS
DEFICIENCY SOURCES
Chromium Potentiates the action of Impaired glucose Unknown Meat, grains,
insulin tolerance, peripheral fruits, and
neuropathy, and vegetables
encephalopathy
Copper Absorbed via Microcytic anemia, Acute: nausea, Vegetables,
specific intestinal osteoporosis, emesis, abdominal grains, nuts, liver,
transporter neutropenia, neurologic pain, coma, and margarine,
Circulates bound to symptoms, hepatic necrosis legumes, corn oil
ceruloplasmin depigmentation of hair Chronic toxicity
Enzyme cofactor and skin (liver and brain
(superoxide injury) occurs in
dismutase, Wilson disease (see
 cytochrome oxidase, Chapter 384.2 ) and
and enzymes secondary to excess
involved in iron intake (see Chapter
metabolism and 384.3 ).
connective tissue
formation)
Fluoride Incorporated into bone Dental caries (see Chronic: dental fluorosis Toothpaste,
Chapter 338 ) (see Chapter 333 ) fluoridated water
Iodine Component of thyroid Hypothyroidism (see Hypothyroidism and Saltwater fish,
hormone (see Chapter Chapters 579 and 580 ) goiter (see Chapters 581 iodized salt
580 ) and 583 ); maternal
excess can cause
congenital
hypothyroidism and
goiter (see Chapter 584.1
).
Iron Component of Anemia (see Chapter Acute (see Chapter Meat,
hemoglobin, myoglobin, 482 ), decreased 77 ): nausea, fortified
cytochromes, and other alertness, impaired vomiting, diarrhea, foods
enzymes learning abdominal pain, and Deficiency
hypotension can also
Chronic excess result from
usually secondary to blood loss
hereditary disorders (hookworm
(see Chapter 489 ); infestation,
causes organ menorrhagia)
dysfunction.
Manganese Enzyme cofactor Hypercholesterolemia, Neurologic Nuts, meat,
weight loss, decreased manifestations, grains, tea
clotting proteins* cholestatic jaundice
Molybdenum Enzyme cofactor Tachycardia, tachypnea, Hyperuricemia and Legumes, grains,
(xanthine oxidase and night blindness, increased risk of gout liver
others) irritability, coma*
Selenium Enzyme cofactor Cardiomyopathy Nausea, diarrhea, Meat, seafood,
(prevents oxidative (Keshan disease ), neurologic whole grains,
damage) myopathy manifestations, nail and garlic
hair changes, garlic odor
Zinc Enzyme cofactor Decreased growth, Abdominal pain, Meat, shellfish,
Constituent of zinc- dermatitis of diarrhea, vomiting whole grains,
finger proteins, extremities and Can worsen copper legumes, cheese
which regulate gene around orifices, deficiency
transcription impaired immunity,
poor wound healing,
hypogonadism,
diarrhea
Supplements are
beneficial in
diarrhea and
improve
neurodevelopmental
outcomes.
* These deficiency states have been reported only in case reports associated with parenteral
nutrition or highly unusual diets.
angiotensin-aldosterone system and intrarenal mechanisms. In hyponatremia or
hypernatremia, the underlying pathophysiology determines the amount of
urinary Na+ , not the serum [Na+ ].

Hypernatremia
Hypernatremia is a [Na+ ] >145 mEq/L, although it is sometimes defined as
>150 mEq/L. Mild hypernatremia is fairly common in children, especially
among infants with gastroenteritis. Hypernatremia in hospitalized patients may
be iatrogenic—caused by inadequate water administration or, less often, by
excessive Na+ administration. Moderate or severe hypernatremia has significant
morbidity because of the underlying disease, the effects of hypernatremia on the
brain, and the risks of overly rapid correction.

Etiology and Pathophysiology

There are 3 basic mechanisms of hypernatremia (Table 68.1 ). Sodium
intoxication is frequently iatrogenic in a hospital setting as a result of correction
of metabolic acidosis with sodium bicarbonate. Baking soda, a putative home
remedy for upset stomach, is another source of sodium bicarbonate; the
hypernatremia is accompanied by a profound metabolic alkalosis. In
hyperaldosteronism, there is renal retention of sodium and resultant
hypertension; hypernatremia may not be present or is usually mild.
Table 68.1
Causes of Hypernatremia
Excessive Sodium

Improperly mixed formula

Excess sodium bicarbonate
Ingestion of seawater or sodium chloride
Intentional salt poisoning (child abuse or Munchausen syndrome by proxy)
Intravenous hypertonic saline
Hyperaldosteronism

Water Deficit
Nephrogenic Diabetes Insipidus

Acquired
X-linked (OMIM 304800)
Autosomal recessive (OMIM 222000)
Autosomal dominant (OMIM 125800)

Central Diabetes Insipidus

Acquired
Autosomal recessive (OMIM 125700)
Autosomal dominant (OMIM 125700)
Wolfram syndrome (OMIM 222300/598500)

Increased Insensible Losses

Premature infants
Radiant warmers
Phototherapy
Inadequate intake:
Ineffective breastfeeding
Child neglect or abuse
Adipsia (lack of thirst)

Water and Sodium Deficits

Gastrointestinal Losses

Diarrhea
Emesis/nasogastric suction
Osmotic cathartics (lactulose)

Cutaneous Losses

Burns
Excessive sweating
Renal Losses

Osmotic diuretics (mannitol)

Diabetes mellitus
Chronic kidney disease (dysplasia and obstructive uropathy)
Polyuric phase of acute tubular necrosis
Postobstructive diuresis

OMIM, database number from the Online Mendelian Inheritance in Man

(http://www.ncbi.nlm.nih.gov/omim ).

The classic causes of hypernatremia from a water deficit are nephrogenic and
central diabetes insipidus (see Chapters 548 and 574 ). Hypernatremia
develops in diabetes insipidus only if the patient does not have access to water or
cannot drink adequately because of immaturity, neurologic impairment, emesis,
or anorexia. Infants are at high risk because of their inability to control their own
water intake. Central diabetes insipidus and the genetic forms of nephrogenic
diabetes insipidus typically cause massive urinary water losses and very dilute
urine. The water losses are less dramatic, and the urine often has the same
osmolality as plasma when nephrogenic diabetes insipidus is secondary to
intrinsic renal disease (obstructive uropathy, renal dysplasia, sickle cell disease).
The other causes of a water deficit are also secondary to an imbalance
between losses and intake. Newborns, especially if premature, have high
insensible water losses. Losses are further increased if the infant is placed under
a radiant warmer or with the use of phototherapy for hyperbilirubinemia. The
renal concentrating mechanisms are not optimal at birth, providing an additional
source of water loss. Ineffective breastfeeding, often in a primiparous mother,
can cause severe hypernatremic dehydration. Adipsia , the absence of thirst, is
usually secondary to damage to the hypothalamus, such as from trauma, tumor,
hydrocephalus, or histiocytosis. Primary adipsia is rare.
When hypernatremia occurs in conditions with deficits of sodium and water,
the water deficit exceeds the sodium deficit. This occurs only if the patient is
unable to ingest adequate water. Diarrhea results in depletion of both Na+ and
water. Because diarrhea is hypotonic—typical Na+ concentration of 35-65
mEq/L—water losses exceed Na+ losses, potentially leading to hypernatremia.
Most children with gastroenteritis do not have hypernatremia because they drink
through diarrhea, may need supplemental water and electrolytes (see Chapter 69
). Sodium intake is reduced if it contributed to the hypernatremia.

Hyponatremia
Hyponatremia, a very common electrolyte abnormality in hospitalized patients,
is a serum sodium level <135 mEq/L. Both total body sodium and TBW
determine the serum sodium concentration. Hyponatremia exists when the ratio
of water to Na+ is increased. This condition can occur with low, normal, or high
levels of body Na+ . Similarly, body water can be low, normal, or high.

Etiology and Pathophysiology

Table 68.2 lists the causes of hyponatremia. Pseudohyponatremia is a
laboratory artifact present when the plasma contains very high concentrations of
protein (multiple myeloma, IVIG infusion) or lipid (hypertriglyceridemia,
hypercholesterolemia). It does not occur when a direct ion-selective electrode
determines the [Na+ ] in undiluted plasma, a technique that is used by ABG
analyzers or POC instruments (see Chapter 68.1 ). In true hyponatremia, the
measured osmolality is low, whereas it is normal in pseudohyponatremia.
Hyperosmolality, as may occur with hyperglycemia, causes a low [Na+ ]
because water moves down its osmotic gradient from the ICS into the ECS,
diluting the [Na+ ]. However, because the manifestations of hyponatremia are a
result of the low plasma osmolality, patients with hyponatremia resulting from
hyperosmolality do not have symptoms of hyponatremia. When the etiology of
the hyperosmolality resolves, such as hyperglycemia in diabetes mellitus, water
moves back into the cells, and the [Na+ ] rises to its “true” value. Mannitol or
sucrose, a component of intravenous immune globulin (IVIG) preparations, may
cause hyponatremia because of hyperosmolality.
Table 68.2
Causes of Hyponatremia
PSEUDOHYPONATREMIA

Hyperlipidemia
Hyperproteinemia
HYPEROSMOLALITY

Hyperglycemia
Iatrogenic (mannitol, sucrose, glycine)

HYPOVOLEMIC HYPONATREMIA
EXTRARENAL LOSSES

Gastrointestinal (emesis, diarrhea)

Skin (sweating or burns)
Third space losses (bowel obstruction, peritonitis, sepsis)

RENAL LOSSES

Thiazide or loop diuretics

Osmotic diuresis
Postobstructive diuresis
Polyuric phase of acute tubular necrosis
Juvenile nephronophthisis (OMIM
256100/606966/602088/604387/611498)
Autosomal recessive polycystic kidney disease (OMIM 263200)
Tubulointerstitial nephritis
Obstructive uropathy
Cerebral salt wasting
Proximal (type II) renal tubular acidosis (OMIM 604278)*
Lack of aldosterone effect (high serum potassium):
Absence of aldosterone (e.g., 21-hydroxylase deficiency [OMIM
201910])
Pseudohypoaldosteronism type I (OMIM 264350/177735)
Urinary tract obstruction and/or infection
Addison disease

EUVOLEMIC HYPONATREMIA

Syndrome of inappropriate antidiuretic hormone secretion

Nephrogenic syndrome of inappropriate antidiuresis (OMIM 304800)
 Desmopressin acetate
Glucocorticoid deficiency
Hypothyroidism
Antidepressant medications
Water intoxication
Iatrogenic (excess hypotonic intravenous fluids)
Feeding infants excessive water products
Swimming lessons
Tap water enema
Child abuse
Psychogenic polydipsia
Diluted formula
Beer potomania
Exercise-induced hyponatremia

HYPERVOLEMIC HYPONATREMIA

Heart failure
Cirrhosis
Nephrotic syndrome
Acute, chronic kidney injury
Capillary leak caused by sepsis
Hypoalbuminemia caused by gastrointestinal disease (protein-losing
enteropathy)

* Most cases of proximal renal tubular acidosis are not caused by this primary

genetic disorder. Proximal renal tubular acidosis is usually part of Fanconi

syndrome, which has multiple etiologies.

OMIM, database number from the Online Mendelian Inheritance in Man

(http://www.ncbi.nlm.nih.gov/omim ).

Classification of hyponatremia is based on the patient's volume status. In

hypovolemic hyponatremia the child has lost Na+ from the body. The water
balance may be positive or negative, but Na+ loss has been higher than water
diagnosis of SIADH is one of exclusion, because other causes of hyponatremia
must be eliminated (Table 68.3 ). Because SIADH is a state of intravascular
volume expansion, low serum uric acid and BUN levels are supportive of the
diagnosis. A rare gain-of-function mutation in the renal ADH receptor causes
nephrogenic syndrome of inappropriate antidiuresis . Patients with this X-
linked disorder appear to have SIADH but have undetectable levels of ADH.
Table 68.3
Diagnostic Criteria for Syndrome of
Inappropriate Antidiuretic Hormone
Secretion

• Absence of:
Renal, adrenal, or thyroid insufficiency
Heart failure, nephrotic syndrome, or cirrhosis
Diuretic ingestion
Dehydration
• Urine osmolality >100 mOsm/kg (usually > plasma)
• Serum osmolality <280 mOsm/kg and serum sodium <135 mEq/L
• Urine sodium >30 mEq/L
• Reversal of “sodium wasting” and correction of hyponatremia with water
restriction

Hyponatremia in hospitalized patients is frequently caused by inappropriate

production of ADH and administration of hypotonic IV fluids (see Chapter 69 ).
Causes of inappropriate ADH production include stress, medications such as
narcotics or anesthetics, nausea, and respiratory illness. The synthetic analog of
ADH, desmopressin acetate, causes water retention and may cause hyponatremia
if fluid intake is not appropriately limited. The main uses of desmopressin
acetate in children are for the management of central diabetes insipidus and
nocturnal enuresis.
Excess water ingestion can produce hyponatremia. In these cases, [Na+ ]
decreases as a result of dilution. This decrease suppresses ADH secretion, and
there is a marked water diuresis by the kidney. Hyponatremia develops only
because the intake of water exceeds the kidney's ability to eliminate water. This
is released by the adrenal cortex in response to increased plasma K+ . Its main
site of action is the cortical collecting duct, where aldosterone stimulates Na+
movement from the tubule into the cells. This movement creates a negative
charge in the tubular lumen, facilitating K+ excretion. In addition, the increased
intracellular Na+ stimulates the basolateral Na+ ,K+ -ATPase, causing more K+ to
move into the cells lining the cortical collecting duct. Glucocorticoids, ADH, a
high urinary flow rate, and high Na+ delivery to the distal nephron also increase
urinary K+ excretion. Insulin, catecholamines, and urinary ammonia decrease K+
excretion. Whereas ADH increases K+ secretion, it also causes water resorption,
decreasing urinary flow. The net effect is that ADH has little overall impact on
K+ balance. Alkalosis causes potassium to move into cells, including the cells
lining the collecting duct. This movement increases K+ secretion, and because
acidosis has the opposite effect, it decreases K+ secretion.
The kidney can dramatically vary K+ excretion in response to changes in
intake. Normally, approximately 10–15% of the filtered load is excreted. In an
adult, excretion of K+ can vary from 5-1,000 mEq/day.

Hyperkalemia
Hyperkalemia—because of the potential for lethal arrhythmias—is one of the
most alarming electrolyte abnormalities.

Etiology and Pathophysiology

Three basic mechanisms cause hyperkalemia (Table 68.4 ). In the individual
patient, the etiology is sometimes multifactorial.
Table 68.4
Causes of Hyperkalemia
Spurious Laboratory Value

Hemolysis
Tissue ischemia during blood drawing
Thrombocytosis
Leukocytosis
 Familial pseudohyperkalemia (OMIM 609153/611184/612126)

Increased Intake

Intravenous or oral
Blood transfusions

Transcellular Shifts

Acidosis
Rhabdomyolysis
Tumor lysis syndrome
Tissue necrosis
Hemolysis/hematomas/gastrointestinal bleeding
Succinylcholine
Digitalis intoxication
Fluoride intoxication
β-Adrenergic blockers
Exercise
Hyperosmolality
Insulin deficiency
Malignant hyperthermia (OMIM 145600/601887)
Hyperkalemic periodic paralysis (OMIM 170500)

Decreased Excretion

Renal failure
Primary adrenal disease
Acquired Addison disease
21-Hydroxylase deficiency (OMIM 201910)
3β-Hydroxysteroid dehydrogenase deficiency (OMIM 201810)
Lipoid congenital adrenal hyperplasia (OMIM 201710)
Adrenal hypoplasia congenita (OMIM 300200)
Aldosterone synthase deficiency (OMIM 203400/610600)
Adrenoleukodystrophy (OMIM 300100)
Hyporeninemic hypoaldosteronism
 Urinary tract obstruction
Sickle cell disease (OMIM 603903)
Kidney transplant
Lupus nephritis
Renal tubular disease
Pseudohypoaldosteronism type I (OMIM 264350/177735)
Pseudohypoaldosteronism type II (OMIM 145260)
Bartter syndrome, type 2 (OMIM 241200)
Urinary tract obstruction
Kidney transplant
Medications
Renin inhibitors
Angiotensin-converting enzyme inhibitors
Angiotensin II blockers
Potassium-sparing diuretics
Calcineurin inhibitors
Nonsteroidal antiinflammatory drugs
Trimethoprim
Heparin
Drospirenone (in some oral contraceptives)

OMIM, database number from the Online Mendelian Inheritance in Man

(http://www.ncbi.nlm.nih.gov/omim ).

Spurious hyperkalemia or pseudohyperkalemia is very common in children

because of the difficulties in obtaining blood specimens. This laboratory result is
usually caused by hemolysis during a heelstick or phlebotomy, but it can be the
result of prolonged tourniquet application or fist clenching, either of which
causes local potassium release from muscle.
The serum [K+ ] is normally 0.4 mEq/L higher than the plasma value,
secondary to K+ release from cells during clot formation. This phenomenon is
exaggerated with thrombocytosis because of K+ release from platelets. For every
100,000/m3 increase in the platelet count, the serum [K+ ] rises by approximately
0.15 mEq/L. This phenomenon also occurs with the marked white blood cell
(WBC) count elevations sometimes seen with leukemia. Elevated WBC counts,
typically >200,000/m3 , can cause a dramatic elevation in the serum [K+ ].
orally. Patiromer is an oral exchange resin for treating hyperkalemia. Some
patients require dialysis for acute K+ removal. Dialysis is often necessary if the
patient has either severe renal failure or an especially high rate of endogenous
K+ release, as is sometimes present with tumor lysis syndrome or
rhabdomyolysis. Hemodialysis rapidly lowers plasma [K+ ]. Peritoneal dialysis
is not nearly as quick or reliable, but it is usually adequate as long as the acute
problem can be managed with medications and the endogenous release of K+ is
not high.
Long-term management of hyperkalemia includes reducing intake through
dietary changes and eliminating or reducing medications that cause
hyperkalemia (see Chapter 550 ). Some patients require medications to increase
potassium excretion, such as SPS, patiromer and loop or thiazide diuretics. Some
infants with chronic renal failure may need to start dialysis to allow adequate
caloric intake without hyperkalemia. It is unusual for an older child to require
dialysis principally to control chronic hyperkalemia. The disorders caused by
aldosterone deficiency respond to replacement therapy with fludrocortisone.

Hypokalemia
Hypokalemia is common in children, with most cases related to gastroenteritis.

Etiology and Pathophysiology

There are 4 basic mechanisms of hypokalemia (Table 68.5 ). Spurious
hypokalemia occurs in patients with leukemia and very elevated WBC counts if
plasma for analysis is left at room temperature, permitting the WBCs to take up
K+ from the plasma. With a transcellular shift, there is no change in total body
K+ , although there may be concomitant potassium depletion resulting from
other factors. Decreased intake, extrarenal losses, and renal losses are all
associated with total body K+ depletion.
Table 68.5
Causes of Hypokalemia
Spurious Laboratory Value

High white blood cell count

Transcellular Shifts

Alkalemia
Insulin
α-Adrenergic agonists
Drugs/toxins (theophylline, barium, toluene, cesium chloride,
hydroxychloroquine)
Hypokalemic periodic paralysis (OMIM 170400)
Thyrotoxic period paralysis
Refeeding syndrome

Decreased Intake

Anorexia nervosa

Extrarenal Losses

Diarrhea
Laxative abuse
Sweating
Sodium polystyrene sulfonate (Kayexalate) or clay ingestion

Renal Losses
With Metabolic Acidosis

Distal renal tubular acidosis (OMIM 179800/602722/267300)

Proximal renal tubular acidosis (OMIM 604278)*
Ureterosigmoidostomy
Diabetic ketoacidosis

Without Specific Acid–Base Disturbance

Tubular toxins: amphotericin, cisplatin, aminoglycosides

Interstitial nephritis
Diuretic phase of acute tubular necrosis
 Postobstructive diuresis
Hypomagnesemia
High urine anions (e.g., penicillin or penicillin derivatives)

With Metabolic Alkalosis

Low urine chloride

Emesis or nasogastric suction
Chloride-losing diarrhea (OMIM 214700)
Cystic fibrosis (OMIM 219700)
Low-chloride formula
Posthypercapnia
Previous loop or thiazide diuretic use
High urine chloride and normal blood pressure
Gitelman syndrome (OMIM 263800)
Bartter syndrome (OMIM
241200/607364/602522/601678/300971/601198/613090)
Autosomal dominant hypoparathyroidism (OMIM 146200)
EAST syndrome (OMIM 612780)
Loop and thiazide diuretics (current)
High urine chloride and high blood pressure
Adrenal adenoma or hyperplasia
Glucocorticoid-remediable aldosteronism (OMIM 103900)
Renovascular disease
Renin-secreting tumor
17β-Hydroxylase deficiency (OMIM 202110)
11β-Hydroxylase deficiency (OMIM 202010)
Cushing syndrome
11β-Hydroxysteroid dehydrogenase deficiency (OMIM 218030)
Licorice ingestion
Liddle syndrome (OMIM 177200)

* Most cases of proximal renal tubular acidosis are not caused by this primary

genetic disorder. Proximal renal tubular acidosis is usually part of Fanconi

syndrome, which has multiple etiologies.
EAST, Epilepsy, ataxia, sensorineural hearing loss, and tubulopathy; OMIM,
database number from the Online Mendelian Inheritance in Man
(http://www.ncbi.nlm.nih.gov/omim ).

Because the intracellular [K+ ] is much higher than the plasma level, a
significant amount of K+ can move into cells without greatly changing the
intracellular [K+ ]. Alkalemia is one of the more common causes of a
transcellular shift. The effect is much greater with a metabolic alkalosis than
with a respiratory alkalosis. The impact of exogenous insulin on K+ movement
into the cells is substantial in patients with DKA. Endogenous insulin may be the
cause when a patient is given a bolus of glucose. Both endogenous (epinephrine
in stress) and exogenous (albuterol) β-adrenergic agonists stimulate cellular
uptake of K+ . Theophylline overdose, barium intoxication, administration of
cesium chloride (a homeopathic cancer remedy), and toluene intoxication from
paint or glue sniffing can cause a transcellular shift hypokalemia, often with
severe clinical manifestations. Children with hypokalemic periodic paralysis, a
rare autosomal dominant disorder, have acute cellular uptake of K+ (see Chapter
629 ). Thyrotoxic periodic paralysis, which is more common in Asians, is an
unusual initial manifestation of hyperthyroidism. Affected patients have
dramatic hypokalemia as a result of a transcellular shift of potassium.
Hypokalemia can occur during refeeding syndrome (see Chapters 58 and 364.8
).
Inadequate K+ intake occurs in anorexia nervosa ; accompanying bulimia and
laxative or diuretic abuse exacerbates the K+ deficiency. Sweat losses of K+ can
be significant during vigorous exercise in a hot climate. Associated volume
depletion and hyperaldosteronism increase renal losses of K+ (discussed later).
Diarrheal fluid has a high concentration of K+ , and hypokalemia as a result of
diarrhea is usually associated with metabolic acidosis resulting from stool losses
of bicarbonate. In contrast, normal acid-base balance or mild metabolic alkalosis
is seen with laxative abuse. Intake of SPS or ingestion of clay because of pica
increases stool losses of potassium.
Urinary potassium wasting may be accompanied by a metabolic acidosis
(proximal or distal RTA). In DKA, although it is often associated with normal
plasma [K+ ] from transcellular shifts, there is significant total body K+ depletion
from urinary losses because of the osmotic diuresis, and the K+ level may
decrease dramatically with insulin therapy (see Chapter 607 ). Both the polyuric
10 mg/dL × 0.25 = 2.5 mmol/L). Dividing the right-column unit by the
conversion factor converts to the units of the left-column unit.

Table 68.6
Conversion Factors for Calcium, Magnesium, and
Phosphorus

UNIT CONVERSION FACTOR UNIT

Calcium mg/dL 0.25 mmol/L
mEq/L 0.5 mmol/L
mg/dL 0.5 mEq/L
Magnesium mg/dL 0.411 mmol/L
mEq/L 0.5 mmol/L
mg/dL 0.822 mEq/L
Phosphorus mg/dL 0.32 mmol/L

Magnesium is a necessary cofactor for hundreds of enzymes. It is important

for membrane stabilization and nerve conduction. Adenosine triphosphate (ATP)
and guanosine triphosphate need associated magnesium when they are used by
ATPases, cyclases, and kinases.

Magnesium Intake
Between 30% and 50% of dietary magnesium is absorbed. Good dietary sources
include green vegetables, cereals, nuts, meats, and hard water, although many
foods contain magnesium. Human milk contains approximately 35 mg/L of
magnesium; formula contains 40-70 mg/L. The small intestine is the major site
of magnesium absorption, but the regulation of magnesium absorption is poorly
understood. There is passive absorption, which permits high absorption in the
presence of excessive intake. It probably occurs by a paracellular mechanism.
Absorption is diminished in the presence of substances that complex with
magnesium (free fatty acids, fiber, phytate, phosphate, oxalate); increased
intestinal motility and calcium also decrease magnesium absorption. Vitamin D
and parathyroid hormone (PTH) may enhance absorption, although this effect is
limited. Intestinal absorption does increase when intake is decreased, possibly by
a saturable, active transport system. If there is no oral intake of magnesium,
obligatory secretory losses prevent the complete elimination of intestinal losses.

Magnesium Excretion
Renal excretion is the principal regulator of magnesium balance. There is no
defined hormonal regulatory system, although PTH may increase tubular
resorption. Approximately 15% of resorption occurs in the proximal tubule, and
70% in the thick ascending limb (TAL) of the loop of Henle. Proximal resorption
may be higher in neonates. High serum magnesium levels inhibit resorption in
the TAL, suggesting that active transport is involved. Approximately 5–10% of
filtered magnesium is resorbed in the distal tubule. Hypomagnesemia increases
absorption in the TAL and the distal tubule.

Hypomagnesemia
Hypomagnesemia is relatively common in hospitalized patients, although most
cases are asymptomatic. Detection requires a high index of suspicion because
magnesium is not measured in most basic metabolic panels.

Etiology and Pathophysiology

Gastrointestinal and renal losses are the major causes of hypomagnesemia (Table
68.7 ). Diarrheal fluid contains up to 200 mg/L of magnesium; gastric contents
have only approximately 15 mg/L, but high losses can cause depletion.
Steatorrhea causes magnesium loss as a result of the formation of magnesium-
lipid salts; restriction of dietary fat can decrease losses. The potassium-lowering
agent patiromer binds magnesium and may cause hypomagnesemia.
Table 68.7
Causes of Hypomagnesemia
Gastrointestinal Losses

Diarrhea
Nasogastric suction or emesis
Inflammatory bowel disease
Celiac disease
Cystic fibrosis
Intestinal lymphangiectasia
Small bowel resection or bypass
Pancreatitis
 Protein-calorie malnutrition
Patiromer
Hypomagnesemia with secondary hypocalcemia (OMIM 602014)*

Renal Disorders

Medications
Amphotericin
Cisplatin
Cyclosporine, tacrolimus
Loop diuretics
Mannitol
Pentamidine
Proton pump inhibitors
Aminoglycosides
Thiazide diuretics
Epidermal growth factor receptor inhibitors (cetuximab)
Diabetes
Acute tubular necrosis (recovery phase)
Postobstructive nephropathy
Chronic kidney diseases
Interstitial nephritis
Glomerulonephritis
Post–renal transplantation
Hypercalcemia
Intravenous fluids
Primary aldosteronism
Genetic diseases
Gitelman syndrome (OMIM 263800)
Bartter syndrome (OMIM
241200/607364/602522/601678/300971/601198/613090)
Familial hypomagnesemia with hypercalciuria and
nephrocalcinosis (OMIM 248250)
Familial hypomagnesemia with hypercalciuria, nephrocalcinosis,
and severe ocular involvement (OMIM 248190)
Autosomal recessive renal magnesium wasting with
normocalciuria (OMIM 611718)
 Renal cysts and diabetes syndrome (OMIM 137920)
Autosomal dominant hypomagnesemia (OMIM
160120/613882/154020)
EAST syndrome (OMIM 612780)
Autosomal dominant hypoparathyroidism (OMIM 146200)
Mitochondrial disorders (OMIM 500005)
Hypomagnesemia after transient neonatal hyperphenylalaninemia
Hypomagnesemia with impaired brain development
Hypomagnesemia with metabolic syndrome
Hyperuricemia, pulmonary hypertension, renal failure, alkalosis syndrome
(HUPRA)
HNF1B nephropathy

Miscellaneous Causes

Poor intake
Hungry bone syndrome
Insulin administration
Pancreatitis
Intrauterine growth restriction
Infants of diabetic mothers
Exchange transfusion

* This disorder is also associated with renal magnesium wasting.

EAST, Epilepsy, ataxia, sensorineural hearing loss, and tubulopathy; OMIM,

database number from the Online Mendelian Inheritance in Man
(http://www.ncbi.nlm.nih.gov/omim ).

Hypomagnesemia with secondary hypocalcemia , a rare autosomal

recessive disorder, is caused by decreased intestinal absorption of magnesium
and renal magnesium wasting. Patients with this disorder have mutations in a
gene expressed in intestine and kidney; TRPM6 codes for a transient receptor
potential cation channel. The patients have seizures, tetany, tremor, or
restlessness at 2-8 wk of life as a result of severe hypomagnesemia (0.2-0.8
 Low plasma phosphorus stimulates the 1α-hydroxylase in the kidney that
converts 25-hydroxyvitamin D (25-D) to 1,25-dihydroxyvitamin D (1,25-D;
calcitriol). Calcitriol increases intestinal absorption of phosphorus and is
necessary for maximal renal resorption of phosphate. The effect of a change in
calcitriol on urinary phosphate is significant only when the level of calcitriol was
initially low, arguing against a role for calcitriol in nonpathologic conditions.

Hypophosphatemia
Because of the wide variation in normal plasma phosphorus levels, the definition
of hypophosphatemia is age dependent (see Table 68.8 ). The normal range
reported by a laboratory may be based on adult normal values and therefore may
be misleading in children. A serum phosphorus level of 3 mg/dL, a normal value
in an adult, indicates clinically significant hypophosphatemia in an infant.
The plasma phosphorus level does not always reflect the total body stores
because only 1% of phosphorus is extracellular. Thus, a child may have
significant phosphorus deficiency despite a normal plasma phosphorus
concentration when there is a shift of phosphorus from the ICS.

Etiology and Pathophysiology

A variety of mechanisms cause hypophosphatemia (Table 68.9 ). A transcellular
shift of phosphorus into cells occurs with processes that stimulate cellular usage
of phosphorus (glycolysis). Usually, this shift causes only a minor, transient
decrease in plasma phosphorus, but if intracellular phosphorus deficiency is
present, the plasma phosphorus level can decrease significantly, producing
symptoms of acute hypophosphatemia. Glucose infusion stimulates insulin
release, leading to entry of glucose and phosphorus into the cells. Phosphorus is
then used during glycolysis and other metabolic processes. A similar
phenomenon can occur during the treatment of DKA, and patients with DKA are
typically phosphorus depleted because of urinary phosphorus losses.
Table 68.9
Causes of Hypophosphatemia
Transcellular Shifts
 Glucose infusion
Insulin
Refeeding
Total parenteral nutrition
Respiratory alkalosis
Tumor growth
Bone marrow transplantation
Hungry bone syndrome

Decreased Intake

Nutritional
Premature infants
Low phosphorus formula
Antacids and other phosphate binders

Renal Losses

Hyperparathyroidism
Parathyroid hormone–related peptide
X-linked hypophosphatemic rickets (OMIM 307800)
Overproduction of fibroblast growth factor-23
Tumor-induced rickets
McCune-Albright syndrome (OMIM 174800)
Epidermal nevus syndrome
Neurofibromatosis
Autosomal dominant hypophosphatemic rickets (OMIM 193100)
Autosomal recessive hypophosphatemic rickets, types 1 and 2
(OMIM 241520/613312)
Fanconi syndrome
Dent disease (OMIM 300009/300555)
Hypophosphatemic rickets with hypercalciuria (OMIM 241530)
Volume expansion and intravenous fluids
Metabolic acidosis
Diuretics
Glycosuria
 Glucocorticoids
Kidney transplantation

Multifactorial

Vitamin D deficiency
Vitamin D–dependent rickets type 1 (OMIM 264700)
Vitamin D–dependent rickets type 2 (OMIM 277440)
Alcoholism
Sepsis
Dialysis

OMIM, database number from the Online Mendelian Inheritance in Man

(http://www.ncbi.nlm.nih.gov/omim ).

Refeeding of patients with protein-calorie malnutrition causes anabolism,

which leads to significant cellular demand for phosphorus. The increased
phosphorus uptake for incorporation into newly synthesized compounds
containing phosphorus leads to hypophosphatemia, which can be severe and
symptomatic. Refeeding hypophosphatemia occurs frequently during treatment
of severe anorexia nervosa. It can occur during treatment of children with
malnutrition from any cause, such as cystic fibrosis, Crohn disease, burns,
neglect, chronic infection, or famine. Hypophosphatemia usually occurs within
the 1st 5 days of refeeding and is prevented by a gradual increase in nutrition
with appropriate phosphorus supplementation. TPN without adequate
phosphorus can cause hypophosphatemia.
Phosphorus moves into the ICS during a respiratory alkalosis and during
recovery from a respiratory acidosis. An acute decrease in the carbon dioxide
concentration, by raising the intracellular pH, stimulates glycolysis, leading to
intracellular use of phosphorus and hypophosphatemia. Because a metabolic
alkalosis has less effect on the intracellular pH (CO2 diffuses across cell
membranes much faster than bicarbonate), transcellular phosphorus movement is
minimal with a metabolic alkalosis.
Tumors that grow rapidly, such as those associated with leukemia and
lymphoma, may use large amounts of phosphorus, leading to hypophosphatemia.
A similar phenomenon may occur during the hematopoietic reconstitution that
specific therapy (see Chapter 64 ).

Hyperphosphatemia
Etiology and Pathophysiology
Renal insufficiency is the most common cause of hyperphosphatemia, with the
severity proportional to the degree of kidney impairment (see Chapter 550 ).
This occurs because GI absorption of the large dietary intake of phosphorus is
unregulated, and the kidneys normally excrete this phosphorus. As renal function
deteriorates, increased excretion of phosphorus is able to compensate. When
kidney function is <30% of normal, hyperphosphatemia usually develops,
although this varies considerably depending on dietary intake. Many of the other
causes of hyperphosphatemia are more likely to develop in the setting of renal
insufficiency (Table 68.10 ).
Table 68.10
Causes of Hyperphosphatemia
Transcellular Shifts

Tumor lysis syndrome

Rhabdomyolysis
Acute hemolysis
Diabetic ketoacidosis and lactic acidosis

Increased Intake

Enemas and laxatives

Cow's milk in infants
Treatment of hypophosphatemia
Vitamin D intoxication

Decreased Excretion

Renal failure
 Hypoparathyroidism or pseudohypoparathyroidism (OMIM
146200/603233/103580/241410/203330)
Acromegaly
Hyperthyroidism
Tumoral calcinosis with hyperphosphatemia (OMIM 211900)

OMIM, database number from the Online Mendelian Inheritance in Man

(http://www.ncbi.nlm.nih.gov/omim ).

Cellular content of phosphorus is high relative to plasma phosphorus, and cell

lysis can release substantial phosphorus. This is the etiology of
hyperphosphatemia in tumor lysis syndrome , rhabdomyolysis , and acute
hemolysis . These disorders cause concomitant potassium release and the risk of
hyperkalemia. Additional features of tumor lysis and rhabdomyolysis are
hyperuricemia and hypocalcemia, whereas indirect hyperbilirubinemia and
elevated lactate dehydrogenase (LDH) values are often present with hemolysis.
An elevated CPK level is suggestive of rhabdomyolysis. During lactic acidosis
or DKA, use of phosphorus by cells decreases, and phosphorus shifts into the
ECS. This problem reverses when the underlying problem is corrected, and
especially with DKA, patients subsequently become hypophosphatemic as a
result of previous renal phosphorus loss.
Excessive intake of phosphorus is especially dangerous in children with renal
insufficiency. Neonates are at risk because renal function is normally reduced
during the 1st few months of life. In addition, they may erroneously be given
doses of phosphorus that are meant for an older child or adult. In infants fed
cow's milk, which has higher phosphorus content than breast milk or formula,
hyperphosphatemia may develop. Fleet Enema has a high amount of
phosphorus that can be absorbed, especially in the patient with an ileus; infants
and children with Hirschsprung disease are especially vulnerable. There is often
associated hypernatremia from sodium absorption and water loss from diarrhea.
Sodium phosphorus laxatives may cause hyperphosphatemia if the dose is
excessive or if renal insufficiency is present. Hyperphosphatemia occurs in
children who receive overaggressive treatment for hypophosphatemia. Vitamin
D intoxication causes excessive GI absorption of both calcium and phosphorus,
and the suppression of PTH by hypercalcemia decreases renal phosphorus
excretion.
The absence of PTH in hypoparathyroidism or PTH responsiveness in
 There are formulas for calculating the appropriate metabolic or respiratory
compensation for the 6 primary simple acid-base disorders (Table 68.11 ). The
appropriate compensation is expected in a simple disorder; it is not optional. If a
patient does not have the appropriate compensation, a mixed acid-base disorder
is present. A patient has a primary metabolic acidosis with a serum [HCO3 − ] of
10 mEq/L. The expected respiratory compensation is [CO2 ] of 23 mm Hg ± 2
(1.5 × 10 + 8 ± 2 = 23 ± 2; Table 68.11 ). If the patient's [CO2 ] is >25 mm Hg, a
concurrent respiratory acidosis is present; [CO2 ] is higher than expected. A
patient may have a respiratory acidosis despite a CO2 level below the “normal”
value of 35-45 mm Hg. In this example, [CO2 ] <21 mm Hg indicates a
concurrent respiratory alkalosis; [CO2 ] is lower than expected.

Table 68.11
Appropriate Compensation During Simple Acid-Base
Disorders

DISORDER EXPECTED COMPENSATION

Metabolic acidosis PCO 2 = 1.5 × [HCO3 − ] + 8 ± 2
Metabolic alkalosis PCO 2 increases by 7 mm Hg for each 10 mEq/L increase in serum [HCO3 − ]
Respiratory Acidosis
Acute [HCO3 − ] increases by 1 for each 10 mm Hg increase in PCO 2
Chronic [HCO3 − ] increases by 3.5 for each 10 mm Hg increase in PCO 2
Respiratory Alkalosis
Acute [HCO3 − ] falls by 2 for each 10 mm Hg decrease in PCO 2
Chronic [HCO3 − ] falls by 4 for each 10 mm Hg decrease in PCO 2

Diagnosis
A systematic evaluation of an arterial blood gas (ABG) sample, combined with
the clinical history, can usually explain the patient's acid-base disturbance.
Assessment of an ABG sample requires knowledge of normal values (Table
68.12 ). In most cases, this is accomplished through a 3-step process (Fig. 68.8 ):

Table 68.12

Normal Values of Arterial Blood Gases

 pH 7.35-7.45
[HCO3 − ] 20-28 mEq/L
PCO 2 35-45 mm Hg

FIG. 68.8 Three-step process for interpreting acid-base disturbances. In step 1,

determine whether the pH is low (acidemia) or high (alkalemia). In step 2, establish an
explanation for the acidemia or alkalemia. In step 3, calculate the expected
compensation (see Table 68.11 ) and determine whether a mixed disturbance is present.
Met. Acid., metabolic acidosis; Met. Alk., metabolic alkalosis; Resp. Acid., respiratory
acidosis; Resp. Alk., respiratory alkalosis.

1. Determine whether acidemia or alkalemia is present.

2. Determine a cause of the acidemia or alkalemia.
3. Determine whether a mixed disorder is present.

Most patients with an acid-base disturbance have an abnormal pH, although

there are 2 exceptions. One exception is in the patient with a mixed disorder in
which the 2 processes have opposite effects on pH (a metabolic acidosis and a
respiratory alkalosis) and cause changes in [H+ ] that are comparable in
magnitude, although opposite. The other exception is in the patient with a simple
chronic respiratory alkalosis; in some cases the appropriate metabolic
compensation is enough to normalize the pH. In both situations the presence of
an acid-base disturbance is deduced because of the abnormal CO2 and
bicarbonate levels. Determining the acid-base disturbance in these patients
Metabolic Acidosis
Metabolic acidosis occurs frequently in hospitalized children; diarrhea is the
most common etiology. For a patient with an unknown medical problem, the
presence of a metabolic acidosis is often helpful diagnostically, because it
suggests a relatively narrow differential diagnosis.
Patients with a metabolic acidosis have a low serum [HCO3 − ], although not
every patient with a low serum [HCO3 − ] has a metabolic acidosis. The
exception is the patient with a respiratory alkalosis, which causes a decrease in
the serum [HCO3 − ] as part of appropriate renal compensation. In a patient with
an isolated metabolic acidosis, there is a predictable decrease in the blood [CO2
], as follows:

A mixed acid-base disturbance is present if the respiratory compensation is
not appropriate. If the PCO 2 is greater than predicted, the patient has a concurrent
respiratory acidosis. A lower PCO 2 than predicted indicates a concurrent
respiratory alkalosis or, less frequently, an isolated respiratory alkalosis. Because
the appropriate respiratory compensation for a metabolic acidosis never
normalizes the patient's pH, the presence of a normal pH and a low [HCO3 − ]
occurs only if some degree of respiratory alkalosis is present. In this situation,
distinguishing an isolated chronic respiratory alkalosis from a mixed metabolic
acidosis and acute respiratory alkalosis may be possible only clinically. In
contrast, the combination of a low serum pH and a low [HCO3 − ] occurs only if a
metabolic acidosis is present.

Etiology and Pathophysiology

There are many causes of a metabolic acidosis (Table 68.13 ), resulting from 3
basic mechanisms:
Table 68.13
Causes of Metabolic Acidosis
Normal Anion Gap

Diarrhea
Renal tubular acidosis (RTA)
Distal (type I) RTA (OMIM 179800/602722/267300)*
Proximal (type II) RTA (OMIM 604278) †
Mixed (type III) RTA (OMIM 259730)
Hyperkalemic (type IV) RTA (OMIM
201910/264350/177735/145260) ‡
Urinary tract diversions
Posthypocapnia
Ammonium chloride intake

Increased Anion Gap

Lactic Acidosis

Tissue hypoxia
Shock
Hypoxemia
Severe anemia
Liver failure
Malignancy
Intestinal bacterial overgrowth
Inborn errors of metabolism
Medications
Nucleoside reverse transcriptase inhibitors
Metformin
Propofol
Linezolid

Ketoacidosis

Diabetic ketoacidosis
Starvation ketoacidosis
Alcoholic ketoacidosis
 Kidney Failure
Poisoning

Ethylene glycol
Methanol
Salicylate
Toluene
Paraldehyde

* Along with these genetic disorders, distal RTA may be secondary to renal

disease or medications.
† Most cases of proximal RTA are not caused by this primary genetic disorder.

Proximal RTA is usually part of Fanconi syndrome, which has multiple

etiologies.
‡ Hyperkalemic RTA can be secondary to a genetic disorder (some of the more

common are listed) or other etiologies.

OMIM, database number from the Online Mendelian Inheritance in Man

(http://www.ncbi.nlm.nih.gov/omim ).

1. Loss of bicarbonate from the body

2. Impaired ability to excrete acid by the kidney
3. Addition of acid to the body (exogenous or endogenous)

Diarrhea, the most common cause of metabolic acidosis in children, causes a

loss of bicarbonate from the body. The amount of bicarbonate lost in the stool
depends on the volume of diarrhea and [HCO3 − ] of the stool, which tends to
increase with more severe diarrhea. The kidneys attempt to balance the losses by
increasing acid secretion, but metabolic acidosis occurs when this compensation
is inadequate. Diarrhea often causes volume depletion as a result of losses of
sodium and water, potentially exacerbating the acidosis by causing shock and a
lactic acidosis. In addition, diarrheal losses of potassium lead to hypokalemia.
Moreover, the volume depletion causes increased production of aldosterone.
This increase stimulates renal retention of sodium, helping to maintain
although a respiratory acidosis also leads to a compensatory elevation of the
serum [HCO3 − ]. With a simple metabolic alkalosis, however, the pH is elevated;
alkalemia is present. Patients with a respiratory acidosis are acidemic. By
decreasing ventilation, a metabolic alkalosis causes appropriate respiratory
compensation. PCO 2 increases by 7 mm Hg for each 10 mEq/L increase in the
serum [HCO3 − ]. Appropriate respiratory compensation never exceeds a PCO 2 of
55-60 mm Hg. The patient has a concurrent respiratory alkalosis if the PCO 2 is
lower than the expected compensation. A greater-than-expected PCO 2 occurs
with a concurrent respiratory acidosis.

Etiology and Pathophysiology

The kidneys normally respond promptly to a metabolic alkalosis by increasing
base excretion. Two processes are therefore usually present to produce a
metabolic alkalosis:(1) the generation of the metabolic alkalosis, which requires
the addition of base to the body, and (2) the maintenance of the metabolic
alkalosis, which requires impairment in the kidney's ability to excrete base.
The etiologies of a metabolic alkalosis are divided into 2 categories on the
basis of urinary chloride level (Table 68.14 ). The alkalosis in patients with a low
urinary [Cl − ] is maintained by volume depletion ; thus volume repletion is
necessary for correction of the alkalosis. The volume depletion in these patients
is caused by losses of Na+ and K+ , but the loss of Cl− is usually greater than the
losses of Na+ and K+ combined. Because Cl− losses are the dominant cause of
the volume depletion, these patients require Cl− to correct the volume depletion
and metabolic alkalosis; they are said to have Cl − -responsive metabolic
alkalosis. In contrast, the alkalosis in a patient with an elevated urinary [Cl− ]
does not respond to volume repletion and so is termed Cl − -resistant metabolic
alkalosis.
Table 68.14
Causes of Metabolic Alkalosis
Chloride-Responsive (Urinary Chloride <15 mEq/L)

Gastric losses
Emesis
 Nasogastric suction
Diuretics (loop or thiazide)
Chloride-losing diarrhea (OMIM 214700)
Low chloride formula
Cystic fibrosis (OMIM 219700)
Posthypercapnia

Chloride-Resistant (Urinary Chloride >20 mEq/L)

High Blood Pressure

Adrenal adenoma or hyperplasia

Glucocorticoid-remediable aldosteronism (OMIM 103900)
Renovascular disease
Renin-secreting tumor
17α-Hydroxylase deficiency (OMIM 202110)
11β-Hydroxylase deficiency (OMIM 202010)
Cushing syndrome
11β-Hydroxysteroid dehydrogenase deficiency (OMIM 218030)
Licorice ingestion
Liddle syndrome (OMIM 177200)

Normal Blood Pressure

Gitelman syndrome (OMIM 263800)

Bartter syndrome (OMIM
241200/607364/602522/601678/300971/601198/613090)
Autosomal dominant hypoparathyroidism (OMIM 146200)
EAST syndrome (OMIM 612780)
Base administration

EAST, Epilepsy, ataxia, sensorineural hearing loss, and tubulopathy; OMIM,

database number from the Online Mendelian Inheritance in Man
(http://www.ncbi.nlm.nih.gov/omim ).

Emesis or nasogastric suction results in loss of gastric fluid , which has a

disturbance, a patient can have a respiratory acidosis and a normal or even low
PCO 2 . This condition may occur in a patient with a metabolic acidosis. A
respiratory acidosis is present if the patient does not have appropriate respiratory
compensation (the PCO 2 is higher than expected from the severity of the
metabolic acidosis).

Etiology and Pathophysiology

The causes of a respiratory acidosis are either pulmonary or nonpulmonary
(Table 68.15 ). CNS disorders can decrease the activity of the central respiratory
center, reducing ventilatory drive. A variety of medications and illicit drugs
suppress the respiratory center. The signals from the respiratory center need to
be transmitted to the respiratory muscles via the nervous system. Respiratory
muscle failure can be secondary to disruption of the signal from the CNS in the
spinal cord, the phrenic nerve, or the neuromuscular junction. Disorders directly
affecting the muscles of respiration can prevent adequate ventilation, causing a
respiratory acidosis.
Table 68.15
Causes of Respiratory Acidosis
Central Nervous System Depression

Encephalitis
Head trauma
Brain tumor
Central sleep apnea
Primary pulmonary hypoventilation (Ondine curse)
Stroke
Hypoxic brain damage
Obesity-hypoventilation (pickwickian) syndrome
Increased intracranial pressure
Medications
Narcotics
Barbiturates
Anesthesia
Benzodiazepines
 Propofol
Alcohols

Disorders of Spinal Cord, Peripheral Nerves, or Neuromuscular

Junction

Diaphragmatic paralysis
Guillain-Barré syndrome
Poliomyelitis
Acute flaccid myelitis
Spinal muscular atrophies
Tick paralysis
Botulism
Myasthenia
Multiple sclerosis
Spinal cord injury
Medications
Vecuronium
Aminoglycosides
Organophosphates (pesticides)

Respiratory Muscle Weakness

Muscular dystrophy
Hypothyroidism
Malnutrition
Hypokalemia
Hypophosphatemia
Medications
Succinylcholine
Corticosteroids

Pulmonary Disease

Pneumonia
 Pneumothorax
Asthma
Bronchiolitis
Pulmonary edema
Pulmonary hemorrhage
Acute respiratory distress syndrome
Neonatal respiratory distress syndrome
Cystic fibrosis
Bronchopulmonary dysplasia
Hypoplastic lungs
Meconium aspiration
Pulmonary thromboembolus
Interstitial fibrosis

Upper Airway Disease

Aspiration
Laryngospasm
Angioedema
Obstructive sleep apnea
Tonsillar hypertrophy
Vocal cord paralysis
Extrinsic tumor
Extrinsic or intrinsic hemangioma

Miscellaneous

Flail chest
Cardiac arrest
Kyphoscoliosis
Decreased diaphragmatic movement due to ascites or peritoneal dialysis

Mild or moderate lung disease often causes a respiratory alkalosis as a result

of hyperventilation secondary to hypoxia or stimulation of lung
mechanoreceptors or chemoreceptors. Only more severe lung disease causes a
respiratory acidosis. Upper airway diseases, by impairing air entry into the lungs,
cyanotic heart disease, causes a much less severe respiratory alkalosis than an
equivalent degree of acute hypoxia. The many causes of hypoxemia or tissue
hypoxia include primary lung disease, severe anemia, and carbon monoxide
(CO) poisoning.
Table 68.16
Causes of Respiratory Alkalosis
Hypoxemia or Tissue Hypoxia

Pneumonia
Pulmonary edema
Cyanotic heart disease
Congestive heart failure
Asthma
Severe anemia
High altitude
Laryngospasm
Aspiration
Carbon monoxide poisoning
Pulmonary embolism
Interstitial lung disease
Hypotension

Lung Receptor Stimulation

Pneumonia
Pulmonary edema
Asthma
Pulmonary embolism
Hemothorax
Pneumothorax
Respiratory distress syndrome (adult or infant)

Central Stimulation
 Central nervous system disease
Subarachnoid hemorrhage
Encephalitis or meningitis
Trauma
Brain tumor
Stroke
Fever
Pain
Anxiety (panic attack)
Psychogenic hyperventilation or anxiety
Liver failure
Sepsis
Pregnancy
Mechanical ventilation
Hyperammonemia
Extracorporeal membrane oxygenation or hemodialysis
Medications
Salicylate intoxication
Theophylline
Progesterone
Exogenous catecholamines
Caffeine

The lungs contain chemoreceptors and mechanoreceptors that respond to

irritants and stretching and send signals to the respiratory center to increase
ventilation. Aspiration or pneumonia may stimulate the chemoreceptors, whereas
pulmonary edema may stimulate the mechanoreceptors. Most of the diseases that
activate these receptors may also cause hypoxemia and can therefore potentially
lead to hyperventilation by 2 mechanisms. Patients with primary lung disease
may initially have a respiratory alkalosis, but worsening of the disease,
combined with respiratory muscle fatigue, often causes respiratory failure and
the development of a respiratory acidosis.
Hyperventilation in the absence of lung disease occurs with direct
stimulation of the central respiratory center. This occurs with CNS diseases such
as meningitis, hemorrhage, and trauma. Central hyperventilation caused by
lesions, such as infarcts or tumors near the central respiratory center in the
midbrain, increases the rate and depth of the respiratory effort. This respiratory
 Maintenance fluids are most often necessary in preoperative and postoperative
surgical patients; many nonsurgical patients also require maintenance fluids. It is
important to recognize when it is necessary to begin maintenance fluids. A
normal teenager who is given nothing by mouth (NPO) overnight for a morning
procedure does not require maintenance fluids because a healthy adolescent can
easily tolerate 12 or 18 hr without oral intake. In contrast, a 6 mo old child
waiting for surgery should begin receiving IV fluids within 8 hr of the last
feeding. Infants become dehydrated more quickly than older patients. A child
with obligatory high urine output from nephrogenic diabetes insipidus should
begin receiving IV fluids soon after being classified as NPO.
Maintenance fluids are composed of a solution of water, glucose, sodium (Na+
), and potassium (K+ ). This solution has the advantages of simplicity, long shelf
life, low cost, and compatibility with peripheral IV administration. Such a
solution accomplishes the major objectives of maintenance fluids (Table 69.1 ).
Patients lose water, Na+ , and K+ in their urine and stool; water is also lost from
the skin and lungs. Maintenance fluids replace these losses, thereby avoiding the
development of dehydration and Na+ or K+ deficiency.
Table 69.1
Goals of Maintenance Fluids
• Prevent dehydration
• Prevent electrolyte disorders
• Prevent ketoacidosis
• Prevent protein degradation

The glucose in maintenance fluids provides approximately 20% of the normal

caloric needs of the patient, prevents the development of starvation ketoacidosis,
and diminishes the protein degradation that would occur if the patient received
no calories. Glucose also provides added osmoles, thus avoiding the
administration of hypotonic fluids that may cause hemolysis.
Maintenance fluids do not provide adequate calories, protein, fat, minerals, or
vitamins. This fact is typically not problematic for a patient receiving IV fluids
for a few days. A patient receiving maintenance IV fluids is receiving inadequate
calories and will lose 0.5–1% of weight each day. It is imperative that patients
not remain on maintenance therapy indefinitely; TPN should be used for
Table 69.2

Body Weight Method for Calculating Daily Maintenance Fluid Volume

BODY WEIGHT FLUID PER DAY
0-10 kg 100 mL/kg
11-20 kg 1,000 mL + 50 mL/kg for each kg >10 kg
>20 kg 1,500 mL + 20 mL/kg for each kg >20 kg*
* The maximum total fluid per day is normally 2,400 mL.

Table 69.3
Hourly Maintenance Water Rate

For body weight 0-10 kg: 4 mL/kg/hr

For body weight 10-20 kg: 40 mL/hr + 2 mL/kg/hr × (wt – 10 kg)
For body weight >20 kg: 60 mL/hr + 1 mL/kg/hr × (wt – 20 kg)*

* The maximum fluid rate is normally 100 mL/hr.

Intravenous Solutions
The components of available solutions are shown in Table 69.4 . These solutions
are available with 5% dextrose (D5), 10% dextrose (D10), or without dextrose.
Except for Ringer lactate (lactated Ringer, LR), they are also available with
added potassium (10 or 20 mEq/L). A balanced IV fluid contains a base (lactate
or acetate), a more physiologic chloride concentration than NS, and additional
physiologic concentrations of electrolytes such as potassium, calcium, and
magnesium. Examples include LR and PlasmaLyte, and there is evidence
suggesting benefit versus NS in certain clinical situations. A hospital pharmacy
can also prepare custom-made solutions with different concentrations of sodium
or potassium. In addition, other electrolytes, such as calcium, magnesium,
phosphate, acetate, and bicarbonate, can be added to IV solutions. Custom-made
solutions take time to prepare and are much more expensive than commercial
solutions. The use of custom-made solutions is necessary only for patients who
have underlying disorders that cause significant electrolyte imbalances. The use
of commercial solutions saves time and expense.
Table 69.4
Composition of Intravenous Solutions*

FLUID [Na+ ] [Cl− ] [K+ ] [Ca2+ ] [LACTATE− ]

Normal saline (0.9% NaCl) 154 154 — — —
Half-normal saline (0.45% NaCl) 77 77 — — —
0.2 normal saline (0.2% NaCl) 34 34 — — —
Ringer lactate 130 109 4 3 28
* Electrolyte concentrations in mEq/L.

A normal plasma osmolality is 285-295 mOsm/kg. Infusing an IV solution

peripherally with a much lower osmolality can cause water to move into red
blood cells, leading to hemolysis. Thus, IV fluids are generally designed to have
an osmolality that is either close to 285 or greater (fluids with moderately higher
osmolality do not cause problems). Thus, 0.2NS (osmolality = 68) should not be
administered peripherally, but D5 0.2NS (osmolality = 346) or D5 NS + 20
mEq/L potassium chloride (KCl) with an osmolality of 472 can be administered.
Controversy surrounds the appropriate sodium content of maintenance fluids,
considering the observation that hypotonic fluids may cause hyponatremia,
which may have serious sequelae. Hypotonic fluids seem more physiologic
given the low Na+ content of breast milk and formula. However, hospitalized
children often have impaired water excretion because of volume depletion or
nonosmotic stimuli for antidiuretic hormone (ADH) production, such as
respiratory disease, central nervous system (CNS) disease, stress, pain, nausea,
and medications (e.g., narcotics). Hypotonic fluids increase the risk of
hyponatremia; hence, isotonic fluids with 5% dextrose are recommended as
standard maintenance fluid except in neonates .

Glucose
Maintenance fluids usually contain D5, which provides 17 calories/100 mL and
nearly 20% of the daily caloric needs. This level is enough to prevent ketone
production and helps minimize protein degradation, but the child will lose
weight on this regimen. The weight loss is the principal reason why a patient
needs to be started on TPN after a few days of maintenance fluids if enteral
feedings are still not possible. Maintenance fluids are also lacking in such crucial
nutrients as protein, fat, vitamins, and minerals.
magnitude of normal water losses. Table 69.5 lists the 3 sources of normal water
loss.
Table 69.5
Sources of Water Loss
• Urine: 60%
• Insensible losses: ≈35% (skin and lungs)
• Stool: 5%

Urine is the most important contributor to normal water loss. Insensible losses
represent approximately one third of total maintenance water (40% in infants;
25% in adolescents and adults). Insensible losses are composed of evaporative
losses from the skin and lungs that cannot be quantitated. The evaporative losses
from the skin do not include sweat, which would be considered an additional
(sensible) source of water loss. Stool normally represents a minor source of
water loss.
Maintenance water and electrolyte needs may be increased or decreased,
depending on the clinical situation. This may be obvious, as in the infant with
profuse diarrhea, or subtle, as in the patient who has decreased insensible losses
while receiving mechanical ventilation. It is helpful to consider the sources of
normal water and electrolyte losses and to determine whether any of these
sources is being modified in a specific patient. It is then necessary to adjust
maintenance water and electrolyte calculations.
Table 69.6 lists a variety of clinical situations that modify normal water and
electrolyte losses. The skin can be a source of very significant water loss,
particularly in neonates, especially premature infants, who are under radiant
warmers or are receiving phototherapy. Very-low-birthweight infants can have
insensible losses of 100-200 mL/kg/24 hr. Burns can result in massive losses of
water and electrolytes, and there are specific guidelines for fluid management in
children with burns (see Chapter 92 ). Sweat losses of water and electrolytes,
especially in a warm climate, can also be significant. Children with cystic
fibrosis and some children with pseudohypoaldosteronism have increased
sodium losses from the skin.

Table 69.6
Adjustments in Maintenance Water

CAUSES OF INCREASED WATER CAUSES OF DECREASED WATER

SOURCE
NEEDS NEEDS
Skin Radiant warmer Incubator (premature infant)
Phototherapy
Fever
Sweat
Burns
Lungs Tachypnea Humidified ventilator
Tracheostomy
Gastrointestinal Diarrhea —
tract Emesis
Nasogastric suction
Renal Polyuria Oliguria/anuria
Miscellaneous Surgical drain
Third spacing

Fever increases evaporative losses from the skin. These losses are somewhat
predictable, leading to a 10–15% increase in maintenance water needs for each
1°C (1.8°F) increase in temperature above 38°C (100.4°F). These guidelines are
for a patient with a persistent fever; a 1 hr fever spike does not cause an
appreciable increase in water needs.
Tachypnea or a tracheostomy increases evaporative losses from the lungs. A
humidified ventilator causes a decrease in insensible losses from the lungs and
can even lead to water absorption via the lungs; a ventilated patient has a
decrease in maintenance water requirements. It may be difficult to quantify the
changes that take place in the individual patient in these situations.

Replacement Fluids
The gastrointestinal (GI) tract is potentially a source of considerable water loss.
GI water losses are accompanied by electrolytes and thus may cause
disturbances in intravascular volume and electrolyte concentrations. GI losses
are often associated with loss of potassium, leading to hypokalemia. Because of
the high bicarbonate concentration in stool, children with diarrhea usually have a
metabolic acidosis , which may be accentuated if volume depletion causes
hypoperfusion and a concurrent lactic acidosis. Emesis or losses from an NG
tube can cause a metabolic alkalosis (see Chapter 68 ).
In the absence of vomiting, diarrhea, or NG drainage, GI losses of water and
electrolytes are usually quite small. All GI losses are considered excessive, and
the increase in the water requirement is equal to the volume of fluid losses.
Because GI water and electrolyte losses can be precisely measured, an
appropriate replacement solution can be used.
It is impossible to predict the losses for the next 24 hr; it is better to replace
excessive GI losses as they occur. The child should receive an appropriate
maintenance fluid that does not consider the GI losses. The losses should then be
replaced after they occur, with use of a solution with a similar electrolyte
concentration as the GI fluid. The losses are usually replaced every 1-6 hr,
depending on the rate of loss, with very rapid losses being replaced more
frequently.
Diarrhea is a common cause of fluid loss in children and can result in
dehydration and electrolyte disorders. In the unusual patient with significant
diarrhea and a limited ability to take oral fluid, it is important to have a plan for
replacing excessive stool losses. The volume of stool should be measured, and
an equal volume of replacement solution should be given. Data are available on
the average electrolyte composition of diarrhea in children (Table 69.4 ). With
this information an appropriate replacement solution can be designed. The
solution shown in Table 69.7 replaces stool losses of Na+ , K+ , Cl− , and
bicarbonate. Each 1 mL of stool should be replaced by 1 mL of this solution. The
average electrolyte composition of diarrhea is just an average, and there may be
considerable variation. It is therefore advisable to consider measuring the
electrolyte composition of a patient's diarrhea if the amount is especially
excessive or if the patient's serum electrolyte levels are problematic.
Table 69.7
Replacement Fluid for Diarrhea
Average Composition of Diarrhea

Sodium: 55 mEq/L
Potassium: 25 mEq/L
Bicarbonate: 15 mEq/L

Approach to Replacement of Ongoing Losses

Solution: D5 NS + 30 mEq/L sodium bicarbonate + 20 mEq/L KCl

Replace stool mL/mL every 1-6 hr
 D5, 5% dextrose; NS, normal saline.

Loss of gastric fluid , through emesis or NG suction, is also likely to cause

dehydration, in that most patients with either condition have impaired oral intake
of fluids. Electrolyte disturbances, particularly hypokalemia and metabolic
alkalosis, are also common. These complications can be avoided by judicious
use of a replacement solution. The composition of gastric fluid shown in Table
69.8 is the basis for designing a replacement solution.
Table 69.8
Replacement Fluid for Emesis or Nasogastric
Losses
Average Composition of Gastric Fluid

Sodium: 60 mEq/L
Potassium: 10 mEq/L
Chloride: 90 mEq/L

Approach to Replacement of Ongoing Losses

Solution: normal saline + 10 mEq/L KCl

Replace output mL/mL every 1-6 hr

Patients with gastric losses frequently have hypokalemia, although the K+

concentration of gastric fluid is relatively low. The associated urinary K+ loss is
an important cause of hypokalemia in this situation (see Chapter 68 ). These
patients may need additional potassium either in their maintenance fluids or in
their replacement fluids to compensate for prior or ongoing urinary losses.
Restoration of the patient's intravascular volume, by decreasing aldosterone
synthesis, lessens the urinary K+ losses.
Urine output is normally the largest cause of water loss. Diseases such as
renal failure and syndrome of inappropriate ADH secretion can lead to a
decrease in urine volume. The patient with oliguria or anuria has a decreased
need for water and electrolytes; continuation of maintenance fluids produces
fluid overload. In contrast, postobstructive diuresis, the polyuric phase of acute
tubular necrosis, diabetes mellitus, and diabetes insipidus increase urine
production. To prevent dehydration, the patient must receive more than standard
maintenance fluids when urine output is excessive. The electrolyte losses in
patients with polyuria are variable. In diabetes insipidus the urine electrolyte
concentration is usually low, whereas children with diseases such as juvenile
nephronophthisis and obstructive uropathy usually have increased losses of both
water and sodium.
The approach to decreased or increased urine output is similar (Table 69.9 ).
The patient receives fluids at a rate to replace insensible losses. This is
accomplished by a rate of fluid administration that is 25–40% of the normal
maintenance rate, depending on the patient's age. Replacing insensible losses in
the anuric child will theoretically maintain an even fluid balance, with the caveat
that 25–40% of the normal maintenance rate is only an estimate of insensible
losses. In the individual patient, this rate is adjusted on the basis of monitoring of
the patient's weight and volume status. Most children with renal insufficiency
receive little or no potassium because the kidney is the principal site of K+
excretion.
Table 69.9
Adjusting Fluid Therapy for Altered Renal
Output
Oliguria/Anuria

Replacement of insensible fluid losses (25–40% of maintenance) with D5

NS
Replace urine output mL/mL with D5 NS ± KCl

Polyuria

Replacement of insensible fluid losses (25–40% of maintenance) with D5

NS ± KCl
Measure urine electrolytes
Replace urine output mL/mL with solution based on measured urine
electrolytes
 D5, 5% dextrose; NS, normal saline.

For the oliguric child, it is important to add a urine replacement solution to

prevent dehydration. This issue is especially important in the patient with acute
renal failure, in whom output may increase, potentially leading to volume
depletion and worsening of renal failure if the patient remains on only insensible
fluids. A replacement solution of D5 NS is usually appropriate initially,
although its composition may have to be adjusted if urine output increases
significantly.
Most children with polyuria (except in diabetes mellitus; see Chapter 607 )
should be started on replacement of insensible fluid plus urine losses. This
approach avoids the need to attempt to calculate the volume of urine output that
is “normal” so that the patient can be given replacement fluid for the excess. In
these patients, urine output is, by definition, excessive, and it is often helpful to
measure Na+ and K+ concentrations of the urine to help in formulating the urine
replacement solution.
Surgical drains and chest tubes can produce measurable fluid output. These
fluid losses should be replaced when they are significant. They can be measured
and replaced with an appropriate solution. Third space losses , which manifest
as edema and ascites, are caused by a shift of fluid from the intravascular space
into the interstitial space. Although these losses cannot be quantitated easily,
third space losses can be large and may lead to intravascular volume depletion,
despite the patient's weight gain. Replacement of third space fluid is empirical
but should be anticipated in patients who are at risk, such as children who have
burns or abdominal surgery. Third space losses and chest tube output are
isotonic, so they usually require replacement with an isotonic fluid, such as NS
or LR. Adjustments in the amount of replacement fluid for third space losses are
based on continuing assessment of the patient's intravascular volume status.
Protein losses from chest tube drainage can be significant, occasionally
necessitating that 5% albumin be used as a replacement solution.

Bibliography
Foster BA, Tom D, Hill V. Hypotonic versus isotonic fluids in
hospitalized children: a systematic review and meta-analysis.
J Pediatr . 2014;165:163–169 [e2].
CHAPTER 70

Deficit Therapy
Larry A. Greenbaum

Dehydration, most often caused by gastroenteritis, is a common problem in

children. Most cases can be managed with oral rehydration (see Chapter 366 ).
Even children with mild to moderate hyponatremic or hypernatremic
dehydration can be managed with oral rehydration.

Clinical Manifestations
The 1st step in caring for the child with dehydration is to assess the degree of
dehydration (Table 70.1 ), which dictates both the urgency of the situation and
the volume of fluid needed for rehydration. The infant with mild dehydration (3–
5% of body weight dehydrated) has few clinical signs or symptoms. The infant
may be thirsty; the alert parent may notice a decline in urine output. The history
is most helpful. The infant with moderate dehydration has clear physical signs
and symptoms. Intravascular space depletion is evident from an increased heart
rate and reduced urine output. This patient needs fairly prompt intervention. The
infant with severe dehydration is gravely ill. The decrease in blood pressure
indicates that vital organs may be receiving inadequate perfusion. Immediate and
aggressive intervention is necessary. If possible, the child with severe
dehydration should initially receive intravenous (IV) therapy. For older children
and adults, mild, moderate, or severe dehydration represents a lower percentage
of body weight lost. This difference occurs because water accounts for a higher
percentage of body weight in infants (see Chapter 68 ).
Table 70.1
Clinical Evaluation of Dehydration
 Mild dehydration (<5% in an infant; <3% in an older child or adult):
Normal or increased pulse; decreased urine output; thirsty; normal
physical findings
Moderate dehydration (5–10% in an infant; 3–6% in an older child or
adult): Tachycardia; little or no urine output; irritable/lethargic; sunken
eyes and fontanel; decreased tears; dry mucous membranes; mild delay in
elasticity (skin turgor); delayed capillary refill (>1.5 sec); cool and pale
Severe dehydration (>10% in an infant; >6% in an older child or
adult): Peripheral pulses either rapid and weak or absent; decreased
blood pressure; no urine output; very sunken eyes and fontanel; no tears;
parched mucous membranes; delayed elasticity (poor skin turgor); very
delayed capillary refill (>3 sec); cold and mottled; limp, depressed
consciousness

Clinical assessment of dehydration is only an estimate; thus the patient must

be continually reevaluated during therapy. The degree of dehydration is
underestimated in hypernatremic dehydration because the movement of water
from the intracellular space (ICS) to the extracellular space (ECS) helps preserve
the intravascular volume.
The history usually suggests the etiology of the dehydration and may predict
whether the patient will have a normal sodium concentration (isotonic
dehydration), hyponatremic dehydration, or hypernatremic dehydration. The
neonate with dehydration caused by poor intake of breast milk often has
hypernatremic dehydration. Hypernatremic dehydration is likely in any child
with losses of hypotonic fluid and poor water intake, as may occur with diarrhea,
and poor oral intake because of anorexia or emesis. Hyponatremic dehydration
occurs in the child with diarrhea who is taking in large quantities of low-salt
fluid, such as water or formula.
Some children with dehydration are appropriately thirsty, but in others the
lack of intake is part of the pathophysiology of the dehydration. Even though
decreased urine output is present in most children with dehydration, good urine
output may be deceptively present if a child has an underlying renal defect, such
as diabetes insipidus or a salt-wasting nephropathy, or in infants with
hypernatremic dehydration.
Physical examination findings are usually proportional to the degree of
dehydration. Parents may be helpful in assessment of the child for the presence
of sunken eyes, because this finding may be subtle. Pinching and gently twisting
PlasmaLyte may be preferable to NS in shock since it is a balanced solution (see
Chapter 69 ); NS may cause a hyperchloremic metabolic acidosis.
Colloids, such as blood, 5% albumin, and plasma, are rarely needed for fluid
boluses. A crystalloid solution (NS or LR) is satisfactory, with both lower risk of
infection and lower cost. Blood is obviously indicated in the child with
significant anemia or acute blood loss. Plasma is useful for children with a
coagulopathy. The child with hypoalbuminemia may benefit from 5% albumin,
although there is evidence that albumin infusions increase mortality in adults.
The volume and the infusion rate for colloids are generally modified compared
with crystalloids (see Chapter 500 ).
The initial resuscitation and rehydration phase is complete when the child has
an adequate intravascular volume. Typically, the child shows clinical
improvement, including a lower heart rate, normalization of blood pressure,
improved perfusion, better urine output, and a more alert affect.
With adequate intravascular volume, it is appropriate to plan the fluid therapy
for the next 24 hr. A general approach is outlined in Table 70.2 , with the caveat
that there are many different approaches to correcting dehydration. A balanced
solution can be substituted for NS. In isonatremic or hyponatremic dehydration,
the entire fluid deficit is corrected over 24 hr; a slower approach is used for
hypernatremic dehydration (discussed later). The volume of isotonic fluids that
the patient has received is subtracted from this total. The remaining fluid volume
is then administered over 24 hr. The potassium concentration may need to be
decreased or, less frequently, increased, depending on the clinical situation.
Potassium is not usually included in the IV fluids until the patient voids and
normal renal function is documented by measurement of BUN and creatinine.
Children with significant ongoing losses need to receive an appropriate
replacement solution (see Chapter 69 ).
Table 70.2
Fluid Management of Dehydration

Restore intravascular volume:

Isotonic fluid (NS or LR): 20 mL/kg over 20 min
Repeat as needed
Calculate 24 hr fluid needs: maintenance + deficit volume
Subtract isotonic fluid already administered from 24 hr fluid needs
Administer remaining volume over 24 hr using 5% dextrose NS + 20
 mEq/L KCl
Replace ongoing losses as they occur

LR, Ringer lactate; NS, normal saline.

Monitoring and Adjusting Therapy

The formulation of a plan for correcting a child's dehydration is only the
beginning of management. All calculations in fluid therapy are only
approximations. This statement is especially true for the assessment of
percentage dehydration. It is equally important to monitor the patient during
treatment and to modify therapy on the basis of the clinical situation. Table 70.3
lists the cornerstones of patient monitoring. The patient's vital signs are useful
indicators of intravascular volume status. The child with decreased blood
pressure and an increased heart rate will probably benefit from a fluid bolus.
Table 70.3
Monitoring Therapy

Vital signs:
Pulse
Blood pressure
Intake and output:
Fluid balance
Urine output
Physical examination:
Weight
Clinical signs of depletion or overload
Electrolytes

The patient's intake and output are critically important in the dehydrated child.
The child who, after 8 hr of therapy, has more output than input because of
continuing diarrhea needs to be started on a replacement solution. See the
guidelines in Chapter 69 for selecting an appropriate replacement solution. Urine
output is useful for evaluating the success of therapy. Good urine output
indicates that rehydration has been successful.
often brought for medical attention with more profound dehydration.
Children with hypernatremic dehydration are often lethargic, and they may be
irritable when touched. Hypernatremia may cause fever, hypertonicity, and
hyperreflexia. More severe neurologic symptoms may develop if cerebral
bleeding or thrombosis occurs.
Overly rapid treatment of hypernatremic dehydration may cause significant
morbidity and mortality. Idiogenic osmoles are generated within the brain
during the development of hypernatremia; they increase the osmolality within
the cells of the brain, providing protection against brain cell shrinkage caused by
movement of water out of the cells and into the hypertonic ECF. Idiogenic
osmoles dissipate slowly during the correction of hypernatremia. With overly
rapid lowering of the extracellular osmolality during the correction of
hypernatremia, an osmotic gradient may be created that causes water movement
from the ECS into the cells of the brain, producing cerebral edema. Symptoms of
the resultant cerebral edema can range from seizures to brain herniation and
death.
To minimize the risk of cerebral edema during the correction of
hypernatremic dehydration, the serum sodium concentration should not decrease
by >10 mEq/L every 24 hr. The deficits in severe hypernatremic dehydration
may need to be corrected over 2-4 days (Table 70.4 ).
Table 70.4
Treatment of Hypernatremic Dehydration
Restore intravascular volume:
Normal saline: 20 mL/kg over 20 min (repeat until intravascular
volume restored)
Determine time for correction on basis of initial sodium
concentration:
• [Na] 145-157 mEq/L: 24 hr
• [Na] 158-170 mEq/L: 48 hr
• [Na] 171-183 mEq/L: 72 hr
• [Na] 184-196 mEq/L: 84 hr
Administer fluid at constant rate over time for correction:
Typical fluid: 5% dextrose + half-normal saline (with 20 mEq/L
KCl unless contraindicated)
Typical rate: 1.25-1.5 times maintenance
 Follow serum sodium concentration
Adjust fluid on basis of clinical status and serum sodium concentration:
Signs of volume depletion: administer normal saline (20 mL/kg)
Sodium decreases too rapidly; either:
• Increase sodium concentration of IV fluid
• Decrease rate of IV fluid
Sodium decreases too slowly; either:
• Decrease sodium concentration of IV fluid
• Increase rate of IV fluid
Replace ongoing losses as they occur

The initial resuscitation of hypernatremic dehydration requires restoration of

the intravascular volume with NS. LR should not be used because it is more
hypotonic than NS and may cause too rapid a decrease in the serum [Na+ ],
especially if multiple fluid boluses are necessary.
To avoid cerebral edema during correction of hypernatremic dehydration, the
fluid deficit is corrected slowly. The rate of correction depends on the initial
sodium concentration (Table 70.4 ). There is no general agreement on the choice
or the rate of fluid administration for correcting hypernatremic dehydration;
these factors are not nearly as important as vigilant monitoring of the serum [Na+
] and adjustment of the therapy according to the result. The rate of decrease of
the serum [Na+ ] is roughly related to the “free water” delivery, although there is
considerable variation between patients. Free water is water without sodium. NS
contains no free water, half-normal saline ( NS) is 50% free water, and water
is 100% free water. Smaller patients, to achieve the same decrease in the sodium
concentration, tend to need higher amounts of free water delivery per kilogram
because of higher insensible fluid losses . Five percent dextrose (D5) with
NS is usually an appropriate starting solution for correction of a patient with
hypernatremic dehydration. Some patients, especially infants with ongoing high
insensible water losses, may rarely need to receive D5 0.2NS, which should be
used with great caution and constant monitoring. Others require D5 NS. A child
with dehydration as a result of pure free water loss, as usually occurs with
diabetes insipidus, usually needs a more hypotonic fluid than a child with
depletion of both sodium and water from diarrhea.
Adjustment in the sodium concentration of the IV fluid is the most common
approach to modify the rate of decrease in the serum concentration (see Table
testing of genetic variations that give rise to interindividual response to drugs.
Examples of pharmacogenetic traits include specific adverse drug reactions, such
as unusually prolonged respiratory muscle paralysis due to succinylcholine,
hemolysis associated with antimalarial therapy, and isoniazid-induced
neurotoxicity, all of which were found to be a consequence of inherited
variations in enzyme activity. The importance of pharmacogenetic differences
has become better understood and is exemplified by the half-life of several drugs
being more similar in monozygotic twins than in dizygotic twins. However, it is
important to note that in addition to pharmacogenetic differences, environmental
factors (diet, smoking status, concomitant drug or toxicant exposure),
physiologic variables (age, sex, disease, pregnancy), and patient adherence all
contribute to variations in drug metabolism and response. Likewise, ethnicity is
another potential genetic determinant of drug variability. Chinese patients who
are HLA-B*1502 positive have an increased risk of carbamazepine-induced
Stevens-Johnson syndrome; white patients who are HLA-B*5701 positive have
an increased risk of hypersensitivity to abacavir (Table 72.1 ).

Table 72.1
Examples of Effects of Gene Polymorphisms on Drug
Response

GENE ENZYME/TARGET DRUG CLINICAL RESPONSE

BCHE Butyrylcholinesterase Succinylcholine Prolonged paralysis
CYP2C9 Cytochrome P450 2C9 Warfarin Individuals having ≥1 reduced function alleles require
lower doses of warfarin for optimal anticoagulation,
especially initial anticoagulant control.
CYP2C19 Cytochrome P450 Clopidogrel Individuals having ≥1 loss-of-function alleles have
2C19 reduced capacity to form pharmacologically active
metabolite of clopidogrel and reduced antiplatelet
effect.
CYP2D6 Cytochrome P450 2D6 Codeine Poor metabolizers—individuals with 2 loss-of-
function alleles—do not metabolize codeine to
morphine and thus experience no analgesic effect.
Ultrarapid metabolizers—individuals with ≥3
functional alleles—may experience morphine
toxicity.
G6PD Glucose-6-phosphate Primaquine (others) Hemolysis
dehydrogenase
HLA- Human leukocyte Carbamazepine Carriers of HLA-A*3101 allele have increased risk of
A*3101 antigen A31 SJS and TEN from carbamazepine.
HLA- Human leukocyte Allopurinol Han Chinese carriers of HLA-B*1502 allele have
B*1502 antigen B15 increased risk of SJS and TEN from carbamazepine.
HLA- Human leukocyte Abacavir Carriers of HLA-B*5701 allele have increased risk of
B*5701 antigen B57 Flucloxacillin hypersensitivity reactions to abacavir- and
 flucloxacillin-induced liver injury.
HLA- Human leukocyte Allopurinol Carriers of HLA-B*5801 allele have increased risk of
B*5801 antigen B58 severe cutaneous adverse reactions to allopurinol,
including hypersensitivity reactions, SJS, and TEN.
NAT2 N -Acetyltransferase 2 Isoniazid, Individuals homozygous for “slow acetylation”
hydralazine polymorphisms are more susceptible to isoniazid
toxicity, or hydralazine-induced systemic lupus
erythematosus.
SLCO1B1 Organic anion– Simvastatin Carriers of the SLCO1B1*5 allele are at increased risk
transporting protein for musculoskeletal side effects from simvastatin.
(OATP) 1B1
TPMT Thiopurine S - Azathioprine Individuals homozygous for an inactivating mutation
methyltransferase 6- have severe toxicity if treated with standard doses of
Mercaptopurine azathioprine or 6-mercaptopurine; rapid metabolism
causes undertreatment.
UGT1A1 Uridine diphospho- Irinotecan UGT1A1*28 allele is associated with decreased
glucuronosyltransferase glucuronidation of SN-38, the active metabolite of
1A1 irinotecan, and increased risk of neutropenia.
VKORC1 Vitamin K Warfarin Individuals with a haplotype associated with reduced
oxidoreductase expression of VKORC1 protein (therapeutic target of
complex 1 warfarin) require lower doses of the drug for stable
anticoagulation.
SJS, Stevens-Johnson syndrome; TEN, toxic epidermal necrolysis.

Pharmacogenomics represents the marriage of pharmacology and genomics

and can be defined as the broader application of genome-wide technologies and
strategies to identify both disease processes that represent new targets for drug
development and factors predictive of efficacy and risk of adverse drug
reactions.
Pharmacokinetics describes what the body does to a drug. It is often studied
in conjunction with pharmacodynamics , which explores what a drug does to
the body. The pharmacokinetic properties of a drug are determined by the
genes that control the drug's disposition in the body (absorption, distribution,
metabolism, excretion). Drug-metabolizing enzymes and drug transporters play a
particularly important role in this process (Table 72.2 ), and the functional
consequences of genetic variations in many drug-metabolizing enzymes have
been described between individuals of both similar and different ethnic groups.
The most common clinical manifestation of pharmacogenetic variability in drug
biotransformation is an increased risk of concentration-dependent toxicity
caused by reduced clearance and consequent drug accumulation. However, an
equally important manifestation of this variability is lack of efficacy caused by
variations in metabolism of prodrugs that require biotransformation to be
converted into a pharmacologically active form of a medication. The
pharmacogenetics of drug receptors and other target proteins involved in signal
transduction or disease pathogenesis can also be expected to contribute
significantly to interindividual variability in drug disposition and response.

Table 72.2
Some Important Relationships Between Drugs and
Cytochrome P450 (CYP) Enzymes* and P-Glycoprotein
Transporter

ENZYME DRUG SUBSTRATES INHIBITORS INDUCERS

CYP1A2 Caffeine, clomipramine (Anafranil † ), clozapine Cimetidine (Tagamet Omeprazole
(Clozaril † ), theophylline † ) (Prilosec † )
Fluvoxamine (Luvox Tobacco
† )

Ciprofloxacin (Cipro
)
CYP2C9 Diclofenac (Voltaren † ), ibuprofen (Motrin † ), Fluconazole Rifampin (Rifadin †
piroxicam (Feldene † ), Losartan (Cozaar ), irbesartan (Diflucan ) )
(Avapro ), celecoxib (Celebrex ), tolbutamide (Orinase † Fluvastatin (Lescol )
Amiodarone
), warfarin (Coumadin † ), phenytoin (Dilantin )
(Cordarone )
Zafirlukast
(Accolate )
CYP2C19 Omeprazole, lansoprazole (Prevacid ), pantoprazole Cimetidine Rifampin
(Protonix ), (S)-mephenytoin, (S) -citalopram (Lexapro Fluvoxamine
); nelfinavir (Viracept ), diazepam (Valium † ),
voriconazole (Vfend )
CYP2D6 CNS-active agents: Atomoxetine (Strattera ), Fluoxetine
amitriptyline (Elavil † ), desipramine (Norpramin † ), (Prozac † )
imipramine (Tofranil † ), paroxetine (Paxil ), haloperidol Paroxetine
(Haldol ), risperidone (Risperdal ), thioridazine
† (Paxil )
(Mellaril † )
Antiarrhythmic agents: Mexiletine (Mexitil ), Amiodarone
propafenone (Rythmol ) (Cordarone † )
Quinidine
(Quinidex † )
β-Blockers: Propranolol (
Inderal † ), metoprolol Terbinafine
(Lopressor † ), timolol (Blocadren † )
Narcotics: Codeine, dextromethorphan, hydrocodone
(Vicodin † )
Others: Tamoxifen (Nolvadex ) Cimetidine
Ritonavir
CYP3A4 Calcium channel blockers: Diltiazem (Cardizem † ), Amiodarone Barbiturates
felodipine (Plendil ), nimodipine (Nimotop ), nifedipine Carbamazepine
(Adalat † ), nisoldipine (Sular ), nitrendipine, verapamil (Tegretol † )
(Calan † ) Phenytoin
(Dilantin † )
Immunosuppressive agents: Cyclosporine A Efavirenz (Sustiva )
(Sandimmune , Neoral † ), tacrolimus (Prograf )
 Corticosteroids: Budesonide (Pulmicort ), cortisol, Fluconazole Nevirapine
17β-estradiol, progesterone, testosterone Ketoconazole (Viramune )
(Nizoral † )
Itraconazole
(Sporanox )
Macrolide antibiotics: Clarithromycin (Biaxin ), Clarithromycin
erythromycin (Erythrocin † ), troleandomycin (TAO ) Erythromycin
Troleandomycin
Anticancer agents: Cyclophosphamide (Cytoxan † ), Imatinib Rifampin
gefitinib (Iressa ), ifosfamide (Ifex ), tamoxifen, Ritonavir ‡
vincristine (Oncovin † ), vinblastine (Velban † ),
Benzodiazepines: Alprazolam (Xanax † ), midazolam St. John's wort
(Versed † ), triazolam (Halcion † )
Opioids: Alfentanil (Alfenta † ), fentanyl (Sublimaze † ),
sufentanil (Sufenta † )
HMG-CoA reductase inhibitors: Lovastatin (Mevacor
) † , simvastatin (Zocor ), atorvastatin (Lipitor )
HIV protease inhibitors: Indinavir (Crixivan ), Ritonavir ‡
nelfinavir, ritonavir (Norvir ), saquinavir (Invirase, Indinavir
Fortovase ), amprenavir (Agenerase )
Others: Quinidine (Quinidex † ), sildenafil (Viagra ), Grapefruit juice
eletriptan (Relpax ), ziprasidone (Geodon ) Nefazodone
(Serzone )
P- Aldosterone, amprenavir, atorvastatin, cyclosporine, Amiodarone Amprenavir
glycoprotein dexamethasone (Decadron † ), digoxin (Lanoxin † ), Carvedilol (Coreg ) Clotrimazole
diltiazem, domperidone (Motilium ), doxorubicin (Mycelex † )
(Adriamycin † ), erythromycin, etoposide (VePesid ), Clarithromycin Phenothiazine
fexofenadine (Allegra ), hydrocortisone, indinavir, Cyclosporine Rifampin
ivermectin (Stromectol ), lovastatin, loperamide Erythromycin Ritonavir ‡
(Imodium † ), nelfinavir, ondansetron (Zofran ), Itraconazole St. John's wort
paclitaxel (Taxol ), quinidine, saquinavir, simvastatin, Ketoconazole
verapamil, vinblastine, vincristine Quinidine
Ritonavir ‡
Tamoxifen
Verapamil
* www.drug-interactions.com .

† Also available generically.

‡ Can be both an inhibitor and an inducer.

CNS, Central nervous system.

From Med Lett 2003;45:47.

Therapeutic drug monitoring (TDM) programs recognize that all patients

are unique and that the serum concentration-time data for an individual patient
theoretically can be used to optimize pharmacotherapy. TDM programs have
been the earliest application of personalized medicine; however, routine TDM
does not necessarily translate to improved patient outcome in all situations.
The UGT gene superfamily catalyzes the conjugation (with glucuronic acid) of
several drugs used clinically in pediatrics, including morphine, acetaminophen,
nonsteroidal antiinflammatory drugs, and benzodiazepines. The effect of
development on glucuronidation capacity has been well described and is
illustrated by hyperbilirubinemia, gray baby syndrome (cardiovascular collapse
associated with high doses of chloramphenicol in newborns), and the 3.5-fold
increase in morphine clearance observed in premature neonates at 24-39 wk
postconception age. As with the CYPs, there are multiple UGT isoforms, and the
acquisition of functional UGT activity appears to be isoform and substrate
specific.
UGT1A1 is the major UGT gene product responsible for bilirubin
glucuronidation, and >100 genetic alterations have been reported (Table 72.3 ),
most of which are rare and are more properly considered mutations rather than
gene polymorphisms. Inheritance of 2 defective alleles is associated with
reduced bilirubin-conjugating activity and gives rise to clinical conditions such
as Crigler-Najjar and Gilbert syndromes. More frequently occurring
polymorphisms involve a dinucleotide (TA) repeat in the atypical TATA box of
the UGT1A1 promoter. The wild-type UGT1A1*1 allele has 6 repeats (TA6 ), and
the TA5 (UGT1A1*33), TA7 (UGT1A1*28), and TA8 (UGT1A1*34) variants are
all associated with reduced activity. UGT1A1*28, the most frequent variant, is a
contributory factor to prolonged neonatal jaundice. This variant is also
associated with impaired glucuronidation and thus toxicity of the active
metabolite SN-38 of the chemotherapeutic agent irinotecan. Allelic variations in
UGT1A7 and UGT1A9 have also been associated with irinotecan toxicity in
adults with colorectal cancer.

Table 72.3
Internet Resources for Pharmacogenetics and
Pharmacogenomics*
INTRODUCTION TO PHARMACOGENOMICS
http://www.pharmgkb.org/
http://www.mayoclinic.org/healthy-lifestyle/consumer-health/in-depth/personalized-medicine/art-20044300
PHARMACOGENETICS: ALLELIC VARIANTS OF DRUG-METABOLIZING ENZYMES
CYP2C9 http://www.cypalleles.ki.se/cyp2c9.htm
CYP2C19 http://www.cypalleles.ki.se/cyp2c19.htm
CYP2D6 http://www.cypalleles.ki.se/cyp2d6.htm
CYP3A4 http://www.cypalleles.ki.se/cyp3a4.htm
CYP3A5 http://www.cypalleles.ki.se/cyp3a5.htm
 UGTs https://www.pharmacogenomics.pha.ulaval.ca/ugt-alleles-nomenclature/
NAT1 and NAT2 http://nat.mbg.duth.gr/
PHARMACOGENETICS: SUBSTRATES OF DRUG-METABOLIZING ENZYMES
http://medicine.iupui.edu/clinpharm/ddis/clinical-table
http://www.mayomedicallaboratories.com/it-mmfiles/Pharmacogenomic_Associations_Tables.pdf
PHARMACOGENETICS-BASED DOSING GUIDELINES
Dosing guidelines incorporating pharmacogenetic data developed by the Clinical Pharmacogenetics
Implementation Consortium are available on the CPIC web page https://cpicpgx.org/ , which is mirrored at
PharmGKB: https://www.pharmgkb.org/page/cpic ,
or through the National Guidelines Clearinghouse website, a publically accessible resource for evidence-based
clinical guidelines sponsored by the Agency for Healthcare Research and Quality (AHRQ), U.S. Department of
Health Services, at https://www.guideline.gov/search?q=CPIC .
CYP2D6, CYP2C19, and antidepressants:
https://cpicpgx.org/guidelines/guideline-for-tricyclic-antidepressants-and-cyp2d6-and-cyp2c19/
CYP2D6 and codeine:
https://cpicpgx.org/guidelines/guideline-for-codeine-and-cyp2d6/
CYP2D6, CYP2C19, and SSRIs:
https://cpicpgx.org/guidelines/guideline-for-selective-serotonin-reuptake-inhibitors-and-cyp2d6-and-cyp2c19/
CYP3A5 and tacrolimus:
https://cpicpgx.org/guidelines/guideline-for-tacrolimus-and-cyp3a5/
HLA-B and abacavir and allopurinol:
https://cpicpgx.org/guidelines/guideline-for-abacavir-and-hla-b/
https://cpicpgx.org/guidelines/guideline-for-allopurinol-and-hla-b/
https://cpicpgx.org/guidelines/guideline-for-carbamazepine-and-hla-b/
SLCO1B1 and simvastatin:
https://cpicpgx.org/guidelines/guideline-for-simvastatin-and-slco1b1/
TPMT and thiopurines:
https://cpicpgx.org/guidelines/guideline-for-thiopurines-and-tpmt/
*
All sites were accessible on July 14, 2017.

The consequences of allelic variation in the UGT2B family are less certain.
The predominant routes of morphine elimination include biotransformation to
the pharmacologically active 6-glucuronide (M6G) and the inactive 3-
glucuronide (M3G). M6G formation is almost exclusively catalyzed by
UGT2B7, whereas several UGTs in the UGT1A subfamily and UGT2B7, both
contribute to M3G formation. Increased M6G:morphine ratios have been
reported in individuals homozygous for the SNPs constituting the UGT2B7*2
allele. Although individuals genotyped as UGT2B7*2/*2 may produce higher-
than-anticipated concentrations of pharmacologically active morphine and its
metabolites, prospective studies addressing phenotype-genotype correlations and
the consequences of morphine analgesia have had conflicting results.

Thiopurine S -Methyltransferase
Thiopurine S -methyltransferase (TPMT ) is a cytosolic enzyme that catalyses
the S -methylation of aromatic and heterocyclic sulfur-containing compounds,
Drug Absorption
Drug absorption mainly occurs through passive diffusion, but active transport or
facilitated diffusion may also be necessary for drug entry into cells. Several
physiologic factors affect this process, one or more of which may be altered in
certain disease states (e.g., inflammatory bowel disease, diarrhea), and thus
produce changes in drug bioavailability. The rate and extent of absorption can be
significantly affected by a child's normal growth and development.

Peroral Absorption
The most important factors that influence drug absorption from the
gastrointestinal (GI) tract are related to the physiology of the stomach, intestine,
and biliary tract (Fig. 73.3C and Table 73.1 ). The rate and extent of peroral
absorption of drugs depend primarily on the pH-dependent passive diffusion and
motility of the stomach and intestinal tract, because both these factors will
influence transit time of the drug. Gastric pH changes significantly throughout
development, with the highest (alkaline) values occurring during the neonatal
period. In the fully mature neonate the gastric pH ranges from 6-8 at birth and
drops to 2-3 within a few hours of birth. However, after the 1st 24 hr of life, the
gastric pH increases because of the immaturity of the parietal cells. As the
parietal cells mature, the gastric acid secretory capacity increases (pH decreases)
over the 1st few months of life, reaching adult levels by age 3-7 yr. As a result,
the peroral bioavailability of acid-labile drugs (e.g., penicillin, ampicillin) is
increased. In contrast, the absorption of weak organic acids (e.g., phenobarbital,
phenytoin) is relatively decreased, a condition that may necessitate
administration of larger doses in very young patients to achieve therapeutic
plasma levels.

Table 73.1
Developmental Alterations in Intestinal Drug Absorption

PHYSIOLOGIC ALTERATION NEONATES INFANTS CHILDREN

Gastric pH >5 4 to 2 Normal (2-3)
Gastric emptying time Irregular Increased Slightly increased
Intestinal motility Reduced Increased Slightly increased
Intestinal surface area Reduced Near adult Adult pattern
Microbial colonization Reduced Near adult Adult pattern
Biliary function Immature Near adult Adult pattern
Direction of alteration given relative to expected normal adult pattern.
Data from Morselli PL: Development of physiological variables important for drug kinetics. In
Morselli PL, Pippenger CE, Penry JK, editors: Antiepileptic drug therapy in pediatrics, New York,
1983, Raven Press.

Gastric emptying time is prolonged throughout infancy and childhood as a

result of reduced motility, which may impair drug passage into the intestine,
where most absorption takes place. Gastric emptying rates reach or exceed adult
values by 6-8 mo of life. As such, intestinal motility is important for the rate of
drug absorption and, as with other factors, is dependent on the age of the child.
Consequently, the rate of absorption of drugs with limited water solubility (e.g.,
phenytoin, carbamazepine) can be dramatically altered consequent to changes in
GI motility. In older infants and young children, more rapid rates of intestinal
drug transit can reduce the bioavailability for some drugs (e.g., phenytoin) and
drug formulations (e.g., sustained-release) by reducing their residency time at
the absorption surfaces in the small intestine.
Neonates, particularly premature neonates, have a reduced bile acid pool and
biliary function, resulting in a decreased ability to solubilize and absorb
lipophilic drugs. Biliary function develops in the 1st few months of life, but it
may be difficult for the neonate and young infant to absorb fat-soluble vitamins
because low concentrations of bile acids are necessary for their absorption.

Extravascular Drug Absorption

Intravenous (IV) drug administration is assumed to be the most dependable and
accurate route for drug delivery, with a bioavailability of 100%. Absorption of
drugs from tissues and organs (e.g., intramuscular, transdermal, rectal) can also
be affected by development (Table 73.2 ). Intramuscular (IM) blood flow
changes with age, which can result in variable and unpredictable absorption.
Reduced muscular blood flow in the 1st few days of life, the relative inefficiency
of muscular contractions (useful in dispersing an IM drug dose), and an
increased percentage of water per unit of muscle mass may delay the rate and
extent of drugs given intramuscularly to the neonate. Muscular blood flow
increases into infancy, and thus the bioavailability of drugs given by the IM
route is comparable to that seen in children and adolescents.

Table 73.2
Influence of Ontogeny on Drug Absorption
 PHYSIOLOGIC ALTERATION NEONATES INFANTS CHILDREN
Oral absorption Erratic Increased Near adult
Intramuscular absorption Variable Increased Near adult
Percutaneous absorption Increased Increased Near adult
Rectal absorption Very efficient Efficient Near adult
Direction of alteration given relative to expected normal adult pattern.
Data from Morselli PL: Development of physiological variables important for drug kinetics. In
Morselli PL, Pippenger CE, Penry JK, editors: Antiepileptic drug therapy in pediatrics, New York,
1983, Raven Press.

In contrast, mucosal permeability (rectal and buccal) in the neonate is

increased and thus may result in enhanced absorption by this route. Transdermal
drug absorption in the neonate and very young infant is increased because of the
thinner and more hydrated stratum corneum (Fig. 73.3E ). In addition, the ratio
of body surface area to body weight is greater in infants and children than in
adults. Collectively, these developmental differences may predispose the child to
increased exposure and risk for toxicity for drugs or chemicals placed on the
skin (e.g., silver sulfadiazine, topical corticosteroids, benzocaine,
diphenhydramine), with higher likelihood of occurrence during the 1st 8-12 mo
of life.
Normal developmental differences in drug absorption from most all
extravascular routes of administration can influence the dose–plasma
concentration relationship in a manner sufficient to alter pharmacodynamics.
The presence of disease states that influence a physiologic barrier for drug
absorption or the time that a drug spends at a given site of absorption can further
influence drug bioavailability and effect.

Drug Distribution
Drug distribution is influenced by a variety of drug-specific physiochemical
factors, including the role of drug transporters, blood-tissue protein binding,
blood-tissue pH, and perfusion. However, age-related changes in drug
distribution are primarily related to developmental changes in body composition
and the quantity of plasma proteins capable of drug binding. Age-dependent
changes in the relative sizes of body water —total body water (TBW) and
extracellular water (ECW)—and fat compartments may alter the apparent
volume of distribution (VD) for a given drug. The absolute amounts and
distribution of body water and fat depend on a child's age and nutritional status.
Also, certain disease states (e.g., ascites, dehydration, burn injuries, skin
Table 73.3
Factors Influencing Drug Binding in Pediatric Patients

PHYSIOLOGIC ALTERATION NEONATES INFANTS CHILDREN

Plasma albumin Reduced Near adult Near adult
Fetal albumin Present Absent Absent
Total proteins Reduced Decreased Near adult
Total globulins Reduced Decreased Near adult
Serum bilirubin Increased Normal Adult pattern
Serum free fatty acids Increased Normal Adult pattern
Direction of alteration given relative to expected normal adult pattern.
Data from Morselli PL: Development of physiological variables important for drug kinetics. In
Morselli PL, Pippenger CE, Penry JK, editors: Antiepileptic drug therapy in pediatrics, New York,
1983, Raven Press.

The extent of drug binding to proteins in the plasma may influence

distribution characteristics. Only free, unbound drug can be distributed from the
vascular space into other body fluids and, ultimately, to tissues where drug-
receptor interaction occurs. Drug protein binding depends on a number of age-
related variables, including the absolute amount of proteins and their available
binding sites, the conformational structure of the binding protein (e.g., reduced
binding of acidic drugs to glycated albumin in patients with poorly controlled
diabetes mellitus), the affinity constant of the drug for the protein, the influence
of pathophysiologic conditions that either reduce circulating protein
concentrations (e.g., ascites, major burn injury, chronic malnutrition, hepatic
failure) or alter their structure (e.g., diabetes, uremia), and the presence of
endogenous or exogenous substances that may compete for protein binding (i.e.,
protein displacement interactions).
Developmentally associated changes in drug binding can occur because of
altered protein concentrations and binding affinity. Circulating fetal albumin in
the neonate has significantly reduced binding affinity for acid drugs such as
phenytoin, which is extensively (94–98%) bound to albumin in adults, compared
to 80–85% in the neonate. The resultant 6-8-fold difference in the free fraction
can result in CNS adverse effects in the neonate when total plasma phenytoin
concentrations are within the generally accepted “therapeutic range” (10-20
mg/L). The importance of reduced drug-binding capacity of albumin in the
neonate is exemplified by interactions between endogenous ligands (e.g.,
bilirubin, free fatty acids) and drugs with greater binding affinity (e.g., ability of
sulfonamides to produce kernicterus).
demonstrate an ontogenic profile with generally low activity at birth and
maturation over months to years (Table 73.4 and Fig. 73.3A ).

Table 73.4
Impact of Development on Drug Metabolism

PHYSIOLOGIC ALTERATION NEONATE INFANTS CHILDREN

Cytochrome P450 activity Reduced Increased Slightly increased
Phase II enzyme activity Reduced Increased Near adult
Blood esterase activity Reduced Normal (by 1 yr) Adult pattern
Presystemic enzyme activity Reduced Increased Near adult
Direction of alteration given relative to expected normal adult pattern.
Data from Morselli PL: Development of physiological variables important for drug kinetics. In
Morselli PL, Pippenger CE, Penry JK, editors: Antiepileptic drug therapy in pediatrics, New York,
1983, Raven Press.

Many enzymes are capable of catalyzing the biotransformation of drugs and

xenobiotics, but quantitatively the most important are represented by cytochrome
P450 (CYP ), a supergene family with at least 16 primary enzymes. The specific
CYP isoforms responsible for the majority of human drug metabolism are
represented by CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and
CYP3A4. These enzymes represent the products of genes that in some cases are
polymorphically expressed, with allelic variants producing enzymes generally
resulting in either no or reduced catalytic activity (a notable exception being the
*17 allele of CYP2C19, which may have increased activity) (see Chapter 72 ).
At birth the concentration of drug-oxidizing enzymes in fetal liver (corrected for
liver weight) appears similar to that in adult liver. However, the activity of these
oxidizing enzyme systems is reduced, which results in slow clearance (and
prolonged elimination) of many drugs that are substrates for them (e.g.,
phenytoin, caffeine, diazepam). Postnatally, the hepatic CYPs appear to mature
at different rates. Within hours after birth, CYP2E1 activity increases rapidly,
with CYP2D6 being detectable soon thereafter. CYP2C (CYP2C9 and
CYP2C19) and CYP3A4 are present within the 1st mo of life, a few months
before CYP1A2. CYP3A4 activity in young infants may exceed that observed in
adults, as reflected by the clearance of drugs that are substrates for this enzyme
(e.g., cyclosporine, tacrolimus).
Compared to phase I drug-metabolizing enzymes, the impact of development
on the activity of phase II enzymes (acetylation, glucuronidation, sulfation) is
not characterized as well. Phase II enzyme activity is decreased in the newborn
activity of enzymes and transporters (see Chapter 72 ) and the impact of
ontogeny on the nonmetabolic routes (e.g., renal drug excretion, salivary/biliary
drug excretion, pulmonary drug excretion), which contribute to the overall drug
clearance (Total CL = CLhepatic + CLrenal + CLnonrenal ).

Renal Drug Elimination

The kidney is the primary organ responsible for the elimination of drugs and
their metabolites. The development of renal function begins during early fetal
development and is complete by early childhood (Fig. 73.3D and Table 73.5 ).
Total renal drug clearance (CLrenal ) can be conceptualized by considering the
following equation:

Table 73.5
Impact of Development on Renal Drug Elimination

PHYSIOLOGIC ALTERATION NEONATE INFANTS CHILDREN

Glomerular filtration Reduced Normal (by 1 yr) Adult pattern
Active tubular secretion Reduced Near normal Adult pattern
Active tubular reabsorption Reduced Near normal Adult pattern
Active drug excretion Reduced Near normal Adult pattern
Passive drug excretion Reduced Increased Adult pattern
Excretion of basic drugs Increased Increased Near normal
Direction of alteration given relative to expected normal adult pattern.
Data from Morselli PL: Development of physiological variables important for drug kinetics. In
Morselli PL, Pippenger CE, Penry JK, editors: Antiepileptic drug therapy in pediatrics, New York,
1983, Raven Press.

where glomerular filtration rate (GFR), active tubular secretion (ATS), and
active tubular reabsorption (ATR) of drugs can contribute to overall clearance.
As for hepatic drug metabolism, only free (unbound) drug and metabolite can be
filtered by a normal glomerulus and secreted or reabsorbed by a renal tubular
transport protein.
Renal clearance is limited in the newborn because of anatomic and functional
immaturity of the nephron unit. In both the term and the preterm neonate, GFR
ATS of β-lactam antibiotics by probenecid). Also, drug-drug interactions may
occur at the level of the receptor (through competitive antagonism); many of
which are intentional and produce therapeutic benefit in pediatric patients (e.g.,
antihistamine reversal of histamine effects, naloxone reversal of opiate adverse
effects).

Table 73.6
Mechanism of Drug Interactions 1

EXAMPLE DRUG
RESULT
COMBINATION
PHARMACODYNAMIC
Additive Use of multiple drugs with similar adverse effect profiles can lead to
additive effects:
Fentanyl + midazolam Increased sedation
Class 1A antiarrhythmic 2 Increased QT prolongation
+ erythromycin 3 Increased potential for nephrotoxicity
Vancomycin + an
aminoglycoside 4
Synergy Penicillin + an Improved bactericidal efficacy against some gram-positive
aminoglycoside 4 organisms; penicillin inhibits bacterial cell wall synthesis, which for
some gram-positive organisms can improve the intracellular
penetration of the aminoglycoside
Antagonism Opioid + naloxone Competitive receptor antagonism; decreased efficacy of the opioid,
reversal of sedation, respiratory depression, and hypotension
Donepezil + an Oppositional effects; acetylcholinesterase inhibitors such as
anticholinergic donepezil increase acetylcholine concentrations by slowing the
degradation of acetylcholine, and anticholinergic drugs antagonize
the effect of acetylcholine
PHARMACOKINETIC
Absorption Inhibition of P-gp 5 :
Amiodarone + digoxin Increased digoxin concentration; gut P-gp is an efflux transporter
that takes drugs from cell cytoplasm and transports them back into
the intestinal lumen for excretion, limiting bioavailability
Complex formation:
Oral quinolone and Decreased antibiotic concentrations due to binding in the gut
tetracycline antibiotics +
divalent/trivalent cations (eg,
Ca2+ , Mg2+ , Fe3+ , Al3+ )
Distribution Ceftriaxone + endogenous Displacement of bilirubin from albumin binding site, increased risk
bilirubin of kernicterus in neonates
Metabolism Induction of CYP isozymes 5 ,
6 :

Rifampin + protease inhibitors Decreased serum concentrations of protease inhibitors metabolized

7 by CYP3A4 due to induction of CYP3A4-mediated metabolism;
may result in subtherapeutic levels and resistance
Inhibition of CYP isozymes 5 ,
 6 :
Azole antifungals 8 + Increased serum concentrations of CYP3A4 substrates due to
CYP3A4 substrates inhibition of CYP3A4-mediated metabolism; may result in drug
toxicity
Elimination Penicillin + probenecid Decreased tubular secretion of penicillin resulting in increased
serum concentrations
Methotrexate + aspirin Inhibition of tubular secretion of methotrexate resulting in increased
methotrexate concentrations
1 Drug interactions from The Medical Letter. Available at: www.medicalletter.org/subDIO .

2 Disopyramide, procainamide, quinidine

3
Woosley RL, Romero KA: QT drugs list. Available at: www.crediblemeds.org
4 Gentamicin, tobramycin, amikacin, streptomycin, neomycin

5
Inhibitors and inducers of CYP enzymes and P-glycoprotein. Med Lett Drugs Ther 2017;
September 18 (epub). Available at: www.medicalletter.org/downloads/CYP_PGP_Tables.pdf
6 Cytochrome P450 (CYP) isozymes that can affect drug metabolism include CYP1A2, 2C8, 2C9,
2C19, 2D6, and 3A4.
7 Some protease inhibitors metabolized by CYP3A4 include atazanavir, darunavir, fosamprenavir,
indinavir, lopinavir/ritonavir, nelfinavir, and saquinavir.
8
Itraconazole, ketoconazole, posaconazole, and voriconazole are strong inhibitors of CYP3A4.
Fluconazole is a moderate CYP3A4 inhibitor.
This table is not an all-inclusive list of drug interactions. The prescriber is encouraged to assess
the possibility of drug interactions when prescribing medications. This table does not address the
chemical compatibility of drugs (eg, IV-line compatibility).
CYP = cytochrome P-450; P-gp = P-glycoprotein.
Modified from Rizack M, Hillman C: The Medical Letter Handbook of Adverse Drug Interactions.
New Rochelle, NY, The Medical Letter, 1989. IBM Micromedex DRUGDEX, Copyright IBM
Corporation 2018; Med Lett Drugs Ther 2018;60:e160.

Drug interactions may also occur at a pharmaceutical level as a result of a

physicochemical incompatibility of 2 medications when combined. Such
interactions generally alter the chemical structure of one or both constituents and
thereby renders them inactive and potentially dangerous (e.g., IV infusion of
crystalline precipitate or unstable suspension). Ceftriaxone should be avoided in
infants <28 days of age if they are receiving or expected to receive IV calcium-
containing products, due to reports of neonatal deaths resulting from crystalline
deposits in the lungs and kidneys. Alternatively, 2 drugs simultaneously
administered perorally may form a complex that can inhibit drug absorption (eg.,
co-administration of doxycycline with a food or drug containing divalent
cations).
Drug-drug interactions at the level of drug metabolism can be somewhat
CHAPTER 74

Anesthesia and Perioperative Care

John P. Scott

The continuum of anesthesia includes varying degrees of sedation (i.e., mild,

moderate, or deep) and general anesthesia. All forms of sedation are
characterized by some preservation of purposeful movement (see Chapter 75 ),
whereas general anesthesia is defined by the complete loss of consciousness.
Potent pharmacologic agents are required to suppress the perception and
physiologic response to noxious stimuli. Perioperatively, the anesthesiologist is
responsible for providing analgesia while preserving physiologic and metabolic
stability (Table 74.1 ). This responsibility begins with the performance of a
comprehensive preanesthesia history (Table 74.2 ). Although anesthetic risk has
greatly decreased with advancements in pharmacology and monitoring
technology, the persistent risk of perioperative morbidity and mortality demands
vigilance. The risk is elevated in certain disease states (Table 74.3 ).
Table 74.1
Goals of Anesthesia
Analgesia
Amnesia
Hypnosis
Akinesia
Maintenance of physiologic homeostasis
Vigilance
Table 74.2
The Preanesthetic History
Child's previous anesthetic and surgical procedures:
• Review previous anesthetic records:
Ease of mask ventilation
Grade of laryngoscopy; type and size of
laryngoscope; endotracheal tube size
Issues during emergence (awakening) from anesthesia
(postoperative vomiting, emergence delirium)
History of hyperthermia or acidosis in the child or
family members.
Perinatal problems (especially for infants):
• Prematurity
• Need for supplemental oxygen or intubation and ventilation
• History of apnea and bradycardia
• History of cardiovascular compromise
Other major illnesses and hospitalizations
Family history of anesthetic complications, malignant hyperthermia, or
pseudocholinesterase deficiency
Respiratory problems:
• Long-term exposure to environmental tobacco smoke
• Obstructive breathing score
• STBUR (snoring, trouble breathing, un-refreshed)
• Cyanosis (especially in infants <6 mo of age)
• Recurrent respiratory infections
• Recent lower respiratory tract infection
• Previous laryngotracheitis (croup) or laryngomalacia
• Reactive airway disease
• Airway abnormalities, facial anomalies, mucopolysaccharidosis
Cardiac problems:
• Murmur or history of congenital heart disease
• Dysrhythmia
• Exercise intolerance
• Syncope
• Cyanosis
Gastrointestinal problems:
• Reflux and vomiting
• Feeding difficulties
• Failure to thrive
 • Liver disease
Exposure to infectious pathogens
Neuromuscular problems:
• Neuromuscular diseases
• Developmental delay
• Myopathy
• Seizure disorder
Hematologic problems:
• Anemia
• Bleeding diathesis
• Tumor
• Immunocompromise
• Prior blood transfusions and reactions
Renal problems:
• Renal insufficiency, oliguria, anuria
• Fluid and electrolyte abnormalities
Psychosocial considerations:
• Drug abuse, use of cigarettes or alcohol
• Physical or sexual abuse
• Family dysfunction
• Previous traumatic medical or surgical experience
• Psychosis, anxiety, depression
Gynecologic considerations:
• Sexual history (sexually transmitted infections)
• Possibility of pregnancy
Current medications:
• Prior administration of corticosteroids
Allergies:
• Drugs
• Iodine
• Latex products
• Surgical tape
• Food (especially soya and egg albumin)
Dental condition (loose or cracked teeth)
When and what the child last ate (especially in emergency procedures)

Table 74.3
Specific Pediatric Diseases and Their Anesthetic
Implications
DISEASE IMPLICATIONS
RESPIRATORY SYSTEM
Asthma Intraoperative bronchospasm that may be life threatening
Pneumothorax or atelectasis
Optimal preoperative medical management is essential.
Difficult airway Special equipment and personnel may be required.
Should be anticipated with dysmorphic features or storage diseases
Patients with trisomy 21 may require atlantooccipital joint evaluation.
Increased risk with acute airway obstruction, epiglottitis, laryngotracheobronchitis, or airway
foreign body
Bronchopulmonary Barotrauma with positive pressure ventilation
dysplasia Oxygen toxicity, pneumothorax a risk
Cystic fibrosis Airway reactivity, bronchorrhea, increased intraoperative pulmonary shunt and hypoxia
Risk of pneumothorax, pulmonary hemorrhage
Atelectasis, risk of prolonged postoperative ventilation
Patient should be assessed for cor pulmonale.
Sleep apnea Pulmonary hypertension and cor pulmonale must be excluded.
Careful postoperative observation for obstruction required
CARDIAC
Bacterial endocarditis prophylaxis as indicated
Use of air filters; careful purging of air from the intravenous equipment
Physician must understand the effects of various anesthetics on the hemodynamics of specific
lesions.
Possible need for preoperative evaluation of myocardial function and pulmonary vascular
resistance
Provide information about pacemaker function and ventricular device function.
HEMATOLOGIC
Sickle cell disease Possible need for simple or exchange transfusion based on preoperative hemoglobin
concentration and percentage of hemoglobin S
Avoid hypoxemia, hypothermia, dehydration, and hyperviscosity states.
Oncology Pulmonary evaluation of patients who have received bleomycin, bis -chloroethyl-nitrosourea,
chloroethyl-cyclohexyl-nitrosourea, methotrexate, or radiation to the chest
Avoidance of high oxygen concentration
Cardiac evaluation of patients who have received anthracyclines; risk of severe myocardial
depression with volatile agents
Potential for coagulopathy
RHEUMATOLOGIC
Limited mobility of the temporomandibular joint, cervical spine, arytenoid cartilages
Careful preoperative evaluation required
Possible difficult airway
GASTROINTESTINAL
Esophageal, gastric Potential for reflux and aspiration
Liver Altered metabolism of many anesthetic drugs
Potential for coagulopathy and uncontrollable intraoperative bleeding
RENAL
Altered electrolyte and acid-base status
Altered clearance of many anesthetic drugs
Need for preoperative dialysis in selected cases
 Succinylcholine to be used with extreme caution and only when the serum potassium level
has recently been shown to be normal
NEUROLOGIC
Seizure disorder Avoidance of anesthetics that may lower the seizure threshold
Optimal control ascertained preoperatively
Preoperative serum anticonvulsant measurements
Increased Avoidance of agents that increase cerebral blood flow
intracranial Maintain cerebral perfusion pressure.
pressure
Neuromuscular Avoidance of depolarizing relaxants; at risk for hyperkalemia
disease Patient may be at risk for malignant hyperthermia; avoid volatile anesthetics in myopathies.
Developmental Patient may be uncooperative during induction and emergence.
delay
Psychiatric Monoamine oxidase inhibitor (or cocaine) may interact with meperidine, resulting in
hyperthermia and seizures.
Selective serotonin reuptake inhibitors may induce or inhibit various hepatic enzymes that
may alter anesthetic drug clearance.
Illicit drugs may have adverse effects on cardiorespiratory homeostasis and may potentiate
the action of anesthetics.
ENDOCRINE
Diabetes Greatest risk is unrecognized intraoperative hypoglycemia; intraoperative blood glucose level
monitoring needed especially when insulin is administered.
SKIN
Burns Difficult airway
Fluid shifts
Bleeding
Risk of rhabdomyolysis and hyperkalemia from succinylcholine following burns for many
months
IMMUNOLOGIC
Retroviral drugs may inhibit benzodiazepine clearance.
Immunodeficiency requires careful infection control practices.
Cytomegalovirus-negative blood products, irradiation, or leukofiltration may be required.
METABOLIC
Careful assessment of glucose homeostasis in infants

Preanesthetic Evaluation
All children presenting for surgery should undergo a preanesthetic history and
multiorgan system assessment with assignment of American Society of
Anesthesiologists Physical Status (ASA-PS) (Table 74.4 ). Children of ASA-
PS I-II generally require a brief history, notation of medical allergies, and
physical examination focusing on the neurologic and cardiorespiratory systems,
with no additional testing. Patients with complex medical history of ASA-PS
≥III require a more comprehensive preanesthetic assessment often with ancillary
preoperative testing. Children should be screened for anesthetic risks, including
drug allergies, previous reactions to anesthetics, and family history of problems
with anesthesia (e.g., sudden perioperative death, hyperthermia after surgery),
which may indicate risk of malignant hyperthermia.
Table 74.4
American Society of Anesthesiology Physical
Status Classification

Class 1: Healthy patient, no systemic disease

Class 2: Mild systemic disease with no functional limitations (mild chronic
renal failure, iron-deficiency anemia, mild asthma)
Class 3: Severe systemic disease with functional limitations (hypertension,
poorly controlled asthma or diabetes, congenital heart disease, cystic
fibrosis)
Class 4: Severe systemic disease that is a constant threat to life (critically
and/or acutely ill patients with major systemic disease)
Class 5: Moribund patients not expected to survive 24 hr, with or without
surgery
Additional classification: “E”—emergency surgery

Copyright American Society of Anesthesiology, http://www.asahq.org . Used

with permission.

Respiratory System
Recent respiratory tract infections should be noted. Clear rhinorrhea without
fever is not associated with increased anesthetic risk. Respiratory illnesses
associated with fever, mucopurulent nasal discharge, productive cough, or lower
respiratory symptoms (wheezing, rales) are associated with increased airway
reactivity and anesthetic complications for up to 6 wk thereafter. There may also
be increased risk of perioperative laryngospasm and bronchospasm, reduced
mucociliary clearance, atelectasis, and hypoxemia. It is recommended that
elective procedures requiring general anesthesia be postponed 4-6 wk in this
setting.
Children with reactive airway disease require a thorough preanesthetic
assessment. Acute, potentially fatal bronchospasm can occur during induction of
anesthesia and endotracheal intubation for routine, minor surgery in children
with asthma. Children at increased risk for anesthetic complications have
experienced asthma exacerbations requiring (1) hospital admission within the
previous year; (2) emergency department (ED) care within the last 6 mo; (3)
previous intensive care unit (ICU) admission; or (4) previous parenteral systemic
corticosteroids. Ideally, children should be free of wheezing for least several
days before surgery, even if this necessitates increased controller medication
administration (β-adrenergic agonist and corticosteroids). Active wheezing is an
indication for delaying elective surgery. Chronic respiratory conditions such as
bronchopulmonary dysplasia and cystic fibrosis are also associated with
significant intraoperative risks. Every effort should be made to ensure that
children with such disorders achieve optimal respiratory status before surgery.

Airway Evaluation
Induction of general anesthesia is associated with reduced spontaneous
ventilation and airway reflexes. Prediction of difficult bag-mask ventilation
and/or intubation before anesthesia is critical. Congenital anomalies associated
with airway compromise include micrognathia, macroglossia, and thoracic
anomalies (Table 74.5 ). Conditions that impair mouth opening (e.g.,
temporomandibular joint disease) should also be noted. A history of wheezing or
stridor may indicate postoperative airway complications and difficult
intraoperative airway management. It is also essential to ask about a history of
sleep-disordered breathing using the STBUR (snoring, trouble breathing, un-
refreshed) index, which may be predictive of perioperative respiratory
complications.
Table 74.5
Common Difficult Airway Syndromes

Achondroplasia
Airway tumors, hemangiomas
Apert syndrome
Beckwith-Wiedemann syndrome
Choanal atresia
Cornelia de Lange syndrome
Cystic hygroma/teratoma
DiGeorge syndrome
Fractured mandible
 Goldenhar syndrome
Juvenile rheumatoid arthritis
Mucopolysaccharidosis
Pierre Robin syndrome
Smith-Lemli-Opitz syndrome
Treacher-Collins syndrome
Trisomy 21
Turner syndrome

Cardiovascular System
Most anesthetic agents possess myocardial depressant properties. All patients
should be screened for the presence of heart disease. Important cardiovascular
considerations include history of congenital heart disease (CHD), cyanosis,
arrhythmias, or cardiomyopathy. Room-air pulse oximetry should be performed
as part of the preanesthetic evaluation. Accurate diagnosis of cardiac murmurs in
neonates is essential. A history of cardiac dysrhythmias should be investigated
because inhalational anesthetics may be arrhythmogenic. A pediatric cardiologist
should evaluate children with known CHD undergoing surgery. Preoperative
ancillary studies may include electrocardiogram (ECG), echocardiogram, or
cardiac catheterization. Lesions associated with increased anesthetic risk include
single-ventricle heart disease, fixed obstructive outflow tract lesions (aortic
valve and pulmonary valve stenosis), and cardiomyopathy. Children with these
conditions should be cared for by a cardiac anesthesia service . Antibiotic
prophylaxis for the prevention of bacterial endocarditis may also be indicated,
and the American Heart Association (AHA) guidelines should be followed.

Hematologic System
Evidence of coagulopathy should be sought. Easy bruising, familial bleeding
disorders, and anticoagulant (e.g., aspirin, heparin, warfarin) use should be
discussed. Preoperative adequacy of hemostatic function (e.g., platelet count,
fibrinogen, prothrombin time, partial thromboplastin time) and correction of
coagulopathic disorders may be indicated for complex procedures associated
with significant risk of perioperative hemorrhage. In neonates, assurance of
vitamin K prophylaxis and adequate coagulation status is critical before any
major surgery. Although anemia may be well tolerated in healthy children,
providing rapid-onset anxiolysis and amnesia.

Genetic Evaluation
Children with genetic conditions may have syndrome-specific anesthetic
considerations. For example, children with trisomy 21 may have cardiac
anomalies, macroglossia, upper airway obstruction, and hypothyroidism (see
Chapter 98.2 ). Atlantoaxial instability, common in trisomy 21, has been linked
to cervical dislocation and spinal cord trauma with neck extension during
intubation. Some anesthesiologists recommend extension and flexion lateral
neck films to detect instability before surgery. For children with other known
genetic disorders it is essential to review specific anesthetic considerations.

Preoperative Preparation
Preoperative Fasting
Preoperative fasting guidelines have been developed to reduce the incidence of
aspiration of gastric contents during anesthesia. Aspiration may lead to
laryngospasm, bronchospasm, and postoperative pneumonitis. Aspiration of
gastric contents may be a potentially lethal complication in children with chronic
lung disease or critical illness. Table 74.6 lists preoperative fasting guidelines
(e.g., nothing by mouth, or nil per os [NPO] status). Clear, sweet liquids (e.g.,
Pedialyte, 5% dextrose in water [D5W]) facilitate gastric emptying, prevent
hypoglycemia, and may be given up to 2 hr before anesthesia. Breast milk may
be given to infants up to 4 hr before surgery. Solids should be avoided for 6-8 hr
before surgery. Many conditions delay gastric emptying and may require
prolonged periods of fasting.

Table 74.6

Guidelines for Preoperative Fasting (“2-4-6-8 Rule”)*

TIME BEFORE SURGERY (hr) ORAL INTAKE
2 Clear, sweet liquids
4 Breast milk
6 Infant formula, fruit juices, gelatin
8 Solid food
* These are general guidelines and may differ among hospitals.
The Full Stomach
Gastric emptying may be delayed for up to 96 hr after an acute episode of
trauma or surgical illness. Because of the serious complications of aspiration of
gastric contents, it is desirable to secure the airway as rapidly as possible during
induction of anesthesia in patients at risk for having a full stomach. Under these
circumstances, rapid sequence induction of anesthesia is indicated (rapid
sequence induction ; see Chapter 89 ).

Parental Presence During Induction of

Anesthesia
Parents may expect to be with their child during the induction of anesthesia.
Removing a fearful child from the comforting arms of a parent is stressful for the
child, parents, and caregivers. When parental separation cannot be achieved
comfortably with premedication and behavioral modification (patient education
and desensitization to the operative environment), there may be a need to defer
parent–child separation until general anesthesia is induced. Premedication with
the oral benzodiazepine midazolam more frequently provides calm, smooth
induction conditions than PPI without pharmacologic preparation. Although PPI
in the hands of a confident, competent anesthesia practitioner may replace the
need for preoperative medication, it does not reliably predict smooth induction.
PPI has not been shown to decrease emergence delirium or postoperative
behavioral changes, and it does not appear to be superior to premedication with
oral midazolam.

General Anesthesia
Analgesia
Pediatric anesthesiologists are responsible for providing analgesia to children for
procedures within operating room (OR) and non-OR settings (Table 74.7 ).
Multimodal techniques exist to provide pain relief during operative procedures
for children of all ages, including critically ill infants. Effective analgesia is
essential to blunt physiologic responses to painful stimuli (surgery) and
modulate the deleterious physiologic and metabolic consequences. The response
to painful and stressful stimuli may provoke systemic inflammatory response
syndrome (SIRS) , which has been linked to increased catabolism, physiologic
instability, and mortality (see Chapter 88 ).
Table 74.7
Definitions of Anesthesia Care
Monitored Anesthesia Care

A designated anesthesia service in which an anesthesiologist has been

requested to participate in the care of a patient undergoing a diagnostic or
therapeutic procedure.
Monitored anesthesia care includes all aspects of anesthesia care: a
preprocedure assessment, intraprocedure care, and postprocedure
anesthesia management.
During monitored anesthesia care, the anesthesiologist or a member of the
anesthesia care team provides a number of specific services, which may
include but are not limited to the following:
• Discussing anesthesia care with the family and child, obtaining
consent for anesthesia, allaying anxiety and answering
questions—family-centered anesthesia care.
• Monitoring of vital signs, maintenance of the patient's airway,
and continual evaluation of vital functions.
• Diagnosing and treating clinical problems that occur during the
procedure.
• Administering sedatives, analgesics, hypnotics, anesthetic
agents, or other medications as necessary to ensure patient
safety and comfort.
• Providing other medical services as needed to accomplish the
safe completion of the procedure.
Anesthesia care often includes the administration of medications for which
the loss of normal protective reflexes or loss of consciousness is likely.
Monitored anesthesia care refers to those clinical situations in which the
patient remains able to protect the airway for the majority of the
procedure.
If the patient is rendered unconscious and/or loses normal protective
reflexes for an extended period, this is considered a general anesthetic.
Light Sedation

Administration of anxiolysis or analgesia that obtunds consciousness but

does not obtund normal protective reflexes (cough, gag, swallow,
hemodynamic), or spontaneous ventilation.

Deep Sedation

Sedation that obtunds consciousness and normal protective reflexes or

possesses a significant risk of blunting normal protective reflexes (cough,
gag, swallow, hemodynamic), hemodynamic and respiratory insufficiency
may occur.

General Anesthesia

Administration of hypnosis, sedation, and analgesia that results in the loss

of normal protective reflexes.

Regional Anesthesia

Induction of neural blockade (either central, neuraxial, epidural, or spinal;

or peripheral nerve block, e.g., digital nerve block, brachial plexus
block), which provides analgesia and is associated with regional motor
blockade.
Consciousness is not obtunded.
Special expertise is required.
Frequently, in children, anxiolysis and sedation are also necessary for this
technique to be successful.
Regional anesthesia (e.g., caudal epidural blockade) is used to supplement
general anesthesia and provide postoperative analgesia.

Local Anesthesia

Provision of analgesia by local infiltration of an appropriate anesthetic

agent.
 Does not require the presence or involvement of an anesthesiologist,
although an anesthesiologist may provide local anesthesia services.

No Anesthesiologist

An anesthesiologist will not be involved in the care of the child.

Hypnosis and Amnesia

The attenuation of both consciousness (hypnosis) and conscious recall
(amnesia) is critical during pediatric anesthesia care. Awareness during
procedures may be as physically and psychologically deleterious as the
experience of pain. A primary goal of anesthetic management is to minimize fear
and anxiety during both painful and nonpainful procedures. Many drugs provide
anxiolysis and amnesia for such events (Table 74.8 ). However, it is important to
remember that sedative-hypnotic agents may alter consciousness without
producing analgesia; analgesia and hypnosis are not synonymous. It is also
possible to provide analgesia (local, spinal, or epidural) without altering
consciousness.

Table 74.8
Selected Drugs Used in Anesthesia

DRUG USES AND IMPLICATIONS

MUSCLE RELAXANTS
Succinylcholine A depolarizing neuromuscular blocking agent with rapid onset and offset properties
Used to facilitate endotracheal intubation and maintain muscle relaxation in emergency
situations; rarely used
Associated with the development of malignant hyperthermia in susceptible patients
Degraded by plasma cholinesterase, which may be deficient in some individuals; such a
deficiency may result in prolonged effect
Fasciculations may be associated with immediate increases in intracranial and intraocular
pressures as well as postoperative muscle pain.
Vecuronium, Nondepolarizing neuromuscular blockers
rocuronium, cis - Have less rapid onset than succinylcholine but are longer acting
atracurium, all Prolonged ICU use may lead to profound muscle weakness.
aminosteroids Vecuronium and rocuronium are metabolized by the liver and excreted in bile; they are the
most commonly used neuromuscular blocking agents.
cis -Atracurium is metabolized by plasma cholinesterase and therefore may be of benefit in
patients with hepatic or renal disease.
HYPNOTICS
Propofol Rapid-acting hypnotic amnestic agent
 No analgesic properties
Respiratory depressant
Increases seizure threshold
Antiemetic
Propofol infusion syndrome may occur with prolonged intravenous infusion (>24 hr).
Etomidate Cardiovascular stability on induction
Inhibits corticosteroid synthesis
Increases ICU mortality after use
Associated with myoclonus and pain on injection
Ketamine Hypnotic analgesic
Causes sialorrhea and should be co-administered with an antisialogue, such as atropine or
glycopyrrolate
Induces endogenous catecholamine release and tachycardia
Bronchodilator
Increases intracranial and intraocular pressures
Decreases the seizure threshold
SEDATIVE-ANXIOLYTICS
Benzodiazepines Produce sedation, anxiolysis, amnesia, and hypnosis
All agents raise the seizure threshold, are metabolized by the liver, and depress respiration,
especially when administered with opioids.
Effective as premedication
Diazepam may be painful on injection and has active metabolites.
Midazolam can be administered by various routes.
Lorazepam has no active metabolites.
Reversed with flumazenil
Dexmedetomidine Produces anxiolysis, sedation, sympatholysis, by α2 -receptor stimulation centrally; has mild
analgesic properties
Side effects include hypertension, hypotension, and bradycardia.
Commonly used for procedural and ICU sedation
Continuous infusion for ICU sedation
ANALGESIC-SEDATIVES
Opioids Gold standard for providing analgesia
All cause respiratory depression.
Morphine and, to a lesser extent, hydromorphone may cause histamine release.
The synthetic opioids fentanyl, sufentanil, and short-acting alfentanil may have a greater
propensity to cause chest wall rigidity when administered rapidly or in high doses and are also
associated with the rapid development of tolerance. These drugs have particular utility in
cardiac surgery because of the hemodynamic stability associated with their use.
Remifentanil is an ultrashort-acting synthetic opioid that is metabolized by plasma
cholinesterase; it may have particular utility when deep sedation and analgesia are required
along with the ability to assess neurologic status intermittently.
INHALATIONAL AGENTS
Nitrous oxide Produces amnesia and analgesia at low concentrations
Danger of hypoxic gas mixture if the oxygen concentration is not monitored and preventive
safety mechanisms are not in place
Potent vapors, “Complete anesthetics”—induce hypnosis, analgesia, and amnesia
sevoflurane, All are myocardial depressants, and some are vasodilators.
desflurane, May trigger malignant hyperthermia in susceptible individuals
isoflurane Sevoflurane is used for induction of anesthesia in children.
All bronchodilate at equipotent concentrations.
Isoflurane and desflurane are associated with laryngospasm and should not be used for
anesthesia induction.
Most anesthetics produce vasodilation and increase venous capacitance,
effectively reducing myocardial preload. Surgical bleeding and insensible/third
space fluid losses further contribute to intravascular volume depletion. Volume
expansion with isotonic salt-containing solutions (normal saline, lactated Ringer,
Plasmalyte) may be required to maintain cardiac output and organ perfusion.
Increased renin-angiotensin-aldosterone axis activation and antidiuretic hormone
(ADH) secretion further complicate fluid regulation.
Intraoperative fluid management must account for (1) deficits acquired during
preoperative fasting, (2) maintenance fluid requirements, (3) surgical blood loss,
and (4) insensible fluid loss. Infants should receive glucose-containing isotonic
fluid to prevent perioperative hypoglycemia. Table 74.9 is a guideline for
determining fluid deficits and maintenance requirements in the OR. For longer
procedures, fluid deficits should be replaced with isotonic fluid over the 1st 3 hr
of intraoperative management. Deficits are generally calculated as the number of
hours of fasting status multiplied by the hourly maintenance rate for the child.
Half the deficit is replaced during the 1st hr and half during the subsequent 2 hr.
If hypotension or tachycardia persists in the early stages of anesthesia, more
rapid replacement of the fluid deficit may be indicated.

Table 74.9
Intraoperative Pediatric Fluid Replacement

INFUSION RATE PATIENT WEIGHT

4 mL/kg/hr 1-10 kg
2 mL/kg/hr 10-20 kg
1 mL/kg/hr per kg >20 kg
Example: 22 kg child requires (4 × 10) + (2 × 10) + (1 × 2) = 62 mL/hr

Third space interstitial fluid losses should be replaced with isotonic salt
solutions. For smaller operations, such as herniorrhaphy, pyloromyotomy, and
minor procedures, fluid replacement at 3-5 mL/kg/hr is indicated for insensible
losses. Complex abdominal or thoracic procedures with large insensible losses
may require an additional 8-10 mL/kg/hr of IV fluid replacement. Crystalloid
solution is indicated for blood loss as a 3 : 1 ratio. Allogenic blood products
should be replaced as a 1 : 1 ratio. Colloid (albumin) administration also
decreases the amount of crystalloid replacement needed for blood loss. During
large-volume transfusions, active fluid warming should be performed to prevent
hypothermia. With major surgery and resultant SIRS, capillary integrity is lost
even for the shortest-acting muscle relaxant, rocuronium, can take several
minutes. An intubating dose of rocuronium to rapidly induce paralysis in
emergency situations may not spontaneously reverse for 20 min or longer
(compared with about 3 min for succinylcholine). The effects of long-acting,
nondepolarizing NMBAs (vecuronium, pancuronium) are invariably reversed.
Residual NMB is common despite reversal with these agents. Sugammadex is
an alternative reversal agent that has a very low rate of residual NMB. Its
mechanism of action involves noncompetitive antagonism through encapsulation
of neuromuscular agents.

Postanesthesia Care Unit

In the postanesthesia care unit (PACU), the child is observed until there is
adequate recovery from anesthesia and sedation. Achievement of spontaneous
breathing, adequate pulse oximetry saturation (> 95%), and hemodynamic
stability are key recovery end-points. The child should be arousable, responsive,
and oriented before discharge from the PACU. The amount of time spent in the
PACU varies based on disposition (transfer to acute care or ICU, transfer to day
surgery postrecovery unit, or discharge to home). Parents should be permitted to
comfort their children in the PACU. Discharge from the PACU depends on the
child's overall functional status—not merely the physiologic end-points, but also
the adequate provision of analgesia and control of postoperative nausea and
vomiting. Various scoring systems have been used for determining readiness for
discharge from the PACU (Table 74.10 ).

Table 74.10
Postanesthesia Recovery Scores

ALDRETE RECOVERY SCORE >9 REQUIRED FOR DISCHARGE

ACTIVITY—VOLUNTARILY OR ON COMMAND
Moves 4 extremities 2
Moves 2 extremities 1
No motion 0
BREATHING
Deep breath, cough, cry 2
Dyspnea or shallow breathing 1
Apnea 0
BLOOD PRESSURE
Within 20% of preanesthetic value 2
Within 20–50% of preanesthetic value 1
>50% outside preanesthetic value 0
COLOR
Pink 2
Pale, blotchy, dusky 1
Cyanotic 0
CONSCIOUSNESS
Fully aware, responds 2
Arouses to stimulus 1
Unresponsive 0
STEWARD RECOVERY SCORE 6 REQUIRED FOR DISCHARGE
ACTIVITY
Moves limbs purposefully 2
Nonpurposeful movement 1
Still 0
CONSCIOUSNESS
Awake 2
Responsive 1
Unresponsive 0
AIRWAY
Coughing on command or crying 2
Maintaining patent airway 1
Requires airway maintenance 0

Postanesthetic Complications
Respiratory insufficiency following general anesthesia is common. Prolonged
emergence from anesthesia and respiratory depression may be caused by the
residual effects of opioids, hypnotic agents, or NMBAs. Pain may also cause
significant hypoventilation, especially after thoracic or abdominal surgery.
Delayed emergence from anesthesia may result from retention of inhaled
anesthetics worsened by hypoventilation. Hypothermia, especially in neonates,
delays metabolism and excretion of anesthetics and prolongs NMB.
Hypoventilation after surgery is associated with the development of atelectasis .
Microatelectasis may lead to postoperative infections. When airway obstruction
is present, maintenance of airway patency may necessitate oropharyngeal or
nasopharyngeal airway placement. In the setting of profound respiratory
depression, endotracheal intubation and mechanical ventilation may be
indicated.
Opioid reversal with naloxone may be indicated in rare instances when
excessive opioid effect is suspected. However, naloxone reverses both the
respiratory depressant and the analgesic effects of opioids. Following naloxone
reversal, a somnolent child with respiratory depression may experience increased
pain. Opioid reversal requires bedside attention by the physician to monitor the
and/or specially trained, experienced, credentialed, and qualified physicians.
Table 75.1
Systematic Approach to Sedation in Children
Comprehensive medical history and organ system assessment, anticipating
underlying medical problems that predispose the patient to anesthetic
complications
Careful physical examination focused on the cardiorespiratory system and
airway
Appropriate fasting
Informed consent
Pediatric drug dosing (mg/kg)
Appropriately sized equipment
Documentation of vital signs and condition on a time-based record
Rapid response (“code”) team to respond to emergencies with “crash cart”
Fully equipped and staffed recovery area
Discharge criteria documenting recovery from sedation

Many pediatric subspecialists provide sedation and anesthesia care for

children. The use of anesthetic agents is not limited to anesthesiologists, but
anesthesiology departments are obligated to help develop, manage, and oversee
sedation services. Together, hospitals and providers, including anesthesiologists,
share responsibility for the oversight and credentialing of individuals
administering sedation and anesthesia.
The elements of a safe pediatric procedural sedation system include the
following:

◆ Clearly defined knowledge and skill sets

◆ Adequate prerequisite training
◆ Credentialing of providers
◆ Maintenance of certification
◆ Ensuring that sedation sites meet recognized
standards
 ◆ Continuous quality improvement
Table 75.2 provides an approach to proper language to help the child cope
with procedural pain.

Table 75.2

Suggested Language for Parents and Health-Care Providers

LANGUAGE TO AVOID LANGUAGE TO USE
You will be fine; there is nothing to What did you do in school today? (distraction)
worry about. (reassurance)
This is going to hurt/this won't hurt. It might feel like a pinch. (sensory information)
(vague; negative focus)
The nurse is going to take some First, the nurse will clean your arm, you will feel the cold alcohol pad, and
blood. (vague information) next … (sensory and procedural information)
You are acting like a baby. Let's get your mind off of it; tell me about that film … (distraction)
(criticism)
It will feel like a bee sting. Tell me how it feels. (information)
(negative focus)
The procedure will last as long as The procedure will be shorter than … (television program or other familiar
… (negative focus) time for child) (procedural information; positive focus)
The medicine will burn. (negative Some children say they feel a warm feeling. (sensory information; positive
focus) focus)
Tell me when you are ready. (too When I count to three, blow the feeling away from your body. (coaching to
much control) cope; distraction-limited control)
I am sorry. (apologizing) You are being very brave. (praise; encouragement)
Don't cry. (negative focus) That was hard; I am proud of you. (praise)
It is over. (negative focus) You did a great job doing the deep breathing, holding still … (labeled
praise)
Adapted from Krauss BS, Calligaris L, Green SM, Barbi E: Current concepts in management of
pain in children in the emergency department, Lancet 387:83–92, 2016.

Bibliography
Coté CJ, Wilson S. Guidelines for monitoring and management
of pediatric patients before, during, and after sedation for
diagnostic and therapeutic procedures: update 2016.
Pediatrics . 2016;138(1):e20161212.
Cramton REM, Gruchala NE. Managing procedural pain in
pediatric patients. Curr Opin Pediatr . 2012;24:530–538.
Doctor K, Roback MG, Teach SJ. An update on pediatric
Pain Categories and Characteristics
PAIN DEFINITION AND
CHARACTERISTICS
CATEGORY EXAMPLES
Somatic Pain resulting In skin and superficial structures: sharp, pulsatile, well localized
from injury to or In deep somatic structures: dull, aching, pulsatile, not well localized
inflammation of
tissues (e.g.,
skin, muscle,
tendons, bone,
joints, fascia,
vasculature)
Examples: burns,
lacerations,
fractures,
infections,
inflammatory
conditions
Visceral Pain resulting Aching and cramping; nonpulsatile; poorly localized (e.g., appendiceal
from injury to or pain perceived around umbilicus) or referred to distant locations (e.g.,
inflammation of angina perceived in shoulder)
viscera
Examples:
angina, hepatitic
distention, bowel
distention or
hypermobility,
pancreatitis
Neuropathic Pain resulting Spontaneous; burning; lancinating or shooting; dysesthesias (pins and
from injury to, needles, electrical sensations); hyperalgesia (amplification of noxious
inflammation of, stimuli); hyperpathia (widespread pain in response to a discrete noxious
or dysfunction of stimulus); allodynia (pain in response to nonpainful stimulation); pain may
the peripheral or be perceived distal or proximal to site of injury, usually corresponding to
central nervous innervation pathways (e.g., sciatica)
system
Examples:
complex regional
pain syndrome
(CRPS),
phantom limb
pain, Guillain-
Barré syndrome,
sciatica

Assessment and Measurement of Pain in

Children
Assessing pain entails much more than merely quantifying it. Whenever feasible,
the physician should ask the patient about the character, location, quality,
duration, frequency, and intensity of the pain. Some children may not report pain
because of fears (often well founded) of talking to strangers, disappointing or
bothering others, receiving an injection if they report pain, returning to the
hospital if they admit to pain, and other negative reactions. For infants and
nonverbal children, their parents, pediatricians, nurses, and other caregivers are
constantly challenged to interpret whether the child's distressed behaviors
represent pain, fear, hunger, or a range of other perceptions or emotions.
Similarly, lack of normal interest in play without behavioral distress signals can
be manifestations of pain. Therapeutic trials of comfort measures (cuddling,
feeding) and analgesic medication may be helpful in clarifying the triggers of the
behaviors.
Behavior and physiologic signs are useful but can be misleading. A toddler
may scream and grimace during an ear examination because of fear rather than
pain. Conversely, children with inadequately relieved persistent pain from
cancer, sickle cell disease, trauma, or surgery may withdraw from their
surroundings and appear very quiet, leading observers to conclude falsely that
these children are comfortable or sedated or, for adolescent patients, are “drug
seeking.” In these situations, increased dosing of analgesics may make the child
become more, not less, interactive and alert. Similarly, neonates and young
infants may close their eyes, furrow their brows, and clench their fists in
response to pain. Adequate analgesia is often associated with eye opening and
increased involvement in surroundings. A child who is experiencing significant
chronic pain may play normally as a way to distract attention away from pain.
This coping behavior is sometimes misinterpreted as evidence of the child's
“faking” or exaggerating pain at other times.

Age-Specific and Developmentally Specific

Measures
Because infants, young children, and nonverbal children cannot express the
quantity of pain they experience, several pain scales have been devised in an
attempt to quantify pain in these populations (Fig. 76.2 and Table 76.2 ).
 FIG. 76.2 Clinically useful pain assessment tools. (Adapted from Burg FD, Ingelfinger
JR, Polin RA, et al, editors: Current pediatric therapy, ed 18, Philadelphia, 2006,
Saunders/Elsevier, p 16; and Hicks CL, von Baeyer CL, Spafford P, et al: The Faces Pain
Scale—revised: toward a common metric in pediatric pain measurement, Pain 93:173–
183, 2001.)

Table 76.2
Pain Measurement Tools
AGE VALIDATION
NAME FEATURES ADVANTAGES LIMITATIONS
RANGE AND USES
Visual Analog Horizontal 10-cm 6-8 yr and Good Acute pain Cannot be used
Scale (VAS) line; subject marks a older psychometric Surgical in younger
spot on the line properties; pain children or in
between anchors of validated for Chronic those with
“no pain” (or neutral research pain cognitive
face) and “most pain purposes limitations
imaginable” (or sad Requires
face) language skills
and numerical
processing;
upper anchor of
“most pain”
requires an
experiential
reference point
 that is lacking in
many children.
Likert Scale Integers from 0-10, 6-8 yr and Good Acute pain Same as for VAS.
inclusive, older psychometric Surgical
corresponding to a properties; pain
range from no pain to validated for Chronic
most pain research pain
purposes
Faces Scales Subjects rate their 4 yr and Can be used at Acute pain Choice of “no pain”
(e.g., FACES-R, pain by identifying older younger ages Surgical face affects responses
Wong-Baker, with line drawings of than VAS and pain (neutral vs smiling);
Oucher, Bieri, faces, or photos of Likert not culturally
McGrath scales) children universal.
Behavioral or Scoring of observed Some work May be used in FLACC, Nonspecific;
combined behaviors (e.g., facial for any ages; both infants and N-PASS: overrates pain in
behavioral- expression, limb some work nonverbal Acute pain toddlers and
physiologic movement) ± heart for specific children Surgical preschool children;
scales (e.g., rate and blood age-groups, pain underrates persistent
FLACC, N- pressure including pain; some measures
PASS, preterm are convenient, but
CHEOPS, OPS, infants others require
FACS, NIPS) videotaping and
complex processing;
vital sign changes
unrelated to pain can
occur and may affect
total score.
Autonomic Scores changes in All ages Can be used at Nonspecific; vital
measures (e.g., heart rate, blood all ages; useful sign changes
heart rate, blood pressure, or measures for patients unrelated to pain may
pressure, heart of heart rate receiving occur, and may
rate spectral variability (e.g., mechanical artifactually increase
analyses) “vagal tone”) ventilation or decrease score.
Hormonal- Plasma or salivary All ages Can be used at Nonspecific; changes
metabolic sampling of “stress” all ages unrelated to pain can
measures hormones (e.g., occur; inconvenient;
cortisol, epinephrine) cannot provide “real-
time” information;
standard normal
values not available
for every age bracket.

The Newborn and Infant

There are several behavioral distress scales for the infant and young child,
mostly emphasizing the patient's facial expressions, crying, and body movement.
Facial expression measures appear most useful and specific in neonates.
Autonomic and vital signs can indicate pain, but because they are nonspecific,
they may reflect other processes, including fever, hypoxemia, and cardiac or
renal dysfunction (Table 76.3 ).
Table 76.3
Signs and Symptoms of Pain in Infants and
Young Children
Physiologic Changes

• Increase in heart rate, respiratory rate, blood pressure, muscle tone

• Oxygen desaturation
• Sweating
• Flushing
• Pallor

Behavioral Changes

• Change in facial expression (grimacing, furrowing of the brow, nasal

flaring, deep nasolabial groove, curving of the tongue, quivering of the
chin)
• Finger clenching
• Thrashing of limbs
• Writhing
• Back arching
• Head banging
• Poor feeding
• Sleep disturbance
• Pseudoparalysis

From Krauss BS, Calligaris L, Green SM, Barbi E: Current concepts in

management of pain in children in the emergency department, Lancet 387:83–
92, 2016.

The Older Child

Children age 3-7 yr become increasingly articulate in describing the intensity,
location, and quality of pain. Pain is occasionally referred to adjacent areas;
and fat. Because of decreased serum concentrations of albumin and α1 -acid
glycoprotein, neonates have reduced protein binding of some drugs, resulting in
higher amounts of free, unbound, pharmacologically active drug.

Acetaminophen, Aspirin, Nonsteroidal Antiinflammatory,

and Coxib Drugs
Acetaminophen and nonsteroidal antiinflammatory drugs (NSAIDs) have
replaced aspirin as the most commonly used antipyretics and oral, nonopioid
analgesics (Table 76.4 ).

Table 76.4

Commonly Used Nonopioid Medications

MEDICATION DOSAGE COMMENT(S)
Acetaminophen 10-15 mg/kg PO q4h Minimal antiinflammatory action; no antiplatelet or adverse
10 mg/kg IV q4h gastric effects; overdosing can produce fulminant hepatic
15 mg/kg IV q6h failure.
10 mg/kg IV q6h (<2 yr)
20-30 mg/kg/PR q4h
40 mg/kg/PR q6-8h
Maximum daily dosing:
90 mg/kg/24 hr
(children)
60 mg/kg/24 hr (<2 yr)
30-45 mg/kg/24 hr
(neonates)
Aspirin 10-15 mg/kg PO q4h Antiinflammatory; prolonged antiplatelet effects; may cause
Maximum daily dosing: gastritis; associated with Reye syndrome.
120 mg/kg/24 hr
(children)
Ibuprofen 8-10 mg/kg PO q6h Antiinflammatory; transient antiplatelet effects; may cause
10 mg/kg IV q4-6h to gastritis; extensive pediatric safety experience.
maximum of 400 mg
Maximum daily dose:
2400 mg
Naproxen 5-7 mg/kg PO q8-12h Antiinflammatory; transient antiplatelet effects; may cause
gastritis; more prolonged duration than that of ibuprofen.
Ketorolac Loading dose 0.5 mg/kg, then Antiinflammatory; reversible antiplatelet effects; may cause
0.25-0.3 mg/kg IV q6h to a gastritis; useful for short-term situations in which oral dosing is
maximum of 5 days; not feasible.
maximum dose 60 mg
loading with maximum
dosing of 30 mg q6h
Diclofenac 2-3 mg/kg/day divided in 2 or Antiinflammatory; reversible antiplatelet effects; lower risk of
sodium 3 doses gastritis and ulceration compared with other NSAIDs.
Choline 10-20 mg/kg PO q8-12h Weak antiinflammatory; lower risk of bleeding and gastritis
magnesium than with conventional NSAIDs.
 salicylate
Celecoxib 3-6 mg/kg PO q12-24h Antiinflammatory; no or minimal antiplatelet or gastric effects;
cross-reactivity with sulfa allergies.
Nortriptyline, 0.1-0.5 mg/kg PO qhs For neuropathic pain; facilitates sleep; may enhance opioid
amitriptyline, Larger doses may be effect; may be useful in sickle cell pain; risk of dysrhythmia in
desipramine divided bid. prolonged QTc syndrome; may cause fatal dysrhythmia in
overdose; FDA states agents may enhance suicidal ideation;
little or no antidepression or antianxiety effects at lower
dosages.
Gabapentin 100 mg bid or tid titrated to For neuropathic pain; associated with sedation, dizziness,
up to 3600 mg/24 hr ataxia, headache, and behavioral changes.
Quetiapine, Quetiapine: 6.25 or 12.5 Useful when arousal is amplifying pain; often used when patient
risperidone, mg PO qd (hs); may use first starting SSRI and then weaned after at least 2 wk; check
chlorpromazine, q6hr prn acute agitation for normal QTc before initiating; side effects include
haloperidol with pain. Escalate dose extrapyramidal reactions (diphenhydramine may be used to
to 25 mg/dose if needed. treat) and sedation; in high doses, can lower the seizure
Risperidone: useful for threshold.
PDD spectrum or tic
disorder and chronic
pain; 0.25-1 mg (in 0.25
mg increments) qd or
bid; see PDR for other
dosing.
Venlafaxine, Venlafaxine: start 37.5 SNRIs with both clinically significant antidepression and
duloxetine mg daily as the XR antianxiety effects as well as analgesic effects.
formulation and titrate up
monthly to effective
dose, 2-4 mg/kg.
Duloxetine: start 20 mg
daily and titrate upward
to effective dose, 1-1.5
mg/kg.
Fluoxetine 10-20 mg PO qd (usually in SSRI for children with anxiety disorders in which arousal
morning) amplifies sensory signaling; useful in PDD spectrum disorders
in very low doses; best to use in conjunction with psychiatric
evaluation.
Sucrose solution Preterm infants Allow 2 min before starting procedure; analgesia may last up to
via pacifier or (gestational age): 8 min; the dose may be repeated once.
gloved finger 28 wk: 0.2 mL swabbed
into mouth
28-32 wk: 0.2-2 mL,
depending on
suck/swallow
>32 wk: 2 mL
Term infants: 1.5-2 mL
PO over 2 min
FDA, U.S. Food and Drug Administration; IV, intravenously; NSAIDs, nonsteroidal
antiinflammatory drugs; PDD, pervasive developmental disorder; PDR, Physicians' Desk
Reference ; PO, orally; PR, rectally; QTc, corrected QT interval on an electrocardiogram; SSRI,
selective serotonin reuptake inhibitor.

Acetaminophen , a generally safe, nonopioid analgesic and antipyretic, has

the advantage of intravenous (IV), rectal, and oral routes of administration.
and severe pain, such as acute postoperative pain, sickle cell crisis pain, and
cancer pain. Opioids can be administered by the oral, rectal, oral transmucosal,
transdermal, intranasal, IV, epidural, intrathecal, subcutaneous (SC), or
intramuscular (IM) route. Regardless of route of administration, the site of action
is at mu (µ) opioid receptors in the peripheral nervous system, spinal cord,
brainstem, and higher CNS centers. Historically, infants and young children have
been underdosed with opioids because of concern about significant respiratory
side effects. Once thought to represent infants' particular sensitivity, the opioids'
respiratory depressant effects are now known to result from infants' lower
metabolic clearance of opioids and higher blood levels with frequent dosing.
With proper understanding of the pharmacokinetic and pharmacodynamics of
opioids, children can receive effective relief of pain and suffering with a good
margin of safety, regardless of pharmacokinetic maturity, age, or size (Tables
76.5 to 76.8 ).
Table 76.5
Practical Aspects of Prescribing Opioids
• Morphine, hydromorphone, or fentanyl is regarded as 1st choice for severe
pain.
• Dosing should be titrated and individualized. There is no “right” dose for
everyone.
• The right dose is the dose that relieves pain with a good margin of safety.
• Dosing should be more cautious in infants, in patients with coexisting
diseases that increase risk or impair drug clearance, and with concomitant
administration of sedatives.
• Hydromorphone is metabolized by CYP2D6 and fentanyl by CYP3A4, and
to some extent 2D6; drugs that compete for 2D6 enzyme will raise blood
levels and increase risk of respiratory depression.
• Morphine is metabolized by glucuronidation to an active metabolite,
morphine-6-glucuronide, which accumulates and causes CNS toxicity in
renal impairment.
• Anticipate and treat peripheral side effects, including constipation, nausea,
and itching.
• Give doses at sufficient frequency to prevent the return of severe pain before
the next dose.
 • Use a drug delivery method, such as patient-controlled anesthesia or
continuous infusions, that avoids the need for “prn” decision-making.
• With opioid dosing for >1 wk, taper gradually to avoid abstinence
syndrome.
• When converting between parenteral and oral opioid doses, use appropriate
potency ratios (see Table 76.6 ).
• Tolerance refers to decreasing drug effect with continued administration of a
drug. Over time a patient will need higher dosing to achieve the same
clinical effect; however, tolerance to sedation and respiratory depression
develop more rapidly than tolerance to analgesia. Thus, with higher doses,
patients do not experience oversedation or respiratory depression.
• Dependence refers to the need for continued drug dosing to prevent
abstinence syndrome when a drug is abruptly discontinued, or its dose
reduced. Abstinence syndrome is characterized by irritability, agitation,
autonomic arousal, nasal congestion, piloerection, diarrhea, jitteriness, and
yawning; it is produced by administration of potent opioids for >5-7 days.
• Addiction, a psychiatric pathology, refers to psychological craving,
compulsive drug-seeking behavior, and drug use despite medical harm.
Addiction has strong genetic and environmental determinants. Opioid
therapy will not lead to addiction in nonsusceptible individuals, and opioid
underdosing does not prevent addiction; it may in fact increase drug-
seeking behavior for relief of pain (e.g., watching the clock), referred to as
“pseudoaddiction.”

Table 76.6
Pediatric Dosage Guidelines for Opioid Analgesics

EQUI-
ANALGESIC PARENTERAL DOSING IV:PO DOSE ORAL DOSING
DRUG DOSES RATIO
IV Oral <50 kg >50 kg <50 kg >50 kg
Fentanyl 10 µg 100 0.5-1 0.5-1 Oral Oral Transdermal
µg µg/kg µg/kg transmucosal: transmucosal: patches
q1-2h q1-2h 1 : 10 10 µg/kg available;
0.5-1.5 0.5-1.5 Transdermal: Transdermal: patch reaches
µg/kg/hr µg/kg/hr 1 : 1 12.5-50 µg/hr steady state at
24 hr and
should be
changed q72h
Hydrocodone N/A 1.5 mg N/A N/A N/A 0.15 mg/kg 10 mg

Hydromorphone 0.2 0.6 mg 0.01 mg 0.01 mg 1 : 3 0.04-0.08 mg/kg 2-4 mg q3-4h

mg q2-4h q2-4h q3-4h
0.002 0.002
mg/kg/hr mg/kg/hr

Meperidine 10 mg 30 mg 0.5 mg/kg 0.5 mg/kg 1 : 4 2-3 mg/kg q3-4h 100-150 mg

q2-4h q2-4h q3-4h

Methadone 1 mg 2 mg 0.1 mg/kg 0.1 mg/kg 1 : 2 0.2 mg/kg q8-12h 2.5 mg TID
q8-24h q8-24h PO; available as
liquid or tablet
 Morphine 1 mg 3 mg 0.05 Bolus: 5-8 1 : 3 Immediate Immediate
mg/kg mg q2-4h release: 0.3 release:
q2-4h mg/kg q3-4h 15-20 mg
0.01- Sustained q3-4h
0.03 release: Sustained
mg/kg/hr 20-35 kg: 10- release:
15 mg q8-12h 30-90 mg
35-50 kg: 15- q8-12h
30 mg q8-12h

Oxycodone N/A 3 mg N/A N/A N/A 0.1-0.2 mg q3-4h; Immediate

available in liquid release: 5-
(1 mg/mL) 10 mg q4h
Sustained
release:
10-120
mg q8-
12h

N/A, not available.

Table 76.7
Management of Opioid-Induced Adverse Effects
Respiratory Naloxone: 0.01-0.02 mg/kg up to a full reversal dose of 0.1 mg/kg. May be given IV, IM,
depression SC, or via ET.
The full reversal dose should initially be used for apnea in opioid-naive patients. In opioid-
tolerant patients, a reduced dose should be given and titrated up slowly to treat symptoms
but prevent acute withdrawal.
Ventilation may need to be supported during this process.
Dose may be repeated every 2 min to a total of 10 mg.
Adult maximum dose is 2 mg/dose. Give with caution to patients who are receiving long-
term opioid therapy, as it may precipitate acute withdrawal.
Duration of effect is 1-4 hr; therefore close observation for re-narcotization is essential to
prevent re-narcotization.
Excessive sedation Methylphenidate * : 0.3 mg/kg per dose PO (typically 10-20 mg/dose to a teenager) before
without evidence of breakfast and lunch. Do not administer to patients receiving clonidine, because
respiratory dysrhythmias may develop.
depression Dextroamphetamine : 2.5-10 mg on awakening and at noon. Not for use in young children
or in patients with cardiovascular disease or hypertension.
Modafinil: Pediatric dose not established. May be useful in selected patients. Typical adult
dose: 50-200 mg/day.
Change opioid or decrease the dose.
Nausea and Metoclopramide † : 0.15 mg/kg IV up to 10 mg/dose q6-12h for 24 hr.
vomiting Trimethobenzamide: PO or PR if weight <15 kg, 100 mg q6h; if >15 kg, 200 mg q6h. (Note:
Suppository contains benzocaine 2%.) Not for use in newborn infants or premature
infants.
5-HT3 receptor blockers:
Ondansetron: 0.15 mg/kg up to 8 mg IV q6-8h not to exceed 32 mg/day (also available as a
sublingual tablet).
Granisetron: 10 to 20 µg/kg IV q12-24h.
Prochlorperazine * (Compazine): >2 yr or >20 kg, 0.1 mg/kg per dose q8h IM or PO up to
10 mg/dose.
Change opioid.
Pruritus Hydroxyzine : 0.5 mg/kg PO q6h.
Nalbuphine: 0.1 mg/kg IV q6h for pruritus caused by intraaxial opioids, especially fentanyl.
Administer slowly over 15-20 min. May cause acute reversal of systemic µ-receptor
effects and leave κ-agonism intact.
Naloxone: 0.003 to 0.1 mg/kg/hr IV infusion (titrate up to decrease pruritus and reduce
infusion if pain increases).
Ondansetron: 0.05 to 0.1 mg/kg IV or PO q8h.
Cyproheptadine † : 0.1-0.2 mg/kg PO q8-12h. Maximum dose 12 mg.
Change opioid.
Constipation Encourage water consumption, high-fiber diet, and vegetable fiber.
Bulk laxatives: Metamucil, Maltsupex.
Lubricants: Mineral oil 15-30 mL PO qd as needed (not for use in infants because of
aspiration risk).
Surfactants: Sodium docusate (Colace):
<3 yr: 10 mg PO q8h
3-6 yr: 15 mg PO q8h
6-12 yr: 50 mg PO q8h
>12 yr: 100 mg PO q8h
Stimulants:
Bisacodyl suppository (Dulcolax):
<2 yr: 5 mg PR qhs
>2 yr: 10 mg PR qhs
Senna syrup (218 mg/5 mL): >3 yr: 5 mL qhs.
Enema: Fleet hypertonic phosphate enema (older children; risk of hyperphosphatemia).
Electrolytic/osmotic: Milk of magnesia; for severe impaction: polyethylene glycol
 (GoLYTELY, MiraLax).
Methylnaltrexone is an opioid antagonist that works in the colon and does not cross the
blood-brain barrier to reverse analgesia; given as subcutaneous injection every day or
every other day (0.15 mg/kg) and is effective in producing stool in 30-60 min in most
patients.
Urinary retention Straight catheterization, indwelling catheter.
*
Avoid in patients taking monoamine oxidase inhibitors.
† May be associated with extrapyramidal side effects, which may be more often seen in children

than in adults.
ET, Endotracheal tube; IV, intravenously; IM, intramuscularly; PO, orally; PR, rectally; SC,
subcutaneously.
Modified from Burg FD, Ingelfinger JR, Polin RA, et al, editors: Current pediatric therapy, ed 18,
Philadelphia, 2006, Saunders/Elsevier, p 16.

Table 76.8
Equianalgesic Doses and Half-Life (T1/2β ) of Some
Commonly Used Opioids

OPIOID IM/IV DOSE (mg) ORAL DOSE (mg) T1/2β (hr)

Morphine 10 30 2-3
Meperidine 100 400 3-4
Oxycodone 15 20-30 2-3
Fentanyl 0.15-0.2 — 3-5
Alfentanil 0.75-1.5 — 1-2
Sufentanil 0.02 — 2-3
Diamorphine 5 60 0.5*
Methadone 10 10-15 15-40
Hydromorphone 1.5 7.5 3-4
Tramadol † 100 100 5-7
Buprenorphine 0.4 0.8 (sublingual) 3-5
Pentazocine 60 150 3-5
Nalbuphine 10-20 — 2-4
Butorphanol 2 — 2-3
* Rapidly hydrolyzed to morphine.

† Only part of its analgesic action results from action on µ-opioid receptors.

NOTES:

• Published reports vary in the suggested doses

considered to be equianalgesic to morphine. Therefore,
titration to clinical response in each patient is necessary.
• Suggested doses are the results of single-dose studies
best managed by specialists in pain management and addiction medicine. Table
76.9 outlines the U.S. Centers for Disease Control and Prevention (CDC) opioid
recommendations for chronic pain (primarily in adults).
Table 76.9
CDC Recommendations for Prescribing
Opioids for Chronic Pain Outside of Active
Cancer, Palliative, and End-of-Life Care
Determining When to Initiate or Continue Opioids for Chronic Pain

1. Nonpharmacologic therapy and nonopioid pharmacologic therapy are

preferred for chronic pain. Clinicians should consider opioid therapy only
if expected benefits for both pain and function are anticipated to
outweigh risks to the patient. If opioids are used, they should be
combined with nonpharmacologic therapy and nonopioid pharmacologic
therapy, as appropriate.
2. Before starting opioid therapy for chronic pain, clinicians should establish
treatment goals with all patients, including realistic goals for pain and
function, and should consider how therapy will be discontinued if
benefits do not outweigh risks. Clinicians should continue opioid therapy
only if there is clinically meaningful improvement in pain and function
that outweighs risks to patient safety.
3. Before starting and periodically during opioid therapy, clinicians should
discuss with patients known risks and realistic benefits of opioid therapy
and patient and clinician responsibilities for managing therapy.

Opioid Selection, Dosage, Duration, Follow-Up, and Discontinuation

4. When starting opioid therapy for chronic pain, clinicians should prescribe
immediate-release opioids instead of extended-release/long-acting
(ER/LA) opioids.
5. When opioids are started, clinicians should prescribe the lowest effective
dosage. Clinicians should use caution when prescribing opioids at any
dosage, should carefully reassess evidence of individual benefits and
risks when increasing dosage to ≥50 morphine milligram equivalents
(MME)/day, and should avoid increasing dosage to ≥90 MME/day or
 carefully justify a decision to titrate dosage to ≥90 MME/day.
6. Long-term opioid use often begins with treatment of acute pain. When
opioids are used for acute pain, clinicians should prescribe the lowest
effective dose of immediate-release opioids and should prescribe no
greater quantity than needed for the expected duration of pain severe
enough to require opioids. Three days or less will often be sufficient;
more than seven days will rarely be needed.
7. Clinicians should evaluate benefits and harms with patients within 1 to 4
weeks of starting opioid therapy for chronic pain or of dose escalation.
Clinicians should evaluate benefits and harms of continued therapy with
patients every 3 months or more frequently. If benefits do not outweigh
harms of continued opioid therapy, clinicians should optimize other
therapies and work with patients to taper opioids to lower dosages or to
taper and discontinue opioids.

Assessing Risk and Addressing Harms of Opioid Use

8. Before starting and periodically during continuation of opioid therapy,

clinicians should evaluate risk factors for opioid-related harms.
Clinicians should incorporate into the management plan strategies to
mitigate risk, including considering offering naloxone when factors that
increase risk for opioid overdose, such as history of overdose, history of
substance use disorder, higher opioid dosages (≥50 MME/day), or
concurrent benzodiazepine use, are present.
9. Clinicians should review the patient's history of controlled substance
prescriptions using state prescription drug monitoring program (PDMP)
data to determine whether the patient is receiving opioid dosages or
dangerous combinations that put him or her at high risk for overdose.
Clinicians should review PDMP data when starting opioid therapy for
chronic pain and periodically during opioid therapy for chronic pain,
ranging from every prescription to every 3 months.
10. When prescribing opioids for chronic pain, clinicians should use urine
drug testing before starting opioid therapy and consider urine drug testing
at least annually to assess for prescribed medications as well as other
controlled prescription drugs and illicit drugs.
11. Clinicians should avoid prescribing opioid pain medication and
benzodiazepines concurrently whenever possible.
 12. Clinicians should offer or arrange evidence-based treatment (usually
medication-assisted treatment with buprenorphine or methadone in
combination with behavioral therapies) for patients with opioid use
disorder.

All recommendations are category A (apply to all patients outside of active

cancer treatment, palliative care, and end-of-life care) except recommendation
10 (designated category B, with individual decision making required); see full
guideline for evidence ratings.

From Dowell D, Haegerich TM, Chou R: CDC guideline for prescribing opioids
for chronic pain—United States, 2016, MMWR 65(1):1–49, 2016.

There is no longer a reason to administer opioids by IM injection. Continuous

IV infusion of opioids is an effective option that permits more constant plasma
concentrations and clinical effects than intermittent IV bolus dosing, without the
pain associated with IM injection. The most common approach in pediatric
centers is to administer a low-dose basal opioid infusion, while permitting
patients to use a patient-controlled analgesia (PCA) device to titrate the dosage
above the infusion (Fig. 76.3 ) (see Chapter 74 ). Compared with children given
intermittent IM morphine, children using PCA reported better pain scores. PCA
has several other advantages: (1) dosing can be adjusted to account for
individual pharmacokinetic and pharmacodynamic variation and for changing
pain intensity during the day; (2) psychologically the patient is more in control,
actively coping with the pain; (3) overall opioid consumption tends to be lower;
(4) therefore fewer side effects occur; and (5) patient satisfaction is generally
much higher. Children as young as 5-6 yr can effectively use PCA. The device
can also be activated by parents or nurses, known as PCA-by-proxy (PCA-P),
which produces analgesia in a safe, effective manner for children who cannot
activate the PCA demand button themselves because they are too young or
intellectually or physically impaired. PCA overdoses have occurred when well-
meaning, inadequately instructed parents pushed the PCA button in medically
complicated situations, with or without the use of PCA-P, highlighting the need
for patient and family education, use of protocols, and adequate nursing
supervision.

FIG. 76.3 Patient-controlled analgesia is more likely to keep blood
concentrations of opioid within the “analgesic corridor” and allows rapid
titration if there is an increase in pain stimulus requiring higher blood levels
of opioid to maintain the analgesia. (From Burg FD, Ingelfinger JR, Polin
RA, et al, editors: Current pediatric therapy, ed 18. Philadelphia, 2006,
Saunders/Elsevier, p 16.)

Because of the high risk of adverse side effects (respiratory depression), the
FDA has issued contraindications for the pediatric use of codeine and tramadol
(Table 76.10 ).
Table 76.10
Summary of FDA Recommendations
• Use of codeine to treat pain or cough in children <12 yr old is
contraindicated.
• Use of tramadol to treat pain in children <12 yr old is contraindicated.
• Use of tramadol for treatment of pain after tonsillectomy or adenoidectomy
in patients <18 yr old is contraindicated. (Codeine was already
contraindicated in such patients).
• Use of codeine or tramadol in children 12-18 yr old who are obese or who
have an increased risk of serious breathing problems, such as those with
obstructive sleep apnea or severe lung disease, is not recommended.
• Use of codeine or tramadol in breastfeeding women should be avoided.

From The Medical Letter: FDA warns against use of codeine and tramadol in
children and breastfeeding women, Med Lett 59(1521):86–88, 2017.
Local Anesthetics
Local anesthetics are widely used in children for topical application, cutaneous
infiltration, peripheral nerve block, neuraxial blocks (intrathecal or epidural
infusions), and IV infusions (Table 76.11 ) (see Chapter 74 ). Local anesthetics
can be used with excellent safety and effectiveness. Local anesthetics interfere
with neural transmission by blocking neuronal sodium channels. Excessive
systemic dosing can cause seizures, CNS depression, and (by cardiac and
arteriolar sodium channel blockade) hypotension, arrhythmias, cardiac
depression, and cardiovascular collapse. Local anesthetics therefore require a
strict maximum dosing schedule. Pediatricians should be aware of the need to
calculate these doses and adhere to guidelines.

Table 76.11
Topical Pharmacologic Management of Acute Pain in
Children

DRUG DOSE NOTES

INTACT SKIN
Lidocaine 2⋅5% and prilocaine <3 mo old or <5 kg: 1 60 min is needed to achieve maximum effect;
2⋅5% (EMLA cream) g cover cream with an occlusive dressing
3–12 mo and >5 kg: 2
g
1–6 yr and >10 kg: 10
g
7–12 yr and >20 kg:
20 g

Lidocaine 70 mg and tetracaine Age ≥3 yr: apply patch 20–30 min needed to achieve maximum effect
70 mg (Synera patch)
Tetracaine 4% (Ametop) >1 mo and <5 yr: 30 min before venipuncture
apply 1 tube of gel (1 45 min before intravenous cannulation
g)
>5 yr: apply up to 5
tubes of gel (5 g)
WOUNDS
Lidocaine, epinephrine, Age ≥1 yr: apply to wound 20 min needed for maximum effect
tetracaine (LET) solution or gel*
* Also referred to as ALA on the basis of alternative names for the constituents: adrenaline,
lignocaine, amethocaine. These mixtures are locally made by hospital formularies, with a common
formula being lidocaine 4% plus epinephrine 0⋅1% plus tetracaine 0⋅5%. The cocaine-based
formulation was historically avoided on wounds of digits, ears, penis, nose, mucous membranes,
close to the eye, or deep wounds involving bone, cartilage, tendon, or vessels. The lidocaine-
based formulation can be used in such settings.
Adapted from Krauss BS, Calligaris L, Green SM, Barbi E: Current concepts in management of
pain in children in the emergency department, Lancet 387:83–92, 2016.

Topical local anesthetic preparations do not generally result in measurable

systemic blood levels and can reduce pain in diverse circumstances: suturing of
lacerations, placement of peripheral IV catheters, lumbar punctures, and
accessing indwelling central venous ports. The application of tetracaine,
epinephrine, and cocaine results in good anesthesia for suturing wounds but
should not be used on mucous membranes. Combinations of tetracaine with
phenylephrine and lidocaine-epinephrine-tetracaine are equally as effective,
eliminating the need to use a controlled substance (cocaine). EMLA, a topical
eutectic mixture of lidocaine and prilocaine used to anesthetize intact skin, is
frequently applied for venipuncture, lumbar puncture, and other needle
procedures. A 5% lidocaine cream (Elemax) is also effective as a topical
anesthetic.
Lidocaine is the most commonly used local anesthetic for cutaneous
infiltration. Maximum safe doses of lidocaine are 5 mg/kg without epinephrine
and 7 mg/kg with epinephrine. Although concentrated solutions (2%) are
commonly available from hospital pharmacies, more dilute solutions (0.25% and
0.5%) are equally as effective as 1–2% solutions. The diluted solutions cause
less burning discomfort on injection and permit use of larger volumes without
achieving toxic doses. In the surgical setting, cutaneous infiltration is more often
performed with bupivacaine 0.25% or ropivacaine 0.2% because of the much
longer duration of effect; maximum dosage of these long-acting amide
anesthetics is 2-3 mg/kg and 3-4 mg/kg, respectively.
Neuropathic pain may respond well to the local application of a lidocaine
topical patch (Lidoderm) for 12 hr/day (Table 76.12 ). Peripheral and central
neuropathic pain also may respond to IV lidocaine infusions, which may be used
in hospital settings for refractory pain, complex regional pain syndromes, and
pain associated with malignancies or the therapy of malignancies, such as oral
mucositis following bone marrow transplantation. In these patients, 1-2 mg/kg/hr
should be administered, and the infusion titrated to achieve a blood lidocaine
level in the 2-5 µg/mL range, with use of twice-daily therapeutic blood
monitoring. Table 76.13 outlines approaches to central neuropathic pain.
Table 76.12
Examples of Neuropathic Pain Syndromes
Peripheral Nervous System Focal and Multifocal Lesions
 Postherpetic neuralgia
Cranial neuralgias (e.g., trigeminal neuralgia, glossopharyngeal neuralgia)
Diabetic mononeuropathy
Nerve entrapment syndromes
Plexopathy from malignancy or irradiation
Phantom limb pain
Posttraumatic neuralgia (e.g., nerve root compression, after thoracotomy)
Ischemic neuropathy
Complex regional pain syndrome types 1 and 2
Erythromelalgia

Peripheral Nervous System Generalized Polyneuropathies

Metabolic/nutritional: Diabetes mellitus, pellagra, beriberi, multiple

nutritional deficiency, hypothyroidism
Toxic: Alcohol-, platinum-, or taxane-based chemotherapy, isoniazid,
antiretroviral drugs
Infective/autoimmune: HIV, acute inflammatory polyneuropathy (Guillain-
Barré syndrome), neuroborreliosis (Bannwarth syndrome)
Hereditary: Fabry disease
Malignancy: Carcinomatosis
Others: Idiopathic small-fiber neuropathy, erythromelalgia

Central Nervous System Lesions

Spinal cord injury

Prolapsed disc
Stroke (brain infarction, spinal infarction)
Multiple sclerosis
Surgical lesions (e.g., rhizotomy, cordotomy)
Complex neuropathic disorders
Complex regional pain syndrome types 1 and 2

Adapted from Freynhagen R, Bennett MI: Diagnosis and management of

neuropathic pain, BMJ 339:b3002, 2009.
Table 76.13
Treatment Recommendations for Central Neuropathic Pain
Adapted From Current Evidence-Based Literature

RECOMMENDED STAGE OF
MEDICATION CLASS/DRUG
TREATMENT
ANTIDEPRESSANTS
Tricyclics (e.g., amitriptyline, nortriptyline) 1st or 2nd
Serotonin and norepinephrine reuptake inhibitors (e.g., duloxetine, 1st or 2nd
venlafaxine)
ANTICONVULSANTS
Pregabalin 1st or 2nd
Gabapentin 1st or 2nd
Lamotrigine 2nd or 3rd (in pain after stroke)
Valproate 3rd
OPIOIDS *
Levorphanol
MISCELLANEOUS
Cannabinoids 2nd (in multiple sclerosis)
Mexiletine 3rd
* 2nd or 3rd treatment stage (no specification).

Adapted from Freynhagen R, Bennett MI: Diagnosis and management of neuropathic pain, BMJ
339:b3002, 2009.

Unconventional Medications in Pediatric

Pain
Unconventional analgesic medication refers to a wide number of drugs
developed for other indications but found to have analgesic properties. These
drugs include some antidepressants, antiepileptic drugs, and neurotropic drugs.
The unconventional analgesics are generally used to manage neuropathic pain
conditions, migraine disorders, fibromyalgia syndrome, and some forms of
functional chronic abdominal pain syndromes. These agents also are used as
components of multimodal analgesia in the management of surgical, somatic,
and musculoskeletal pain. Fig. 76.4 presents a decision-making tree to help the
physician select the appropriate analgesic category for various types of pain.
simple and efficacious, especially for home use, the ladder presents a framework
for rationally using them before applying other drugs and techniques of drug
administration.
Table 76.14
World Health Organization Analgesic Ladder
for Cancer Pain
Step 1

Patients who present with mild to moderate pain should be treated with a
nonopioid.

Step 2

Patients who present with moderate to severe pain or for whom the step 1
regimen fails should be treated with an oral opioid for moderate pain
combined with a nonopioid analgesic.

Step 3

Patients who present with very severe pain or for whom the step 2 regimen
fails should be treated with an opioid used for severe pain, with or
without a nonopioid analgesic.

Oral medications are the first line of analgesic treatment. Because NSAIDs
affect platelet adhesiveness, they are typically not used. Opioid therapy is the
preferred approach for moderate or severe pain. Nonopioid analgesics are used
for mild pain, a weak opioid is added for moderate pain, and strong opioids are
administered for more severe pain. Adjuvant analgesics can be added, and side
effects and comorbid symptoms are actively managed. Determining the type and
sources of the pain will help develop an effective analgesic plan. Certain
treatments, such as the chemotherapeutic agent vincristine, are associated with
neuropathic pain. Such pain might require anticonvulsants or TCAs. Organ-
stretching pain from tumor growth within an organ might require strong opioids
and/or radiation therapy if the tumor is radiosensitive. Organ obstruction, such as
and aliphatic hydrocarbons were significant causes of mortality.

Table 77.1

Common Agents Potentially Toxic to Young Children (<6 yr) in Small Doses*
SUBSTANCE TOXICITY
Aliphatic hydrocarbons (e.g., gasoline, kerosene, lamp Acute lung injury
oil)
Antimalarials (chloroquine, quinine) Seizures, dysrhythmias
Benzocaine Methemoglobinemia
β-Adrenergic receptor blockers † Bradycardia, hypotension
Calcium channel blockers Bradycardia, hypotension, hyperglycemia
Camphor Seizures
Caustics (pH <2 or >12) Airway, esophageal and gastric burns
Clonidine Lethargy, bradycardia, hypotension
Diphenoxylate and atropine (Lomotil) CNS depression, respiratory depression
Hypoglycemics, oral (sulfonylureas and meglitinides) Hypoglycemia, seizures
Laundry detergent packets (pods) Airway issues, respiratory distress, altered mental status
Lindane Seizures
Monoamine oxidase inhibitors Hypertension followed by delayed cardiovascular
collapse
Methyl salicylate Tachypnea, metabolic acidosis, seizures
Opioids (especially methadone, buprenorphine) CNS depression, respiratory depression
Organophosphate pesticides Cholinergic crisis
Phenothiazines (especially chlorpromazine, Seizures, dysrhythmias
thioridazine)
Theophylline Seizures, dysrhythmias
Tricyclic antidepressants CNS depression, seizures, dysrhythmias, hypotension
* ”Small dose” typically implies 1 or 2 pills or 5 mL.

† Lipid-soluble β-blockers (e.g., propranolol) are more toxic than water-soluble β-blockers (e.g.,
atenolol).
CNS, Central nervous system.

Poison prevention education should be an integral part of all well-child visits,

starting at the 6 mo visit. Counseling parents and other caregivers about potential
poisoning risks, poison-proofing a child's environment, and actions in the event
of an ingestion diminishes the likelihood of serious morbidity or mortality.
Poison prevention education materials are available from the American
Academy of Pediatrics (AAP) and regional PCCs. Through a U.S. network of
PCCs, anyone at any time can contact a regional poison center by calling the
toll-free number 1-800-222-1222 . Parents should be encouraged to share this
number with grandparents, relatives, babysitters, and any other caregivers.
Product safety measures, poison prevention education, early recognition of
exposures, and around-the-clock access to regionally based PCCs all contribute
 Next, it is important to clarify the timing of the ingestion and to obtain some
estimate of how much of the substance was ingested. It is better to overestimate
the amount ingested to prepare for the worst-case scenario. Counting pills or
measuring the remaining volume of a liquid ingested can sometimes be useful in
generating estimates. For inhalational, ocular, or dermal exposures, the
concentration of the agent and the length of contact time with the material
should be determined, if possible.

Symptoms
Obtaining a description of symptoms experienced after ingestion, including their
timing of onset relative to the time of ingestion and their progression, can
generate a list of potential toxins and help anticipate the severity of the ingestion.
Coupled with physical exam findings, reported symptoms assist practitioners in
identifying toxidromes, or recognized poisoning syndromes, suggestive of
toxicity from specific substances or classes of substances (Tables 77.2 to 77.4 ).

Table 77.2
Selected Historical and Physical Findings in Poisoning

SIGN TOXIN
ODOR
Bitter almonds Cyanide
Acetone Isopropyl alcohol, methanol, paraldehyde, salicylates
Rotten eggs Hydrogen sulfide, sulfur dioxide, methyl mercaptans (additive to natural gas)
Wintergreen Methyl salicylate
Garlic Arsenic, thallium, organophosphates, selenium
OCULAR SIGNS
Miosis Opioids (except propoxyphene, meperidine, and pentazocine), organophosphates and other
cholinergics, clonidine, phenothiazines, sedative-hypnotics, olanzapine
Mydriasis Anticholinergics (e.g., antihistamines, TCAs, atropine), sympathomimetics (cocaine,
amphetamines, PCP), post–anoxic encephalopathy, opiate withdrawal, cathinones, MDMA
Nystagmus Anticonvulsants, sedative-hypnotics, alcohols, PCP, ketamine, dextromethorphan
Lacrimation Organophosphates, irritant gas or vapors
Retinal hyperemia Methanol
CUTANEOUS SIGNS
Diaphoresis Cholinergics (organophosphates), sympathomimetics, withdrawal syndromes
Alopecia Thallium, arsenic
Erythema Boric acid, elemental mercury, cyanide, carbon monoxide, disulfiram, scombroid,
anticholinergics, vancomycin
Cyanosis Methemoglobinemia (e.g., benzocaine, dapsone, nitrites, phenazopyridine), amiodarone,
(unresponsive to silver
oxygen)
ORAL SIGNS
Salivation Organophosphates, salicylates, corrosives, ketamine, PCP, strychnine
 Oral burns Corrosives, oxalate-containing plants
Gum lines Lead, mercury, arsenic, bismuth
GASTROINTESTINAL SIGNS
Diarrhea Antimicrobials, arsenic, iron, boric acid, cholinergics, colchicine, opioid withdrawal
Hematemesis Arsenic, iron, caustics, NSAIDs, salicylates
Constipation Lead
CARDIAC SIGNS
Tachycardia Sympathomimetics, anticholinergics, antidepressants, antipsychotics, methylxanthines
(theophylline, caffeine), salicylates, cellular asphyxiants (cyanide, carbon monoxide,
hydrogen sulfide), withdrawal (ethanol, sedatives, clonidine, opioids), serotonin syndrome,
neuroleptic malignant syndrome, MDMA, cathinones
Bradycardia β-Blockers, calcium channel blockers, digoxin, clonidine, organophosphates, opioids,
sedative-hypnotics
Hypertension Sympathomimetics, anticholinergics, monoamine oxidase inhibitors, serotonin syndrome,
neuroleptic malignant syndrome, clonidine withdrawal
Hypotension β-Blockers, calcium channel blockers, cyclic antidepressants, iron, antipsychotics,
barbiturates, clonidine, opioids, arsenic, amatoxin mushrooms, cellular asphyxiants (cyanide,
carbon monoxide, hydrogen sulfide), snake envenomation
RESPIRATORY SIGNS
Depressed Opioids, sedative-hypnotics, alcohol, clonidine, barbiturates
respirations
Tachypnea Salicylates, sympathomimetics, caffeine, metabolic acidosis, carbon monoxide, hydrocarbon
aspiration
CENTRAL NERVOUS SYSTEM SIGNS
Ataxia Alcohols, anticonvulsants, sedative-hypnotics, lithium, dextromethorphan, carbon monoxide,
inhalants
Coma Opioids, sedative-hypnotics, anticonvulsants, antidepressants, antipsychotics, ethanol,
anticholinergics, clonidine, GHB, alcohols, salicylates, barbiturates
Seizures Sympathomimetics, anticholinergics, antidepressants (especially TCAs, bupropion,
venlafaxine), cholinergics (organophosphates), isoniazid, camphor, lindane, salicylates, lead,
nicotine, tramadol, water hemlock, withdrawal
Delirium/psychosis Sympathomimetics, anticholinergics, LSD, PCP, hallucinogens, lithium, dextromethorphan,
steroids, withdrawal, MDMA, cathinones
Peripheral Lead, arsenic, mercury, organophosphates, nicotine
neuropathy
GHB, γ-Hydroxybutyrate; LSD, lysergic acid diethylamide; MDMA, 3,4-
methylenedioxymethamphetamine (Ecstasy); NSAIDs, nonsteroidal antiinflammatory drugs; PCP,
phencyclidine; TCAs, tricyclic antidepressants.

Table 77.3
Recognizable Poison Syndromes (“Toxidromes”)

SIGNS
POSSIBLE
TOXIDROME Mental Bowel
Vital Signs Pupils Skin Other TOXINS
Status Sounds
Sympathomimetic Hypertension, Agitation, Dilated Diaphoretic Normal to Amphetamines,
tachycardia, psychosis, increased cocaine, PCP,
hyperthermia delirium, bath salts
violence (cathinones),
 ADHD
medication
Anticholinergic Hypertension, Agitated, Dilated Dry, hot Diminished Ileus urinary Antihistamines,
tachycardia, delirium, retention TCAs, atropine,
hyperthermia coma, jimsonweed
seizures
Cholinergic Bradycardia, Confusion, Small Diaphoretic Hyperactive Diarrhea, Organophosphates
BP, and temp coma, urination, (insecticides,
typically fasciculations bronchorrhea, nerve agents),
normal bronchospasm, carbamates
emesis, (physostigmine,
lacrimation, neostigmine,
salivation pyridostigmine)
Alzheimer
medications,
myasthenia
treatments
Opioids Respiratory Depression, Pinpoint Normal Normal to Methadone,
depression coma, decreased buprenorphine,
bradycardia, euphoria morphine,
hypotension, oxycodone,
hypothermia heroin, etc.
Sedative- Respiratory Somnolence, Small or Normal Normal Barbiturates,
hypnotics depression, coma normal benzodiazepines,
HR normal to ethanol
decreased, BP
normal to
decreased,
temp normal
to decreased
Serotonin Hyperthermia, Agitation, Dilated Diaphoretic Increased Neuromuscular SSRIs, lithium,
syndrome (similar tachycardia, confusion, hyperexcitability: MAOIs, linezolid,
findings with hypertension coma clonus, tramadol,
neuroleptic or hyperreflexia meperidine,
malignant hypotension (lower > upper dextromethorphan
syndrome) (autonomic extremities)
instability)
Salicylates Tachypnea, Agitation, Normal Diaphoretic Normal Nausea, Aspirin and
hyperpnea, confusion, vomiting, aspirin-containing
tachycardia, coma tinnitus, ABGs products, methyl
hyperthermia with primary salicylate
respiratory
alkalosis and
primary
metabolic
acidosis; tinnitus
or difficulty
hearing
Withdrawal Tachycardia, Agitation, Dilated Diaphoretic Increased Lack of access to
(sedative- tachypnea, tremor, ethanol,
hypnotic) hyperthermia seizure, benzodiazepines,
hallucinosis, barbiturates,
delirium GHB, or
tremens excessive use of
flumazenil
 Withdrawal Tachycardia Restlessness, Dilated diaphoretic Hyperactive Nausea, Lack of access to
(opioid) anxiety vomiting, opioids or
diarrhea excessive use of
naloxone

ABGs, Arterial blood gases; ADHD, attention-deficit/hyperactivity disorder; BP, blood pressure;
GHB, γ-hydroxybutyrate; HR, heart rate; MAOIs, monoamine oxidase inhibitors; PCP,
phencyclidine; SSRIs, selective serotonin reuptake inhibitors; temp, temperature; TCAs, tricyclic
antidepressants.

Table 77.4

Mini-Toxidromes
TOXIDROME SYMPTOMS AND SIGNS EXAMPLES
α1 -Adrenergic CNS depression, tachycardia, Chlorpromazine, quetiapine, clozapine, olanzapine,
receptor miosis risperidone
antagonists
α2 -Adrenergic CNS depression, bradycardia, Clonidine, oxymetazoline, tetrahydrozoline, tizanidine,
receptor agonist hypertension (early), dexmedetomidine
hypotension (late), miosis
Clonus/myoclonus CNS depression, myoclonic Carisoprodol, lithium, serotonergic agents, bismuth,
jerks, clonus, hyperreflexia organic lead, organic mercury, serotonin or neuroleptic
malignant syndrome
Sodium channel CNS toxicity, wide QRS Cyclic antidepressants and structurally related agents,
blockers propoxyphene, quinidine/quinine, amantadine,
antihistamines, bupropion, cocaine
Potassium channel CNS toxicity, long QT interval Antipsychotics, methadone, phenothiazines
blockers
Cathinones, Hyperthermia, tachycardia, See Chapter 140 .
synthetic delirium, agitation, mydriases
cannabinoids
CNS, Central nervous system.
From Ruha AM, Levine M: Central nervous system toxicity. Emerg Med Clin North Am 32(1):205–
221, 2014, p 208.

Past Medical and Developmental History

Underlying diseases can make a child more susceptible to the effects of a toxin.
Concurrent drug therapy can also increase toxicity because certain drugs may
interact with the toxin. A history of psychiatric illness can make patients more
prone to substance abuse, misuse, intentional ingestions, and polypharmacy
complications. Pregnancy is a common precipitating factor in adolescent suicide
attempts and can influence both evaluation of the patient and subsequent
treatment. A developmental history is important to ensure that the exposure
history provided is appropriate for the child's developmental stage (e.g., report of
postpubertal female patients. Based on the clinical presentation and the
presumed poison, additional lab tests may also be helpful. Acetaminophen is a
widely available medication and a commonly detected co-ingestant with the
potential for severe toxicity. There is an effective antidote to acetaminophen
poisoning that is time dependent. Given that patients might initially be
asymptomatic and might not report or be aware of acetaminophen ingestion, an
acetaminophen level should be checked in all patients who present after an
intentional exposure or ingestion.
Table 77.5
Laboratory Clues in Toxicologic Diagnosis
Anion Gap Metabolic Acidosis (Mnemonic = Mudpiles Cat)

M ethanol, metformin
U remia
D iabetic ketoacidosis
P ropylene glycol
I soniazid, iron, massive ibuprofen
L actic acidosis
E thylene glycol
S alicylates
C ellular asphyxiants (cyanide, carbon monoxide, hydrogen sulfide)
A lcoholic ketoacidosis
T ylenol (clinical significance depends upon presence or absence of liver
injury)

Elevated Osmolar Gap

Alcohols: ethanol, isopropyl, methanol, ethylene glycol

Hypoglycemia (Mnemonic = Hobbies)

H ypoglycemics, oral: sulfonylureas, meglitinides

O ther: quinine, unripe ackee fruit
B eta B lockers
 I nsulin
E thanol
S alicylates (late)

Hyperglycemia

Salicylates (early)
Calcium channel blockers
Caffeine

Hypocalcemia

Ethylene glycol
Fluoride

Rhabdomyolysis

Neuroleptic malignant syndrome, serotonin syndrome

Statins
Mushrooms (Tricholoma equestre )
Any toxin causing prolonged immobilization (e.g., opioids, antipsychotics)
or excessive muscle activity or seizures (e.g., sympathomimetics)

Radiopaque Substance on Kub (Mnemonic = Chipped)

C hloral hydrate, calcium carbonate

H eavy metals (lead, zinc, barium, arsenic, lithium, bismuth)
I ron
P henothiazines
P lay-Doh, potassium chloride
E nteric-coated pills
D ental amalgam, drug packets

KUB, Kidney-ureter-bladder radiograph.

gold standard measurement for legal purposes.

Additional Diagnostic Testing

An electrocardiogram (ECG) is a quick and noninvasive bedside test that can
yield important clues to diagnosis and prognosis. Particular attention should be
paid to the ECG intervals (Table 77.6 ). A widened QRS interval, putting the
patient at risk for monomorphic ventricular tachycardia, suggests blockade of
fast sodium channels. A widened QTc interval suggests effects at the potassium
rectifier channels and portends a risk of torsades de pointes (polymorphic
ventricular tachycardia).
Table 77.6
Electrocardiographic Findings in Poisoning
Pr Interval Prolongation

Digoxin
Lithium

QRS Prolongation

Tricyclic antidepressants
Diphenhydramine
Carbamazepine
Cardiac glycosides
Chloroquine, hydroxychloroquine
Cocaine
Lamotrigine
Quinidine, quinine, procainamide, disopyramide
Phenothiazines
Propoxyphene
Propranolol
Bupropion, venlafaxine (rare)

QTc Prolongation*
 Amiodarone
Antipsychotics (typical and atypical)
Arsenic
Cisapride
Citalopram
Clarithromycin, erythromycin
Disopyramide, dofetilide, ibutilide
Fluconazole, ketoconazole, itraconazole
Methadone
Pentamidine
Phenothiazines
Sotalol

* This is a select list of important toxins, other medications are also associated

with QTc prolongation.

Chest radiography may reveal signs of pneumonitis (e.g., hydrocarbon

aspiration), noncardiogenic pulmonary edema (e.g., salicylate toxicity), or a
foreign body. Abdominal radiography is most helpful in screening for the
presence of lead paint chips or other foreign bodies. It may detect a bezoar
(concretion), demonstrate radiopaque tablets, or reveal drug packets in a “body
packer.” Further diagnostic testing is based on the differential diagnosis and
pattern of presentation.

Principles of Management
The principles of management of the poisoned patient are supportive care,
decontamination, directed therapy (antidotes, ILE), and enhanced elimination.
Few patients meet criteria for all these interventions, although clinicians should
consider each option in every poisoned patient so as not to miss a potentially
lifesaving intervention. Antidotes are available for relatively few poisons (Tables
77.7 and 77.8 ), thus emphasizing the importance of meticulous supportive care
and close clinical monitoring.

Table 77.7
Common Antidotes for Poisoning

ADVERSE EFFECTS,
POISON ANTIDOTE DOSAGE ROUTE
WARNINGS, COMMENTS
Acetaminophen N -Acetylcysteine 140 mg/kg loading, PO Vomiting (patient-tailored
(Mucomyst) followed by 70 mg/kg regimens are the norm)
q4h
N -Acetylcysteine 150 mg/kg over 1 hr, IV Anaphylactoid reactions
(Acetadote) followed by 50 mg/kg (most commonly seen with
over 4 hr, followed by loading dose)
100 mg/kg over 16 hr (Higher doses of the infusion
are often recommended
depending on acetaminophen
level or degree of injury)
Anticholinergics Physostigmine 0.02 mg/kg over 5 min; IV/IM Bradycardia, seizures,
may repeat q5-10 min bronchospasm
to 2 mg max Note: Do not use if
conduction delays on ECG.
Benzodiazepines Flumazenil 0.2 mg over 30 sec; if IV Agitation, seizures from
response is inadequate, precipitated withdrawal
repeat q1min to 1 mg (doses over 1 mg)
max Do not use for unknown or
polypharmacy ingestions.
β-Blockers Glucagon 0.15 mg/kg bolus IV Vomiting, relative lack of
followed by infusion of efficacy
0.05-0.15 mg/kg/hr
Calcium channel Insulin 1 unit/kg bolus IV Hypoglycemia
blockers followed by infusion of Follow serum potassium and
0.5-1 unit/kg/hr glucose closely.
Calcium salts Dose depends on the IV
specific calcium salt
Carbon monoxide Oxygen 100% FIO 2 by non- Inhalation Some patients may benefit from
rebreather mask (or ET hyperbaric oxygen (see text).
if intubated)
Cyanide Hydroxocobalamin 70 mg/kg (adults: 5 g) IV Flushing/erythema, nausea, rash,
(Cyanokit) given over 15 min chromaturia, hypertension,
headache
Digitalis Digoxin-specific 1 vial binds 0.6 IV Allergic reactions (rare), return of
Fab antibodies mg of digitalis condition being treated with
(Digibind, DigiFab) glycoside; digitalis glycoside
#vials = digitalis
level × weight in
kg/100
Ethylene glycol, Fomepizole 15 mg/kg load; 10 IV Infuse slowly over 30 min.
methanol mg/kg q12h × 4 doses; If fomepizole is not
15 mg/kg q12h until available, can treat with oral
ethylene glycol level is ethanol (80 proof)
<20 mg/dL
Iron Deferoxamine Infusion of 5-15 IV Hypotension (minimized by
mg/kg/hr (max: 6 g/24 avoiding rapid infusion rates)
hr)
Isoniazid (INH) Pyridoxine Empirical dosing: IV May also be used for Gyromitra
70 mg/kg (max mushroom ingestions
 dose = 5 g)
If ingested dose is
known: 1 g per
gram of INH
Lead and other BAL (dimercaprol) 3-5 mg/kg/dose q4h, Deep IM Local injection site pain and
heavy metals (e.g., for the 1st day; sterile abscess, vomiting,
arsenic, inorganic subsequent dosing fever, salivation,
mercury) depends on the toxin nephrotoxicity
Caution: prepared in peanut
oil; contraindicated in
patients with peanut allergy
Calcium disodium 35-50 mg/kg/day × 5 IV Vomiting, fever, hypertension,
EDTA days; may be given as arthralgias, allergic reactions,
a continuous infusion local inflammation,
or 2 divided doses/day nephrotoxicity (maintain
adequate hydration; follow UA
and renal function)
Dimercaptosuccinic 10 mg/kg/dose q8h × 5 PO Vomiting, hepatic transaminase
acid (succimer, days, then 10 mg/kg elevation, rash
DMSA, Chemet) q12h × 14 days
Methemoglobinemia Methylene blue, 0.1-0.2 mL/kg (1-2 IV Vomiting, headache, dizziness,
1% solution mg/kg) over 5-10 min; blue discoloration of urine
may be repeated q30-
60 min
Opioids Naloxone 1 mg if patient not IV, Acute withdrawal symptoms
likely to be intranasal, if given to addicted patients
addicted. IO, IM, May also be useful for
0.04-0.4 mg if nebulized clonidine ingestions
possibly addicted; (typically at higher doses)
repeated as
needed; may need
continuous
infusion
Organophosphates Atropine 0.05-0.1 mg/kg IV/ET Tachycardia, dry mouth, blurred
repeated q5-10 min as vision, urinary retention
needed
Pralidoxime (2- 25-50 mg/kg over 5-10 IV/IM Nausea, dizziness, headache,
PAM) min (max: 200 tachycardia, muscle rigidity,
mg/min); can be bronchospasm (rapid
repeated after 1-2 hr, administration)
then q10-12h as
needed
Salicylates Sodium Bolus 1-2 mEq/kg IV Follow potassium closely
bicarbonate followed by and replace as necessary.
continuous infusion Goal urine pH: 7.5-8.0
Sulfonylureas Octreotide and 1-2 µg/kg/dose (adults IV/SC
dextrose 50-100 µg) q6-8h
Tricyclic Sodium Bolus 1-2 mEq/kg; IV Indications: QRS widening (≥110
antidepressants bicarbonate repeated bolus dosing msec), hemodynamic instability;
as needed to keep QRS follow potassium.
<110 msec
BAL, British antilewisite; DMSA, dimercaptosuccinic acid; ECG, electrocardiogram; FIO 2 , fraction
of inspired oxygen; EDTA, ethylenediaminetetraacetic acid; ET, endotracheal tube; IO,
intraosseous; max, maximum; UA, urinalysis.
Table 77.8

Other Antidotes
ANTIDOTES TOXIN OR POISON
Latrodectus antivenin Black widow spider
Botulinum antitoxin Botulinum toxin
Diphenhydramine and/or Dystonic reactions
benztropine
Calcium salts Fluoride, calcium channel blockers
Protamine Heparin
Folinic acid Methotrexate, trimethoprim, pyrimethamine
Crotalidae-specific Fab antibodies Rattlesnake envenomation
Sodium bicarbonate Sodium channel blockade (tricyclic antidepressants, type 1
antiarrhythmics)

Poison control center personnel are specifically trained to provide expertise in

the management of poisoning exposures. Parents should be instructed to call the
poison control center (1-800-222-1222 ) for any concerning exposure. PCC
specialists can assist parents in assessing the potential toxicity and severity of the
exposure. They can further determine which children can be safely monitored at
home and which children should be referred to the emergency department for
further evaluation and care. Although up to one third of calls to PCCs involve
hospitalized patients, and 90% of all calls for exposures in children <6 yr old are
managed at home. The AAPCC has generated consensus statements for out-of-
hospital management of common ingestions (e.g., acetaminophen, iron, calcium
channel blockers) that serve to guide poison center recommendations.

Supportive Care
Careful attention is paid first to the “ABCs” of airway, breathing, and
circulation; there should be a low threshold to aggressively manage the airway of
a poisoned patient because of the patient's propensity to quickly become
comatose. In fact, endotracheal intubation is often the only significant
intervention needed in many poisoned patients. An important caveat is the
tachypneic patient with a clear lung examination and normal oxygen saturation.
This should alert the clinician to the likelihood that the patient is compensating
for an acidemia. Paralyzing such a patient and underventilating might prove
fatal. If intubation is absolutely necessary for airway protection or a tiring
patient, a good rule of thumb is to match the ventilatory settings to the patient's
preintubation minute ventilation.
recommended.

Single-Dose Activated Charcoal

Activated charcoal is a potentially useful method of GI decontamination.
Charcoal is “activated” by heating to extreme temperatures, creating an
extensive network of pores that provides a very large adsorptive surface area that
many (but not all) toxins will bind to, preventing absorption from the GI tract.
Charged molecules (i.e., heavy metals, lithium, iron) and liquids do not bind well
to activated charcoal (Table 77.9 ). Charcoal is most likely to be effective when
given within 1 hr of ingestion. Administration should also be avoided after
ingestion of a caustic substance, as it can impede subsequent endoscopic
evaluation. A repeat dose of activated charcoal may be warranted in the cases of
ingestion of an extended-release product or, more frequently, with a significant
salicylate poisoning as a result of its delayed and erratic absorption pattern.
Table 77.9
Substances Poorly Adsorbed by Activated
Charcoal
Alcohols
Caustics: alkalis and acids
Cyanide
Heavy metals (e.g., lead)
Hydrocarbons
Iron
Lithium

The dose of activated charcoal, with or without sorbitol, is 1 g/kg in children

or 50-100 g in adolescents and adults. Before administering charcoal, one must
ensure that the patient's airway is intact or protected and that the patient has a
benign abdominal examination. In the awake, uncooperative adolescent or child
who refuses to drink the activated charcoal, there is little utility and potential
morbidity associated with forcing activated charcoal down a nasogastric (NG)
tube, and such practice should be avoided. In young children, practitioners can
attempt to improve palatability by adding flavorings (chocolate or cherry syrup)
or giving the mixture over ice cream. Approximately 20% of children vomit
present. Thus the diagnosis of APAP toxicity cannot be based on clinical
symptoms alone, but instead requires consideration of the combination of the
patient's history, symptoms, and laboratory findings.

Table 77.10

Classic Stages in Clinical Course of Acetaminophen Toxicity

TIME AFTER
STAGE CHARACTERISTICS
INGESTION
I 0.5-24 hr Anorexia, vomiting, malaise
Lab tests typically normal, except for acetaminophen level
II 24-48 hr Resolution of earlier symptoms; right upper quadrant abdominal pain and tenderness;
elevated hepatic transaminases (aspartate > alanine), INR
III 3-5 days Peak transaminase elevations; development of liver failure, multi organ-system
failure, death or recovery begins
IV 4 days to 2 wk Resolution of liver function abnormalities
Clinical recovery precedes histologic recovery

If a toxic ingestion is suspected, a serum APAP level should be measured 4 hr

after the reported time of ingestion. For patients who present to medical care
more than 4 hr after ingestion, a stat APAP level should be obtained. APAP levels
obtained <4 hr after ingestion, unless “nondetectable,” are difficult to interpret
and cannot be used to estimate the potential for toxicity. Other important
baseline lab tests include hepatic transaminases, renal function tests, and
coagulation parameters.

Treatment.
When considering the treatment of a patient poisoned or potentially poisoned
with APAP, and after assessment of the ABCs, it is helpful to place the patient
into one of the following four categories.

1 Prophylactic.
By definition, these patients have a normal aspartate transaminase (AST). If the
APAP level is known and the ingestion is within 24 hr of the level being drawn,
treatment decisions are based on where the level falls on the Rumack-Matthew
nomogram (Fig. 77.1 ). Any patient with a serum APAP level in the possible or
probable hepatotoxicity range per the nomogram should be treated with N -
acetylcysteine (NAC). This nomogram is only intended for use in patients who
present within 24 hr of a single acute APAP ingestion with a known time of
ingestion. If treatment is recommended, they should receive NAC as either oral
Pathophysiology.
SSRIs selectively block the reuptake of serotonin in the CNS. In contrast to
TCAs and atypical antidepressants, SSRIs do not directly interact with other
receptor types.

Clinical and Laboratory Manifestations.

In overdose, the principal manifestations of toxicity are sedation and
tachycardia. Cardiac conduction abnormalities (primarily QTc prolongation) and
seizures have been described in significant overdoses, especially after ingestions
of citalopram. An ECG should be part of the initial assessment after SSRI
ingestion. Serum creatine kinase (CK) levels are almost always elevated in a
patient with clinically significant serotonin syndrome . Although seen more
often after therapeutic use or overdose of several serotonergic agents in
combination, the serotonin syndrome has also been described in ingestion of
SSRIs alone (Table 77.11 ). Clinically, serotonin syndrome describes a spectrum
of altered mental status, autonomic instability, fever, and neuromuscular
hyperactivity (hyperreflexia, tremors, clonus in lower extremities > upper
extremities). One or all of these signs may be present to varying degrees.

Table 77.11

Drugs Associated With the Serotonin Syndrome

DRUG TYPE DRUGS
Selective Sertraline, fluoxetine, fluvoxamine, paroxetine, citalopram
serotonin
reuptake
inhibitors
Antidepressant Trazodone, nefazodone, buspirone, clomipramine, venlafaxine
drugs
Monoamine Phenelzine, moclobemide, clorgyline, isocarboxazid
oxidase
inhibitors
Anticonvulsants Valproate
Analgesics Meperidine, fentanyl, tramadol, pentazocine
Antiemetic Ondansetron, granisetron, metoclopramide
agents
Antimigraine Sumatriptan
drugs
Bariatric Sibutramine
medications
Antibiotics Linezolid (a monoamine oxidase inhibitor), ritonavir (through inhibition of cytochrome P450
enzyme isoform 3A4)
Nonprescription Dextromethorphan
 cough and cold
remedies
Drugs of abuse Methylenedioxymethamphetamine (MDMA, “Ecstasy”), lysergic acid diethylamide (LSD), 5-
methoxydiisopropyltryptamine (“foxy methoxy”), Syrian rue (contains harmine and harmaline,
both monoamine oxidase inhibitors)
Dietary Tryptophan, Hypericum perforatum (St. John's wort), Panax ginseng (ginseng)
supplements and
herbal products
Other Lithium
From Boyer EW, Shannon M: The serotonin syndrome, N Engl J Med 352:1112–1120, 2005.

Treatment.
Initial management includes a careful assessment for signs and symptoms of
serotonin syndrome and an ECG. Most patients simply require supportive care
and observation until their mental status improves and tachycardia, if present,
resolves. Management of serotonin syndrome is directed by the severity of
symptoms; possible therapeutic interventions include benzodiazepines in mild
cases and intubation, sedation, and paralysis in patients with severe
manifestations (e.g., significant hyperthermia). Because agonism at the 5-HT2A
serotonin receptor is thought to be primarily responsible for the development of
serotonin syndrome, use of the 5-HT2A receptor antagonist cyproheptadine may
also be helpful. Cyproheptadine is only available in an oral form.

Atypical Antidepressants.
The atypical antidepressant class includes agents such as venlafaxine and
duloxetine (SNRIs), bupropion (dopamine, norepinephrine, and some serotonin
reuptake blockade), and trazodone (serotonin reuptake blockade and peripheral
α-receptor antagonism). The variable receptor affinities of these agents lead to
some distinctions in their clinical manifestations and management.

Clinical and Laboratory Manifestations.

In overdose, venlafaxine and other SNRIs have been associated with cardiac
conduction defects, including QRS and QTc prolongation, and seizures.
Bupropion warrants special consideration because it is one of the most common
etiologies of toxicant-induced seizures in the United States. After ingestion of
SR or extended-release (ER) preparations, seizures can occur as late as 18-20 hr
after ingestion. In addition, bupropion can cause tachycardia, agitation, and QRS
and QTc prolongation. These cardiac effects are thought to result from a
reduction in cardiac intracellular coupling caused by inhibition at gap junctions
glycol poisoning will almost always recover complete renal function within 2-6
wk. Consultation with a PCC, medical toxicologist, and nephrologist may be
helpful in managing toxic alcohol ingestions.

Plants
Exposure to plants, both inside the home and outside in backyards and fields, is
one of the most common causes of unintentional poisoning in children.
Fortunately, the majority of ingestions of plant parts (leaves, seeds, flowers)
result in either no toxicity or mild, self-limiting effects. However, ingestion of
certain plants can lead to serious toxicity (Table 77.12 ).

Table 77.12

Commonly Ingested Plants With Significant Toxic Potential

PLANT SYMPTOMS MANAGEMENT
Autumn crocus (Colchicum autumnale ) Vomiting Activated charcoal decontamination
Diarrhea Aggressive fluid resuscitation and
Initial leukocytosis supportive care
followed by bone
marrow failure
Multisystem organ
failure
Belladonna alkaloids: jimson weed Anticholinergic Supportive care, benzodiazepines
(Datura stramonium ) toxidrome Consider physostigmine if patient is a
Belladonna (“deadly nightshade”; Seizures threat to self or others; only use if no
Atropa belladonna ) conduction delays on ECG
Cardiac glycoside–containing plants Nausea Digoxin-specific Fab fragments
(foxglove, lily of the valley, oleander, Vomiting
yellow oleander, etc) Bradycardia
Dysrhythmias (AV
block, ventricular
ectopy)
Hyperkalemia
Jequirity bean and other abrin- Oral pain Supportive care, including aggressive volume
containing species (e.g., rosary pea, Vomiting resuscitation and correction of electrolyte
precatory bean) Diarrhea abnormalities
Shock
Hemolysis
Renal failure
Monkshood (Aconitum species) Numbness and Atropine for bradycardia
tingling of Supportive care
lips/tongue
Vomiting
Bradycardia
Oxalate-containing plants: Local tissue injury Supportive care, pain control
Philodendron, Dieffenbachia, Colocasia Oral pain
 (“elephant ear”) Vomiting
Poison hemlock (Conium maculatum) Vomiting Supportive care
Agitation followed
by CNS depression
Paralysis
Respiratory failure
Pokeweed Hemorrhagic Supportive care
gastroenteritis
Burning of mouth
and throat
Rhododendron Vomiting Atropine for symptomatic bradycardia
Diarrhea Supportive care
Bradycardia
Tobacco Vomiting Supportive care
Agitation
Diaphoresis
Fasciculations
Seizures
Water hemlock (Cicuta species) Abdominal pain Supportive care, including benzodiazepines
Vomiting for seizures
Delirium
Seizures
Yew (Taxus species) GI symptoms Supportive care
QRS widening Atropine for bradycardia
Hypotension Sodium bicarbonate does not appear to
CV collapse be effective
AV, Atrioventricular; CNS, central nervous system; CV, cardiovascular; ECG, electrocardiogram;
Fab, fragment, antigen binding; GI, gastrointestinal.

The potential toxicity of a particular plant is highly variable, depending on the

part of the plant involved (flowers are generally less toxic than the root or seed),
the time of year, growing conditions, and the route of exposure. Assessment of
the potential severity after an exposure is also complicated by the difficulty in
properly identifying the plant. Many plants are known by several common
names, which can vary among communities. Poison control centers have access
to professionals who can assist in properly identifying plants. They also are well
versed in the common poisonous plants in their service area and the seasons
when they are more abundant. For these reasons, consultation with the local PCC
may be very helpful in the management of these ingestions.
For potentially toxic plant ingestions, consider decontamination with activated
charcoal in patients who present within 1-2 hr of ingestion; otherwise, treatment
is primarily supportive and based on symptoms. The most common
manifestation of toxicity after plant ingestion is GI upset, which can be managed
with antiemetics and fluid and electrolyte support. Table 77.12 outlines
management strategies for a few specific toxicities.
In a 2014 survey the American Pain Society identified 48 pediatric chronic pain
clinics, with most offering some type of integrative medicine or behavioral
health strategies with conventional medicine. For example, integrative therapies
are increasingly being used in pediatric chronic pain clinics to treat functional
bowel disorders. Recent reviews include supplements (e.g., ginger, peppermint
oil) and mind-body techniques (e.g., hypnotherapy, biofeedback,
acupuncture/acupressure) with traditional medical management for these
common pediatric conditions.

Dietary Supplements
Under the 1994 U.S. Dietary Supplement Health and Education Act, a dietary
supplement is a product taken by mouth that contains a dietary ingredient
intended to supplement the diet. These may include vitamins, minerals, herbs or
other botanicals, amino acids, and substances such as enzymes, organ tissues,
glands, and metabolites. Dietary supplements are the most frequently used
complementary therapies for children and adolescents (Table 78.1 ). Some uses
are common and recommended, such as vitamin D supplements for breastfed
infants and probiotics to prevent antibiotic-associated diarrhea, whereas other
uses are more controversial, such as using herbal products to treat otitis media.

Table 78.1
Commonly Used Dietary Supplements in Pediatrics

PRODUCT USES
VITAMINS
B2 (riboflavin) Migraine headache prophylaxis
B6 Pyridoxine-dependent epilepsy; neuropathy; nausea associated with pregnancy
(pyridoxine)
B9 (folate) Prevention of neural tube defects
D Prevention of rickets; treatment of vitamin D deficiencies
Multivitamins General health promotion
MINERALS
Iodine (salt) Prevent goiter and mental retardation
Iron Prevent and treat iron-deficiency anemia
Magnesium Constipation, asthma, migraine prevention
Zinc Diarrhea in nutrient-poor populations
HERBS
Aloe vera Mild burns
Chamomile Mild sedative, dyspepsia
Echinacea Prevention of upper respiratory infections
 Ginger Nausea
Lavender Mild sedative
(aromatherapy)
Peppermint Irritable bowel syndrome
Tea tree oil Antibacterial (acne remedies), pediculicide (lice)
OTHER
Melatonin Insomnia
Omega-3 fatty ADHD, allergies, inflammation, anxiety and mood disorders
acids
Probiotics Antibiotic-associated diarrhea; Clostridium difficile –associated diarrhea; constipation; irritable
bowel syndrome; pouchitis; inflammatory bowel disorders
ADHD, Attention-deficit/hyperactivity disorder.

In the United States, dietary supplements do not undergo the same stringent
evaluation and postmarketing surveillance as prescription medications. Although
they may not claim to prevent or treat specific medical conditions, product labels
may make structure-function claims. For example, a label may claim that a
product “promotes a healthy immune system,” but it may not claim to cure the
common cold.
According to the 2012 National Health Interview Survey, 5% of U.S. children
used non-vitamin/mineral dietary supplements. (e.g., fish oil, melatonin,
prebiotics, probiotics) Use of dietary supplements is most common among
children whose families have higher income and education and whose parents
use supplements, among older children, and among those with chronic
conditions.
Despite this widespread use, many patients and their parents who use dietary
supplements do not talk with their physician about their use. Several guidelines
have called for more complete dietary supplement history taking by healthcare
professionals. The Joint Commission recommends that clinicians routinely ask
patients about their use of dietary supplements and include this information as
part of the medication reconciliation process.

Dietary Supplement Safety

Dietary supplements may have safety issues in children, but toxicity is much less
common with nonprescription dietary supplements than with prescription
medications (Table 78.2 ). Toxicity depends on dose, use of other therapies, and
the child's underlying medical condition. Current use of a dietary supplement
(e.g., ephedra for weight loss) may not reflect its traditional use (e.g., ephedra as
a component of a traditional Chinese medicine tea in small doses to improve
allergic or respiratory symptoms). Moreover, herbs that are apparently safe for
most adults may be more hazardous in specific conditions (e.g., newborns,
patients with impaired renal or hepatic function), under special circumstances
(e.g., after organ transplantation or other surgery), or when combined with
prescription medications. Some natural products are toxic in and of themselves.
Even when a product is safe when used correctly, it can cause mild or severe
toxicity when used incorrectly. For example, although peppermint is a
commonly used and usually benign gastrointestinal spasmolytic included in
after-dinner mints, it can exacerbate gastroesophageal reflux.

Table 78.2
Clinical Toxicity of Selected Herbs

COMMON BOTANICAL
THERAPEUTIC USES POTENTIAL TOXICITY
NAME NAME
Aconite Aconitum spp. Sedative, analgesic, antihypertensive Cardiac arrhythmias
(monkshood,
wolfsbane)
Aloe Aloe spp. Burns, skin diseases Nephritis, GI upset
Betel nut Areca catechu Mood elevation Bronchoconstriction, oral cancers
Bloodroot Sanguinaria Emetic, cathartic, eczema GI upset, vertigo, visual
canadensis disturbances
Chaparral Larrea Aging, free radical scavenging Hepatitis
(greasewood) tridentata
Compound Q Trichosanthes Anthelmintic, cathartic Diarrhea, hypoglycemia, CNS
kirilowii toxicity
Dandelion Taraxacum Diuretic, heartburn remedy Anaphylaxis
officinale
Figwort (xuan Scrophularia Antiinflammatory, antibacterial Cardiac stimulation
shen) spp.
Ginseng Panax Antihypertensive, aphrodisiac, Ginseng abuse syndrome
quinquefolium stimulant, mood elevation, digestive aid
Goldenseal Hydrastis Digestive aid, mucolytic, anti-infective Uterine, cardiac stimulation; GI
canadensis upset, leukopenia
Hellebore Veratrum spp. Antihypertensive Vomiting, bradycardia, hypotension
Hyssop Hyssopus Asthma, mucolytic Seizures
officinalis
Juniper Juniperus Hallucinogen GI upset, seizures, renal injury,
communis hypotension, bradycardia
Kava kava Piper Sedative Inebriation
methysticum
Kombucha Stimulant Metabolic acidosis, hepatotoxicity,
death
Licorice Glycyrrhiza Indigestion Mineralocorticoid effects
spp.
Lily of the valley Convallaria Cardiotonic GI (nausea, vomiting), cardiac
spp. arrhythmias
Linn (willow) Salix caprea Purgative Hemolysis with glucose-6-
phosphate dehydrogenase
 deficiency
Lobelia (Indian Lobelia spp. Stimulant Nicotine intoxication
tobacco)
Ma Huang Ephedra Stimulant Sympathetic crisis, especially with
sinica monamine oxidase inhibitors
Mandrake Mandragora Hallucinogen Anticholinergic syndrome
officinarum
Mormon tea Ephedra Stimulant, asthma, antipyretic Hypertension, sympathomimetic
nevadensis
Nutmeg Myristica Hallucinogen, abortifacient Hallucinations, GI upset
fragrans
Oleander Nerium Cardiac stimulant Cardiac arrhythmias
oleander
Passionflower Passiflora Hallucinogen Hallucinations, seizures,
caeruliea hypotension
Periwinkle Vinca spp. Antiinflammatory, diabetes Alopecia, seizures, hepatotoxicity
Pokeweed Phytolacca Arthritis, chronic pain GI upset, seizures, death
spp.
Sabah Sauropus Weight loss, vision Pulmonary injury
androgynus
Sage Salvia spp. CNS stimulant Seizures
Snakeroot Rauwolfia Sedative, antihypertensive Bradycardia, coma
serpentina
Squill Urginea Arthritis, cardiac stimulant Seizures, arrhythmias, death
maritima
Thorn apple Datura Hallucinations Anticholinergic
(jimsonweed) stramonium
Tonka bean Dipteryx Anticoagulant Bleeding diathesis
odorata
Valerian root Valeriana spp. Sedative Sedation, obtundation
Wild (squirting) Ecballium Constipation, antiinflammatory, Airway obstruction
cucumber elaterium rheumatic disease
Wormwood Artemisia spp. Stimulant, hallucinogen Hallucinations, seizures, uterine
(mugwort) stimulation
Yohimbine Corynanthe Aphrodisiac, stimulant Hypertension, sympathetic crisis
yohimbe
CNS, Central nervous system; GI, gastrointestinal.
From Kingston RL, Foley C: Herbal, traditional, and alternative medicines. In Haddad and
Winchester's clinical management of poisoning and drug overdose, ed 4, Philadelphia, 2007,
Saunders/Elsevier, p 1081.

Although there are good manufacturing practices for dietary supplements in

the United States, dietary supplement labels might not accurately reflect the
contents or concentrations of ingredients. Because of natural variability,
variations of 10-1,000–fold have been reported for several popular herbs, even
across lots produced by the same manufacturer. Herbal products may be
contaminated with pesticides, microbial agents or products, or the wrong herb
misidentified during harvesting. Products from developing countries (e.g.,
Ayurvedic products from South Asia) might contain toxic levels of mercury,
cadmium, arsenic, or lead, either from unintentional contamination during
manufacturing or from intentional additions by producers who believe that these
metals have therapeutic value. Approximately 30–40% of Asian patent
medicines include potent pharmaceuticals, such as analgesics, antibiotics,
hypoglycemic agents, or corticosteroids; typically the labels for these products
are not written in English and do not note the inclusion of pharmaceutical agents.
Even conventional mineral supplements, such as calcium, have been
contaminated with lead or had significant problems with product variability.
Many families use supplements concurrently with medications, posing
hazards of interactions (Table 78.3 ). Using the same principles of drug-drug
interactions can help determine if a supplement-drug interaction is a concern.
For example, St. John's wort induces CYP3A4 activity of the cytochrome P450
enzyme system and thus can enhance elimination of most drugs that use this
pathway, including digoxin, cyclosporine, protease inhibitors, oral
contraceptives, and numerous antibiotics, leading to subtherapeutic serum levels.

Table 78.3
Common Herbal Dietary Supplement (HDS)–Drug
Interactions

HDS DRUGS POTENTIAL CONSEQUENCES/REACTIONS

Aloe vera Glibenclamide (glyburide) ↑ Oral aloe vera gel can cause additive glycemic-lowering
effects when taken concurrently with a hypoglycemic
agent.
Bitter Phenelzine ↑ Risk of hypertensive crisis
orange
Garlic Ritonavir ↓ Effect of ritonavir
Saquinavir ↓ Effect of saquinavir
Licorice Warfarin ↑ Risk of bleeding
Grapefruit Calcium channel blockers Grapefruit juice has been found to increase bioavailability
of certain drugs by inhibition of cytochrome P450 (CYP)
3A4 isozyme in liver and gut wall.
Melatonin Zolpidem ↑ Sedative effects
Valerian Alprazolam, phenobarbital ↑ Central nervous system depression
Goldenseal Inhibition of CYP2D6 and CYP3A4 May affect approximately 50% of common
pharmaceutical agents
St. John's Cyclosporine, tacrolimus, warfarin, May decrease drug effectiveness
wort protease inhibitors, digoxin, theophylline,
venlafaxine, oral contraceptives
↓, Decreasing; ↑, increasing.
Mind-Body Therapies
Mind-body therapies such as slow, deep breathing, meditation, guided imagery,
biofeedback, hypnosis, tai chi, and yoga are also frequently used complementary
therapies in pediatrics. These practices can be learned informally through books,
YouTube videos, compact discs, digital video discs, smartphone apps, or classes,
as well as in therapeutic sessions with health professionals, such as psychologists
and social workers (Table 78.4 ). Substantial research suggests that such
practices can aid in reducing anxiety, insomnia, and stress-related conditions,
including migraine headaches and functional abdominal pain. These therapies
can also help patients struggling with chronic pain.

Table 78.4

Commonly Used Mind-Body Practices in Pediatrics

PRACTICE USES
Biofeedback Preventing migraine headaches; reducing stress and anxiety; encopresis/constipation treatment;
treatment of stress incontinence; neurofeedback is experimental for ADHD.
Deep Relaxation; stress management
breathing
Guided Stress management; anxiety reduction; pain relief
imagery
Hypnosis Correcting habit disorders; preventing headaches; managing pain
Meditation Stress management; improving concentration
Tai chi Improving balance, coordination, concentration, and discipline
Yoga Improving balance, coordination, and concentration
ADHD, Attention-deficit/hyperactivity disorder.

Acupuncture
Modern acupuncture incorporates treatment traditions from China, Japan, Korea,
France, and other countries. In the United States, acupuncturists are licensed to
practice in 45 states. Acupuncture can be delivered to pediatric patients in
hospital and clinic settings to treat a variety of ailments. Acupuncture is
particularly useful for children experiencing pain, and acupuncture services are
offered alongside conventional medicine and psychology by >50% of North
American academic pediatric chronic pain programs. The technique that has
undergone most scientific study involves penetrating the skin with thin, solid,
metallic needles manipulated by hand or by electrical stimulation. Variants
known to all office staff. Outdated medication, a laryngoscope with a failed light
source, or an empty oxygen tank represents a potential catastrophe in a
resuscitation scenario. Such an incident can be easily avoided if an equipment
checklist and regular maintenance schedule are implemented. A pediatric kit that
includes posters, laminated cards, or a color-coded length-based resuscitation
tape specifying emergency drug doses and equipment size are invaluable in
avoiding critical therapeutic errors during resuscitation.

Table 79.1
Recommended Drugs and Equipment for Pediatric Office
Emergencies

DRUGS/EQUIPMENT PRIORITY
DRUGS
Oxygen E
Albuterol for inhalation E
Epinephrine (1 : 1,000 [1 mg/mL]) E
Activated charcoal S
Antibiotics S
Anticonvulsants (diazepam/lorazepam) S
Corticosteroids (parenteral/oral) S
Dextrose (25%) S
Diphenhydramine (parenteral, 50 mg/mL) S
Epinephrine (1 : 10,000 [0.1 mg/mL]) S
Atropine sulfate (0.1 mg/mL) S
Naloxone (0.4 mg/mL) S
Sodium bicarbonate (4.2%) S
INTRAVENOUS FLUIDS
Normal saline (0.9 NS) or lactated Ringer solution (500 mL bags) S
5% dextrose, 0.45 NS (500 mL bags) S
EQUIPMENT FOR AIRWAY MANAGEMENT
Oxygen and delivery system E
Bag-valve-mask (450 mL and 1,000 mL) E
Clear oxygen masks, breather and non-rebreather, with reservoirs (infant, child, adult) E
Suction device, tonsil tip, bulb syringe E
Nebulizer (or metered-dose inhaler with spacer/mask) E
Oropharyngeal airways (sizes 00-5) E
Pulse oximeter E
Nasopharyngeal airways (sizes 12-30F) S
Magill forceps (pediatric, adult) S
Suction catheters (sizes 5-16F and Yankauer suction tip) S
Nasogastric tubes (sizes 6-14F) S
Laryngoscope handle (pediatric, adult) with extra batteries, bulbs S
Laryngoscope blades (straight 0-2; curved 2-3) S
Endotracheal tubes (uncuffed 2.5-5.5; cuffed 6.0-8.0) S
Stylets (pediatric, adult) S
 Esophageal intubation detector or end-tidal carbon dioxide detector S
EQUIPMENT FOR VASCULAR ACCESS AND FLUID MANAGEMENT
Butterfly needles (19-25 gauge) S
Catheter-over-needle device (14-24 gauge) S
Arm boards, tape, tourniquet S
Intraosseous needles (16 and 18 gauge) S
Intravenous tubing, micro-drip S
MISCELLANEOUS EQUIPMENT AND SUPPLIES
Color-coded tape or preprinted drug doses E
Cardiac arrest board/backboard E
Sphygmomanometer (infant, child, adult, thigh cuffs) E
Splints, sterile dressings E
Automated external defibrillator with pediatric capabilities S
Spot glucose test S
Stiff neck collars (small/large) S
Heating source (overhead warmer/infrared lamp) S
E, Essential; S, strongly suggested.
From Frush K, American Academy of Pediatrics, Committee on Pediatric Emergency Medicine:
Policy statement-preparation for emergencies in the offices of pediatricians and pediatric primary
care providers, Pediatrics 120:200–212, 2007. Reaffirmed Pediatrics 128:e748, 2011.

To facilitate emergency response when a child needs rapid intervention in the

office, all personnel should have designated roles. Organizing a “code team”
within the office ensures that necessary equipment is made available to the
physician in charge, that an appropriate medical record detailing all interventions
and the child's response is generated, and that the 911 call for EMS response or a
transport team is made in a timely fashion.

Transport
Once the child has been stabilized, a decision must be made on how best to
transport a child to a facility capable of providing definitive care. If a child has
required airway or cardiovascular support, has altered mental state or unstable
vital signs, or has significant potential to deteriorate en route, it is not
appropriate to send the child via privately owned vehicle, regardless of
proximity to a hospital. Even when an ambulance is called, it is the PCP's
responsibility to initiate essential life support measures and to attempt to
stabilize the child before transport.
In metropolitan centers with numerous public and private ambulance agencies,
the PCP must be knowledgeable about the level of service provided by each. The
availability of BLS vs ALS services, the configuration of the transport team, and
pediatric expertise vary greatly among agencies and across jurisdictions. BLS
services provide basic support of airway, breathing, and circulation, whereas
https://emscimprovement.center/ .
Baseline readiness standards must be met by all EDs that care for children, to
ensure that children receive the best emergency care possible. Specific
recommendations on equipment, supplies, and medications for the ED are listed
and updates available on the AAP website. Table 79.2 lists sample policies,
procedures, and protocols specifically addressing the needs of children in the
ED.
Table 79.2
Guidelines for Pediatric-Specific Policies,
Procedures, and Protocols for the Emergency
Department (ED)
Illness and injury triage
Pediatric patient assessment and reassessment
Documentation of pediatric vital signs, abnormal vital signs, and actions to
be taken for abnormal vital signs
Immunization assessment and management of the underimmunized patient
Sedation and analgesia for procedures, including medical imaging
Consent (including situations in which a parent is not immediately
available)
Social and mental health issues
Physical or chemical restraint of patients
Child maltreatment (physical and sexual abuse, sexual assault, and neglect)
mandated reporting criteria, requirements, and processes
Death of the child in the ED
Do-not-resuscitate orders
Family-centered care, including:
1. Involving families in patient care decision-making and in
medication safety processes.
2. Family presence during all aspects of emergency care,
including resuscitation.
3. Education of the patient, family, and regular caregivers.
4. Discharge planning and instruction.
5. Bereavement counseling.
Communication with patient's medical home or primary healthcare
 provider
Medical imaging policies that address age- or weight-appropriate dosing
for children receiving studies that impart ionizing radiation, consistent
with ALARA (as low as reasonably achievable) principles
All-hazard disaster preparedness plan that addresses the following pediatric
issues:
a. Availability of medications, vaccines, equipment, and
appropriately trained providers for children in disasters.
b. Pediatric surge capacity for both injured and noninjured
children.
c. Decontamination, isolation, and quarantine of families and
children of all ages.
d. A plan that minimizes parent-child separation and includes
system tracking of pediatric patients, allowing for the timely
reunification of separated children with their families.
e. Access to specific medical and mental health therapies, as well
as social services, for children in the event of a disaster.
f. Disaster drills, which should include a pediatric mass casualty
incident at least every 2 yr.
g. Care of children with special healthcare needs.
h. A plan that includes evacuation of pediatric units and pediatric
specialty units.

Adapted from Gausche-Hill M, Krug SE, American Academy of Pediatrics

Committee on Pediatric Emergency Medicine; American College of Emergency
Physicians Pediatric Committee; Emergency Nurses Association Pediatric
Committee: Joint policy statement—guidelines for care of children in the
emergency department, Pediatrics 124:1233–1243, 2009. Reaffirmed Pediatrics
132:e281, 2013.

The way the family supports the child during a crisis, and consequently how
the family is supported in the ED when caring for the child, are critical to patient
recovery, family satisfaction, and mitigation of behavioral and mental health
impact. Commitment to patient- and family-centered care in the ED ensures that
the patient and family experience guides the practice of culturally sensitive care
and promotes patient dignity, comfort, and autonomy. In the ED setting,
particular issues, such as family presence, deserve specific attention. Surveys of
reflect physician behavior or [lack of] experience). Therefore, some other
assessment is needed that incorporates information on how sick the patient is, or
their specific diagnosis.
Table 79.3 provides a list of outcome measures for pediatric ED care
developed by Emergency Medical Services for Children Innovation and
Improvement Cente r supported by the Health Resources and Services
Administration of the U.S. Department of Health and Human Services.
Table 79.3
Stakeholder-Endorsed Outcome Measures for
Pediatric Emergency Care
• Overall patient satisfaction with ED visit—nurses
• Overall patient satisfaction with ED visit—physicians
• Parent/caregiver understanding of ED discharge instructions
• ED length of stay for patients <18 yr of age
• Percentage of patients <18 yr of age left without being seen (LWBS)
• Effective pediatric procedural sedation
• Acute fracture patients with documented reduction in pain within 90 min of
ED arrival
• Improvement in asthma severity score for patients with acute exacerbations
• ED revisit within 48 hr resulting in admission
• Medication error rates
• Global sentinel never events
• Unplanned return visit within 72 hr for the same/related asthma
exacerbation
• Failure to achieve seizure control within 30 min of ED arrival
• Return visits within 48 hr resulting in admission for all urgent and
emergency patients

Risk Adjustment
The purpose of measuring outcomes in the ED is to evaluate performance and
therefore to offer EDs and other components of the healthcare system the
ward care. A number of disease-specific acuity scoring systems are available for
use in the ED population, predominantly for those involved in trauma (e.g.,
Injury Severity Score, Trauma Score, Pediatric Trauma Score).

Risk Adjustment Tools in the ED

In the ED the choice of a risk adjustment tool depends on the outcomes of
interest. Two general risk adjustment tools have been developed specifically for
PEM, the second-generation Pediatric Risk of Admission (PRISA II) score and
the Revised Pediatric Emergency Assessment Tool (RePEAT).

Pediatric Risk of Admission II

PRISA II uses components of acute and chronic medical history and physiology
to determine the probability of hospitalization. The outcome measure of interest
is mandatory hospital admission (admissions utilizing therapies best delivered as
an inpatient). Table 79.4 lists the patient-related attributes contributing to the
PRISA II risk adjustment score. Analytic models, including the PRISA II score,
have good calibration (how well the probabilities predicted from the model
correlated with the observed outcomes in the population) and discrimination
(the ability to categorize subjects correctly into the categories of interest) with
respect to mandatory hospital admission. Construct validity of the PRISA score
has been demonstrated by measuring rates of the secondary outcomes:
mandatory admission, PICU admission, and mortality. As the probability of
hospital admission rises, the proportion of patients with these increasing care
requirements also increases. This finding supports the use of the PRISA II score
as a measure of severity of illness. PRISA II has also been used to demonstrate
racial/ethnic differences in severity-adjusted hospitalization rates. One study
demonstrated that teaching hospitals had higher-than-expected severity-adjusted
admission rates than nonteaching hospitals.
Table 79.4
Elements of the PRISA II Score

• Age <90 days

• Minor injury
• Abdominal pain in an adolescent
 • Immunodeficiency
• Indwelling medical device
• Controller asthma medication
• Referral status
• Temperature
• Decreased mental status
• Low systolic blood pressure (<70 neonates and infants; <83 children; <100
adolescents)
• High diastolic blood pressure (>59 neonates and infants; >70 children; >90
adolescents)
• Low serum bicarbonate value (<20 mEq/L)
• High potassium value (>4.9 mEq/L)
• High blood urea nitrogen value (>80 mg/dL)
• High white blood cell count (>20,000/mm3 )
• Oxygen therapy other than during inhaled bronchodilator treatments
• Low bicarbonate and high potassium values

Revised Pediatric Emergency Assessment Tool

RePEAT uses a limited set of data collected at the time of ED triage to model
severity of illness as reflected by the level of care provided in the ED, for
example, routine assessment (clinical examination only ± nonprescription
medicine) vs specific ED care (ED diagnostics and/or therapeutics) vs hospital
admission. It is assumed that patients needing a higher level of care have a
higher severity of illness. Table 79.5 lists the patient-related attributes
contributing to the RePEAT risk adjustment score. Analytic models such as
RePEAT have good calibration and discrimination with respect to predicting ED
care and hospital admission. Furthermore, analytic models that compare costs
and ED length of stay between EDs are improved by adjustment for severity of
illness using the RePEAT score. RePEAT is a reasonable objective marker of
severity of illness that could be used in the administrative process comparing
outcomes between EDs.
Table 79.5
Elements of the RePEAT Score
 • Age
• Chief complaint
• Triage category
• Current use of prescription medications
• Arrival via EMS (ground/air)
• Heart rate
• Respiratory rate
• Temperature

Bibliography
Alessandrini EA, Alpern ER, Chamberlain JM, et al.
Developing a diagnosis-based severity classification system
for use in emergency medical services for children. Acad
Emerg Med . 2012;19:70–78.
Bradman K, Borland M, Pascoe E. Predicting patient
disposition in a paediatric emergency department. J Paediatr
Child Health . 2014;50:E39–E44.
Chamberlain JM, Joseph JG, Pollack MM. Differences in
severity-adjusted pediatric hospitalization rates are associated
with race/ethnicity. Pediatrics . 2007;119:e1319–e1324.
Chamberlain JM, Patel KM, Pollack MM. The association of
emergency department care factors with admission and
discharge decisions for pediatric patients. J Pediatr .
2006;149:644–649.
Chamberlain JM, Patel KM, Pollack MM. The pediatric risk of
hospital admission score: a second-generation severity-of-
illness score for pediatric emergency patients. Pediatrics .
2005;115:388–395.
Defining quality performance measures for pediatric emergency
care. www.childrensnational.org/EMSC/PubRes/toolbox.aspx
.
Donabedian A. The quality of care: how can it be assessed?
the WHO manuals Prehospital Trauma Care Systems and Guidelines for
Essential Trauma Care both focus on guidelines for prehospital and trauma care
systems that are affordable and sustainable. The AAP course Pediatric Education
for Prehospital Professionals is a dynamic, modularized teaching tool designed
to provide specific pediatric prehospital education that can be adapted to any
EMS system. Table 79.6 describes additional prehospital resources.
Table 79.6
Pediatric Emergency Care Resources
Prehospital

Advanced Medical Life Support (AMLS)

Newest course developed by the National Association of Emergency
Medical Technicians (NAEMT) to provide more clinical teaching and
reasoning around emergent medical problems. Course is open to
physicians, nurses EMTs and paramedics.
www.naemt.org/education/amls/amls.aspx
Prehospital Trauma Life Support
Available in 33 countries, PHTLS is the leading continuing education
program for prehospital emergency trauma care.
www.phtls.org
International Trauma Life Support
Training course for prehospital trauma care.
www.itrauma.org
Pediatric Education for Prehospital Professionals (PEPP)
Curriculum designed specifically to teach prehospital professionals how to
assess and manage ill or injured children.
www.peppsite.org

Hospital Care

Pocket Book of Hospital Care for Children

WHO publication providing guidelines for the management of common
illnesses with limited resources; incorporates both the Emergency Triage
Assessment and Treatment (ETAT) and Integrated Management of
Childhood Illness (IMCI) guidelines.
 www.who.int/maternal_child_adolescent/documents/9241546700/en/index.html
AFEM Handbook of Acute and Emergency Care
Management strategies based on available resources. It leads providers
through a rapid, systematic, and integrated approach to stabilization and
resuscitation of patients stratified to 3 resource levels: where there are no
available resources, where there are minimal resources, and where there
are full resources.
Available for purchase online.
Where There Is No Doctor: A Village Health Handbook
Healthcare manual for health workers, clinicians, and others involved in
primary healthcare delivery and health promotion programs around the
world. Available for purchase or as a free download.
www.hesperian.org
International Federation for Emergency Medicine
2012 International Standards of Care for Children in Emergency
Departments.
https://www.ifem.cc/wp-content/uploads/2016/07/International-Standards-
for-Children-in-Emergency-Departments-V2.0-June-2014-1.pdf

Humanitarian Emergencies

CHILDisaster Network
Registry for those with education and experience in humanitarian
emergencies to volunteer their time when needed in a disaster.
www.aap.org/disaster
The Sphere Project
Downloadable modules on disaster preparedness.
www.sphereproject.org
Management of Complex Humanitarian Emergencies: Focus on
Children and Families
Training course offered by the Children in Disasters Project, sponsored by
the Rainbow Center for Global Child Health (RCGCH) in Cleveland,
OH. Held in early June annually.
Manual for the Health Care of Children in Humanitarian Emergencies
WHO publication that provides comprehensive guidance on childcare in
emergencies; includes information on care of traumatic injuries and
mental health emergencies.
 www.who.int/child_adolescent_health/documents/9789241596879/en/index.html

Access to Academic Publications Relevant to PEM

PEMdatabase.org
A website devoted to pediatric emergency medicine (PEM). Contains links
to conferences, evidence-based medicine reviews, research networks, and
professional organizations.
www.pemdatabase.org
HINARI Access to Research Initiative
Program established by WHO and others to enable developing countries to
gain access to one of the world's largest collections of biomedical and
health literature.
www.who.int/hinari/en

Involvement

ACEP Ambassador Program

Provides the names of U.S.-boarded emergency medicine physicians who
can provide advice and information on issues pertaining to the progress
and status of emergency medicine in their assigned countries.
www.acep.org/content.aspx?id=25138
Section on International Emergency Medicine, American College of
Emergency Physicians
This group maintains a list of international organizations and clinical
opportunities, many of which involve emergency care of children.
http://www.acep.org/_InternationalSection/International-Emergency-
Medicine-Related-Resources/
Section of International Child Health, American Academy of
Pediatrics
Lists non-U.S. clinical opportunities, many of which involve emergency
care.
http://www2.aap.org/sections/ich/working_overseas.htm

Organizations Involved in International PEM Activities

 U.S. Agency for International Development (USAID)
Government agency providing U.S. economic and humanitarian assistance
worldwide.
www.usaid.gov
World Health Organization (WHO)
Publication catalog, media resources, health articles, and current health
news.
www.who.int/topics/child_health/en
United Nations Children's Fund (UNICEF)
Organization dedicated to providing lifesaving assistance to children
affected by disasters and to protecting their rights in any circumstances;
formerly United Nations International Children's Emergency Fund.
www.unicef.org
Safe Kids Worldwide
The first and only international nonprofit organization dedicated solely to
preventing unintentional childhood injury.
www.safekids.org

Although most middle- and high-income countries have a system of trained

EMS workers, low-income countries lack this advanced tier of emergency care.
In these countries, commercial drivers, volunteers, and willing bystanders
provide the first line of care. Training a cadre of first responders can rely on
existing networks of aid or can be drawn from specific populations, such as
students, soldiers, or public servants. Training needs to emphasize basic
lifesaving and limb-saving interventions, including how to stop bleeding and
support breathing, access advanced care, and splint broken limbs. In Ghana, for
example, taxi drivers participated in a first-aid course that relied heavily on
demonstration and practice rather than knowledge transfer through didactic
sessions. Taxi drivers were selected because they already provided much of the
transport for injured patients, either voluntarily or for pay by the family. Two
years after the course, external evaluators favorably rated the quality of their care
compared with untrained drivers. In rural areas, such first responders become
vital in providing emergency interventions when more definitive care is distant.
Thus a system of trained first responders forms the foundation of an effective
prehospital system.

Methods of Transport
ended questions that help distinguish between benign and potentially life-
threatening disease entities. The most common complaints leading to acute care
visits among children include fever, headache and altered mental status, trauma,
abdominal pain and vomiting, respiratory distress, and chest pain. Table 80.1
describes signs and symptoms that should prompt immediate transfer to an ED
or, if already in the ED, initiation of rapid intervention.

Table 80.1
History and Examination Findings That Should Prompt
Immediate Intervention and/or Transfer to Emergency
Department

HISTORY AND EXAM FINDINGS RISK FACTORS

RED FLAGS FOR RESPIRATORY FAILURE
Tachycardia Tracheostomy
Tachypnea Ventilator dependence
Cyanosis History of critical airway
Apnea
Brief resolved unexplained event (BRUE) with cyanosis or
change in tone
Suspected button-battery ingestion
Foreign body aspiration with respiratory distress
Respiratory distress with hypoxemia and/or altered mental
status
RED FLAGS FOR CIRCULATORY FAILURE
Tachycardia Oncology (or other immunosuppressed) patients
Tachypnea Bone marrow or solid-organ transplants
Cyanosis Sickle cell (or otherwise asplenic) patients
Apnea Infants <56 days old
Petechial or purpuric rashes Cardiac patient with change from baseline pulse
Erythroderma oximetry
Peritonitis Bleeding disorder with trauma
Bilious emesis
Posttonsillectomy or postadenoidectomy with bleeding
Extremity trauma with neurovascular deficits
RED FLAGS FOR NEUROLOGIC FAILURE
Tachycardia Ventriculoperitoneal shunt
Bradycardia-hypertension Diabetes or metabolic disease with altered mental
Double vision status
Unequal pupils Hypoxic-ischemic encephalopathy
Apnea Clotting disorder with neurologic change(s)
Frequent or prolonged seizure(s)
Focal neurologic deficit(s)
Acute onset of severe headache
Suicidal or homicidal ideation, psychosis
Adapted from Farah MM, Tay Y, Lavelle J. A general approach to ill and injured children. In Shaw
KN, Bachur RG, editors: Fleischer and Ludwig's textbook of pediatric emergency medicine,
Once the emergency response system has been activated and the child is
determined not to need CPR, the caregiver should proceed with a primary
assessment that includes a brief, hands-on assessment of cardiopulmonary and
neurologic function and stability. This assessment includes a limited physical
examination, evaluation of vital signs, and measurement of pulse oximetry if
available. The American Heart Association, in its Pediatric Advanced Life
Support (PALS) curriculum, supports the structured format of airway,
breathing, circulation, disability, exposure (ABCDE) . The goal of the
primary assessment is to obtain a focused, systems-based assessment of the
child's injuries or abnormalities, so that resuscitative efforts can be directed to
these areas; if the caregiver identifies a life-threatening abnormality, further
evaluation is postponed until appropriate corrective action has been taken.
The exam and vital sign data can be interpreted only if the caregiver has a
thorough understanding of normal values. In pediatrics, normal respiratory rate,
heart rate, and blood pressure have age-specific norms (Table 81.1 ). These
ranges can be difficult to remember, especially if used infrequently. However,
several standard principals apply: (1) a child's respiratory rate should not be >60
breaths/min for a sustained period; (2) normal heart rate is 2-3 times normal
respiratory rate for age; and (3) a simple guide for pediatric blood pressure is
that the lower limit of systolic blood pressure should be ≥60 mm Hg for
neonates; ≥70 mm Hg for 1 mo-1 yr olds; ≥70 mm Hg + (2 × age) for 1-10 yr
olds; and ≥90 mm Hg for any child older than 10 yr.

Table 81.1
Normal Vital Signs According to Age
HEART RATE BLOOD PRESSURE (mm RESPIRATORY RATE
AGE
(beats/min) Hg) (breaths/min)
Premature 120-170* 55-75/35-45 † 40-70 ‡
0-3 mo 100-150* 65-85/45-55 35-55
3-6 mo 90-120 70-90/50-65 30-45
6-12 mo 80-120 80-100/55-65 25-40
1-3 yr 70-110 90-105/55-70 20-30

3-6 yr 65-110 95-110/60-75 20-25

6-12 yr 60-95 100-120/60-75 14-22
12+ yr 55-85 110-135/65-85 12-18
* In sleep, infant heart rates may drop significantly lower, but if perfusion is maintained, no
intervention is required.
† A blood pressure cuff should cover approximately two thirds of the arm; too small a cuff yields
Table 81.2

AVPU Neurologic Assessment

A The child is awake, alert, and interactive with parents and care providers.
V The child responds only if the care provider or parents call the child's name or speak loudly.
P The child responds only to painful stimuli, such as pinching the nail bed of a toe or finger.
U The child is unresponsive to all stimuli.
A, Alert; V, verbal, P, pain, U, unresponsive.
From Ralston M, Hazinski MF, Zaritsky AL, et al, editors: Pediatric advanced life support course
guide and PALS provider manual: provider manual, Dallas, 2007, American Heart Association.

Glasgow Coma Scale.

Although it has not been systematically validated as a prognostic scoring system
for infants and young children as it has in adults, GCS is frequently used in the
assessment of pediatric patients with an altered level of consciousness. The GCS
is the most widely used method of evaluating a child's neurologic function and
has 3 components. Individual scores for eye opening, verbal response, and motor
response are added together, with a maximum of 15 points (Table 81.3 ). Patients
with a GCS score ≤8 require aggressive management, generally including
stabilization of the airway and breathing with endotracheal intubation and
mechanical ventilation, respectively, and if indicated, placement of an
intracranial pressure monitoring device. The Full Outline of Unresponsiveness
(FOUR) score is another useful assessment and monitoring tool (see Table 85.1
).

Table 81.3
Glasgow Coma Scale
EYE OPENING (TOTAL POSSIBLE POINTS 4)
Spontaneous 4
To voice 3
To pain 2
None 1
VERBAL RESPONSE (TOTAL POSSIBLE POINTS 5)
Older Children Infants and Young Children
Oriented 5 Appropriate words; smiles, fixes, and follows 5
Confused 4 Consolable crying 4
Inappropriate 3 Persistently irritable 3
Incomprehensible 2 Restless, agitated 2
None 1 None 1
 MOTOR RESPONSE (TOTAL POSSIBLE POINTS 6)
Obeys 6
Localizes pain 5
Withdraws 4
Flexion 3
Extension 2
None 1
Adapted from Teasdale G, Jennett B: Assessment of coma and impaired consciousness: a
practical scale, Lancet 2:81–84, 1974.

Exposure
Exposure is the final component of the pediatric primary assessment. This
component of the exam is reached only after the child's airway, breathing, and
circulation have been assessed and determined to be stable or have been
stabilized through simple interventions. In this setting, exposure stands for the
dual responsibility of the provider to both expose the child to assess for
previously unidentified injures and consider prolonged exposure in a cold
environment as a possible cause of hypothermia and cardiopulmonary instability.
The provider should undress the child (as is feasible and reasonable) to perform
a focused physical exam, assessing for burns, bruising, bleeding, joint laxity, and
fractures. If possible, the provider should assess the child's temperature. All
maneuvers should be performed with careful maintenance of cervical spine
precautions.

Secondary Assessment
For healthcare providers in community or outpatient settings, transfer of care of
a child to emergency or hospital personnel may occur before a full secondary
assessment is possible. However, before the child is removed from the scene and
separated from witnesses or family, a brief history should be obtained for
medical providers at the accepting facility. The components of a secondary
assessment include a focused history and focused physical examination.
The history should be targeted to information that could explain
cardiorespiratory or neurologic dysfunction and should take the form of a
SAMPLE history : signs/symptoms, allergies, medications, past medical
history, timing of last meal, and events leading to this situation. Medical
personnel not engaged in resuscitative efforts can be dispatched to elicit history
from witnesses or relatives. The physical examination during the secondary
assessment is a thorough head-to-toe exam, although the severity of the child's

FIG. 81.12 A-E, Intubation technique. (From Fleisher G, Ludwig S:
Textbook of pediatric emergency medicine, Baltimore, 1983, Williams &
Wilkins, p. 1250.)

Table 81.4
Rapid Sequence Intubation

STEP PROCEDURE COMMENT/EXPLANATION

1 Obtain a brief Rule out drug allergies; examine the airway anatomy (e.g., micrognathia, cleft palate).
history and
perform an
 assessment.
2 Assemble ETT: select the proper size for the age and weight of the child.
equipment, Laryngoscope blades: a variety of Miller and the Macintosh blades.
medications,
etc.
3 Preoxygenate With bag/mask, nasal cannula, hood or blow-by.
the patient.
4 Position the Patient supine; neck is extended moderately to the “sniffing” position.
patient.
5 Premedicate Lidocaine minimizes the ICP rise with intubation and can be applied topically to the
the patient with airway mucosa for local anesthesia.
lidocaine, Atropine helps blunt the bradycardia associated with upper airway manipulation and
atropine. reduces airway secretions.
6 Perform a Pressure on the cricoid cartilage, to occlude the esophagus and prevent regurgitation or
Sellick aspiration.
maneuver.
7 Induce sedation Sedatives
and analgesia. Midazolam (0.1 mg/kg): onset ~1 min; elimination in 30-40 min.
Ketamine (2 mg/kg, may repeat as clinically indicated): onset 1-2 min; elimination in 30-
40 min. May cause hallucinations if used alone; can cause higher ICP, mucous
secretions, increased vital signs, and bronchodilation.
Analgesics
Fentanyl (3-5 µg/kg, may repeat as clinically indicated): onset ~1 min; elimination in 20-
30 min. Rapid administration risks “tight chest” response, with no effective ventilation.
Effects wear off in 20-30 min.
Morphine (0.05-0.1 mg/kg dose): may last 30-60 min; may lead to hypotension in
hypovolemic patients.
8 Administer Option 1: Rocuronium (1 mg/kg): rapid onset and short duration. Other nondepolarizing
muscle agents include vecuronium and pancuronium, both dosed at 0.1 mg/kg.
relaxants. Option 2: Succinylcholine dose is 1-2 mg/kg; causes initial contraction of muscles, then
relaxation. This depolarization can, however, increase ICP and blood pressure. Onset of
paralysis in 30-40 sec; duration is 5-10 min. Pretreat with a small dose of a
nondepolarizing paralytic agent, with intent of diminishing the depolarizing effect of
succinylcholine.
9 Perform Performed by trained personnel.
endotracheal
intubation.
10 Secure the ETT secured with tape to the cheeks and upper lip or to an adhesive patch applied to the
tube, and verify skin near the mouth.
position with
radiograph.
11 Begin Verify tube placement before ventilating with positive pressure; if an ETT is in 1
mechanical bronchus, barotraumas may occur.
ventilation.
ETT, Endotracheal tube; ICP, intracranial pressure.

Once the patient is intubated, proper ETT placement should be assessed by

auscultation of breath sounds, evidence of symmetric chest rise, and analysis of
exhaled carbon dioxide (CO2 ) by a colorimetric device placed within the
respiratory tubing near the ETT or a device that directly measures CO2
elimination (capnogram or capnograph). Chest radiography is necessary to
Table 81.5

Potentially Treatable Conditions Associated With Cardiac Arrest

COMMON CLINICAL
CONDITION CORRECTIVE ACTIONS
SETTINGS
Acidosis Preexisting acidosis, diabetes, Reassess the adequacy of cardiopulmonary resuscitation,
diarrhea, drugs and toxins, oxygenation, and ventilation; reconfirm endotracheal
prolonged resuscitation, renal tube placement.
disease, and shock Hyperventilate.
Consider intravenous bicarbonate if pH <7.2 after above
actions have been taken.
Cardiac Hemorrhagic diathesis, cancer, Administer fluids; obtain bedside echocardiogram, if
tamponade pericarditis, trauma, after available.
cardiac surgery, and after Perform pericardiocentesis; immediate surgical
myocardial infarction intervention is appropriate if pericardiocentesis is
unhelpful but cardiac tamponade is known or highly
suspected.
Hypothermia Alcohol abuse, burns, central If hypothermia is severe (temperature <30°C [86°F]),
nervous system disease, limit initial shocks for ventricular fibrillation or pulseless
debilitated patient, drowning, ventricular tachycardia to 3; initiate active internal
drugs and toxins, endocrine rewarming and cardiopulmonary support.
disease, history of exposure, If hypothermia is moderate (temperature 30-34°C [86-
homelessness, extensive skin 93.2°F]), proceed with resuscitation (space medications
disease, spinal cord disease, at longer intervals than usual), passively rewarm child,
and trauma and actively rewarm truncal body areas.
Hypovolemia, Major burns, diabetes, Administer fluids.
hemorrhage, gastrointestinal losses, Transfuse packed red blood cells if hemorrhage or
anemia hemorrhage, hemorrhagic profound anemia is present.
diathesis, cancer, pregnancy, Thoracotomy is appropriate when a patient has cardiac
shock, and trauma arrest from penetrating trauma and a cardiac rhythm and
the duration of cardiopulmonary resuscitation before
thoracotomy is <10 min.
Hypoxia Consider in all patients with Reassess the technical quality of cardiopulmonary
cardiac arrest. resuscitation, oxygenation, and ventilation; reconfirm
endotracheal tube placement.
Hypomagnesemia Alcohol abuse, burns, diabetic Administer 1-2 g magnesium sulfate intravenously over 2
ketoacidosis, severe diarrhea, min.
diuretics, and drugs (e.g.,
cisplatin, cyclosporine,
pentamidine)
Poisoning Alcohol abuse, bizarre or Consult a toxicologist for emergency advice on
puzzling behavioral or resuscitation and definitive care, including an
metabolic presentation, classic appropriate antidote.
toxicologic syndrome, Prolonged resuscitation efforts may be appropriate;
occupational or industrial immediate cardiopulmonary bypass should be
exposure, and psychiatric considered, if available.
disease
Hyperkalemia Metabolic acidosis, excessive If hyperkalemia is identified or strongly suspected, treat*
administration of potassium, with all the following: 10% calcium chloride (5-10 mL by
drugs and toxins, vigorous slow IV push; do not use if hyperkalemia is secondary to
exercise, hemolysis, renal digitalis poisoning), glucose and insulin (50 mL of 50%
disease, rhabdomyolysis, dextrose in water and 10 units of regular insulin IV), sodium
tumor lysis syndrome, and bicarbonate (50 mmol IV; most effective if concomitant
 clinically significant tissue metabolic acidosis is present), and albuterol (15-20 mg
injury nebulized or 0.5 mg by IV infusion).
Hypokalemia Alcohol abuse, diabetes, use of If profound hypokalemia (<2.0-2.5 mmol of potassium) is
diuretics, drugs and toxins, accompanied by cardiac arrest, initiate urgent IV replacement
profound gastrointestinal (2 mmol/min IV for 10-15 mmol);* then reassess.
losses, hypomagnesemia
Pulmonary Hospitalized patient, recent Administer fluids; augment with vasopressors as
embolism surgical procedure, peripartum, necessary.
known risk factors for venous Confirm the diagnosis, if possible; consider immediate
thromboembolism, history of cardiopulmonary bypass to maintain patient's viability.
venous thromboembolism, or Consider definitive care (e.g., thrombolytic therapy,
prearrest presentation embolectomy by interventional radiology or surgery).
consistent with a diagnosis of
acute pulmonary embolism
Tension Placement of a central catheter, Needle decompression, followed by chest tube insertion.
pneumothorax mechanical ventilation,
pulmonary disease (including
asthma, chronic obstructive
pulmonary disease, and
necrotizing pneumonia),
thoracentesis, and trauma
*
Adult dose. Adjust for size of child. See Table 81.6 .
From Eisenbery MS, Mengert TJ: Cardiac resuscitation, N Engl J Med 344:1304–1313, 2001.

Tachyarrhythmias
Tachyarrhythmias represent a wide variety of rhythm disturbances of atrial and
ventricular origin (see Chapter 462 ). Sinus tachycardia is a normal physiologic
response to the body's need for increased cardiac output or oxygen delivery, as
occurs with fever, exercise, or stress. It can also occur in more pathologic states,
such as hypovolemia, anemia, pain, anxiety, and metabolic stress.
Tachyarrhythmias that do not originate in the sinus node are often categorized as
narrow complex rhythms (i.e., originating in the atrium, such as atrial flutter or
supraventricular tachycardia, SVT) and wide complex rhythms (i.e., rhythms of
ventricular origin, such as ventricular tachycardia).
The initial management of tachycardia includes confirmation that the child has
an adequate airway and life-sustaining breathing and circulation (Fig. 81.14 ).
For children with persistent symptoms, further treatment is based on whether the
QRS complex of the electrocardiogram (ECG) is narrow (≤0.09 sec) or wide
(>0.09 sec). For narrow complex tachycardia, providers must distinguish
between sinus tachycardia and SVT. In sinus tachycardia , (a) the history and
onset are consistent with a known cause of tachycardia, such as fever or
dehydration, and (b) P waves are consistently present, are of normal morphology,
 FIG. 81.18 Pediatric advanced life support pulseless arrest algorithm. CPR,
Cardiopulmonary resuscitation; IO/IV, intraosseous/intravenous; PEA, pulseless
electrical activity; VF/VT, ventricular fibrillation/tachycardia. (From Kleinman ME,
Chameides L, Schexnayder SM, et al: 2010 American Heart Association guidelines for
cardiopulmonary resuscitation and emergency cardiovascular care. Part 14, Circulation
122[Suppl 3]:S876–S908, 2010, Fig 1, p S885.)

For those children with pulseless VT or VF, emergency defibrillation is

indicated (Fig. 81.18 ). Providers should apply the pads to the child's bare chest
and back and follow the verbal instructions given by the AED. For younger
children, a defibrillator (if available) set to the dose of 2 J/kg should be used.
Ideally, the AED used in a child ≤8 yr of age should be equipped with an
attenuated adult dose or should be designed for children; if neither device is
available, a standard adult AED should be used. CPR should be immediately
restarted after defibrillation. Emergency dose epinephrine can also be
administered with another 5 cycles of CPR to ensure its circulation throughout
the child's body. If the ECG rhythm continues to show VF or VT, defibrillation
can be alternated with epinephrine. For refractory VF or VT, an IV
antiarrhythmic, such as lidocaine or amiodarone, can be given (Tables 81.6 and
81.7 ). Some adult studies have suggested that a combination of epinephrine,
vasopressin, and methylprednisolone improves intact survival after CPR.

Table 81.6
Medications for Pediatric Resuscitation and Arrhythmias

MEDICATION DOSE REMARKS

Adenosine 0.1 mg/kg (max: 6 mg) Monitor ECG.
Repeat: 0.2 mg/kg (max: 12 mg) Rapid IV/IO bolus.
Amiodarone 5 mg/kg IV/IO; repeat up to 15 Monitor ECG and blood pressure.
mg/kg
Max: 300 mg Adjust administration rate to urgency (give more slowly
when perfusing rhythm is present).
Use caution when administering with other drugs that
prolong QT interval (consider expert consultation).
Atropine 0.02 mg/kg IV/IO Higher doses may be used with organophosphate
0.03 mg/kg ETT* poisoning.
Repeat once if needed
Minimum dose: 0.1 mg
Minimum single dose:
Child, 0.5 mg
Adolescent, 1 mg
Calcium 20 mg/kg IV/IO (0.2 mL/kg) Slowly
chloride (10%) Adult dose: 5-10 mL
 Epinephrine 0.01 mg/kg (0.1 mL/kg 1 : 10,000) May repeat every 3-5 min
IV/IO
0.1 mg/kg (0.1 mL/kg 1 : 1,000)
ETT*
Max dose: 1 mg IV/IO; 10 mg ET
Glucose 0.5-1 g/kg IV/IO D10W: 5-10 mL/kg
D25W: 2-4 mL/kg
D50W: 1-2 mL/kg
Lidocaine Bolus: 1 mg/kg IV/IO
Max dose: 100 mg
Infusion: 20-50 µg/kg/min
ETT* : 2-3 mg
Magnesium 25-50 mg/kg IV/IO over 10-20
sulfate min; faster in torsades de pointes
Max dose: 2 g
Naloxone <5 yr or ≤20 kg: 0.1 mg/kg Use lower doses to reverse respiratory depression
IV/IO/ETT* associated with therapeutic opioid administration (1-15
≥5 yr or >20 kg: 2 mg IV/IO/ETT* µg/kg).
Procainamide 15 mg/kg IV/IO over 30-60 min Monitor EGG and blood pressure.
Adult dose: 20 mg/min IV infusion Use caution when administering with other drugs that
up to total max dose of 17 mg/kg prolong QT interval (consider expert consultation).
Sodium 1 mEq/kg/dose IV/IO slowly After adequate ventilation
bicarbonate
* Flush with 5 mL of normal saline and follow with 5 ventilations.

ECG, Electrocardiogram; ETT, endotracheal tube; IO, intraosseous; IV, intravenous.

From ECC Committee, Subcommittees and Task Forces of the American Heart Association: 2005
American Heart Association guidelines for cardiopulmonary resuscitation and emergency
cardiovascular care, Circulation 112:IV1–203, 2005.

Table 81.7

Medications to Maintain Cardiac Output and for Postresuscitation Stabilization*

MEDICATION DOSE RANGE COMMENT
Inamrinone 0.75-1 mg/kg IV/IO over 5 min; may repeat Inodilator
2×; then: 2-20 µg/kg/min
Dobutamine 2-20 µg/kg/min IV/IO Inotrope; vasodilator
Dopamine 2-20 µg/kg/min IV/IO in low doses; pressor Inotrope; chronotrope; renal and splanchnic
in higher doses vasodilator
Epinephrine 0.1-1 µg/kg/min IV/IO Inotrope; chronotrope; vasodilator in low doses;
vasopressor in higher doses
Milrinone 50-75 µg/kg IV/IO over 10-60 min then 0.5- Inodilator
0.75 µg/kg/min
Norepinephrine 0.1-2 µg/kg/min Inotrope; vasopressor
Sodium 1-8 µg/kg/min Vasodilator; prepare only in D5W
nitroprusside
* Alternative formula for calculating an infusion: Infusion rate (mL/hr) = [weight (kg) × dose
(µg/kg/min) × 60 (min/hr)]/concentration µg/mL).
Score use these parameters to predict patient outcome. The AIS and ISS are used
together. First, the AIS is used numerically to score injuries—as 1 minor, 2
moderate, 3 serious, 4 severe, 5 critical, or 6 probably lethal—in each of 6 ISS
body regions: head/neck, face, thorax, abdomen and pelvic contents, extremities
and bony pelvis, and external. The ISS is the sum of the squares of the highest 3
AIS region scores.

Table 82.1
Pediatric Trauma Score*
COMPONENT +2 +1 −1
Size ≥20 kg 10-20 kg <10 kg
Airway Normal Maintainable Unmaintainable
Systolic BP ≥90 mm Hg 50-90 mm Hg <50 mm Hg
CNS Awake Obtunded/LOC Coma/decerebrate
Open wound None Minor Major/penetrating
Skeletal None Closed fracture Open/multiple fractures
Sum total points
* Children with a Pediatric Trauma Score ≤6 are at increased risk of mortality as well as morbidity.

BP, Blood pressure; CNS, central nervous system; LOC, loss of consciousness.
From Tepas JJ 3rd, Mollitt DL, Talbert JL, et al: The Pediatric Trauma Score as a predictor of
injury severity in the injured child, J Pediatr Surg 22:14–18, 1987 (Table 1, p 15).

Primary Survey
During the primary survey, the physician quickly assesses and treats any life-
threatening injuries. The principal causes of death shortly after trauma are
airway obstruction, respiratory insufficiency, shock from hemorrhage, and
central nervous system (CNS) injury. The primary survey addresses the
ABCDEs : Airway, Breathing, Circulation, neurologic Deficit, and Exposure of
the patient and control of the Environment.

Airway/Cervical Spine
Optimizing oxygenation and ventilation, while protecting the cervical spine (C-
spine) from potential further injury, is of paramount importance. Initially, C-
spine injury should be suspected in any child sustaining multiple, blunt trauma.
Although C-spine injuries occur less often in children than adults, children are at
monitoring should also be used as an adjunct; however, it is less reliable in
patients with shock. In addition to looking visually for cyanosis, pulse oximetry
is standard. If ventilation is inadequate, bag-valve-mask ventilation with 100%
oxygen must be initiated immediately, followed by endotracheal intubation. End-
expiratory carbon dioxide (CO2 ) detectors or capnography help verify accurate
tube placement.
Head trauma is the most common cause of respiratory insufficiency. An
unconscious child with severe head injury may have a variety of breathing
abnormalities, including Cheyne-Stokes respiration, slow irregular breaths, and
apnea.
Although less common than a pulmonary contusion, tension pneumothorax
and massive hemothorax are immediately life threatening (Tables 82.2 and 82.3
). Tension pneumothorax occurs when air accumulates under pressure in the
pleural space. The adjacent lung is compacted, the mediastinum is pushed
toward the opposite hemithorax, and the heart, great vessels, and contralateral
lung are compressed or kinked (see Chapter 439 ). Both ventilation and cardiac
output are impaired. Characteristic findings include cyanosis, tachypnea,
retractions, asymmetric chest rise, contralateral tracheal deviation, diminished
breath sounds on the ipsilateral (more than contralateral) side, and signs of
shock. Needle thoracentesis, followed by thoracostomy tube insertion, is
diagnostic and lifesaving. Hemothorax results from injury to the intercostal
vessels, lungs, heart, or great vessels. When ventilation is adequate, fluid
resuscitation should begin before evacuation, because a large amount of blood
may drain through the chest tube, resulting in shock.

Table 82.2
Differential Diagnosis of Immediately Life-Threatening
Cardiopulmonary Injuries

MASSIVE CARDIAC
TENSION PNEUMOTHORAX
HEMOTHORAX TAMPONADE
Breath sounds Ipsilaterally decreased more than Ipsilaterally decreased Normal
contralaterally
Percussion Hyperresonant Dull Normal
note
Tracheal Contralaterally shifted Midline or shifted Midline
location
Neck veins Distended Flat Distended
Heart tones Normal Normal Muffled
Modified from Cooper A, Foltin GL: Thoracic trauma. In Barkin RM, editor: Pediatric emergency
medicine , ed 2, St Louis, 1997, Mosby, p 325.

Table 82.3
Life-Threatening Chest Injuries
Tension Pneumothorax

One-way valve leak from the lung parenchyma or tracheobronchial tree

Lung collapse with mediastinal and tracheal shift to the side opposite the
leak
Compromises venous return and decreases ventilation of the other lung
Clinically, manifests as respiratory distress, unilateral absence of breath
sounds, tracheal deviation, distended neck veins, tympany to percussion
of the involved side, and cyanosis
Relieve first with needle aspiration, then with chest tube drainage

Open Pneumothorax (Sucking Chest Wound)

Effect on ventilation depends on size

Major Flail Chest

Usually caused by blunt injury resulting in multiple rib fractures

Loss of bone stability of the thoracic cage
Major disruption of synchronous chest wall motion
Mechanical ventilation and positive end-expiratory pressure required

Massive Hemothorax

Must be drained with a large-bore tube

Initiate drainage only with concurrent vascular volume replacement

Cardiac Tamponade
 Beck's triad:
1. Decreased or muffled heart sounds
2. Jugular venous distention
3. Hypotension (with narrow pulse pressure)
Must be drained

Modified from Krug SE: The acutely ill or injured child. In Behrman RE,
Kliegman RM, editors: Nelson essentials of pediatrics , ed 4, Philadelphia, 2002,
Saunders, p 97.

Circulation
Signs of shock include tachycardia; weak pulse; delayed capillary refill; cool,
mottled, pale skin; and altered mental state (see Chapter 88 ). The most common
type of shock in trauma is hypovolemic shock caused by hemorrhage. Cardiac
tamponade, which is a form of obstructive shock, may be suspected clinically or
diagnosed by focused assessment with sonography in trauma (FAST)
examination or echocardiography. Cardiac tamponade is best managed by
thoracotomy or pericardial window, although pericardiocentesis may be
necessary as a temporizing maneuver (see Table 82.3 ).
Early in shock, blood pressure remains normal because of compensatory
increases in heart rate and peripheral vascular resistance (Table 82.4 ). Some
individuals can lose up to 30% of blood volume before blood pressure declines.
It is important to note that 25% of blood volume equals 20 mL/kg, which is only
200 mL in a 10 kg child. Losses >40% of blood volume cause severe
hypotension that, if prolonged, may become irreversible. Direct pressure should
be applied to control external hemorrhage. When direct pressure does not control
hemorrhage, a tourniquet should be applied to a proximal pressure point. Blind
clamping of bleeding vessels, which risks damaging adjacent structures, is not
advisable.

Table 82.4
Systemic Responses to Blood Loss in Pediatric Patients

MILD BLOOD MODERATE BLOOD LOSS

SYSTEM SEVERE BLOOD LOSS (>45%)
LOSS (<30%) (30–45%)
Cardiovascular Increased heart rate; Markedly increased heart rate; Tachycardia followed by bradycardia;
weak, thready weak, thready central pulses; central pulses very weak or absent;
 peripheral pulses; peripheral pulses absent; low peripheral pulses absent; hypotension;
normal systolic blood normal systolic blood pressure; narrowed pulse pressure (or
pressure; normal pulse narrowed pulse pressure undetectable diastolic blood pressure).
pressure
Central Anxiety; irritability; Lethargy; dulled response to Coma
nervous confusion pain
Skin Cool, mottled; Cyanotic; capillary refill Pale and cold
capillary refill markedly prolonged
prolonged
Urine output Low to very low Minimal None
Adapted from American College of Surgeons Committee on Trauma: Advanced trauma life
support for doctors: student course manual, ed 9, Chicago, 2012, American College of Surgeons.

Cannulating a larger vein, such as an antecubital vein, is usually the quickest

way to achieve intravenous (IV) access. A short, large-bore catheter offers less
resistance to flow, allowing for more rapid fluid administration. Ideally, a 2nd
catheter should be placed within the first few minutes of resuscitation in a
severely injured child. If IV access is not rapidly obtainable, an intraosseous (IO)
needle should be inserted; all medications and fluids can be administered
intraosseously. Other alternatives are central venous access using the Seldinger
technique (e.g., in the femoral vein) and, rarely, surgical cutdown (e.g., in
saphenous vein). Ultrasonography should be used to facilitate central venous
catheter placement, if possible.
Traditionally, fluids are administered aggressively early in hemorrhagic shock
to reverse and prevent further clinical deterioration. Isotonic crystalloid solution,
such as lactated Ringer injection or normal saline (20 mL/kg), should be infused
rapidly. When necessary, repeated crystalloid boluses may be given. Most
children are stabilized with administration of crystalloid solution alone.
However, if the patient remains in shock after boluses totaling 40-60 mL/kg of
crystalloid, packed red blood cells should be transfused. Massive transfusion
protocols (including fresh-frozen plasma) should be initiated early to prevent
coagulopathy. When shock persists despite these measures, surgery to stop
internal hemorrhage is usually indicated. Although literature is emerging
regarding the benefits of permissive hypotension, hemostatic resuscitation, and
damage control surgery for adult trauma patients, currently there are no pediatric
data.

Neurologic Deficit
Neurologic status is briefly assessed by determining the level of consciousness
and evaluating pupil size and reactivity. The level of consciousness can be
the primary diagnostic tool, particularly in patients with abnormal GCS scores
and/or significant injury mechanisms, recognizing that CT is more sensitive in
detecting bony injury than plain radiographs. CT is also helpful if an odontoid
fracture is suspected, because young children typically do not cooperate enough
to obtain an open-mouth (odontoid) radiographic view. Use of cervical spine CT
scan must be balanced with the knowledge that CT exposes thyroid tissue to 90-
200 times the amount of radiation from plain films. MRI is indicated in a child
with suspected SCIWORA and in the evaluation of children who remain
obtunded.
Table 82.5
National Emergency X-Radiography
Utilization Study (NEXUS) to Rule Out
Cervical Spine Injury Following Blunt
Trauma
If none of the following is present, the patient is at very low risk for
clinically significant cervical spine injury:
Midline cervical tenderness
Evidence of intoxication
Altered level of alertness
Focal neurologic deficit
Distracting painful injury

Data from Hoffman JR, Mower WR, Wolfson AB, et al: Validity of a set of
clinical criteria to rule out injury to the cervical spine in patients with blunt
trauma, N Engl J Med 343:94–99, 2000; and Viccellio P, Simon H, Pressman
BD, et al: A prospective multicenter study of cervical spine injury in children,
Pediatrics 108:e20, 2001.

Rapid diagnosis of spinal cord injury is essential. Initiating high-dose IV

methylprednisolone within 8 hr of spinal cord injury has been reported to
improve motor outcome, but this treatment has become controversial.

Thoracic Trauma
Pulmonary contusions occur frequently in young children with blunt chest
trauma. A child's chest wall is relatively pliable; therefore, less force is absorbed
by the rib cage, and more is transmitted to the lungs. Respiratory distress may be
noted initially or may develop during the 1st 24 hr after injury.
Rib fractures result from significant external force. They are noted in patients
with more severe injuries and are associated with a higher mortality rate. Flail
chest, which is caused by multiple rib fractures, is rare in children. Table 82.6
lists indications for operative management in thoracic trauma. (See Table 82.2
for the differential diagnosis of immediately life-threatening cardiopulmonary
injuries.)
Table 82.6
Indications for Operation in Thoracic Trauma
Thoracotomy Immediately or Shortly After Injury

Massive continuing pneumothorax or large air leak from tracheobronchial

injury (cannot expand lung and ventilate)
Cardiac tamponade
Open pneumothorax
Esophageal injury
Aortic or other vascular injury
Acute rupture of the diaphragm

Delayed Thoracotomy

Chronic rupture of the diaphragm

Clotted hemothorax
Persistent chylothorax
Traumatic intracardiac defects
Evacuation of large foreign bodies
Chronic atelectasis from traumatic bronchial stenosis

Modified from O'Neill JA Jr: Principles of pediatric surgery, ed 2, St Louis,

2003, Mosby, p 157.
studies have prognostic importance. A large base deficit is associated with a
higher mortality rate, and elevated lactate values correlate with poor prognosis.
There are some limitations in standard tests. The lateral cervical spine
radiograph can miss clinically significant injuries. Hemoglobin and hematocrit
values provide baseline values in the ED, but they may not have yet equilibrated
after a hemorrhage. Abnormal liver function test results or elevated serum
amylase and lipase values may be noted in patients with significant abdominal
trauma, but most patients with significant trauma to the abdomen already have
clinical indications for CT scanning or surgery. The majority of previously
healthy children have normal coagulation profiles; these may become abnormal
after major head trauma. Although routine urinalysis or dipstick urine testing for
blood has been recommended for children, other data suggest that this evaluation
may be unnecessary in patients without gross hematuria, hypotension, or other
associated abdominal injuries.
Clinical prediction rules that combine patient history with physical
examination findings have been developed to identify those at low risk of injury
for whom specific radiographic and laboratory studies may not be necessary. The
NEXUS C-spine rule is a sensitive, easily applicable rule that was validated for
adults and children, although there were fewer young patients studied (see Table
82.5 ). Several clinical prediction rules have been developed to identify children
at low risk of traumatic brain injury (Table 82.7 ). Another clinical prediction
rule has been developed to identify children at very low risk of clinically
important intraabdominal injuries following blunt trauma (Table 82.8 ).
Although this rule has an NPV of 99.9%, it needs to be externally validated
before widespread implementation.
Table 82.7
Prediction Rule for Identification of Children
at Very Low Risk of Clinically Important
Brain Injuries After Head Trauma

Children <2 yr old are at very low risk of clinically important traumatic
brain injury if they have none of the following:
Severe mechanism of injury
History of LOC >5 sec
GCS ≤14 or other signs of altered mental status
 Not acting normally per parent
Palpable skull fracture
Occipital/parietal/temporal scalp hematoma
Children 2-18 yr old are at very low risk of clinically important traumatic
brain injury if they have none of the following:
Severe mechanism of injury
History of LOC
History of vomiting
GCS ≤14 or other signs of altered mental status
Severe headache in the ED
Signs of basilar skull fracture

ED, Emergency department; GCS, Glasgow Coma Scale score; LOC, loss of
consciousness.

Modified from Kuppermann N, Holmes JF, Dayan PS, et al: Identification of

children at very low risk of clinically-important brain injuries after head trauma:
a prospective cohort study, Lancet 374:1160–1170, 2009.
Table 82.8
Prediction Rule for Identification of Children
at Very Low Risk of Clinically Important
Intraabdominal Injuries After Blunt Trauma

If none of the following is present, the patient is at very low risk for
clinically significant intraabdominal injury:
Glasgow Coma Scale score <14
Vomiting
Evidence of thoracic wall trauma
Decreased breath sounds
Evidence of abdominal wall trauma or seatbelt sign
Abdominal pain
Abdominal tenderness

Modified from Holmes JF, Lillis K, Monroe D, et al: Identifying children at very
low risk of clinically important blunt abdominal injuries, Ann Emerg Med
Commonly Used Coma Scores

POINTS DESCRIPTION
GLASGOW COMA SCALE (GCS) SCORE
Eye Opening
1 Does not open eyes
2 Opens eyes in response to noxious stimuli
3 Opens eyes in response to voice
4 Opens eyes spontaneously
Verbal Output
1 Makes no sounds
2 Makes incomprehensible sounds
3 Utters inappropriate words
4 Confused and disoriented
5 Speaks normally and oriented
Motor Response (Best)
1 Makes no movements
2 Extension to painful stimuli
3 Abnormal flexion to painful stimuli
4 Flexion/withdrawal to painful stimuli
5 Localized to painful stimuli
6 Obeys commands
FULL OUTLINE OF UNRESPONSIVENESS (FOUR) SCORE
Eye Response
4 Eyelids open or opened, tracking, or blinking to command
3 Eyelids open but not tracking
2 Eyelids closed but open to loud voice
1 Eyelids closed but open to pain
0 Eyelids remain closed with pain
Motor Response
4 Thumbs-up, fist, or “peace” sign
3 Localizing to pain
2 Flexion response to pain
1 Extension response to pain
0 No response to pain or generalized myoclonus status
Brainstem Reflexes
4 Pupil and corneal reflexes present
3 One pupil wide and fixed
2 Pupil or corneal reflexes absent
1 Pupil and corneal reflexes absent
0 Absent pupil, corneal, and cough reflex
Respiration
4 Not intubated, regular breathing pattern
3 Not intubated, Cheyne-Stokes breathing pattern
2 Not intubated, irregular breathing
1 Breathes above ventilatory rate
0 Breathes at ventilator rate or apnea
Adapted from Edlow JA, Rabinstein A, Traub SJ, Wijdicks EFM: Diagnosis of reversible causes of
coma, Lancet 384:2064-2076, 2014.

The most studied monitoring device in clinical practice is the ICP monitor .
such as electroencephalography (EEG) and cerebral blood flow (CBF) studies
are sometimes used to assist in making the diagnosis, repeated clinical
examination is the standard for diagnosis. The 3 components for determining
brain death are demonstration of coexisting irreversible coma with a known
cause , absence of brainstem reflexes , and apnea .
Before a determination of brain death may be made, it is of utmost importance
that the cause of the coma be determined using the history, any radiology, and
laboratory data, to rule out a reversible condition. Potentially reversible causes
of coma include metabolic disorders, toxins, sedative drugs, paralytic agents,
hypothermia, hypoxia, hypotension/shock, recent cardiopulmonary resuscitation
(CPR), hypo-/hyperglycemia, hypo-/hypernatremia, hypercalcemia,
hypermagnesemia, nonconvulsive status epilepticus, hypothyroidism,
hypocortisolism, hypercarbia, liver or renal failure, sepsis, meningitis,
encephalitis, subarachnoid hemorrhage, and surgically remediable brainstem
lesions. Confounding factors must be corrected before initiation of brain death
assessment.

Coma
The state of coma requires that the patient be unresponsive, even to noxious
stimuli. Any purposeful motor response, such as localization, does not constitute
coma. Likewise, any posturing (decerebrate or decorticate) is not consistent with
coma, and therefore not consistent with brain death. The presence of spinal cord
reflexes—even complex reflexes—does not preclude the diagnosis of brain
death.

Brainstem Reflexes
Brainstem reflexes must be absent. Table 86.1 lists the brainstem reflexes to be
tested, the brainstem location of each reflex, and the result of each test that is
consistent with a diagnosis of brain death.

Table 86.1
Brainstem Reflex Testing to Determine Brain Death

BRAINSTEM AREA HOW TO PERFORM

EXPLANATION OF RESULTS
REFLEX TESTED EXAM
Pupillary light Cranial Shine a light into the eyes Midposition (4-6 mm) or fully dilated pupils
 reflex nerves while closely observing that are not reactive to light are consistent
(CNs) II pupillary size. with brain death.
and III, Pinpoint pupils, even if nonreactive, suggest
midbrain intact function of the Edinger-Westphal
nucleus in the midbrain and are therefore not
consistent with brain death.
Oculocephalic CNs III, VI, Manually rotate the In the intact patient, the eyes remain fixed on
reflex (doll's and VIII; patient's head side to side a distant spot, as if maintaining eye contact
eyes reflex) midbrain; and closely watch the with that spot.
pons position of the eyes. In an exam consistent with brain death, the
Should not be performed eyes move in concert with the patient's head
in a patient with a movement.
cervical spine injury.
Corneal reflex CNs III, V, Touch the patient's cornea In the intact patient, the touch results in eyelid
and VII; with a cotton swab. closure, and the eye may rotate upward.
pons In an exam consistent with brain death, there
is no response.
Oculovestibular CNs III, IV, Irrigate the tympanic Absence of eye movement is consistent with brain
reflex VI, and membrane with iced water or death.
VIII; pons; saline and look for eye
midbrain movement.
Gag and cough CNs IX and Touch the posterior Absence of both a cough and a gag is consistent
reflex X, medulla pharynx with a tongue with brain death.
depressor or a cotton-
tipped swab to stimulate a
gag.
Advance a suction
catheter through the
endotracheal tube to the
carina to stimulate a
cough.

Apnea
Apnea is the absence of respiratory effort in response to an adequate stimulus.
An arterial partial pressure of carbon dioxide (PaCO 2 ) value ≥60 mm Hg and
>20 mm Hg above baseline is a sufficient stimulus. Apnea is clinically
confirmed through the apnea test. Because the apnea test has the potential to
destabilize the patient, it is performed only if the 1st 2 criteria for brain death
(irreversible coma and absence of brainstem reflexes) are already confirmed.
The apnea test assesses the function of the medulla in driving ventilation. It is
performed by first ensuring appropriate hemodynamics and temperature (>35°C)
and the absence of apnea-producing drug effects or significant metabolic
derangements. The patient is then preoxygenated with 100% oxygen for
approximately 10 min, and ventilation is adjusted to achieve a PaCO 2 of
approximately 40 mm Hg. A baseline arterial blood gas (ABG) result documents
CHAPTER 87

Syncope
Aarti S. Dalal, George F. Van Hare

Syncope is defined as a sudden transient loss of consciousness with inability to

maintain postural tone. The most common cause of syncope in the normal
pediatric population is neurocardiogenic syncope (vasovagal syncope,
fainting). Vasovagal syncope is classically associated with a prodrome that
includes diaphoresis, warmth, pallor, or feeling lightheaded and is often
triggered by a specific event or situation such as pain, medical procedures, or
emotional distress (Table 87.1 ). This type of syncope is characterized by
hypotension and bradycardia. Approximately 30–50% of children will have had
a fainting episode before 18 yr of age.
Table 87.1
Noncardiac Causes of Syncope
Reflex vasodepressor syncope
Neurocardiogenic (vasovagal)
Emotion (seeing blood)
Pain (needle phobia)
Miscellaneous situational reflex
Tussive
Sneeze
Exercise, after exercise
Swallowing
Stretching
Defecation
Micturition
Hair grooming
 Valsalva (increased intrathoracic pressure)
Trumpet playing
Weightlifting
Breath-holding spells
Systemic illness
Hypoglycemia
Anemia
Infection
Hypovolemia, dehydration
Adrenal insufficiency
Narcolepsy, cataplexy
Pulmonary embolism
Pheochromocytoma
Mastocytosis
Ruptured ectopic pregnancy
Central nervous system
Seizure (atonic, absence, myoclonic-astatic)
Stroke, transient ischemic attack
Subarachnoid hemorrhage
Dysautonomia
Myotonic dystrophy
Kearns-Sayre syndrome
Friedreich ataxia
Basilar artery migraine
Drug effects
β-Blocking agents
Vasodilating agents
Opiates
Sedatives
Drugs prolonging QT interval
Diuretics
Anticonvulsant agents
Antihistamines
Antidepressant agents
Anxiolytic agents
Drugs of abuse
Insulin, oral hypoglycemic agents
 Carbon monoxide
Other etiologies
Carotid sinus sensitivity
Subclavian steal
Panic attack, anxiety
Conversion disorder

Most patients with a vasovagal syncope episode will have prodromal features
followed by loss of motor tone. Once in a horizontal position, consciousness
returns rapidly, in 1-2 min; some patients may have 30 sec of tonic-clonic motor
activities, which should not be confused with a seizure (Table 87.2 ). Syncope
must also be distinguished from vertigo and ataxia (Table 87.3 ).

Table 87.2

Comparison of Clinical Features of Syncope and Seizures

FEATURES SYNCOPE SEIZURES
Relation to posture Common No
Time of day Diurnal Diurnal or nocturnal
Precipitating factors Emotion, injury, pain, crowds, heat, exercise, fear, Sleep loss, drug/alcohol
dehydration, coughing, micturition withdrawal
Skin color Pallor Cyanosis or normal
Diaphoresis Common Rare
Aura or premonitory Long Brief
symptoms
Convulsion Rare, brief Common
Other abnormal Minor twitching Rhythmic jerks
movements
Injury Rare Common (with
convulsive seizures)
Urinary incontinence Rare Common
Tongue biting No Can occur with
convulsive seizures
Postictal confusion Rare Common
Postictal headache No Common
Focal neurologic signs No Occasional
Cardiovascular signs Common (cardiac syncope) No
Abnormal findings on Rare (generalized slowing may occur during the event) Common
EEG
From Bruni J: Episodic impairment of consciousness. In Daroff RB, Jankovic JM, Mazziotta JC,
Pomeroy SL, editors: Bradley's neurology in clinical practice, ed 7, Philadelphia, 2016, Elsevier.

Table 87.3
Syncope and Dizziness

VERTIGO PRESYNCOPE DISEQUILIBRIUM LIGHTHEADEDNESS

Patient “My head is “I feel I might pass “I feel unsteady.” “I feel dizzy.”
complaint spinning.” out.” “My balance is “I feel disconnected,
“The room is “I feel faint.” off.” drugged.”
whirling.” “I feel like blacking
out.”
Associated Motion, swaying, Syncope: loss of Poor balance Anxiety,
features spinning, nystagmus postural tone, brief No vertigo or hyperventilation,
loss of consciousness ataxia paresthesias, respiratory
Situational alkalosis, panic attacks
Usual Vestibular disorders Impaired cerebral Sensory and/or Anxiety and/or
cause perfusion central neurologic depressive disorders
dysfunction
Key Peripheral Neurocardiogenic (vagal) Sensory deficit vs Anxiety/depression vs
differential (labyrinthine-cochlear) vs cardiac syncope vs central neurologic hyperventilation vs
diagnoses vs central neurologic neuropsychiatric syncope disease medication effects
disorder
From Cohen G: Syncope and dizziness. In Nelson pediatric symptom-based diagnosis,
Philadelphia, 2018, Elsevier (Table 6.1, p 84).

Although this type of syncope is very common in adolescence and has an

excellent prognosis, other causes for loss of consciousness are more dangerous;
thus syncope may be the first sign of more serious conditions (Table 87.4 ).
Indeed, the occurrence of syncope may well be the pediatrician's best
opportunity to diagnose a life-threatening condition before the patient
subsequently succumbs. The task of the clinician, therefore, is not only to
counsel the family and the patient concerning the common form, but also to rule
out a number of important life-threatening cardiac problems.
Table 87.4
Life-Threatening Cardiac Causes as Risk
With Syncope

Long QT syndromes (congenital and drug induced)

Short QT syndromes
Cardiomyopathies
Hypertrophic cardiomyopathy
Dilated cardiomyopathy
Arrhythmogenic right ventricular dysplasia
Brugada syndrome
 Catecholaminergic polymorphic ventricular tachycardia
Myocarditis
Lyme myocarditis
Chagas disease
Wolff-Parkinson-White syndrome
Coronary artery anomalies
Late postoperative arrhythmias
Adult congenital heart patients
Congenital or acquired complete atrioventricular block
Aortic, mitral, or pulmonic valve stenosis
Primary pulmonary hypertension
Eisenmenger syndrome
Dissecting aortic aneurysm (Marfan syndrome)
Cardiac tumor
Pacemaker malfunction
Takotsubo cardiomyopathy

Mechanisms
Syncope by whatever mechanism is caused by a lack of adequate cerebral blood
flow with loss of consciousness and inability to remain upright.
Primary cardiac causes of syncope (Table 87.4 ) include arrhythmias such as
long QT syndrome (LQTS), Wolff-Parkinson-White syndrome (particularly with
atrial fibrillation), ventricular tachycardia (VT), and occasionally
supraventricular tachycardia (see Chapter 462 ). VT may be associated with
hypertrophic cardiomyopathy (HCM), arrhythmogenic cardiomyopathy, repaired
congenital heart disease, or a genetic cause such as catecholaminergic
polymorphous ventricular tachycardia (CPVT). Other arrhythmias that may lead
to syncope are bradyarrhythmias such as sinus node dysfunction and high-grade
second- or third-degree atrioventricular (AV) block. Patients with congenital
complete AV block may present with syncope. Syncope may also be caused by
cardiac obstructive lesions, such as critical aortic stenosis, or coronary artery
anomalies, such as an aberrant left coronary artery arising from the right sinus of
Valsalva. Patients with primary pulmonary hypertension or Eisenmenger
syndrome may experience syncope. In all the obstructive forms of syncope,
exercise increases the likelihood of an episode because the obstruction interferes
with the ability of the heart to increased cardiac output in response to exercise.
 Noncardiac causes of loss of consciousness include epilepsy, as well as
basilar artery migraine, hysterical syncope, and pseudoseizures (see Table 87.1 ).
Occasionally, patients with narcolepsy may present with syncope. Hypoglycemia
and hyperventilation may also present as syncope.

Evaluation
The most important goal in the evaluation of the new patient with syncope is to
diagnose life-threatening causes of syncope so that these causes can be managed.
Many patients presenting with sudden cardiac arrest caused by conditions such
as LQTS will have previously experienced an episode of syncope, so the
presentation with syncope is an opportunity to prevent sudden death.
The most important tool in evaluation is a careful history . The characteristics
of cardiac syncope differ significantly from the prodrome seen in
neurocardiogenic syncope (Table 87.5 ). Several red flags can be identified that
should lead the clinician to suspect that the mechanism is a life-threatening
cardiac cause rather than simple fainting (Table 87.6 ). The occurrence during
exercise suggests an arrhythmia or coronary obstruction. Injury because of an
episode of syncope indicates sudden occurrence with a lack of adequate
prodromal symptoms and suggests an arrhythmia. The occurrence of syncope
while recumbent would be quite unusual in a patient with neurocardiogenic
syncope and therefore suggests a cardiac or neurologic cause. Occasionally, a
patient with syncope caused by a tachyarrhythmia will report the sensation of a
racing heart before the event, but this is unusual.

Table 87.5
Differentiating Features for Causes of Syncope
NEUROCARDIOGENIC
Symptoms after prolonged motionless standing, sudden unexpected pain, fear, or unpleasant sight, sound, or
smell; pallor
Syncope in a well-trained athlete after exertion (without heart disease)
Situational syncope during or immediately after micturition, cough, swallowing, or defecation
Syncope with throat or facial pain (glossopharyngeal or trigeminal neuralgia)
ORGANIC HEART DISEASE (PRIMARY ARRHYTHMIA, OBSTRUCTIVE HYPERTROPHIC
CARDIOMYOPATHY, PULMONARY HYPERTENSION)
Brief sudden loss of consciousness, no prodrome, history of heart disease
Syncope while sitting or supine
Syncope with exertion
History of palpitations
 Family history of sudden death
NEUROLOGIC
Seizures: preceding aura, post event symptoms lasting > 5 min (includes postictal state of decreased level of
consciousness, confusion, headache or paralysis)
Migraine: syncope associated with antecedent headaches with or without aura
OTHER VASCULAR
Carotid sinus: syncope with head rotation or pressure on the carotid sinus (as in tumors, shaving, tight collars)
Orthostatic hypotension: syncope immediately on standing especially after prolonged bed rest
DRUG INDUCED
Patient is taking a medication that may lead to long QT syndrome, orthostasis, or bradycardia
PSYCHIATRIC ILLNESS
Frequent syncope, somatic complaints, no heart disease
From Cohen G: Syncope and dizziness. In Kliegman RM, Lye PS, Bordini BJ, et al, editors:
Nelson pediatric symptom-based diagnosis. Philadelphia, 2018, Elsevier, Table 6.4.

Table 87.6
Red Flags in Evaluation of Patients With
Syncope
Syncope with activity or exercise or supine
Syncope not associated with prolonged standing
Syncope precipitated by loud noise or extreme emotion
Absence of presyncope or lightheadedness
Family history of syncope, drowning, sudden death, familial ventricular
arrhythmia syndromes,* cardiomyopathy
Syncope requiring CPR
Injury with syncope
Anemia
Other cardiac symptoms
Chest pain
Dyspnea
Palpitations
History of cardiac surgery
History of Kawasaki disease
Implanted pacemaker
Abnormal physical examination
Murmur
Gallop rhythm
Loud and single second heart sound
Systolic click
 Increased apical impulse (tachycardia)
Irregular rhythm
Hypo- or hypertension
Clubbing
Cyanosis

* Long QT syndrome, Brugada syndrome, catecholamine polymorphic

ventricular tachycardia, arrhythmogenic right ventricular dysplasia.

A careful family history is essential in evaluation of syncope. Specifically, if

there are first-degree relatives with inherited syndromes, such as a LQTS or
HCM, this should lead to more specific evaluation of the patient. Also, if
relatives died suddenly at a young age without a clear and convincing cause,
inherited cardiac arrhythmias or cardiomyopathies should also be suspected.
Patients with a history of heart disease, especially cardiac repair, may have
causes that are specific to their repair. Sinus node dysfunction is common after
the Senning or Mustard procedure for transposition of the great vessels. VT may
be seen after repair of tetralogy of Fallot. A patient with a history of septal defect
repair should be evaluated for the late occurrence of AV block, and patients with
an implanted pacemaker should be evaluated for pacemaker lead failure.
The physical examination may also offer clues (Table 87.6 ). Patients with
HCM may have a prominent cardiac impulse and/or an ejection murmur, as will
patients with aortic stenosis. The patient with primary pulmonary hypertension
will have a loud and single second heart sound and may also have an ejection
click and the murmur of pulmonary insufficiency. Scars from prior cardiac
surgery and pacemaker implantation would be evident.
All patients presenting with a first episode of syncope must have an
electrocardiogram obtained, looking primarily for QT interval prolongation,
preexcitation, ventricular hypertrophy, T-wave abnormalities, and conduction
abnormalities. Other tests that may be needed depending on the results of the
initial evaluation may include echocardiography, exercise testing, cardiac MRI,
or 24 hr Holter monitoring. In patients for whom there is a strong suspicion of a
paroxysmal arrhythmia, an implantable loop recorder may be the most effective
means of diagnosis. Additional tests to look for anemia, hypoglycemia, drugs of
abuse, and other etiologies noted in Table 87.1 will be determined by the history
and physical examination.

Treatment
Therapy for vasovagal syncope includes avoiding triggering events (if possible),
fluid and salt supplementation, and if needed, midodrine (see Chapter 87.1 ,
Table 87.7 ). Immediately after the event, the patient should remain supine until
symptoms abate to avoid recurrence.

Table 87.7
First-Line Medications in Treatment of Postural
Tachycardia Syndrome (POTS)

TREATMENT
DRUG MECHANISM OF ACTION SIDE EFFECTS
GUIDELINES
Fludrocortisone Low dose: sensitizes α receptors Peripheral edema, headache, Monitor basic
Higher doses: mineralocorticoid effect irritability, hypokalemia, metabolic panel and
hypomagnesemia, acne magnesium.
Midodrine α1 -Agonist; produces vasoconstriction Scalp tingling, urinary Monitor supine
retention, goose bumps, blood pressure 30-
headache, supine 60 min after dose.
hypertension
Metoprolol β-Blocker Worsening of asthma, Use with
succinate/tartrate dizziness, fatigue caution in
asthma.
If fatigue is
severe, use at
bedtime.
Propranolol Nonselective β-blocker Bradycardia, gastrointestinal Use with caution in
symptoms, lightheadedness, diabetes and
sleepiness, hypotension, asthma.
syncope
Pyridostigmine Peripheral acetylcholinesterase inhibitor Symptoms of excessive Very useful if
that increases synaptic acetylcholine in cholinergic activity patient has
autonomic ganglia and at peripheral (diarrhea, urinary POTS and
muscarinic receptors incontinence, salivation) constipation.
Use with
caution in
asthma.
Contraindicated
in urinary or
bowel
obstruction.

Treatment for cardiac causes of syncope will be determined by the diagnosis.

If a reentrant tachycardia (AVNRT, AVRT) is found, then a catheter ablation is
hypovolemic, cardiogenic, distributive, obstructive, and septic (Table 88.1 ).
Hypovolemic shock , the most common cause of shock in children worldwide,
is most frequently caused by diarrhea, vomiting, or hemorrhage. Cardiogenic
shock is seen in patients with congenital heart disease (before or after surgery,
including heart transplantation) or those with congenital or acquired
cardiomyopathies, including acute myocarditis. Obstructive shock stems from
any lesion that creates a mechanical barrier that impedes adequate cardiac
output, which includes pericardial tamponade, tension pneumothorax, pulmonary
embolism, and ductus-dependent congenital heart lesions. Distributive shock is
caused by inadequate vasomotor tone, which leads to capillary leak and
maldistribution of fluid into the interstitium. Septic shock is often discussed
synonymously with distributive shock, but the septic process usually involves a
more complex interaction of distributive, hypovolemic, and cardiogenic shock.

Table 88.1
Types of Shock

HYPOVOLEMIC CARDIOGENIC DISTRIBUTIVE SEPTIC OBSTRUCTIVE

Decreased preload Cardiac pump Abnormalities of Encompasses multiple Decreased cardiac
secondary to failure secondary to vasomotor tone forms of shock output secondary to
internal or external poor myocardial from loss of venous Hypovolemic: third direct impediment to
losses function and arterial spacing of fluids into right- or left-sided
capacitance the extracellular, heart outflow or
interstitial space restriction of all
Distributive: early cardiac chambers
shock with decreased
afterload
Cardiogenic: depression
of myocardial
function by
endotoxins
POTENTIAL ETIOLOGIES
Blood loss: Congenital heart Anaphylaxis Bacterial Tension
hemorrhage disease Neurologic: loss of Viral pneumothorax
Plasma loss: burns, Cardiomyopathies: sympathetic Fungal Pericardial tamponade
nephrotic infectious or vascular tone (immunocompromised Pulmonary embolism
syndrome acquired, dilated secondary to patients are at Anterior mediastinal
Water/electrolyte or restrictive spinal cord or increased risk) masses
loss: vomiting, Ischemia brainstem injury Critical coarctation of
diarrhea Arrhythmias Drugs aorta

Pathophysiology
An initial insult triggers shock, leading to inadequate oxygen delivery to organs
and tissues. Compensatory mechanisms attempt to maintain blood pressure (BP)
by increasing cardiac output and systemic vascular resistance (SVR). The body
also attempts to optimize oxygen delivery to the tissues by increasing oxygen
extraction and redistributing blood flow to the brain, heart, and kidneys at the
expense of the skin and gastrointestinal (GI) tract. These responses lead to an
initial state of compensated shock in which BP is maintained. If treatment is not
initiated or is inadequate during this period, decompensated shock develops,
with hypotension and tissue damage that may lead to multisystem organ
dysfunction and, ultimately, death (Tables 88.2 and 88.3 ).

Table 88.2
Criteria for Organ Dysfunction

ORGAN
CRITERIA FOR DYSFUNCTION
SYSTEM
Cardiovascular Despite administration of isotonic intravenous fluid bolus ≥60 mL/kg in 1 hr: decrease in BP
(hypotension) systolic BP <90 mm Hg, mean arterial pressure <70 mm Hg, <5th percentile for
age, or systolic BP <2 SD below normal for age
or
Need for vasoactive drug to maintain BP in normal range (dopamine >5 µg/kg/min or
dobutamine, epinephrine, or norepinephrine at any dose)
or
Two of the following:
Unexplained metabolic acidosis: base deficit >5.0 mEq/L
Increased arterial lactate: >1 mmol/L or >2× upper limit of normal
Oliguria: urine output <0.5 mL/kg/hr
Prolonged capillary refill: >5 sec
Core-to-peripheral temperature gap: >3°C (5.4°F)
Respiratory PaO 2 /FIO 2 ratio <300 in absence of cyanotic heart disease or preexisting lung disease
or
PaCO 2 >65 torr or 20 mm Hg over baseline PaCO 2
or
Need for >50% FIO 2 to maintain saturation ≥92%
or
Need for nonelective invasive or noninvasive mechanical ventilation
Neurologic GCS score ≤11
or
Acute change in mental status with decrease in GCS score ≥3 points from abnormal baseline
Hematologic Platelet count <100,000/mm3 or decline of 50% in platelet count from highest value recorded
over last 3 days (for patients with chronic hematologic or oncologic disorders)
or
INR >1.5
or
Activated prothrombin time >60 sec
Renal Serum creatinine >0.5 mg/dL, ≥2× upper limit of normal for age, or 2-fold increase in baseline
creatinine value
 Hepatic Total bilirubin ≥4 mg/dL (not applicable for newborn)
Alanine transaminase level 2× upper limit of normal for age
BP, Blood pressure; FIO 2 , fraction of inspired oxygen; GCS, Glasgow Coma Scale; INR,
international normalized ratio; PaCO 2 , arterial partial pressure of carbon dioxide; PaO 2 , partial
pressure arterial oxygen; SD, standard deviations.

Table 88.3
Signs of Decreased Perfusion

ORGAN SYSTEM ↓ PERFUSION ↓↓ PERFUSION ↓↓↓ PERFUSION

Central nervous — Restless, apathetic, anxious Agitated/confused, stuporous,
system coma
Respiration — ↑ Ventilation ↑↑ Ventilation
Metabolism — Compensated metabolic Uncompensated metabolic
acidemia acidemia
Gut — ↓ Motility Ileus
Kidney ↓ Urine volume Oliguria (<0.5 mL/kg/hr) Oliguria/anuria
↑ Urinary specific
gravity
Skin Delayed capillary refill Cool extremities Mottled, cyanotic, cold
extremities
Cardiovascular ↑ Heart rate ↑↑ Heart rate ↑↑ Heart rate
system ↓ Peripheral pulses ↓ Blood pressure, central pulses
only

In the early phases of shock, multiple compensatory physiologic mechanisms

act to maintain BP and preserve tissue perfusion and oxygen delivery.
Cardiovascular effects include increases in heart rate (HR), stroke volume, and
vascular smooth muscle tone, which are regulated through sympathetic nervous
system activation and neurohormonal responses. Respiratory compensation
involves greater carbon dioxide (CO2 ) elimination in response to the metabolic
acidosis and increased CO2 production from poor tissue perfusion. Renal
excretion of hydrogen ions (H+ ) and retention of bicarbonate (HCO3 − ) also
increase in an effort to maintain normal body pH (see Chapter 68.7 ).
Maintenance of intravascular volume is facilitated via sodium regulation through
the renin-angiotensin-aldosterone and atrial natriuretic factor axes, cortisol and
catecholamine synthesis and release, and antidiuretic hormone secretion. Despite
these compensatory mechanisms, the underlying shock and host response lead to
vascular endothelial cell injury and significant leakage of intravascular fluids
into the interstitial extracellular space.
Another important aspect of the initial pathophysiology of shock is the impact
on cardiac output. All forms of shock affect cardiac output through several
mechanisms, with changes in HR, preload, afterload, and myocardial
contractility occurring separately or in combination (Table 88.4 ). Hypovolemic
shock is characterized primarily by fluid loss and decreased preload.
Tachycardia and an increase in SVR are the initial compensatory responses to
maintain cardiac output and systemic BP. Without adequate volume replacement,
hypotension develops, followed by tissue ischemia and further clinical
deterioration. When there is preexisting low plasma oncotic pressure (caused by
nephrotic syndrome, malnutrition, hepatic dysfunction, acute severe burns, etc.),
even further volume loss and exacerbation of shock may result from endothelial
breakdown and worsening capillary leak.
Table 88.4
Pathophysiology of Shock
Extracorporeal Fluid Loss

Hypovolemic shock may be a result of direct blood loss through

hemorrhage or abnormal loss of body fluids (diarrhea, vomiting, burns,
diabetes mellitus or insipidus, nephrosis).

Lowering Plasma Oncotic Forces

Hypovolemic shock may also result from hypoproteinemia (liver injury, or

as a progressive complication of increased capillary permeability).

Abnormal Vasodilation

Distributive shock (neurogenic, anaphylaxis, or septic shock) occurs when

there is loss of vascular tone—venous, arterial, or both (sympathetic
blockade, local substances affecting permeability, acidosis, drug effects,
spinal cord transection).

Increased Vascular Permeability

Sepsis may change the capillary permeability in the absence of any change
in capillary hydrostatic pressure (endotoxins from sepsis, excess
 histamine release in anaphylaxis).

Cardiac Dysfunction

Peripheral hypoperfusion may result from any condition that affects the
heart's ability to pump blood efficiently (ischemia, acidosis, drugs,
constrictive pericarditis, pancreatitis, sepsis).

In contrast, the underlying pathophysiologic mechanism leading to

distributive shock is a state of abnormal vasodilation and decreased SVR.
Sepsis, hypoxia, poisoning, anaphylaxis, spinal cord injury, or mitochondrial
dysfunction can cause vasodilatory shock (Fig. 88.3 ). The lowering of SVR is
accompanied initially by a maldistribution of blood flow away from vital organs
and a compensatory increase in cardiac output. This process leads to significant
decreases in both preload and afterload. Therapies for distributive shock must
address both these problems simultaneously.

FIG. 88.3 Mechanisms of vasodilatory shock. Septic shock and states of prolonged
shock causing tissue hypoxia with lactic acidosis increase nitric oxide synthesis,
activate the adenosine triphosphate (ATP)–sensitive and calcium-regulated potassium
channels (KATP and KCa , respectively) in vascular smooth muscle, and lead to depletion
of vasopressin. cGMP, Cyclic guanosine monophosphate. (From Landry DW, Oliver JA:
 The pathogenesis of vasodilatory shock, N Engl J Med 345:588.595, 2001.)

Cardiogenic shock may be seen in patients with myocarditis,

cardiomyopathy, arrhythmias and congenital heart disease (generally following
cardiac surgery) (see Chapter 461 ). In these patients, myocardial contractility is
affected, leading to systolic and/or diastolic dysfunction. The later phases of all
forms of shock frequently have a negative impact on the myocardium, leading to
development of a cardiogenic component to the initial shock state.
Septic shock is generally a unique combination of distributive, hypovolemic,
and cardiogenic shock. Hypovolemia from intravascular fluid losses occurs
through capillary leak. Cardiogenic shock results from the myocardial-
depressant effects of sepsis, and distributive shock is the result of decreased
SVR. The degree to which a patient exhibits each of these responses varies, but
there are frequently alterations in preload, afterload, and myocardial
contractility.
In septic shock, it is important to distinguish between the inciting infection
and the host inflammatory response. Normally, host immunity prevents the
development of sepsis through activation of the reticular endothelial system
along with the cellular and humoral immune systems. This host immune
response produces an inflammatory cascade of toxic mediators, including
hormones, cytokines, and enzymes. If this inflammatory cascade is uncontrolled,
derangement of the microcirculatory system leads to subsequent organ and
cellular dysfunction.
The systemic inflammatory response syndrome (SIRS ) is an inflammatory
cascade that is initiated by the host response to an infectious or noninfectious
trigger (Table 88.5 ). This inflammatory cascade is triggered when the host
defense system does not adequately recognize and/or eliminate the triggering
event. The inflammatory cascade initiated by shock can lead to hypovolemia,
cardiac and vascular failure, acute respiratory distress syndrome (ARDS), insulin
resistance, decreased cytochrome P450 activity (decreased steroid synthesis),
coagulopathy, and unresolved or secondary infection. Tumor necrosis factor
(TNF) and other inflammatory mediators increase vascular permeability, causing
diffuse capillary leak, decreased vascular tone, and an imbalance between
perfusion and metabolic demands of the tissues. TNF and interleukin (IL)-1
stimulate the release of proinflammatory and antiinflammatory mediators,
causing fever and vasodilation. Proinflammatory mediators include IL-6, IL-12,
interferon-γ, and macrophage migration inhibitory factor; antiinflammatory
cytokines include IL-10, transforming growth factor-β, and IL-4. Arachidonic
acid metabolites lead to the development of fever, tachypnea, ventilation-
perfusion abnormalities, and lactic acidosis. Nitric oxide (NO), released from the
endothelium or inflammatory cells, is a major contributor to hypotension.
Myocardial depression is caused directly by myocardial-depressant factors, TNF,
and some interleukins and is further depressed by depleted catecholamines,
increased β-endorphin, and production of myocardial NO.
Table 88.5
Differential Diagnosis of Systemic
Inflammatory Response Syndrome (SIRS)
Infection

Bacteremia or meningitis (Streptococcus pneumoniae, Haemophilus

influenzae type b, Neisseria meningitidis, group A streptococcus,
Staphylococcus aureus )
Viral illness (influenza, enteroviruses, hemorrhagic fever group, herpes
simplex virus, respiratory syncytial virus, cytomegalovirus, Epstein-Barr
virus)
Encephalitis (arboviruses, enteroviruses, herpes simplex virus)
Rickettsiae (Rocky Mountain spotted fever, Ehrlichia, Q fever)
Syphilis
Vaccine reaction (pertussis, influenza, measles)
Toxin-mediated reaction (toxic shock, staphylococcal scalded skin
syndrome)

Cardiopulmonary

Pneumonia (bacteria, virus, mycobacteria, fungi, allergic reaction)

Pulmonary emboli
Heart failure
Arrhythmia
Pericarditis
Myocarditis
Metabolic-Endocrine

Adrenal insufficiency (adrenogenital syndrome, Addison disease,

corticosteroid withdrawal)
Electrolyte disturbances (hypo- or hypernatremia; hypo- or hypercalcemia)
Diabetes insipidus
Diabetes mellitus
Inborn errors of metabolism (organic acidosis, urea cycle, carnitine
deficiency, mitochondrial disorders)
Hypoglycemia
Reye syndrome

Gastrointestinal

Gastroenteritis with dehydration

Volvulus
Intussusception
Appendicitis
Peritonitis (spontaneous, associated with perforation or peritoneal dialysis)
Necrotizing enterocolitis
Hepatitis
Hemorrhage
Pancreatitis

Hematologic

Anemia (sickle cell disease, blood loss, nutritional)

Methemoglobinemia
Splenic sequestration crisis
Leukemia or lymphoma
Hemophagocytic syndromes

Neurologic

Intoxication (drugs, carbon monoxide, intentional or accidental overdose)

 Intracranial hemorrhage
Infant botulism
Trauma (child abuse, accidental)
Guillain-Barré syndrome
Myasthenia gravis

Other

Anaphylaxis (food, drug, insect sting)

Hemolytic-uremic syndrome
Kawasaki disease
Erythema multiforme
Hemorrhagic shock–encephalopathy syndrome
Poisoning
Toxic envenomation
Macrophage activation syndrome
Idiopathic systemic capillary leak (Clarkson) syndrome

The inflammatory cascade is initiated by toxins or superantigens through

macrophage binding or lymphocyte activation (Fig. 88.4 ). The vascular
endothelium is both a target of tissue injury and a source of mediators that may
cause further injury. Biochemical responses include the production of
arachidonic acid metabolites, release of myocardial-depressant factors and
endogenous opiates, activation of the complement system, and production and
release of other mediators, which may be proinflammatory or antiinflammatory.
The balance among these mediator groups for an individual patient contributes
to the progression (and resolution) of disease and affects the prognosis.
Table 88.6
Hemodynamic Variables in Different Shock States

SYSTEMIC MEAN CAPILLARY CENTRAL

TYPE OF CARDIAC
VASCULAR ARTERIAL WEDGE VENOUS
SHOCK OUTPUT
RESISTANCE PRESSURE PRESSURE PRESSURE
Hypovolemic ↓ ↑ ↔ or ↓ ↓↓↓ ↓↓↓
Cardiogenic*
Systolic ↓↓ ↑↑↑ ↔ or ↓ ↑↑ ↑↑
Diastolic ↔ ↑↑ ↔ ↑↑ ↑
Obstructive ↓ ↑ ↔ or ↓ ↑↑ † ↑↑ †
Distributive ↑↑ ↓↓↓ ↔ or ↓ ↔ or ↓ ↔ or ↓
Septic
Early ↑↑↑ ↓↓↓ ↔ or ↓ ‡ ↓ ↓
Late ↓↓ ↓↓ ↓↓ ↑ ↑ or ↔
* Systolic or diastolic dysfunction.

† Wedge pressure, central venous pressure, and pulmonary artery diastolic pressures are equal.

‡ Wide pulse pressure.

Sepsis is defined as SIRS resulting from a suspected or proven infectious

etiology. The clinical spectrum of sepsis begins when a systemic (e.g.,
bacteremia, rickettsial disease, fungemia, viremia) or localized (e.g., meningitis,
pneumonia, pyelonephritis, peritonitis, necrotizing fasciitis) infection progresses
from sepsis to severe sepsis (i.e., presence of sepsis combined with organ
dysfunction). Further clinical deterioration leads to septic shock (severe sepsis
plus the persistence of hypoperfusion or hypotension despite adequate fluid
resuscitation or a requirement for vasoactive agents), MODS, and possibly death
(Table 88.7 ). This is a complex spectrum of clinical problems that is a leading
cause of mortality in children worldwide. Mortality can be mitigated and
outcomes improved with early recognition and treatment.
Table 88.7
International Consensus Definitions for
Pediatric Sepsis
Infection

Suspected or proven infection or a clinical syndrome associated with high

probability of infection.
Systemic Inflammatory Response Syndrome (SIRS)

Two of 4 criteria, 1 of which must be abnormal temperature or abnormal

leukocyte count:
1. Core temperature >38.5°C (101.3°F) or <36°C (96.8°F) (rectal, bladder,
oral, or central catheter)
2. Tachycardia:
Mean heart rate >2 SD above normal for age in absence of
external stimuli, chronic drugs or painful stimuli
or
Unexplained persistent elevation over 0.5-4 hr
or
In children <1 yr old, persistent bradycardia over 0.5 hr (mean
heart rate <10th percentile for age in absence of vagal stimuli,
β-blocker drugs, or congenital heart disease)
3. Respiratory rate >2 SD above normal for age or acute need for mechanical
ventilation not related to neuromuscular disease or general anesthesia
4. Leukocyte count elevated or depressed for age (not secondary to
chemotherapy) or >10% immature neutrophils

Sepsis

SIRS plus a suspected or proven infection

Severe Sepsis

Sepsis plus 1 of the following:

1. Cardiovascular organ dysfunction, defined as:
Despite >40 mL/kg of isotonic intravenous fluid in 1 hr:
• Hypotension <5th percentile for age or systolic blood pressure <2
SD below normal for age
or
• Need for vasoactive drug to maintain blood pressure
or
Two of the following:
• Unexplained metabolic acidosis: base deficit >5 mEq/L
 • Increased arterial lactate: >2 times upper limit of normal
• Oliguria: urine output <0.5 mL/kg/hr
• Prolonged capillary refill: >5 sec
• Core-to-peripheral temperature gap: >3°C (5.4°F)
2. Acute respiratory distress syndrome (ARDS), as defined by the presence
of a PaO 2 /FIO 2 ratio ≤300 mm Hg, bilateral infiltrates on chest
radiograph, and no evidence of left-sided heart failure.
or
Sepsis plus ≥2 organ dysfunctions (respiratory, renal, neurologic,
hematologic, or hepatic).

Septic Shock

Sepsis plus cardiovascular organ dysfunction as defined above.

Multiple-Organ Dysfunction Syndrome (MODS)

Presence of altered organ function such that homeostasis cannot be

maintained without medical intervention.

FIO 2 , Fraction of inspired oxygen; PaO 2 , partial pressure of arterial oxygen;

SD, standard deviations.

Although septic shock is primarily distributive in nature, multiple other

elements of pathophysiology are represented in this disease process. The initial
signs and symptoms of sepsis include alterations in temperature regulation
(hyperthermia or hypothermia), tachycardia, and tachypnea. In the early stages
(hyperdynamic phase, low SVR, or warm shock), cardiac output increases to
maintain adequate oxygen delivery and meet the greater metabolic demands of
the organs and tissues. As septic shock progresses, cardiac output falls in
response to the effects of numerous inflammatory mediators, leading to a
compensatory elevation in SVR and the development of cold shock.

Diagnosis
Shock
SYSTEM DISORDERS GOALS THERAPIES
Respiratory Acute respiratory Prevent/treat: hypoxia and Oxygen
distress respiratory acidosis Noninvasive ventilation
syndrome
Respiratory Prevent barotrauma Early endotracheal intubation and
muscle fatigue Decrease work of breathing mechanical ventilation
Central apnea Positive end-expiratory pressure
(PEEP)
Permissive hypercapnia
High-frequency ventilation
Extracorporeal membrane
oxygenation (ECMO)
Renal Prerenal failure Prevent/treat: hypovolemia, Judicious fluid resuscitation
Renal failure hypervolemia, hyperkalemia, Establishment of normal urine output
metabolic acidosis, and blood pressure for age
hypernatremia/hyponatremia, Furosemide (Lasix)
and hypertension Dialysis, ultrafiltration, hemofiltration
Monitor serum electrolytes
Hematologic Coagulopathy Prevent/treat: bleeding Vitamin K
(disseminated Fresh-frozen plasma
intravascular Platelets
coagulation)
Thrombosis Prevent/treat: abnormal clotting Heparinization
Gastrointestinal Stress ulcers Prevent/treat: gastric bleeding Histamine H2 -receptor–blocking
Ileus Avoid aspiration, abdominal agents or proton pump inhibitors
distention Nasogastric tube
Bacterial Avoid mucosal atrophy Early enteral feedings
translocation
Endocrine Adrenal Prevent/treat: adrenal crisis Stress-dose steroids in patients
insufficiency, previously given steroids
primary or Physiologic dose for presumed
secondary to primary insufficiency in sepsis
chronic steroid
therapy
Metabolic Metabolic acidosis Correct etiology Treatment of hypovolemia (fluids),
Normalize pH poor cardiac function (fluids,
inotropic agents)
Improvement of renal acid excretion
Low-dose (0.5-2.0 mEq/kg) sodium
bicarbonate if patient is not showing
response, pH <7.1, and ventilation
(CO2 elimination) is adequate

Table 88.9
Recommendations for Shock: Initial
Resuscitation and Infection Issues—Adults
Initial Resuscitation
 1. Protocolized, quantitative resuscitation of patients with sepsis-induced
tissue hypoperfusion (defined as hypotension persisting after initial fluid
challenge or blood lactate concentration ≥4 mmol/L). Goals during the
1st 6 hr of resuscitation:
a. Central venous pressure 8-12 mm Hg
b. Mean arterial pressure (MAP) ≥65 mm Hg
c. Urine output ≥0.5 mL kg−1 hr
d. Central venous (superior vena cava) or mixed venous oxygen
saturation: 70% or 65%, respectively
2. In patients with elevated lactate levels, targeting resuscitation to normalize
lactate as rapidly as possible.

Screening for Sepsis and Performance Improvement

1. Routine screening of potentially infected seriously ill patients for severe

sepsis to allow earlier implementation of therapy.
2. Hospital-based performance improvement efforts in severe sepsis.

Diagnosis

1. Cultures as clinically appropriate before antimicrobial therapy if no

significant delay (>45 min) in the start of antimicrobial(s). At least 2 sets
of blood cultures (both aerobic and anaerobic bottles) should be obtained
before antimicrobial therapy with at least 1 drawn percutaneously and 1
drawn through each vascular access device, unless the device was
recently (<48 hr) inserted.
2. Use of the 1,3 β-D -glucan assay, mannan and antimannan antibody
assays, if available, and invasive candidiasis is in differential diagnosis of
cause of infection.
3. Imaging studies performed promptly to confirm a potential source of
infection.

Antimicrobial Therapy

1. Administration of effective intravenous antimicrobials within the 1st hr of

 recognition of septic shock and severe sepsis without septic shock as the
goal of therapy.
2a. Initial empirical antiinfective therapy of 1 or more drugs that have activity
against all likely pathogens (bacterial and/or fungal or viral) and that
penetrate in adequate concentrations into tissues presumed to be the source
of sepsis.
2b. Antimicrobial regimen should be reassessed daily for potential
deescalation.
3. Use of low procalcitonin levels or similar biomarkers to assist the clinician
in the discontinuation of empirical antibiotics in patients who initially
appeared septic, but have no subsequent evidence of infection.
4a. Combination empirical therapy for neutropenic patients with severe sepsis
and for patients with difficult-to-treat, multidrug-resistant bacterial
pathogens such as Acinetobacter and Pseudomonas spp.
For patients with severe infections associated with respiratory
failure and septic shock, combination therapy with an extended-
spectrum β-lactam and either an aminoglycoside or a
fluoroquinolone is for Pseudomonas aeruginosa bacteremia. A
combination of β-lactam and macrolide for patients with septic
shock from bacteremic Streptococcus pneumoniae infections.
4b. Empirical combination therapy should not be administered for more than
3-5 days. Deescalation to the most appropriate single therapy should be
performed as soon as the susceptibility profile is known.
5. Duration of therapy typically 7-10 days; longer courses may be appropriate
in patients who have a slow clinical response, undrainable foci of infection,
bacteremia with Staphylococcus aureus , some fungal and viral infections,
or immunodeficiencies (e.g., neutropenia).
6. Antiviral therapy initiated as early as possible in patients with severe sepsis
or septic shock of viral origin.
7. Antimicrobial agents should not be used in patients with severe
inflammatory states determined to be of noninfectious cause.

Source Control

1. A specific anatomic diagnosis of infection requiring consideration for

 emergent source control should be sought and diagnosed or excluded as
rapidly as possible, and intervention undertaken for source control within
the 1st 12 hr after the diagnosis is made, if feasible.
2. When infected peripancreatic necrosis is identified as a potential source of
infection, definitive intervention is best delayed until adequate
demarcation of viable and nonviable tissues has occurred.
3. When source control in a severely septic patient is required, the effective
intervention associated with the least physiologic insult should be used
(e.g., percutaneous rather than surgical drainage of an abscess).
4. If intravascular access devices are a possible source of severe sepsis or
septic shock, these should be removed promptly after other vascular
access has been established.

Infection Prevention

1a. Selective oral decontamination and selective digestive decontamination

should be introduced and investigated as a method to reduce the incidence
of ventilator-associated pneumonia; this infection control measure can then
be instituted in healthcare settings and regions where this methodology is
found to be effective.
1b. Oral chlorhexidine gluconate be used as a form of oropharyngeal
decontamination to reduce the risk of ventilator-associated pneumonia in
ICU patients with severe sepsis.

Adapted from Dellinger PR, Levy MM, Rhodes A, et al: Surviving sepsis
campaign: International guidelines for management of severe sepsis and septic
shock: 2012, Crit Care Med 41(2):580–637, 2013 (Table 5, p 589).
Table 88.10
Surviving Sepsis Campaign: Care Bundles

To be completed within 3 hr:

1. Measure lactate level.
2. Obtain blood cultures before administration of antibiotics.
3. Administer broad-spectrum antibiotics.
4. Administer 30 mL/kg crystalloid for hypotension or lactate ≥4 mmol/L.
 To completed within 6 hr:
5. Apply vasopressors (for hypotension that does not respond to initial fluid
resuscitation) to maintain a mean arterial pressure (MAP) ≥65 mm Hg.
6. In the event of persistent arterial hypotension despite volume resuscitation
(septic shock) or initial lactate ≥4 mmol/L (36 mg/dL):
Measure central venous pressure (CVP).*
Measure central venous oxygen saturation (ScvO 2 ).*
7. Remeasure lactate if initial lactate was elevated.*

* Targets for quantitative resuscitation included in the guidelines are CVP of ≥8

mm Hg, ScvO2 of ≥70%, and normalization of lactate.

Adapted from Dellinger PR, Levy MM, Rhodes A, et al: Surviving Sepsis
campaign: international guidelines for management of severe sepsis and septic
shock: 2012. Crit Care Med 41(2):580–637, 2013 (Fig 1, p 591).
Table 88.11
Recommendations for Shock: Hemodynamic
Support and Adjunctive Therapy—Adults
Fluid Therapy of Severe Sepsis

1. Crystalloids as the initial fluid of choice in the resuscitation of severe

sepsis and septic shock.
2. Against the use of hydroxyethyl starches for fluid resuscitation of severe
sepsis and septic shock.
3. Albumin in the fluid resuscitation of severe sepsis and septic shock when
patients require substantial amounts of crystalloids.
4. Initial fluid challenge in patients with sepsis-induced tissue hypoperfusion
with suspicion of hypovolemia, to achieve a minimum of 30 mL/kg of
crystalloids (a portion of this may be albumin equivalent). More rapid
administration and greater amounts of fluid may be needed in some
patients.
5. Fluid challenge technique be applied in which fluid administration is
continued as long as there is hemodynamic improvement either based on
 dynamic (e.g., change in pulse pressure, stroke volume variation) or
static (e.g., arterial pressure, heart rate) variables.

Vasopressors

1. Vasopressor therapy initially to target a mean arterial pressure (MAP) of

65 mm Hg.
2. Norepinephrine as the first-choice vasopressor.
3. Epinephrine (added to and potentially substituted for norepinephrine)
when an additional agent is needed to maintain adequate blood pressure.
4. Vasopressin 0.03 units/min can be added to norepinephrine (NE) with
intent of either raising MAP or decreasing NE dosage.
5. Low-dose vasopressin is not recommended as the single initial
vasopressor for treatment of sepsis-induced hypotension, and vasopressin
doses >0.03-0.04 units/min should be reserved for salvage therapy
(failure to achieve adequate MAP with other vasopressor agents).
6. Dopamine as an alternative vasopressor agent to NE only in highly
selected patients (e.g., with low risk of tachyarrhythmias and absolute or
relative bradycardia).
7. Phenylephrine is not recommended in the treatment of septic shock except
in circumstances where (a) NE is associated with serious arrhythmias, (b)
cardiac output is known to be high and blood pressure persistently low,
or (c) as salvage therapy when combined inotrope/vasopressor drugs and
low-dose vasopressin have failed to achieve MAP target.
8. Low-dose dopamine should not be used for renal protection.
9. All patients requiring vasopressors have an arterial catheter placed as soon
as practical if resources are available.

Inotropic Therapy

1. A trial of dobutamine infusion up to 20 µg/kg/min be administered or

added to vasopressor (if in use) in the presence of (a) myocardial
dysfunction as suggested by elevated cardiac filling pressures and low
cardiac output, or (b) ongoing signs of hypoperfusion, despite achieving
adequate intravascular volume and adequate MAP.
2. Not using a strategy to increase cardiac index to predetermined
 supranormal levels.

Corticosteroids

1. Not using intravenous hydrocortisone to treat adult septic shock patients,

if adequate fluid resuscitation and vasopressor therapy are able to restore
hemodynamic stability (see goals for Initial Resuscitation). In the event
this is not achievable, we suggest IV hydrocortisone alone at a dose of
200 mg/day.
2. Not using the ACTH stimulation test to identify adults with septic shock
who should receive hydrocortisone.
3. In treated patients, hydrocortisone tapered when vasopressors are no
longer required.
4. Corticosteroids should not be administered for the treatment of sepsis in
the absence of shock.
5. When hydrocortisone is given, use continuous flow.

Adapted from Dellinger PR, Levy MM, Rhodes A, et al: Surviving Sepsis
campaign: international guidelines for management of severe sepsis and septic
shock: 2012, Crit Care Med 41(2):580–637, 2013 (Table 6, p 596).
Table 88.12
Recommendations for Shock: Special
Considerations in Pediatric Patients
Initial Resuscitation

1. For respiratory distress and hypoxemia, start with face mask oxygen or, if
needed and available, high-flow nasal cannula oxygen or nasopharyngeal
CPAP (NP CPAP). For improved circulation, peripheral intravenous
access or intraosseous access can be used for fluid resuscitation and
inotrope infusion when a central line is not available. If mechanical
ventilation is required, cardiovascular instability during intubation is less
likely after appropriate cardiovascular resuscitation.
2. Initial therapeutic end-points of resuscitation of septic shock: capillary
refill of ≤2 sec, normal blood pressure for age, normal pulses with no
 differential between peripheral and central pulses, warm extremities,
urine output >1 mL kg−1 hr−1 , and normal mental status. ScvO 2
saturation ≥70% and cardiac index between 3.3 and 6.0 L/min/m2 should
be targeted thereafter.
3. Follow American College of Critical Care Medicine–Pediatric Advanced
Life Support (ACCM-PALS) guidelines for the management of septic
shock.
4. Evaluate for and reverse pneumothorax, pericardial tamponade, or
endocrine emergencies in patients with refractory shock.

Antibiotics and Source Control

1. Empirical antibiotics should be administered within 1 hr of the

identification of severe sepsis. Blood cultures should be obtained before
administering antibiotics when possible, but this should not delay
administration of antibiotics. The empirical drug choice should be
changed as epidemic and endemic ecologies dictate (e.g., H1N1,
methicillin-resistant Staphylococcus aureus [MRSA], chloroquine-
resistant malaria, penicillin-resistant pneumococci, recent ICU stay,
neutropenia).
2. Clindamycin and antitoxin therapies for toxic shock syndromes with
refractory hypotension.
3. Early and aggressive source control.
4. Clostridium difficile colitis should be treated with enteral antibiotics if
tolerated. Oral vancomycin is preferred for severe disease.

Fluid Resuscitation

1. In the industrialized world with access to inotropes and mechanical

ventilation, initial resuscitation of hypovolemic shock begins with
infusion of isotonic crystalloids or albumin with boluses of up to 20
mL/kg crystalloids (or albumin equivalent) over 5-10 min, titrated to
reversing hypotension, increasing urine output, and attaining normal
capillary refill, peripheral pulses, and level of consciousness without
inducing hepatomegaly or rales. If hepatomegaly or rales present,
inotropic support should be implemented, not fluid resuscitation. In
 nonhypotensive children with severe hemolytic anemia (severe malaria
or sickle cell crises), blood transfusion is considered superior to
crystalloid or albumin bolus.

Inotropes, Vasopressors, and Vasodilators

1. Begin peripheral inotropic support until central venous access can be

attained in children who are not responsive to fluid resuscitation.
2. Patients with low cardiac output and elevated systemic vascular resistance
states with normal blood pressure should be given vasodilator therapies
in addition to inotropes.

Extracorporeal Membrane Oxygenation

1. Consider ECMO for refractory pediatric septic shock and respiratory

failure.

Corticosteroids

1. Timely hydrocortisone therapy in children with fluid-refractory,

catecholamine-resistant shock and suspected or proven absolute (classic)
adrenal insufficiency.

Protein C and Activated Protein Concentrate

No recommendations (no longer available).

Blood Products and Plasma Therapies

1. Similar hemoglobin targets in children as in adults. During resuscitation of

low superior vena cava oxygen saturation shock (<70%), hemoglobin
levels of 10 g/dL are targeted. After stabilization and recovery from
shock and hypoxemia, a lower target (>7.0 g/dL) can be considered
reasonable.
2. Similar platelet transfusion targets in children as in adults.
 3. Use plasma therapies in children to correct sepsis-induced thrombotic
purpura disorders, including progressive disseminated intravascular
coagulation, secondary thrombotic microangiopathy, and thrombotic
thrombocytopenic purpura.

Mechanical Ventilation

1. Lung-protective strategies during mechanical ventilation.

Sedation, Analgesia, and Drug Toxicities

1. We recommend use of sedation with a sedation goal in critically ill,

mechanically ventilated patients with sepsis.
2. Monitor drug toxicity lab results because drug metabolism is reduced
during severe sepsis, putting children at greater risk of adverse drug-
related events.

Glycemic Control

1. Control hyperglycemia using a similar target as in adults (≤180 mg/dL).

Glucose infusion should accompany insulin therapy in newborns and
children because some hyperglycemic children make no insulin whereas
others are insulin resistant.

Diuretics and Renal Replacement Therapy

1. Use diuretics to reverse fluid overload when shock has resolved, and if
unsuccessful, use continuous venovenous hemofiltration (CVVH) or
intermittent dialysis to prevent >10% total body weight fluid overload.

Deep Vein Thrombosis (DVT) Prophylaxis

No recommendation on the use of DVT prophylaxis in prepubertal children

with severe sepsis.
Stress Ulcer (SU) Prophylaxis

No recommendation on the use of SU prophylaxis in prepubertal children

with severe sepsis.

Nutrition

1. Enteral nutrition given to children who can be fed enterally, and parenteral
feeding in those who cannot (grade 2C).

CPAP, Continuous positive airway pressure.

Adapted from Dellinger PR, Levy MM, Rhodes A, et al: Surviving Sepsis
campaign: I nternational guidelines for management of severe sepsis and septic
shock: 2012, Crit Care Med 41(2):580–637, 2013 (Table 9, p 614).

Given the predominance of sepsis and hypovolemia as the most common

causes of shock in the pediatric population, most therapeutic regimens are based
on guidelines established in these settings. Immediately following establishment
of intravenous (IV) or intraosseous (IO) access, aggressive, early goal-directed
therapy should be initiated unless there are significant concerns for cardiogenic
shock as an underlying pathophysiology. Rapid IV administration of 20 mL/kg
isotonic fluid should be initiated to reverse the shock state. This bolus should be
repeated quickly up to 60-80 mL/kg; it is not unusual for severely affected
patients to require this volume within the 1st 3 hr of treatment.
Rapid fluid resuscitation totaling 60-80 mL/kg or more is associated with
improved survival without an increased incidence of pulmonary edema. Fluid
resuscitation in increments of 20 mL/kg should be titrated to normalize HR
(according to age-based HRs), urine output (to 1 mL/kg/hr), capillary refill time
(to <2 sec), and mental status. If shock remains refractory following 60-80
mL/kg of volume resuscitation, vasopressor therapy (e.g., norepinephrine,
epinephrine) should be instituted while additional fluids are administered.
Pediatric guidelines for septic shock unresponsive to fluid resuscitation suggest
epinephrine (Fig. 88.2 ) or dopamine (Fig. 88.1 ), whereas adult guidelines
recommend norepinephrine.
Fluid resuscitation may sometimes require as much as 200 mL/kg or greater. It
 Distributive shock that is not secondary to sepsis is caused by a primary
abnormality in vascular tone. Cardiac output in affected patients is usually
maintained and may initially be supranormal. These patients may benefit
temporarily from volume resuscitation, but the early initiation of a
vasoconstrictive agent to increase SVR is an important element of clinical care.
Patients with spinal cord injury and spinal shock may benefit from either
phenylephrine or vasopressin to increase SVR; epinephrine is the treatment of
choice for patients with anaphylaxis (Table 88.13 ). Epinephrine has peripheral
α-adrenergic as well as inotropic effects that may improve the myocardial
depression seen with anaphylaxis and its associated inflammatory response (see
Chapter 174 ).

Table 88.13
Cardiovascular Drug Treatment of Shock

DOSING
DRUG EFFECT(S) COMMENT(S)
RANGE
Dopamine ↑ Cardiac contractility 3-20 ↑ Risk of arrhythmias at high doses
Significant peripheral vasoconstriction µg/kg/min
at >10 µg/kg/min
Epinephrine ↑ Heart rate and ↑ cardiac contractility 0.05-3.0 May ↓ renal perfusion at high doses
Potent vasoconstrictor µg/kg/min ↑ Myocardial O2 consumption
Risk of arrhythmia at high doses
Dobutamine ↑ Cardiac contractility 1-10 —
Peripheral vasodilator µg/kg/min
Norepinephrine Potent vasoconstriction 0.05-1.5 ↑ Blood pressure secondary to ↑ systemic
µg/kg/min vascular resistance
No significant effect on cardiac ↑ Left ventricular afterload
contractility
Phenylephrine Potent vasoconstriction 0.5-2.0 Can cause sudden hypertension
µg/kg/min ↑ O2 consumption

Patients with cardiogenic shock have poor cardiac output secondary to

systolic and/or diastolic myocardial depression, often with a compensatory
elevation in SVR. These patients may show poor response to fluid resuscitation
and may decompensate quickly when fluids are administered. Smaller boluses of
fluid (5-10 mL/kg) should be given in cardiogenic shock to replace deficits and
maintain preload. In any patient with shock whose clinical status deteriorates
with fluid resuscitation, a cardiogenic etiology should be considered, and further
administration of IV fluids should be provided judiciously. Early initiation of
myocardial support with epinephrine or dopamine to improve cardiac output is
important in this context, and early consideration should be given to
administration of an inodilator, such as milrinone.
Despite adequate cardiac output with the support of inotropic agents, a high
SVR with poor peripheral perfusion and acidosis may persist in cardiogenic
shock. Therefore, if not already started, milrinone therapy may improve systolic
function and decrease SVR without causing a significant increase in HR.
Furthermore, this agent has the added benefit of enhancing diastolic relaxation.
Dobutamine or other vasodilating agents, such as nitroprusside, may also be
considered in this setting (Table 88.14 ). Titration of these agents should target
clinical end-points, including increased urine output, improved peripheral
perfusion, resolution of acidosis, and normalization of mental status. Even
though they may be beneficial in other forms of shock, agents that improve BP
by increasing SVR, such as norepinephrine and vasopressin, should generally be
avoided in patients with cardiogenic shock. These agents may cause further
decompensation and potentially precipitate cardiac arrest as a result of the
increased afterload and additional work imposed on the myocardium. The
combination of inotropic and vasoactive agents must be tailored to the
pathophysiology of the individual patient with close and frequent reassessment
of the patient's cardiovascular status.

Table 88.14
Vasodilators/Afterload Reducers in Treatment of Shock

DOSING
DRUG EFFECT(S) COMMENT(S)
RANGE
Nitroprusside Vasodilator (mainly arterial) 0.5-4.0 Rapid effect
µg/kg/min Risk of cyanide toxicity with
prolonged use (>96 hr)
Nitroglycerin Vasodilator (mainly venous) 1-20 Rapid effect
µg/kg/min Risk of increased intracranial
pressure
Prostaglandin Vasodilator 0.01-0.2 Can lead to hypotension
E1 Maintains an open ductus arteriosus in the µg/kg/min Risk of apnea
newborn with ductal-dependent congenital
heart disease
Milrinone Increased cardiac contractility Load 50 Phosphodiesterase inhibitor—slows
µg/kg cyclic adenosine monophosphate
over 15 breakdown
min
Improves cardiac diastolic function 0.5-1.0
Peripheral vasodilation µg/kg/min

For patients with obstructive shock , fluid resuscitation may be briefly

temporizing in maintaining cardiac output, but the primary insult must be
rapid. Rapid and deep breathing without other respiratory signs should alert the
physician to possible nonpulmonary or nonthoracic causes of respiratory
distress, such as response to metabolic acidosis (e.g., diabetic ketoacidosis, renal
tubular acidosis) or stimulation of the respiratory center (e.g., encephalitis,
ingestion of central nervous system stimulants). Chest wall, suprasternal, and
subcostal retractions are manifestations of increased inspiratory effort, weak
chest wall, or both. Inspiratory stridor indicates airway obstruction above the
thoracic inlet, whereas expiratory wheezing results from airway obstruction
below the thoracic inlet. Grunting is most commonly heard in diseases with
decreased functional residual capacity (e.g., pneumonia, pulmonary edema) and
peripheral airway obstruction (e.g., bronchiolitis).

Respiratory Disease Manifesting as Respiratory

Distress
Clinical examination is important in localizing the site of pathology (see Chapter
400 ). Extrathoracic airway obstruction occurs anywhere above the thoracic
inlet. Inspiratory stridor, suprasternal, chest wall, and subcostal retractions; and
prolongation of inspiration are hallmarks of extrathoracic airway obstruction. By
comparison, features of intrathoracic airway obstruction are prolongation of
expiration and expiratory wheezing. Typical manifestations of alveolar
interstitial pathology are rapid, shallow respirations, chest wall retractions, and
grunting. The site of pathology can be localized and the differential diagnosis
established on the basis of the clinical signs and symptoms (Tables 89.1 and 89.2
).

Table 89.1
Typical Localizing Signs for Pulmonary Pathology

SITE OF PATHOLOGY RESPIRATORY RATE RETRACTIONS AUDIBLE SOUNDS

Extrathoracic airway ↑ ↑↑↑↑ Stridor
Intrathoracic extrapulmonary ↑ ↑↑ Wheezing
Intrathoracic intrapulmonary ↑↑ ↑↑ Wheezing
Alveolar interstitial ↑↑↑ ↑↑↑ Grunting

Table 89.2
Examples of Anatomic Sites of Lesions Causing
Respiratory Failure

LUNG RESPIRATORY PUMP

CENTRAL AIRWAY OBSTRUCTION THORACIC CAGE
Choanal atresia Kyphoscoliosis
Tonsilloadenoidal hypertrophy Diaphragmatic hernia
Retropharyngeal/peritonsillar abscess Flail chest
Laryngomalacia Eventration of diaphragm
Epiglottitis Asphyxiating thoracic dystrophy
Vocal cord paralysis Prune-belly syndrome
Laryngotracheitis Dermatomyositis
Subglottic stenosis Abdominal distention
Vascular ring/pulmonary sling
Mediastinal mass
Foreign body aspiration
Obstructive sleep apnea
PERIPHERAL AIRWAY OBSTRUCTION BRAINSTEM
Asthma Arnold-Chiari malformation
Bronchiolitis Central hypoventilation syndrome
Foreign body aspiration CNS depressants
Aspiration pneumonia Trauma
Cystic fibrosis Increased intracranial pressure
α1 -Antitrypsin deficiency CNS infections
ALVEOLAR-INTERSTITIAL DISEASE SPINAL CORD
Lobar pneumonia Trauma
ARDS, hyaline membrane disease Transverse myelitis
Interstitial pneumonia Spinal muscular atrophy
Hydrocarbon pneumonia Poliomyelitis
Pulmonary hemorrhage/hemosiderosis Tumor/abscess
Acute flaccid myelitis
NEUROMUSCULAR
Phrenic nerve injury
Birth trauma
Infant botulism
Guillain-Barré syndrome
Muscular dystrophy
Myasthenia gravis
Organophosphate poisoning
ARDS, Acute respiratory distress syndrome; CNS, central nervous system.

Respiratory Distress Without Respiratory

Disease
Although respiratory distress most frequently results from diseases of lungs,
airways, and chest wall, pathology in other organ systems can manifest as
respiratory distress and lead to misdiagnosis and inappropriate management
(Table 89.3 ). Respiratory distress resulting from heart failure or diabetic
ketoacidosis may be misdiagnosed as asthma and improperly treated with
albuterol, resulting in worsened hemodynamic state or ketoacidosis. Careful
history and physical examination provide essential clues in avoiding
misdiagnosis.

Table 89.3
Nonpulmonary Causes of Respiratory Distress

SYSTEM EXAMPLE(S) MECHANISM(S)

Cardiovascular Left-to-right shunt ↑ Pulmonary blood/water content
Congestive heart failure Metabolic acidosis
Cardiogenic shock Baroreceptor stimulation
Central Increased intracranial Stimulation of brainstem respiratory centers
nervous pressure
Encephalitis
Neurogenic pulmonary
edema
Toxic encephalopathy
Metabolic Diabetic ketoacidosis Stimulation of central and peripheral chemoreceptors
Organic acidemia
Hyperammonemia
Renal Renal tubular acidosis Stimulation of central and peripheral chemoreceptors
Hypertension Left ventricular dysfunction → increased pulmonary blood/water
content
Sepsis Toxic shock syndrome Cytokine stimulation of respiratory centers
Meningococcemia Baroreceptor stimulation from shock
Metabolic acidosis

Cardiovascular Disease Manifesting as Respiratory

Distress
A child with cardiovascular pathology may present with respiratory distress
caused by either decreased lung compliance or cardiogenic shock (Table 89.4 ).
Diseases that result in increased pulmonary arterial blood flow (e.g., left-to-right
shunts) or increased pulmonary venous pressure (e.g., left ventricular
dysfunction from hypertension or myocarditis, obstructed total anomalous
pulmonary venous return) cause an increase in pulmonary capillary pressure and
transudation of fluid into the pulmonary interstitium and alveoli. The increased
pulmonary blood and water content lead to decreased lung compliance and result
in rapid shallow breathing.
Table 89.4
Cardiovascular Pathology Manifesting as
Respiratory Distress

I. Decreased lung compliance

A. Left-to-right shunts
1. Ventricular septal defect, atrial septal defect, patent
ductus arteriosus, atrioventricular canal, truncus
arteriosus
2. Cerebral or hepatic arteriovenous fistula
B. Ventricular failure
1. Left heart obstructive lesions
a. Aortic stenosis
b. Coarctation of the aorta
c. Mitral stenosis
d. Interrupted aortic arch
e. Hypoplastic left heart syndrome
2. Myocardial infarction
a. Anomalous left coronary artery arising
from the pulmonary artery
3. Hypertension
a. Acute glomerulonephritis
4. Inflammatory/infectious
a. Myocarditis
b. Pericardial effusion
5. Idiopathic
a. Dilated cardiomyopathy
b. Hypertrophic obstructive cardiomyopathy
C. Pulmonary venous obstruction
1. Total anomalous pulmonary venous return with
obstruction
2. Cor triatriatum
II. Shock resulting in metabolic acidosis
A. Left heart obstructive lesions
B. Acute ventricular failure
1. Myocarditis, myocardial infarction

It is important to recognize that interstitial lung edema cannot only manifest as

alveolar fluid, but as small airway obstruction as well. Wheezing as a sign of
congestive cardiac disease is common in infants and young children and should
be recognized. Patients with cardiac lesions, resulting in low cardiac output,
often present in shock. For example, obstructive lesions of left side of the heart
and acquired or congenital cardiomyopathy result in decreased perfusion and
metabolic acidosis, as well as respiratory distress because of chemoreceptor and
baroreceptor stimulation. The likelihood of a particular cardiovascular illness
manifesting as respiratory distress depends on age at presentation (Table 89.5 ).

Table 89.5
Typical Chronology of Heart Disease Presentation in
Children
AGE MECHANISM DISEASE
Newborn (1-10 ↑ Arteriovenous pressure difference Arteriovenous fistula (brain, liver)
days) Ductal closure Single ventricle lesions or severe ventricular outflow
obstruction
Independent pulmonary and systemic Transposition of the great arteries
blood flow
Pulmonary venous obstruction Total anomalous pulmonary venous return (TAPVR)
Young infant (1-6 ↓ Pulmonary vascular resistance Left-to-right shunt
mo) ↓ Pulmonary artery pressure Anomalous left coronary artery to the pulmonary
artery
Any age Rate disturbance Tachy- or bradyarrhythmias
Infection Myocarditis, pericarditis
Abnormal cardiac myocytes Cardiomyopathy
Excess afterload hypertension

Neurologic Disease Manifesting as Respiratory Distress

Central nervous system (CNS) dysfunction can lead to alterations in respiratory
patterns and manifest as respiratory distress. Increased intracranial pressure
(ICP) may manifest as respiratory distress. Early rise in intracranial pressure
(ICP) results in stimulation of respiratory centers, leading to increases in the rate
(tachypnea ) and depth (hyperpnea ) of respiration. The resultant decrease in
arterial blood partial pressure of carbon dioxide (PaCO 2 ) and elevation of
cerebrospinal fluid (CSF) pH lead to cerebral vasoconstriction and amelioration
of intracranial hypertension. Stereotypical respiratory patterns are associated
with dysfunction at multiple levels of the brain. Cerebral hemisphere and
midbrain lesions result in hyperpnea as well as tachypnea. In such situations,
arterial blood gas (ABG) measurements typically show respiratory alkalosis
without hypoxemia. Pathology affecting the pons and medulla manifests as
irregular breathing patterns such as apneustic breathing (prolonged inspiration
with brief expiratory periods), Cheyne-Stokes breathing (alternate periods of
rapid and slow breathing), and irregular, ineffective breathing or apnea (Table
89.6 ). Along with respiratory changes, other manifestations of CNS dysfunction
and increased ICP may be present, such as focal neurologic signs, pupillary
changes, hypertension, and bradycardia (see Chapter 85 ). Occasionally, severe
CNS dysfunction can result in neurogenic pulmonary edema and respiratory
distress, which may follow excessive sympathetic discharge resulting in
increased pulmonary venous hydrostatic pressure as well as increased pulmonary
capillary permeability. Central neurogenic hyperventilation is
characteristically observed in CNS involvement by illnesses such as urea cycle
defects and encephalitis. Bradycardia and apnea may be caused by CNS-
depressant medications, poisoning, prolonged hypoxia, trauma, or infection (see
Table 89.2 ).

Table 89.6

Respiratory Patterns in Neurologic Disease

INJURY PATTERN* COMMENTS
Normal Variable VT with normal respiratory pauses and
sighs
Cortex Hyperpnea and tachypnea

Midbrain Cheyne-Stokes breathing : Gradually increasing

and decreasing VT

Pons Apneustic breathing : Prolonged inspiration

followed by prolonged expiration

Medulla and Biot's breathing : Rapid and irregular respirations

pons with pauses

* Lung volume vs time.

VT , Tidal volume.

Toxic Metabolic States Manifesting as Respiratory Distress

adults. The current pediatric definition differs in chest imaging findings,
definition of oxygenation, consideration of both noninvasive and invasive
mechanical ventilation, and consideration of special populations (Table 89.7 and
Fig. 89.1 ).

Table 89.7
Pediatric Acute Respiratory Distress Syndrome (PARDS)
Definition

BERLIN DEFINITION PARDS

Age Adults and children Excludes patients with perinatal-
related lung disease
Timing Within 1 wk of known clinical insult or new or worsening Within 1 wk of a known clinical
respiratory symptoms insult
Origin of Respiratory failure not fully explained by cardiac failure or fluid Respiratory failure not fully
edema overload. Need objective assessment (e.g., echocardiography) to explained by cardiac failure or
exclude hydrostatic edema, even if no risk factor present. fluid overload
Chest Bilateral opacities not fully explained by effusions, lobar/lung Chest imaging findings of new
imaging collapse, or nodules. (Illustrative clinical cases and chest infiltrate(s) consistent with acute
a radiographs have been provided.) pulmonary parenchymal disease
Oxygenation b
Mild 200 mm Hg < PaO 2 /FIO 2 ≤300 mm Hg with PEEP, or CPAP ≥5 cm Noninvasive mechanical
H2 O c ventilation:
PARDS (No severity
Moderate 100 mm Hg < PaO 2 /FIO 2 ≤200 mm Hg with PEEP ≥5 cm H2 O
stratification)
Severe PaO 2 /FIO 2 <100 mm Hg with PEEP ≥5 cm H2 O Full face-mask bilevel ventilation
or CPAP >5 cm H2 O e
PF ratio <300
SF ratio <264 d
Invasive mechanical
ventilation f :
Mild: 4 < OI <8, or 5 < OSI <7.5
d
Moderate: 8 < OI <16, or 7.5 <
OSI <12.3 d
Severe: OI >16, or OSI >12.3 d
a Chest radiograph or CT scan in Berlin criteria only.

b If altitude is >1,000 m, the correction factor should be calculated as follows: PaO /FIO ×
2 2
Barometric pressure/760.
c This may be delivered noninvasively in the mild acute respiratory distress syndrome group.

d Use PAO -based metric when available. If PaO not available, wean FIO to maintain SpO
2 2 2 2
<97% to calculate OSI or SF ratio.
e For nonintubated patients treated with supplemental oxygen or nasal modes of noninvasive
ventilation, refer to reference below for “At Risk Criteria.”
of 1) between 30% and 65%. If more precise delivery of oxygen is desired, other
mask devices should be used.
A Venturi mask provides preset FIO 2 through a mask and reservoir system by
entraining precise flow rates of room air into the reservoir along with high-flow
oxygen. The adapter at the end of each mask reservoir determines the flow rate
of entrained room air and the subsequent FIO 2 . (Adapters provide FIO 2 of 0.30-
0.50.) Oxygen flow rates of 5-10 L/min are recommended to achieve the desired
FIO 2 and to prevent rebreathing. Partial rebreather and non-rebreather masks use
a reservoir bag attached to a mask to provide higher FIO 2 . Partial rebreather
masks have 2 open exhalation ports and contain a valveless oxygen reservoir
bag. Some exhaled gas can mix with reservoir gas, although most exhaled gas
exits the mask via the exhalation ports. Through these same ports, room air is
entrained, and the partial rebreather mask can provide FIO 2 up to 0.60, for as
long as oxygen flow is adequate to keep the bag from collapsing (typically 10-15
L/ min). As with nasal cannulas, smaller children with smaller tidal volumes
entrain less room air, and their Fio2 values will be higher. Non-rebreather
masks include 2 one-way valves, 1 between the oxygen reservoir bag and the
mask and the other on 1 of the 2 exhalation ports. This arrangement minimizes
mixing of exhaled and fresh gas and entrainment of room air during inspiration.
The 2nd exhalation port has no valve, a safeguard to allow some room air to
enter the mask in the event of disconnection from the oxygen source. A non-
rebreather mask can provide FIO 2 up to 0.95. The use of a non-rebreather mask
in conjunction with an oxygen blender allows delivery of FIO 2 between 0.50 and
0.95 (Table 89.8 ). When supplemental oxygen alone is inadequate to improve
oxygenation, or when ventilation problems coexist, additional therapies may be
necessary.

Table 89.8

Approximate Oxygen Delivery According to Device and Flow Rates in Infants and
Older Children*
DEVICE FLOW (L/min) FIO 2 DELIVERED
Nasal cannula 0.1-6 0.21-0.4
Simple face mask 5-10 0.4-0.6
Partial rebreather 6-15 0.55-0.7
Non-rebreather 6-15 0.7-0.95
Venturi mask 5-10 0.25-0.5
 Hood/tent 7-12 0.21-1.0
High-flow systems 1-40 0.21-1.0
* Individual delivery varies and depends on the patient's size, respiratory rate, and volume moved

with every breath.

Airway Adjuncts
Maintenance of a patent airway is a critical step in maintaining adequate
oxygenation and ventilation. Artificial pharyngeal airways may be useful in
patients with oropharyngeal or nasopharyngeal airway obstruction and in those
with neuromuscular weakness in whom inherent extrathoracic airway resistance
contributes to respiratory compromise. An oropharyngeal airway is a stiff
plastic spacer with grooves along each side that can be placed in the mouth to
run from the teeth along the tongue to its base just above the vallecula. The
spacer prevents the tongue from opposing the posterior pharynx and occluding
the airway. Because the tip sits at the base of the tongue, it is usually not
tolerated by patients who are awake or whose gag reflex is strong. The
nasopharyngeal airway , or nasal trumpet , is a flexible tube that can be
inserted into the nose to run from the nasal opening along the top of the hard and
soft palate with the tip ending in the hypopharynx. It is useful in bypassing
obstruction from enlarged adenoids or from contact of the soft palate with the
posterior nasopharynx. Because it is inserted past the adenoids, a nasopharyngeal
airway should be used with caution in patients with bleeding tendencies.

Inhaled Gases
Helium-oxygen mixture (heliox) is useful in overcoming airway obstruction
and improving ventilation. Helium is much less dense and slightly more viscous
than nitrogen. When substituted for nitrogen, helium helps maintain laminar
flow across an obstructed airway, decreases airway resistance, and improves
ventilation. It is especially helpful in diseases of large airways obstruction in
which turbulent airflow is more common, such as acute
laryngotracheobronchitis, subglottic stenosis, and vascular ring. It is also used in
patients with severe status asthmaticus. To be effective, helium should be
administered in concentrations of at least 60%, so associated hypoxemia may
limit its use in patients requiring >40% oxygen.
Inhaled nitric oxide (iNO) is a powerful inhaled pulmonary vasodilator. Its
use may improve pulmonary blood flow and V̇/Q̇ mismatch in patients with
common pharmacologic regimen for facilitating intubation. In fact, sedation and
paralysis with neuromuscular blocking agents should be considered standard
unless contraindicated. The particular type and dose of each agent often depends
on the underlying disease and clinician preference. Table 89.10 lists commonly
used agents. Dexmedetomidine has been a standard sedating agent for
maintenance during mechanical ventilation. An alternative to this pharmacologic
approach is rapid sequence intubation , used when endotracheal intubation is
urgent, or the patient is suspected of having a full stomach and at increased risk
of aspiration (see Chapter 81 ).

Table 89.9
Average Size and Depth Dimensions for Tracheal Tubes

PATIENT INTERNAL DIAMETER OROTRACHEAL DEPTH NASOTRACHEAL DEPTH

AGE (mm) (cm) (cm)
Premature 2.0-3.0 8-9 9-10
Full-term 3.0-3.5 10 11
neonate
6 mo 4.0 11 13
12-24 mo 4.5 13-14 16-17
4 yr 5.0 15 17-18
6 yr 5.5 17 19-20
8 yr 6.0 19 21-22
10 yr 6.5 20 22-23
12 yr 7.0 21 23-24
14 yr 7.5 22 24-25
Adult 8.0-9.0 23-25 25-28

Table 89.10
Medications Commonly Used for Intubation

DRUG DOSE ONSET (min) DURATION (min) COMMENTS

SEDATIVES/ANESTHETICS
Midazolam 0.1 mg/kg IV 3-5 60-120 Amnesia
Respiratory depression
Lorazepam 0.1 mg/kg IV 3-5 120-240 Amnesia
Respiratory depression
Ketamine 1-2 mg/kg IV 2-3 10-15 ↑ HR, BP, and ICP
4-6 mg/kg IM Bronchodilation
Propofol 1-3 mg/kg IV 0.5-2 10-15 ↓ BP
Apnea
Thiopental 4-7 mg/kg IV 0.5-1 5-10 ↓ BP
Apnea
 ANALGESICS
Fentanyl 2-5 µg/kg IV 3-5 30-90 Respiratory depression
Chest wall rigidity
Morphine 0.1 mg/kg IV 5-15 120-240 ↓ BP
Respiratory depression
NEUROMUSCULAR BLOCKING AGENTS
Vecuronium 0.1 mg/kg IV 2-3 30-75 ↑ HR
Renal elimination
Rocuronium 0.6-1.2 mg/kg IV 5-15 15-60 ↑ HR
1 mg/kg IM Renal elimination
Cisatracurium 0.1 mg/kg IV 2-3 25-30 Histamine release
Nonrenal elimination
BP, Blood pressure; HR, heart rate; ICP, intracranial pressure; IM, intramuscularly; IV,
intravenously.

Once adequate sedation and/or paralysis have been achieved, ventilation

should be assisted with a bag-mask device . After optimal preoxygenation,
intubation can be performed. The clinician uses the dominant hand to open the
patient's mouth and insert the laryngoscope blade gently along the tongue to its
base. The airway opening can be visualized by applying lift up-and-away from
the clinician, along the axis of the laryngoscope handle. When a straight (Miller)
laryngoscope blade is used to visualize the glottis, the tip of the blade lifts the
epiglottis anteriorly. When a curved (Macintosh) blade is used to visualize the
glottis, the tip of the blade should be advanced into the vallecula and then lifted.
Secretions often obscure visualizations at this step and should be suctioned clear.
Once clear visualization of the vocal cords is accomplished, the ETT can be
placed through the vocal cords. Rapid confirmation of ETT placement is
essential and should be assessed by as many of the following steps as possible:
presence of PetCO 2 determined by a monitor attached in-line with ETT;
auscultation of both lung fields as well as the epigastrium for equal breath
sounds; and, good air movement and evaluation of the abdomen for increasing
distention. Adequate, bilateral chest expansion and misting inside the ETT with
each breath confirm proper tube placement. An increasing heart rate, if heart rate
has decreased during the attempt, and a rising or normal SpO 2 reading are
suggestive of successful tube placement. Preoxygenation may significantly delay
any drop in SpO 2 with improper tube placement, leading to a significant delay in
its recognition. Confirmation of exhaled PetCO 2 is mandatory, using a disposable
colorimetric CO2 detector or with capnography. In situations of very low
pulmonary perfusion, such as cardiac arrest, PetCO 2 may not be detected. A chest
radiograph should also be obtained to confirm proper placement of the ETT,
 Gallagher TJ: Respiratory failure in the adult: ventilatory support. In Kirby RR, Smith
RA, Desautels DA, editors: Mechanical ventilation , New York, 1985, Churchill
Livingstone.)

Assist-Control Mode.
In assist-control (AC) mode, every patient breath is triggered by pressure or flow
generated by patient inspiratory effort and “assisted” with either preselected
inspiratory pressure or volume. The rate of respirations is therefore determined
by the patient's inherent rate. A backup total (patient and ventilator) obligatory
rate is set to deliver a minimum number of breaths. On AC mode, with a backup
rate of 20 breaths/min and a patient's inherent rate of 15 breaths/min; the
ventilator will assist all the patient's breaths, and the patient will receive 5
additional breaths/min. On the other hand, a patient with an inherent rate of 25
breaths/min will receive all 25 breaths assisted. Although useful in some
patients, the AC mode cannot be used in the weaning process, which involves
gradual decrease in ventilator support.

Control Variable
Once initiated, either the VT or the pressure delivered by the machine can be
controlled. The machine-delivered breath is thus referred to as either volume
controlled or pressure controlled (Table 89.11 ). With volume-controlled
ventilation (VCV) , machine-delivered volume is the primary control, and the
inflation pressure generated depends on the respiratory system's compliance and
resistance. Changes in respiratory system compliance and resistance are
therefore easily detected from changes observed in inflation pressure. In
pressure-controlled ventilation (PCV) the pressure change above the baseline
is the primary control, and the Vt delivered to the lungs depends on the
respiratory system's C and R. Changes in respiratory system C and R do not
affect inflation pressure and may therefore go undetected unless the exhaled Vt
is monitored.

Table 89.11

Characteristics of Pressure-Controlled and Volume-Controlled Methods of Ventilation

PRESSURE-CONTROLLED
VOLUME-CONTROLLED VENTILATION
VENTILATION

Control setting(s) Inflation pressure Tidal volume

Inspiratory time Flow rate
 Inspiratory time Flow rate
Rise time Inspiratory flow pattern (constant vs
decelerating)
Machine- Depends on respiratory system compliance Constant
delivered volume and resistance
Inflation pressure Constant Depends on respiratory system compliance and
resistance
Endotracheal Somewhat compensated Leaked volume part of tidal volume
tube leak
Distribution of More uniform in lungs with varying time Less uniform in lungs with varying time
ventilation constant units constant units
Patient comfort Possibly compromised Possibly enhanced
Weaning Inflation pressure adjustment required to Tidal volume remains constant; inflation
deliver desired tidal volume pressure automatically weaned

VCV and PCV have their own advantages and disadvantages (Table 89.11 ).
Generally speaking, PCV is more efficient than VCV in terms of amount of VT
delivered for a given inflation pressure during ventilation of a lung that has
nonuniform TC, as in asthma. In VCV, relatively less-obstructed airways are
likely to receive more of the machine-delivered volume throughout inspiration
than relatively more-obstructed airways with longer TC (Fig. 89.11 A ). This
situation would result in uneven ventilation, higher peak inspiratory pressure
(PIP), and a decrease in CDYN . In PCV, because of a constant inflation pressure
that is held throughout inspiration, relatively less-obstructed lung units with
shorter TC would achieve pressure equilibration earlier during inspiration than
the relatively more-obstructed areas. Thus, units with shorter TCs would attain
their final volume earlier in inspiration, and those with longer TCs would
continue to receive additional volume later in inspiration (Fig. 89.11 B ). This
situation would result in more even distribution of inspired gas, delivery of more
VT for the same inflation pressure, and improved CDYN compared with VCV.
withdrawal manifestations, and prolonged neuromuscular blockade is associated
with neuromyopathy in critically ill patients. The benefits of sedation and
pharmacologic paralysis therefore should be carefully balanced with the risks,
and periodic assessments should be made to determine the need for their
continuation.

Cardiopulmonary Interactions
Mechanical ventilation can have salutary as well as adverse effects on cardiac
performance. By decreasing oxygen consumption necessary for work of
breathing, oxygen supply to vital organs is improved. Positive pressure breathing
decreases LV afterload, thus enhancing stroke volume and cardiac output in
patients with failing myocardium (e.g., myocarditis). On the other hand, the
decreased systemic venous return may further compromise stroke volume in
hypovolemic patients. Such patients will require intravascular fluid loading.
Also, an increase in pulmonary vascular resistance (PVR) caused by positive
intrathoracic pressure may result in further decompensation of a poorly
performing right ventricle. PVR is at its lowest value at an optimum FRC. When
FRC is too low or too high, PVR (and therefore the right ventricular afterload) is
increased. Both desirable and undesirable effects of cardiopulmonary
interactions may coexist and require ongoing assessment and necessary
interventions (Table 89.12 ).

Table 89.12

Suggested Mechanical Ventilation Strategies in Various Clinical Situations

SITUATION DISEASE STRATEGY
Low compliance, normal resistance ARDS PCV, APRV, HFO,
HFJV
Normal compliance, high resistance Asthma PVC, PRVC
Normal compliance, normal resistance, for Head trauma, drug overdose, subglottic VCV
weaning stenosis
APRV, Airway pressure release ventilation; ARDS, acute respiratory distress syndrome; HFO,
high-frequency oscillation; HFJV, high-frequency jet ventilation; PCV, pressure-controlled
ventilation; PRVC, pressure-regulated volume control; VCV, volume-controlled ventilation.

Monitoring Respiratory Mechanics

pulmonary vascular reactivity and a higher risk of pulmonary hypertension, and
are also more likely to have OSA and hypoventilation. Children with sickle cell
anemia who live at sea level should reconsider travel to altitude, or else ascend
carefully because sickle cell crisis may occur at as low as 1,500 m (~5,000 ft).
Those with sickle cell trait may become symptomatic at altitudes above 2,500 m
(~8,200 ft).
Acetazolamide is commonly prescribed as prophylaxis against AMS because
of its ability to stimulate respiration and increase alveolar and arterial
oxygenation. It acts as a carbonic anhydrase inhibitor that induces a renal
bicarbonate diuresis, causing a metabolic acidosis that increases ventilation and
arterial oxygenation. However, prophylactic pharmacologic therapy with
acetazolamide in children is generally not recommended because
preacclimatization with slow ascent achieves the same effect. Exceptions include
children with previous susceptibility to AMS and an unavoidably rapid ascent,
such as flying to La Paz, Bolivia (3,700 m, 12,100 ft), or Cusco, Peru (3,400 m,
11,200 ft), from sea level. The pediatric dose of acetazolamide is 2.5 mg/kg
(maximum, 125 mg/dose) every 12 hr (Table 90.1 ). In adults, it is recommended
that prophylaxis begin 24 hr before arriving at altitude and be continued for 48
hr at altitude, or until the final destination high altitude is reached. The
respiratory stimulation caused by acetazolamide also improves sleep by
eradicating periodic breathing. Side effects are common and include
paresthesias, polyuria, lightheadedness, dry mouth, and metallic taste with
carbonated beverages. Acetazolamide is a nonbacteriostatic sulfonamide drug, so
a history of anaphylactic reaction to sulfa medications is a contraindication to its
use. Acetazolamide should be avoided in breastfeeding mothers and pregnant
women. Dexamethasone is another agent that has been used for AMS
prophylaxis in the adult population. However, it should not be used for
prophylaxis in children because of the potential for side effects; pancreatitis,
pseudotumor cerebri, and interference with normal growth. Low-risk children
should not need medications for prophylaxis and should use gradual ascent to
prevent illness.

Table 90.1
Medications for Treatment of Altitude-Associated Illness in
Children (No Studies in Children for High-Altitude
Indications)
 MEDICATION CLASSIFICATION INDICATION DOSE AND ROUTE ADVERSE EFFECTS
Acetazolamide Carbonic anhydrase AMS 2.5 mg/kg PO every 12 Collateral effects include
inhibitor prevention* hr; max 125 mg/dose paresthesias and taste
alteration
AMS treatment 2.5 mg/kg PO every 12
hr; max 250 mg/dose
Dexamethasone Steroid AMS Risk of adverse effects
prevention † precludes prophylactic use
AMS HACE 0.15 mg/kg PO/IM/IV Hypertension, gastrointestinal
treatment ‡ every 6 hr; max 4 hemorrhage, pancreatitis,
mg/dose growth inhibition
Nifedipine Calcium channel HAPE 0.5 mg/kg PO every 4-8 Hypotension
blocker treatment hr; max 20 mg/dose
(small
children) §
HAPE 30 mg SR PO every 12
treatment (>60 hr or 20 mg SR PO
kg) § every 8 hr
Reentry HAPE Same dose as HAPE
prevention treatment
Sildenafil Phosphodiesterase-5 HAPE ¶ 0.5 mg/kg/dose PO
inhibitor every 4-8 hr; max 50
mg/dose every 8 hr
*
AMS prophylaxis is not routinely recommended in children. It is indicated when rapid ascent
profile is unavoidable or with previous altitude illness in child about to undergo similar ascent
profile. Doses as low as 1.25 mg/kg every 12 hr have been successful in some children.
† Use not warranted due to risk of adverse effects. Use slow, graded ascent or acetazolamide.

‡ Oxygen and descent are the treatment of choice for severe AMS. If acetazolamide is not
tolerated, dexamethasone may be used. Oxygen, descent, and dexamethasone should be used in
HACE.
§ In emergency settings where oxygen and descent are not an option, nifedipine is indicated.

¶
In emergency settings where oxygen and descent are not an option, if nifedipine is not well
tolerated, sildenafil may provide an alternative.
AMS, Acute mountain sickness; HACE, high-altitude cerebral edema; HAPE, high-altitude
pulmonary edema, IM, intramuscularly; IV, intravenously; PO, orally; SR, sustained release.

Diagnosis
AMS is easily identified in older children and adolescents using the Self-Report
Lake Louise AMS Scoring System . The criteria require that the individual be
in the setting of a recent gain in altitude, be at the new altitude for at least several
hours, and report a headache plus at least 1 of the following symptoms:
gastrointestinal (GI) upset (anorexia, nausea, or vomiting), general weakness or
fatigue, dizziness or lightheadedness, or difficulty sleeping. Shortness of breath
minimal admixture with other populations, represent the extreme of adaptation
to high altitude and rarely experience HAPE. Other native populations residing
at high altitude, such as Andeans, do not appear to be protected from HAPE, and
certain populations may have genetic polymorphisms associated with pulmonary
edema.
A number of conditions may predispose a child to HAPE (Table 90.2 ).
Preexisting viral respiratory infections have been linked to HAPE, especially in
children. Cardiorespiratory conditions associated with pulmonary hypertension,
such as atrial and ventricular septal defects, pulmonary vein stenosis, congenital
absence of a pulmonary artery, and OSA, also predispose to HAPE. Down
syndrome is a risk factor for HAPE development, as are previously repaired
congenital heart defects and the presence of hypoplastic lungs. Undiagnosed
structural cardiopulmonary abnormalities may result in severe hypoxia and/or
altitude illness once ascent occurs.
Table 90.2
Conditions Associated With Increased Risk of
High-Altitude Pulmonary Edema (HAPE)
Environmental

Ascent above 2,500 m (~8,200 ft)

Rapid rate of ascent (generally >1,000 m [~3,300 ft] per day)
Cold exposure

Cardiac

Anomalies causing increased pulmonary blood flow or increased

pulmonary artery pressure
Ventricular septal defect, atrial septal defect, patent foramen ovale, patent
ductus arteriosus
Anomalous pulmonary venous return or pulmonary vein stenosis
Unilateral absent pulmonary artery or isolated pulmonary artery of ductal
origin
Coarctation of the aorta
Congestive heart failure
Pulmonary

Chronic lung disease

Bronchopulmonary dysplasia
Pulmonary hypoplasia
Supplemental oxygen requirement at sea level
Pulmonary hypertension
Perinatal respiratory distress
Persistent pulmonary hypertension of the newborn
Perinatal asphyxia or depression
Sleep apnea

Infectious

Upper respiratory tract infection

Bronchitis/bronchiolitis
Pneumonitis
Otitis media

Pharmacologic

Any medication causing central nervous system and respiratory depression

Alcohol
Sympathomimetics

Systemic

Down syndrome (trisomy 21)

History of premature birth or low birthweight

Pathophysiology
Alveolar hypoxia results in vasoconstriction of pulmonary arterioles just
proximal to the alveolar capillary bed. Hypoxic pulmonary vasoconstriction is a
normal physiologic response to optimize ventilation/perfusion (V̇/Q̇) matching
preventive strategy for exposure to all water types and all ages is ensuring
appropriate supervision . Pediatricians should define for parents what
constitutes appropriate supervision at the various developmental levels of
childhood. Many parents either underestimate the importance of adequate
supervision or are simply unaware of the risks associated with water. Even
parents who say that constant supervision is necessary will often admit to brief
lapses while their child is alone near water. Parents also overestimate the
supervisory abilities of older siblings; many bathtub drownings occur when an
infant or toddler is left with a child <5 yr old.

Table 91.1
Approach to Prevention Strategies for Drowning

HOME RECREATION NEIGHBORHOOD

Water Swimming pools Playing in water-swimming, Irrigation ditches
hazards Ponds wading Watering holes
Bathtubs Playing near water Water drainage
Large buckets Being on water—boating
Common Lapse in supervision Lapse in supervision Lapse in supervision,
risks Unexpected toddler Change in weather particularly when caregiver
exposure Unfamiliarity with or is socializing
Delayed discovery of child change(s) in water Risky behavior when with
Reliance on water wings or conditions: peers
pool toys Steep drop-off
Reliance on sibling or bath Current/tide
seat for bathing supervision Low temperature
Alcohol use
Peer pressure
Prevention Recognize hazards and Provide constant adult Identify hazardous bodies
strategies risks. supervision. of water.
Provide constant adult Swim in lifeguarded areas. Prevent access to water
supervision around water. Know when and how to with barriers.
Install 4-sided, isolation wear U.S. Coast Guard– Provide fenced-in “safe
fencing of pools. approved PFDs. area” for water recreation.
Install rescue equipment Avoid alcohol and other Provide lifeguarded swim
and phone at poolside. drugs. sites.
Learn swimming and water Learn swimming and water Provide access to low-cost
survival skills. survival skills. swim/water survival
Avoid bath; instead shower, Teach children about water lessons.
if a child/teen with seizure safety.
disorder. Be aware of current weather
Learn first aid and CPR. and water conditions.
Learn first aid and CPR.
CPR, Cardiopulmonary resuscitation; PFDs, personal floatation devices.

Supervision of infants and young children means that a responsible adult

should be with the child every moment. The caregiver must be alert, must not be
burn injuries (Table 92.1 ). Effective first aid and triage can decrease both the
extent (area) and the severity (depth) of injuries. The use of flame-retardant
clothing and smoke detectors, control of hot water temperature (thermostat
settings) to 48.9°C (120°F) within buildings, and prohibition of cigarette
smoking have been partially successful in reducing the incidence of burn
injuries. Treatment of children with significant burn injuries in dedicated burn
centers facilitates medically effective care, improves survival, and leads to
greater cost efficiency. Survival of at least 80% of patients with burns of 90% of
the body surface area (BSA) is possible; the overall survival rate of children with
burns of all sizes is 99%. Death is more likely in children with irreversible
anoxic brain injury sustained at the time of the burn. It is well known that burns
occur in predictable patterns. Sources of burns include, by season:
Table 92.1
Burn Prophylaxis
Prevent Fires

Install and use smoke detectors.

Control the hot water thermostat; in public buildings, maximum water
temperature should be 48.9°C (120°F).
Keep fire, matches, and lighters out of the reach of children.
Avoid cigarette smoking, especially in bed.
Do not leave lit candles unattended.
Use flame retardant–treated clothing.
Use caution when cooking, especially with oil.
Keep cloth items off heaters.

Prevent Injury

Roll, but do not run, if clothing catches fire; wrap in a blanket.

Practice escape procedures.
Crawl beneath smoke if a fire occurs indoors.
Use educational materials.*
* National Fire Protection Association pamphlets and videos.

Winter :
◆ Glass front fireplaces/pellet stoves and radiators increase hand
burns.
◆ Treadmill injuries as more people exercise inside—child
imitates adults or young child touches belt.
Summer :
◆ Fireworks, sparkler—temperatures reach 537.8°C (1,000°F).
◆ Burn contact with hot grill; hand/feet burn from hot embers.
◆ Lawnmowers
Spring/Fall :
◆ Burning leaves
◆ Gasoline burns
◆ Tap water scalds are essentially preventable through a
combination of behavioral and environmental changes.

Pediatricians can play a major role in preventing the most common burns by
educating parents and healthcare providers. Simple, effective, efficient, and cost-
effective preventive measures include the use of appropriate clothing and smoke
detectors and the planning of routes for emergency exit from the home. The
National Fire Protection Association (NFPA) recommends replacing smoke
detector batteries annually and the smoke detector alarm every 10 yr (or earlier,
if indicated on the device). Child neglect and abuse must be seriously considered
when the history of the injury and the distribution of the burn do not match.

Acute Care, Resuscitation, and

Assessment
Indications for Admission
Burns covering >10% of total body surface area (BSA), burns associated with
smoke inhalation, burns resulting from high-tension (voltage) electrical injuries,
and burns associated with suspected child abuse or neglect should be treated as
emergencies and the child hospitalized (Table 92.2 ). Small 1st- and 2nd-degree
burns of the hands, feet, face, perineum, and joint surfaces also require
admission if close follow-up care is difficult to provide. Children who have been
in enclosed-space fires and those who have face and neck burns should be
hospitalized for at least 24 hr for observation for signs of central nervous system
(CNS) effects of anoxia from carbon monoxide (CO) poisoning and pulmonary
effects from smoke inhalation.
Table 92.2
Indications for Hospitalization for Burns
Burns affecting >10% of BSA
Burns >10–20% of BSA in adolescent/adult
3rd-degree burns
Electrical burns caused by high-tension wires or lightning
Chemical burns
Inhalation injury, regardless of the amount of BSA burned
Inadequate home or social environment
Suspected child abuse or neglect
Burns to the face, hands, feet, perineum, genitals, or major joints
Burns in patients with preexisting medical conditions that may complicate
the acute recovery phase
Associated injuries (fractures)
Pregnancy

BSA, Body surface area.

First Aid Measures

Acute care should include the following measures:

1. Extinguish flames by rolling the child on the ground; cover the child
with a blanket, coat, or carpet.
2. After determining that the airway is patent, remove smoldering clothing
or clothing saturated with hot liquid. Jewelry, particularly rings and
bracelets, should be removed or cut away to prevent constriction and
vascular compromise during the edema phase in the first 24-72 hr after
burn injury.
3. In cases of chemical injury , brush off any remaining chemical, if
 powdered or solid; then use copious irrigation or wash the affected area
with water. Call the local poison control center for the neutralizing agent
to treat a chemical ingestion.
4. Cover the burned area with clean, dry sheeting and apply cold (not iced)
wet compresses to small injuries. Significant large-burn injury (>15% of
BSA) decreases body temperature control and contraindicates the use of
cold compresses.
5. If the burn is caused by hot tar , use mineral oil to remove the tar.
6. Administer analgesic medications.

Emergency Care
Supportive measures are as follows (Table 92.3 and Table 92.4 )
Table 92.3
Acute Treatment of Burns

First aid, including washing of wounds and removal of devitalized tissue

Fluid resuscitation
Provision of energy requirements
Control of pain
Prevention of infection—early excision and grafting
Prevention of excessive metabolic expenditures
Control of bacterial wound flora
Use of biologic and synthetic dressings to close the wound

Table 92.4

Four Phases of Burn Care, With Physiologic Changes and Objectives

PHYSIOLOGIC
PHASE AND TIMING OBJECTIVES
CHANGES
1 : Initial evaluation and Massive capillary leak Accurate fluid resuscitation and thorough evaluation
resuscitation, 0 to 72 hr and burn shock
2 : Initial wound excision and Hyperdynamic and Accurately identify and remove all full-thickness
biologic closure, days 1-7 catabolic state with high wounds and achieve biologic closure
risk of infection
3 : Definitive wound closure, Continued catabolic Replace temporary with definitive covers, and close
day 7 to week 6 state and risk of small complex wounds
nonwound septic events
4 : Rehabilitation, Waning catabolic state Initially to maintain range of motion and reduce
 reconstruction, and and recovering strength edema; subsequently to strengthen and facilitate return
reintegration, day 1 through to home, work, and school
discharge
From Sheridan RL: Burns, including inflammation injury. In Vincent JL, Abraham E, Moore FA, et
al, editors: Textbook of critical care, ed 7, Philadelphia, 2017, Elsevier (Table 168-1, p. 1173).

1. Rapidly review the cardiovascular and pulmonary status and document

preexisting or physiologic lesions (asthma, congenital heart disease,
renal or hepatic disease).
2. Ensure and maintain an adequate airway, and provide humidified oxygen
by mask or endotracheal intubation (Fig. 92.1 ). The latter may be
needed in children who have facial burns or a burn sustained in an
enclosed space, before facial or laryngeal edema becomes evident. If
hypoxia or CO poisoning is suspected, 100% oxygen should be used
(see Chapters 81 and 89 ).
depth of the injury (Table 92.5 and Fig. 92.2 ). 1st-degree burns involve only
the epidermis and are characterized by swelling, erythema, and pain (similar to
mild sunburn). Tissue damage is usually minimal, and there is no blistering. Pain
resolves in 48-72 hr; in a small percentage of patients, the damaged epithelium
peels off, leaving no residual scars.

Table 92.5
Categories of Burn Depth

1ST-DEGREE 2ND-DEGREE, OR PARTIAL- 3RD-DEGREE, OR FULL-

BURN THICKNESS, BURN THICKNESS, BURN
Surface Dry, no Moist blebs, blisters Dry, leathery eschar
appearance blisters Underlying tissue is mottled pink and Mixed white, waxy, khaki,
Minimal or white, with fair capillary refill mahogany, soot-stained
no edema Bleeds No blanching or bleeding
Erythematous
Blanches,
bleeds
Pain Very painful Very painful Insensate
Histologic Epidermal layers Epidermis, papillary, and reticular Down to and may include fat,
depth only layers of dermis subcutaneous tissue, fascia, muscle,
May include domes of subcutaneous and bone
layers
Healing 2-5 days with no Superficial: 5-21 days with no Large areas require grafting, but
time scarring grafting small areas may heal from the edges
Deep partial: 21-35 days with no after weeks
infection; if infected, converts to full-
thickness burn

FIG. 92.2 Diagram of different burn depths. (From Hettiaratchy S, Papini R: Initial
outpatient basis unless family support is judged inadequate or there are issues of
child neglect or abuse. These outpatients do not require a tetanus booster (unless
not fully immunized) or prophylactic penicillin therapy. Blisters should be left
intact and dressed with bacitracin or silver sulfadiazine cream (Silvadene).
Dressings should be changed once daily, after the wound is washed with
lukewarm water to remove any cream left from the previous application. Very
small wounds, especially those on the face, may be treated with bacitracin
ointment and left open. Debridement of the devitalized skin is indicated when
the blisters rupture. A variety of wound dressings and wound membranes (e.g.,
AQUACEL Ag dressing [ConvaTec USA, Skillman, NJ] in soft felt-like material
impregnated with silver ion) may be applied to 2nd-degree burns and wrapped
with a dry sterile dressing. Similar wound membranes provide pain control,
prevent wound desiccation, and reduce wound colonization (Table 92.6 ). These
dressings are usually kept on for 7-10 days but are checked twice a week.

Table 92.6

Select Common Wound Membranes for Burns

MEMBRANE CHARACTERISTIC(S)
Porcine xenograft Adheres to coagulum
Excellent pain control
Biobrane Bilaminate
Fibrovascular in growth into inner layer
Acticoat Nonadherent dressing that delivers silver
AQUACEL Ag Absorptive hydrofiber that delivers silver
Various semipermeable membranes Provide vapor and bacterial barrier
Various hydrocolloid dressings Provide vapor and bacterial barrier
Absorb exudates
Various impregnated gauzes Provide barrier while allowing drainage

Burns to the palm with large blisters usually heal beneath the blisters; they
should receive close follow-up on an outpatient basis. The great majority of
superficial burns heal in 10-20 days. Deep 2nd-degree burns take longer to heal
and may benefit from enzymatic debridement ointment (collagenase) applied
daily on the wound, which aids in the removal of the dead tissue. These
ointments should not be applied to the face, to avoid the risk of getting into the
eyes.
The depth of scald injuries is difficult to assess early; conservative treatment
is appropriate initially, with the depth of the area involved determined before
grafting is attempted (Fig. 92.4 ). This approach obviates the risk of anesthesia
large open wound, reduction of the patient's host resistance, and malnutrition.
These abnormalities set the stage for life-threatening bacterial infection
originating from the burn wound. Wound treatment and prevention of wound
infection also promote early healing and improve aesthetic and functional
outcomes. Topical treatment of the burn wound with 0.5% silver nitrate solution,
silver sulfadiazine cream, or mafenide acetate (Sulfamylon) cream or topical
solution at a concentration of 2.5–5% to be used for wounds with multidrug–
resistant bacteria aims at prevention of infection (Table 92.7 ). These 3 agents
have tissue-penetrating capacity. Regardless of the choice of topical
antimicrobial agent, it is essential that all 3rd-degree burn tissue be fully excised
before bacterial colonization occurs, and that the area is grafted as early as
possible to prevent deep wound sepsis. Children with a burn of >30% BSA
should be housed in a bacteria-controlled nursing unit to prevent cross-
contamination and to provide a temperature- and humidity-controlled
environment to minimize hypermetabolism.

Table 92.7
Topical Agents Used for Burns

AGENT EFFECTIVENESS EASE OF USE

Silver sulfadiazine cream Good penetration Changed once daily
(Silvadene) Residue must be washed off with each dressing
change
Mafenide acetate cream* Broad spectrum, including Closed dressings
(Sulfamylon) Pseudomonas Changed twice daily
Rapid and deep wound Residue must be washed off with each dressing
penetration changed
0.5% Silver nitrate solution Bacteriostatic Closed bulky dressing soaked every 2 hr and
Broad spectrum, including changed once daily
some fungi
Superficial penetration
AQUACEL Ag Dressing impregnated with Applied directly to 2nd-degree burn; occlusive
silver dressing kept for 10 days
* Mafenide acetate solution at concentrations of 2.5% or 5% for use on heavily colonized,
multidrug-resistant organisms to be used for 5 days only.

Deep 3rd-degree burns of >10% BSA benefit from early excision and grafting.
To improve outcome, sequential excision and grafting of 3rd-degree and deep
2nd-degree burns is required in children with large burns. Prompt excision with
immediate wound closure is achieved with autografts , which are often meshed
to increase the efficiency of coverings. Alternatives for wound closure, such as
recovery. Table 92.8 lists the long-term disabilities and complications of burns.
Table 92.8
Common Long-Term Complications and
Disabilities in Patients With Burn Injuries
Complications Affecting the Skin and Soft Tissue

Hypertrophic scars
Susceptibility to minor trauma
Dry skin
Contractures
Itching and neuropathic pain
Alopecia
Chronic open wounds
Skin cancers

Orthopedic Disabilities

Amputations
Contractures
Heterotopic ossification
Temporary reduction in bone density

Metabolic Disabilities

Heat sensitivity
Obesity

Psychiatric and Neurologic Disabilities

Sleep disorders
Adjustment disorders
Posttraumatic stress disorder
Depression
 Body image issues
Neuropathy and neuropathic pain
Long-term neurologic effects of carbon monoxide poisoning
Anoxic brain injury

Long-Term Complications of Critical Care

Deep vein thrombosis, venous insufficiency, or varicose veins

Tracheal stenosis, vocal cord disorders, or swallowing disorders
Renal or adrenal dysfunction
Hepatobiliary or pancreatic disease
Cardiovascular disease
Reactive airway disease or bronchial polyposis

Preexisting Disabilities That Contributed to the Injuries

Risk-taking behavior
Untreated or poorly treated psychiatric disorder

Modified from Sheridan RL, Schultz JT, Ryan CM, et al: Case records of the
Massachusetts General Hospital. Weekly clinicopathological exercises. Case 6-
2004: a 35-year-old woman with extensive, deep burns from a nightclub fire, N
Engl J Med 350:810–821, 2004.

Electrical Burns
There are 3 types of electrical burns: extension cord (minor), high-tension wire,
and lightning. Minor electrical burns usually occur as a result of biting on an
extension cord. These injuries produce localized burns to the mouth, which
usually involve the portions of the upper and lower lips that come in contact with
the extension cord. The injury may involve or spare the corners of the mouth.
Because these are nonconductive injuries (do not extend beyond the site of
injury), hospital admission is not necessary, and care is focused on the area of
the injury visible in the mouth, ensuring it is low voltage and does not cause
entry or exit wounds or cardiac issues. Treatment with topical antibiotic creams
Table 92.9
Electrical Injury: Clinical Considerations

SYSTEM CLINICAL MANIFESTATIONS MANAGEMENT

General — Extricate the patient.
Perform ABCs of
resuscitation; immobilize
the spine.
Obtain history: voltage, type
of current.
Obtain complete blood count
with platelets, electrolytes,
BUN, creatinine, and glucose.
Cardiac Dysrhythmias: asystole, ventricular fibrillation, sinus Treat dysrhythmias.
tachycardia, sinus bradycardia, premature atrial contractions, Provide cardiac monitor,
premature ventricular contractions, conduction defects, atrial electrocardiogram, and
fibrillation, ST-T wave changes radiographs with
suspected thoracic injury.
Perform creatinine
phosphokinase with
isoenzyme measurements if
indicated.
Pulmonary Respiratory arrest, acute respiratory distress, aspiration Protect and maintain the
syndrome airway.
Provide mechanical
ventilation if indicated, chest
radiograph, and arterial blood
gas levels.
Renal Acute kidney injury, myoglobinuria Provide aggressive fluid
management unless central
nervous system injury is
present.
Maintain adequate urine
output, >1 mL/kg/hr.
Consider central venous or
pulmonary artery pressure
monitoring.
Measure urine myoglobin;
perform urinalysis; measure
BUN, creatinine.
Neurologic Immediate: loss of consciousness, motor paralysis, visual Treat seizures.
disturbances, amnesia, agitation; intracranial hematoma Provide fluid restriction
if indicated.
Secondary: pain, paraplegia, brachial plexus injury, syndrome of Consider spine radiographs
inappropriate antidiuretic hormone secretion, autonomic and MRI, especially cervical.
disturbances, cerebral edema
Delayed: paralysis, seizures, headache, peripheral neuropathy Perform CT or MRI scan of
the brain if indicated.
Cutaneous/oral Oral commissure burns, tongue and dental injuries; skin burns Search for the entrance
resulting from ignition of clothes, entrance and exit burns, and and exit wounds.
arc burns Treat cutaneous burns;
determine patient's
 tetanus status.
Obtain consultation for
plastic surgery of ear, nose,
and throat, if indicated.
Electrical burns to mouth could include oral commissures and Ensure no entry or exit
lips; low-voltage electrical burns secondary to high conductivity wounds and no cardiac
of saliva involvement.
Confirm all injuries are
localized.
Management is
observation until eschar
sloughs off and
granulation tissue fills in.
Obtain plastic surgeon
evaluation after first
healing, usually with scar
formation.
Abdominal Viscus perforation and solid-organ damage; ileus; abdominal Place nasogastric tube if
injury rare without visible abdominal burns patient has airway
compromise or ileus.
Obtain serum ALT, AST,
amylase, BUN, and creatinine
measurements and CT scans
as indicated.
Musculoskeletal Compartment syndrome from subcutaneous necrosis limb edema Monitor patient for possible
and deep burns compartment syndrome.
Long-bone fractures, spine injuries Obtain radiographs and
orthopedic/general surgery
consultations as indicated.
Ocular Visual changes, optic neuritis, cataracts, extraocular muscle Obtain an ophthalmology
paresis consultation as indicated.
AST, Aspartate transaminase; ALT, alanine transaminase; BUN, blood urea nitrogen.
Adapted from Hall ML, Sills RM: Electrical and lightning injuries. In Barkin RM, editor: Pediatric
emergency medicine, St Louis, 1997, Mosby, p 484.

Lightning burns occur when a high-voltage current directly strikes a person

(most dangerous) or when the current strikes the ground or an adjacent (in-
contact) object. A step voltage burn is observed when lightning strikes the
ground and travels up one leg and down the other (the path of least resistance).
Lightning burns depend on the current path, the type of clothing worn, the
presence of metal, and cutaneous moisture. Entry, exit, and path lesions are
possible; the prognosis is poorest for lesions of the head or legs. Internal organ
injury along the path is common and does not relate to the severity of the
cutaneous burn. Linear burns, usually 1st or 2nd degree, are in the locations
where sweat is present. Feathering, or an arborescent pattern, is characteristic of
lightning injury. Lightning may ignite clothing or produce serious cutaneous
burns from heated metal in the clothing. Internal complications of lightning
burns include cardiac arrest caused by asystole, transient hypertension,
hypothermia, whereas others may cause reduced metabolism or clearance during
hypothermia (Table 93.1 ).
Table 93.1
Drugs Displaying Reduced Metabolism or
Clearance in Hypothermia

Atropine
Digoxin
Fentanyl
Gentamicin
Lidocaine
Phenobarbital
Procaine
Propranolol
Sulfanilamide (AVC cream)
Succinylcholine
D -Tubocurarine

Adapted from Bope ET, Kellerman RD, editors: Conn's current therapy 2014 ,
Philadelphia, 2014, Elsevier/Saunders (Box 3, p 1135).

Hypothermia occurs when the body can no longer sustain normal core
temperature by physiologic mechanisms, such as vasoconstriction, shivering,
muscle contraction, and nonshivering thermogenesis. When shivering ceases, the
body is unable to maintain its core temperature; when the body core temperature
falls to <35°C (95°F), the syndrome of hypothermia occurs. Wind chill, wet or
inadequate clothing, and other factors increase local injury and may cause
dangerous hypothermia, even in the presence of an ambient temperature that is
not <17-20°C (50-60°F).

Clinical Manifestations
Frostnip
Frostnip results in the presence of firm, cold, white areas on the face, ears, or
Application of petrolatum (Vaseline) to the nose and ears helps protect against
frostbite.
Treatment at the scene aims at prevention of further heat loss and early
transport to adequate shelter (Table 93.2 ). Dry clothing should be provided as
soon as practical, and transport should be undertaken if the victim has a pulse. If
no pulse is detected at the initial review, cardiopulmonary resuscitation is
indicated (Fig. 93.1 ) (see Chapter 81 ). During transfer, jarring and sudden
motion should be avoided because of the risk of ventricular arrhythmia. It is
often difficult to attain a normal sinus rhythm during hypothermia.
Table 93.2
Management of Hypothermia
History and Physical Examination

Gentle handling of the patient to prevent arrhythmias

ABCDE: cardiopulmonary resuscitation for ventricular fibrillation and
asystole
Underlying disease diagnosis and treatment
Vital signs, pulse oximetry, electrocardiogram
Wet or cold clothing removed and patient placed in warm environment

Laboratory Tests

Arterial blood gas analysis corrected for temperature

Electrolytes, BUN, creatinine, Ca, Mg, P
CBC with differential, PT/PTT, fibrinogen
Glucose, amylase/lipase
Liver function tests
Additional lab tests, if appropriate, such as toxicology screen

Passive Rewarming

≥32°C (89.6°F) in patients who are capable of spontaneous thermogenesis

Active Rewarming
 <32°C (89.6°F), cardiovascular instability, patients at risk for developing
hypothermia
Close monitoring for core-temperature afterdrop
Acute: external and/or core rewarming
Chronic (<32°C [89.6°F] for >24 hr): core rewarming
Extracorporeal membrane oxygenation
Availability of rapid deployment

ABCDE, A irway and possibly a ntibiotics, b reathing, c irculation, d isability

or neurologic and possible d extrose, e xtracorporeal support if all else fails;
BUN, blood urea nitrogen; Ca, calcium; CBC, complete blood count; Mg,
magnesium; P, phosphorus; PT, prothrombin time; PTT, partial thromboplastin
time.

Adapted from Burg FD, Ingelfinger JR, Polin RA, Gershon AA, editors: Current
pediatric therapy, ed 18, Philadelphia, 2006, Saunders/Elsevier (Table 4, p 174).
than one disease gene contributes to a complex, or “blended,” phenotype. The
ability to sequence hundreds to thousands of genes at once has provided insight
into this added layer of complexity in disease pathogenesis.

Table 94.1
Approaches for Genetic Testing

TYPE OF
SAMPLE
MUTATION RESOLUTION ADVANTAGES DISADVANTAGES
REQUIREMENTS
TESTING
Linkage Depends on Possible when Can give only diagnostic Requires multiple
analysis location of specific disease- probability based on likelihood of family members with
polymorphic causing genetic genetic recombination between documented mendelian
markers near mutation is not presumed DNA mutation and pattern of inheritance
putative disease identifiable or polymorphic markers within family
gene found
Array Several hundred Able to detect Can miss small deletions or Single patient sample
comparative base pairs to small deletion or insertions depending on sufficient, but having
genomic several duplications within resolution of the array used sample from biological
hybridization hundreds of 1 or more genes parents can help with
(aCGH) kilobases interpretation
Direct DNA- Single–base-pair High specificity if Can miss deletion or duplication Single patient sample
based testing changes previously of a segment of gene sufficient, but having
(e.g., DNA described sample from biological
sequencing) deleterious parents can help with
mutation is found interpretation

Linkage testing involves tracking a genetic trait through a family using

closely linked polymorphic markers as a surrogate for the trait (Fig. 94.1 ). It
requires testing an extended family and is vulnerable to several pitfalls, such as
genetic recombination, genetic heterogeneity, and incorrect diagnosis in the
proband. Genetic recombination occurs between any pair of loci, the frequency
being proportional to the distance between them. This problem can be
ameliorated by using very closely linked markers and, if possible, using markers
that flank the specific gene. Genetic heterogeneity can be problematic for a
linkage-based test if there are multiple distinct genomic loci that can cause the
same phenotype, resulting in the risk that the locus tested for is not the one
responsible for disease in the family. Incorrect diagnosis in the proband also
leads to tracking the wrong gene. Linkage testing remains useful for several
genetic conditions, but it is increasingly being superseded by the availability of
direct DNA sequencing of either single genes or of the whole collection of genes
that encode all proteins. It is critically important that genetic counseling be
provided to the family to explain the complexities of interpretation of test
which would be medically actionable. At the same time, the discovery of
apolipoprotein E variants in a child that increase Alzheimer disease risk
susceptibility may not be medically actionable. Therefore, counseling for
patients undergoing these tests is important so that only wanted results are
reported back to the patient. Guidelines are currently evolving for reporting of
incidental findings for WES by the American College of Medical Genetics
(www.acmg.net ). Practice varies among institutions and recommendations vary
among international genetic organizations about the approach for revealing
incidental findings from WES/WGS to patients; many leave the choice up to the
patient and family. Most require revealing to the patient and/or family significant
diseases (actionable) with a specific and successful treatment or prevention
strategy (Table 94.2 ).

Table 94.2

Variants That Are Incidental Findings Are Assigned to 1 of 4 Categories

Childhood onset Medically actionable*
Childhood onset Not medically actionable †
Adult onset Medically actionable*
Adult onset Not medically actionable †
* “Medically actionable” refers to a variant in a gene in which knowledge of the particular variant

will affect medical decision-making, such as initiation of a treatment or family planning.

† “Not medically actionable” refers to variants that increase the individual's risk for a disease in
which no treatment is proven to significantly change medical decision-making.
From Bick D, Dimmock D: Whole exome and whole genome sequencing. Curr Opin Pediatr
23:594–600, 2011.

Genetic testing is interpreted by 3 factors: analytic validity, clinical validity,

and clinical utility. Analytical validity is test accuracy: Does the test correctly
detect the presence or absence of mutation? Most genetic tests have a very high
analytical validity, assuming that human error, such as sample mix-up, has not
occurred. Human errors are possible, and unlike most medical tests, a genetic
test is unlikely to be repeated, because it is assumed that the result will not
change over time. Therefore, human errors can go undetected for long periods of
time. However, it may be reinterpreted over time as our knowledge base of what
are disease-causing mutations and genes increases over time.
Clinical validity is the degree to which the test correctly predicts presence or
absence of disease. False-positive and false-negative test results can occur.
Indications for Genetic Counseling

Advanced parental age

• Maternal age ≥35 yr
• Paternal age ≥40 yr
Previous child with or family history of:
• Congenital abnormality
• Dysmorphology
• Intellectual disability
• Isolated birth defect
• Metabolic disorder
• Chromosome abnormality
• Single-gene disorder
Adult-onset genetic disease (presymptomatic testing)
• Cancer
• Huntington disease
Pharmacogenomics
Consanguinity
Teratogen exposure (occupational, abuse)
Repeated pregnancy loss or infertility
Pregnancy screening abnormality
• Maternal serum α-fetoprotein
Maternal 1st-trimester screen
• Maternal triple or quad screen or variant of this test
• Fetal ultrasonography
Noninvasive prenatal testing (NIPT)
• Fetal karyotype
Heterozygote screening based on ethnic risk
• Sickle cell anemia
• Tay-Sachs, Canavan, and Gaucher diseases
• Thalassemias
Universal carrier screening panels
Follow-up to abnormal neonatal genetic testing
Prior to whole genome or exome sequencing
Prior to preimplantation genetic testing
CHAPTER 95

The Genetic Approach in Pediatric

Medicine
Daryl A. Scott, Brendan Lee

Since the completion of the Human Genome Project, we have seen an

unprecedented expansion in our understanding of how human health is impacted
by variations in genomic sequence and epigenetic , non-sequence-based,
changes that affect gene expression. This period has also seen the development
and implementation of new clinical tests that have made it easier for physicians
to detect such changes. In addition, there has been a dramatic increase in the
availability of information about the genetic aspects of pediatric diseases,
particularly on the internet (Table 95.1 ).

Table 95.1

Useful Internet Genetic Reference Sites

RESOURCE WEB ADDRESS
National Center for Biotechnology Information. A general reference maintained www.ncbi.nlm.nih.gov
by the National Library of Medicine.
Online Mendelian Inheritance in Man. A useful resource for clinicians www.ncbi.nlm.nih.gov/omim
containing information on all known mendelian disorders and >12,000 genes.
Information focuses on the relationship between phenotype and genotype.
Genetic Testing Registry. A resource that provides information on individual www.ncbi.nlm.nih.gov/gtr/
genes, genetic tests, clinical laboratories, and medical conditions. This resource
also provides access to GeneReviews, a collection of expert-authored reviews
on a variety of genetic disorders.
Genetics Home Reference. A resource that provides consumer-friendly www.ghr.nlm.nih.gov
information about the effects of genetic variations on human health.
National Human Genome Research Institute. A resource for information about www.genome.gov
human genetics and ethical issues.
Human Gene Mutation Database. A searchable index of all described mutations www.hgmd.cf.ac.uk
in human genes with phenotypes and references.
DECIPHER. A database designed to aid physicians in determining the potential http://decipher.sanger.ac.uk
consequences of chromosomal deletions and duplications.
 Database of Genomic Variants. A database of chromosomal alterations seen in http://dgv.tcag.ca/dgv/app/home
normal controls.
Gene Letter . An online magazine of genetics. www.geneletter.com
American Society of Human Genetics www.ashg.org
American College of Medical Genetics www.acmg.net

The Burden of Genetic Disorders in

Childhood
Medical problems associated with genetic disorders can appear at any age, with
the most obvious and serious problems typically manifesting in childhood. It has
been estimated that 53/1,000 children and young adults can be expected to have
diseases with an important genetic component. If congenital anomalies are
included, the rate increases to 79/1,000. In 1978 it was estimated that just over
half of admissions to pediatric hospitals were for a genetically determined
condition. By 1996, because of changes in healthcare delivery and a greater
understanding of the genetic basis of many disorders, that percentage rose to
71%, in one large pediatric hospital in the United States, with 96% of chronic
disorders leading to admission having an obvious genetic component or being
influenced by genetic susceptibility.
Major categories of genetic disorders include single-gene, genomic,
chromosomal, and multifactorial conditions.
Individually, each single-gene disorder is rare, but collectively they represent
an important contribution to childhood disease. The hallmark of a single-gene
disorder is that the phenotype is overwhelmingly determined by changes that
affect an individual gene. The phenotypes associated with single-gene disorders
can vary from one patient to another based on the severity of the change
affecting the gene and additional modifications caused by genetic,
environmental, and stochastic factors. This feature of genetic disease is termed
variable expressivity . Common single-gene disorders include sickle cell
anemia and cystic fibrosis. Some identifiable syndromes and diseases can be
caused by more than one gene (e.g., Noonan syndrome by RAF1, NF1, NRAS,
PTPN11, SOS1, SOS2, KRAS, BRAF, SOC2, LZTR1, and RIT1 ). In addition,
mutations affecting a single gene may produce different phenotypes (e.g.,
SCN5A and Brugada syndrome, long QT syndrome 3, dilated cardiomyopathy,
familial atrial fibrillation, and congenital sick sinus syndrome).
Single-gene disorders tend to occur when changes in a gene have a profound
 FIG. 96.3 Various types of intragenic sequence variants. Promoter variants alter rate of
transcription or disrupt gene regulation. Base changes within exons can have various
effects, as shown. Variants within introns can lead to inclusion of some intronic
sequence in the final processed mRNA, or it can lead to exon skipping.

Table 96.1
Main Classes, Groups, and Types of Sequence Variants
and Their Effects on Protein Products

CLASS GROUP TYPE EFFECT ON PROTEIN PRODUCT

Substitution Synonymous Silent* Same amino acid
Nonsynonymous Missense* Altered amino acid—may affect protein function or
stability
Nonsense* Stop codon—loss of function or expression from
degradation of mRNA
Splice site Aberrant splicing—exon skipping or intron retention
Promoter Altered gene expression
Deletion Multiple of 3 (codon) In-frame deletion of 1 or more amino acid(s)—may affect
protein function or stability
Not multiple of 3 Frameshift Likely to result in premature termination with loss of
function or expression
Large deletion Partial gene May result in premature termination with loss of function
deletion or expression
Whole gene Loss of expression
deletion
Insertion Multiple of 3 (codon) In-frame insertion of 1 or more amino acid(s)—may affect
protein function or stability
Not multiple of 3 Frameshift Likely to result in premature termination with loss of
 function or expression
Large insertion Partial gene May result in premature termination with loss of function
duplication or expression
Whole gene May have an effect because of increased gene dosage
duplication
Expansion of Dynamic Altered gene expression or altered protein stability or
trinucleotide repeat mutation function
* Some have been shown to cause aberrant splicing.

From Turnpenny P, Ellard S (Editors): Emery's elements of medical genetics, ed 14, Philadelphia,
2012, Elsevier/Churchill Livingstone, p 23.

Genetic changes can also include insertions or deletions . Insertions or

deletions of a nonintegral multiple of 3 bases into the coding sequence leads to a
frameshift, altering the grouping of bases into triplets. This leads to translation
of an incorrect amino acid sequence and often a premature stop to translation.
Insertion or deletion of an integral multiple of 3 bases into the coding sequence
will insert or delete a corresponding number of amino acids from the protein,
leading to in-frame alterations that maintain the amino acid sequence outside
the deleted or duplicated amino acids. Larger-scale insertions or deletions can
disrupt a coding sequence or result in complete deletion of an entire gene or
group of genes.
Pathogenic variants usually can be classified as causing a loss of function or a
gain of function. Loss-of-function variants cause a reduction in the level of
protein function as a result of decreased expression or production of a protein
that does not work as efficiently. In some cases, loss of protein function from 1
gene is sufficient to cause disease. Haploinsufficiency describes the situation in
which maintenance of a normal phenotype requires the proteins produced by
both copies of a gene, and a 50% decrease in gene function results in an
abnormal phenotype. Thus, haploinsufficient phenotypes are, by definition,
dominantly inherited. Loss-of-function variants can also have a dominant
negative effect when the abnormal protein product actively interferes with the
function of the normal protein product. Both these situations lead to diseases
inherited in a dominant fashion. In other cases, loss-of-function variants must be
present in both copies of a gene before an abnormal phenotype results. This
situation typically results in diseases inherited in a recessive fashion (see
Chapter 97 ).
Gain-of-function variants typically cause dominantly inherited diseases.
These variants can result in production of a protein molecule with an increased
ability to perform a normal function or can confer a novel property on the
protein. The gain-of-function variant in achondroplasia , the most common of
FIG. 97.1 Common pedigree symbols, definitions, and abbreviations. (From Bennett
RL, French KS, Resta RG, et al: Standardized human pedigree nomenclature: update
and assessment of the recommendations of the National Society of Genetic
Counselors, J Genet Couns 17:424–433, 2008.)
FIG. 97.2 Pedigree line definitions. (From Bennett RL, French KS, Resta RG, et al:
Standardized human pedigree nomenclature: update and assessment of the
recommendations of the National Society of Genetic Counselors, J Genet Couns
17:424–433, 2008.)
FIG. 97.3 Assisted reproductive technology symbols and definitions. (From Bennett
RL, French KS, Resta RG, et al: Standardized human pedigree nomenclature: update
and assessment of the recommendations of the National Society of Genetic
Counselors, J Genet Couns 17:424–433, 2008.)
 FIG. 97.4 Pedigree symbols of genetic evaluation and testing information. (From
Bennett RL, French KS, Resta RG, et al: Standardized human pedigree nomenclature:
update and assessment of the recommendations of the National Society of Genetic
Counselors, J Genet Couns 17:424–433, 2008.)

A 3 to 4–generation pedigree should be obtained for every new patient as an

initial screen for genetic disorders segregating within the family. The pedigree
can provide clues to the inheritance pattern of these disorders and can aid the
clinician in determining the risk to the proband and other family members. The
closer the relationship of the proband to the person in the family with the genetic

FIG. 97.15 Pedigree of a mitochondrial disorder, exhibiting maternal
inheritance. Black, Affected patients.

Table 97.1
Representative Examples of Disorders Caused by
Mutations in Mitochondrial DNA and Their Inheritance

MOST FREQUENT HOMOPLASMY

DISEASE PHENOTYPE MUTATION IN vs INHERITANCE
mtDNA MOLECULE HETEROPLASMY
Leber hereditary Rapid optic nerve atrophy, Substitution Homoplasmic Maternal
optic leading to blindness in p.Arg340His in ND1 (usually)
neuropathy young adult life; sex bias gene of complex I of
approximately 50% males electron transport
with visual loss, only 10% chain; other complex I
females missense mutations
NARP, Leigh N europathy, a taxia, r Point mutations in Heteroplasmic Maternal
disease etinitis p igmentosa, ATPase subunit 6 gene
developmental delay,
intellectual disability lactic
academia
MELAS M itochondrial e Point mutation in Heteroplasmic Maternal
ncephalomyopathy, l actic a tRNALeu
cidosis, and s trokelike
episodes; may manifest only
as diabetes mellitus or
deafness
MERRF M yoclonic e pilepsy, r Point mutation in Heteroplasmic Maternal
agged r ed f ibers in muscle, tRNALys
ataxia, sensorineural
deafness
Deafness Progressive sensorineural m.1555A>G mutation Homoplasmic Maternal
deafness, often induced by in 12S rRNA
aminoglycoside antibiotics
Nonsyndromic sensorineural m.7445A>G mutation Homoplasmic Maternal
deafness in 12S rRNA
Chronic Progressive weakness of The common MELAS Heteroplasmic Maternal if point
 progressive extraocular muscles, point mutation in mutations
external cardiomyopathy, ptosis, tRNALys ; large
ophthalmoplegia heart block, ataxia, retinal deletions similar to
(CPEO) pigmentation, diabetes KSS
Pearson Pancreatic insufficiency, Large deletions Heteroplasmic Sporadic,
syndrome pancytopenia, lactic acidosis somatic
mutations
Kearns-Sayre PEO of early onset with 5-kb large deletion Heteroplasmic Sporadic,
syndrome (KSS) heart block, retinal somatic
pigmentation mutations
mtDNA, Mitochondrial DNA; rRNA, ribosomal RNA; tRNA, transfer RNA.
From Nussbaum RL, McInnes RR, Willard HF, editors: Thompson & Thompson genetics in
medicine, ed 6, Philadelphia, 2001, Saunders, p 246.

The mitochondria are the cell's suppliers of energy, and it is not surprising that
the organs that are most affected by the presence of abnormal mitochondria are
those that have the greatest energy requirements, such as the brain, muscle,
heart, and liver (see Chapters 105.4 , 388 , 616.2 , and 629.4 ) (Fig. 97.16 ).
Common manifestations include developmental delay, seizures, cardiac
dysfunction, decreased muscle strength and tone, and hearing and vision
problems.
screening tests for mitochondrial disorders.

Triplet Repeat Expansion Disorders

Triplet repeat expansion disorders are distinguished by the special dynamic
nature of the disease-causing variant. Triplet repeat expansion disorders include
fragile X syndrome, myotonic dystrophy, Huntington disease, and
spinocerebellar ataxias (Table 97.2 and Fig. 97.18 ). These disorders are caused
by expansion in the number of 3-bp repeats. The fragile X gene, FMR1,
normally has 5-40 CGG triplets. An error in replication can result in expansion
of that number to a level in the gray zone between 41 and 58 repeats, or to a
level referred to as premutation , which comprises 59-200 repeats. Some
premutation carriers, more often males, develop fragile X–associated
tremor/ataxia syndrome (FXTAS) as adults. Female premutation carriers are at
risk for fragile X–associated primary ovarian insufficiency (FXPOI ). Persons
with a premutation are also at risk for having the repeat expand further in
subsequent meiosis, thus crossing into the range of a full mutation (>200
repeats) in offspring. With this number of repeats, the FMR1 gene becomes
hypermethylated, and protein production is lost.

Table 97.2
Diseases Associated With Polynucleotide Repeat
Expansions

PARENT IN
WHOM LOCATION
REPEAT NORMAL ABNORMAL
DISEASE DESCRIPTION EXPANSION OF
SEQUENCE RANGE RANGE
USUALLY EXPANSION
OCCURS
CATEGORY 1
Huntington disease Loss of motor CAG 6-34 36-100 or More often Exon
control, more through father
dementia,
affective disorder
Spinal and bulbar Adult-onset CAG 11-34 40-62 More often Exon
muscular atrophy motor-neuron through father
disease
associated with
androgen
insensitivity
Spinocerebellar ataxia Progressive CAG 6-39 41-81 More often Exon
type 1 ataxia, through father
dysarthria,
 dysmetria
Spinocerebellar ataxia Progressive CAG 15-29 35-59 — Exon
type 2 ataxia, dysarthria
Spinocerebellar ataxia Dystonia, distal CAG 13-36 68-79 More often Exon
type 3 (Machado- muscular through father
Joseph disease) atrophy, ataxia,
external
ophthalmoplegia
Spinocerebellar ataxia Progressive CAG 4-16 21-27 — Exon
type 6 ataxia,
dysarthria,
nystagmus
Spinocerebellar ataxia Progressive CAG 7-35 38-200 More often —
type 7 ataxia, through father
dysarthria,
retinal
degeneration
Spinocerebellar ataxia Progressive CAG 29-42 47-55 — Exon
type 17 ataxia, dementia,
bradykinesia,
dysmetria
Dentatorubral- Cerebellar CAG 7-25 49-88 More often Exon
pallidoluysian atrophy, ataxia, through father
atrophy/Haw River myoclonic
syndrome epilepsy,
choreoathetosis,
dementia
CATEGORY 2
Pseudoachondroplasia, Short stature, GAC 5 6-7 — Exon
multiple epiphyseal joint laxity,
dysplasia degenerative
joint disease
Oculopharyngeal Proximal limb GCG 6 7-13 — Exon
muscular dystrophy weakness,
dysphagia, ptosis
Cleidocranial Short stature, GCG, GCT, 17 27 (expansion — Exon
dysplasia open skull GCA observed in 1
sutures with family)
bulging calvaria,
clavicular
hypoplasia,
shortened
fingers, dental
anomalies
Synpolydactyly Polydactyly and GCG, GCT, 15 22-25 — Exon
syndactyly GCA
CATEGORY 3
Myotonic dystrophy Muscle loss, CTG 5-37 100 to several Either parent, 3′ untranslated
(DM1; chromosome cardiac thousand but expansion region
19) arrhythmia, to congenital
cataracts, frontal form through
balding mother
Myotonic dystrophy Muscle loss, CCTG <75 75-11,000 — 3′ untranslated
(DM2; chromosome 3) cardiac region
arrhythmia,
 cataracts, frontal
balding
Friedreich ataxia Progressive limb GAA 7-2 200-900 or Autosomal Intron
ataxia, more recessive
dysarthria, inheritance, so
hypertrophic disease alleles
cardiomyopathy, are inherited
pyramidal from both
weakness in legs parents
Fragile X syndrome Intellectual CGG 6-52 200-2,000 or Exclusively 5′ untranslated
(FRAXA) impairment, more through region
large ears and mother
jaws,
macroorchidism
in males
Fragile site (FRAXE) Mild intellectual GCC 6-35 >200 More often 5′ untranslated
impairment through region
mother
Spinocerebellar ataxia Adult-onset CTG 16-37 107-127 More often 3′ untranslated
type 8 ataxia, through region
dysarthria, mother
nystagmus
Spinocerebellar ataxia Ataxia and ATTCT 12-16 800-4,500 More often Intron
type 10 seizures through father
Spinocerebellar ataxia Ataxia, eye CAG 7-28 66-78 — 5′ untranslated
type 12 movement region
disorders;
variable age at
onset
Progressive myoclonic Juvenile-onset 12-bp repeat 2-3 30-75 Autosomal 5′ untranslated
epilepsy type 1 convulsions, motif recessive region
myoclonus, inheritance, so
dementia transmitted by
both parents
From Jorde LB, Carey JC, Bamshad MJ, et al: Medical genetics , ed 3, St Louis, 2006, Mosby, p
82.
CHAPTER 98

Cytogenetics
Carlos A. Bacino, Brendan Lee

Clinical cytogenetics is the study of chromosomes: their structure, function,

inheritance, and abnormalities. Chromosome abnormalities are very common
and occur in approximately 1–2% of live births, 5% of stillbirths, and 50% of
early fetal losses in the 1st trimester of pregnancy (Table 98.1 ). Chromosome
abnormalities are more common among individuals with intellectual disability
and play a significant role in the development of some neoplasias.

Table 98.1
Incidence of Chromosomal Abnormalities in Newborn
Surveys

TYPE OF ABNORMALITY NUMBER APPROXIMATE INCIDENCE

SEX CHROMOSOME ANEUPLOIDY
Males (43,612 newborns)
47,XXY 45 1/1,000*
47,XYY 45 1/1,000
Other X or Y aneuploidy 32 1/1,350
Total 122 1/360 male births
Females (24,547 newborns)
45,X 6 1/4,000
47,XXX 27 1/900
Other X aneuploidy 9 1/2,700
Total 42 1/580 female births
AUTOSOMAL ANEUPLOIDY (68,159 NEWBORNS)
Trisomy 21 82 1/830
Trisomy 18 9 1/7,500
Trisomy 13 3 1/22,700
Other aneuploidy 2 1/34,000
Total 96 1/700 live births
STRUCTURAL ABNORMALITIES (68,159 NEWBORNS)
Balanced Rearrangements
Robertsonian 62 1/1,100
 Other 77 1/885
Unbalanced Rearrangements
Robertsonian 5 1/13,600
Other 38 1/1,800
Total 182 1/375 live births
All chromosome abnormalities 442 1/154 live births
*
Recent studies show the prevalence is currently 1:580.
Data from Hsu LYF: Prenatal diagnosis of chromosomal abnormalities through amniocentesis. In
Milunsky A, editor: Genetic disorders and the fetus , ed 4, Baltimore, 1998, Johns Hopkins
University Press, pp 179–248.

Chromosome analyses are indicated in persons presenting with multiple

congenital anomalies, dysmorphic features, and/or intellectual disability. The
specific indications for studies include advanced maternal age (>35 yr), multiple
abnormalities on fetal ultrasound (prenatal testing), multiple congenital
anomalies, unexplained growth restriction in the fetus, postnatal problems in
growth and development, ambiguous genitalia, unexplained intellectual
disability with or without associated anatomic abnormalities, primary
amenorrhea or infertility, recurrent miscarriages (≥3) or prior history of
stillbirths and neonatal deaths, a first-degree relative with a known or suspected
structural chromosome abnormality, clinical findings consistent with a known
anomaly, some malignancies, and chromosome breakage syndromes (e.g.,
Bloom syndrome, Fanconi anemia).

98.1
Methods of Chromosome Analysis
Carlos A. Bacino, Brendan Lee

Cytogenetic studies are usually performed on peripheral blood lymphocytes,

although cultured fibroblasts obtained from a skin biopsy may also be used.
Prenatal (fetal) chromosome studies are performed with cells obtained from the
amniotic fluid (amniocytes), chorionic villus tissue, and fetal blood or, in the
case of preimplantation diagnosis, by analysis of a blastomere (cleavage stage)
 Although the internationally accepted system for human chromosome
classification relies largely on the length and banding pattern of each
chromosome, the position of the centromere relative to the ends of the
chromosome also is a useful distinguishing feature (Fig. 98.3 ). The centromere
divides the chromosome in 2, with the short arm designated the p arm and the
long arm designated the q arm . A plus or minus sign before the number of a
chromosome indicates that there is an extra or missing chromosome,
respectively. Table 98.2 lists some of the abbreviations used for the descriptions
of chromosomes and their abnormalities. A metaphase chromosome spread
usually shows 450-550 bands. Prophase and prometaphase chromosomes are
longer, are less condensed, and often show 550-850 bands. High-resolution
analysis may detect small chromosome abnormalities although has been mostly
replaced by chromosome microarray studies (array CGH or aCGH).

FIG. 98.3 Example of different chromosome types according to the position of the
centromere. On the left is a chromosome 1 pair with the centromere equidistant from
the short and long arm (also known as metacentric ). In the center is a chromosome 11
pair that is submetacentric. On the right is a chromosome 13 pair that is an example of
an acrocentric chromosome. Acrocentric chromosomes contain a very small short arm,
stalks, and satellite DNA. The black arrow indicates the position of the centromere. The
blue arrow shows the long arm of a chromosome. The red arrow shows the short arm
of a chromosome. The green arrow highlights the satellite region, which is made of
DNA repeats. The light area between the short arm and the satellite is known as the
stalk.

Table 98.2
Some Abbreviations Used for Description of
Chromosomes and Their Abnormalities

ABBREV MEANING EXAMPLE CONDITION

XX Female 46,XX Normal female karyotype
XY Male 46,XY Normal male karyotype
[##] Number [#] 46,XY[12]/47,XXY[10] Number of cells in each clone, typically inside brackets
 of cells Mosaicism in Klinefelter syndrome with 12 normal cells
and 10 cells with an extra X chromosome
cen Centromere
del Deletion 46,XY,del(5p) Male with deletion of chromosome 5 short arm
der Derivative 46,XX,der(2),t(2p12;7q13) Female with a structurally rearranged chromosome 2 that
resulted from a translocation between chromosomes 2
(short arm) and 7 (long arm)
dup Duplication 46,XY,dup(15)(q11-q13) Male with interstitial duplication in the long arm of
chromosome 15 in the Prader-Willi/Angelman syndrome
region
ins Insertion 46,XY,ins(3)(p13q21q26) Male with an insertion within chromosome 3
A piece between q21q26 has reinserted on p13
inv Inversion 46,XY,inv(2)(p21q31) Male with pericentric inversion of chromosome 2 with
breakpoints at bands p21 and q31
ish Metaphase 46,XX.ish del(7) Female with deletion in the Williams syndrome region
FISH (q11.23q11.23) detected by in situ hybridization
nuc ish Interphase nuc ish(DXZ1 × 3) Interphase in situ hybridization showing 3 signals for the
FISH X chromosome centromeric region
mar Marker 47,XY,+mar Male with extra, unidentified chromosome material
mos Mosaic mos 45,X[14]/46,XX[16] Turner syndrome mosaicism (analysis of 30 cells showed
that 14 cells were 45,X and 16 cells were 46,XX)
p Short arm 46,XY,del(5)(p12) Male with a deletion on the short arm of chromosome 5,
band p12 (short nomenclature)
q Long arm 46,XY,del(5)(q14) Male with a deletion on the long arm of chromosome 5,
band 14
r Ring 46,X,r(X)(p21q27) Female with 1 normal X chromosome and a ring X
chromosome chromosome
t Translocation t(2;8)(q33;q24.1) Interchange of material between chromosomes 2 and 8
with breakpoints at bands 2q33 and 8q24.1
ter Terminal 46,XY,del(5)(p12-pter) Male with a deletion of chromosome 5 between p12 and
the end of the short arm (long nomenclature)
/ Slash 45,X/46,XY Separate lines or clones
Mosaicism for monosomy X and a male cell line
+ Gain of 47,XX,+21 Female with trisomy 21
− Loss of 45,XY,−21 Male with monosomy 21

Molecular techniques (e.g., FISH, CMA, aCGH) have filled a significant void
for the diagnosing cryptic chromosomal abnormalities. These techniques identify
subtle abnormalities that are often below the resolution of standard cytogenetic
studies. Fluorescence in situ hybridization (FISH) is used to identify the
presence, absence, or rearrangement of specific DNA segments and is performed
with gene- or region-specific DNA probes. Several FISH probes are used in the
clinical setting: unique sequence or single-copy probes, repetitive-sequence
probes (alpha satellites in the pericentromeric regions), and multiple-copy probes
(chromosome specific or painting) (Fig. 98.4A and B ). FISH involves using a
unique, known DNA sequence or probe labeled with a fluorescent dye that is
complementary to the studied region of disease interest. The labeled probe is
exposed to the DNA on a microscope slide, typically metaphase or interphase
with a trisomy exhibit a consistent and specific phenotype depending on the
chromosome involved.
FISH is a technique that can be used for rapid diagnosis in the prenatal
detection of common fetal aneuploidies, including chromosomes 13, 18, and 21,
as well as sex chromosomes (see Fig. 98.4C and D ). Direct detection of fetal
cell-free DNA from maternal plasma for fetal trisomy is a safe and highly
effective screening test for fetal aneuploidy. The most common numerical
abnormalities in liveborn children include trisomy 21 (Down syndrome), trisomy
18 (Edwards syndrome), trisomy 13 (Patau syndrome), and sex chromosomal
aneuploidies: Turner syndrome (usually 45,X), Klinefelter syndrome (47,XXY),
47,XXX, and 47,XYY. By far the most common type of trisomy in liveborn
infants is trisomy 21 (47,XX,+21 or 47,XY,+21) (see Table 98.1 ). Trisomy 18
and trisomy 13 are relatively less common and are associated with a
characteristic set of congenital anomalies and severe intellectual disability (Table
98.3 ). The occurrence of trisomy 21 and other trisomies increases with
advanced maternal age (≥35 yr). Because of this increased risk, women who are
≥35 yr old at delivery should be offered genetic counseling and prenatal
diagnosis (including serum screening, ultrasonography, and cell-free fetal DNA
detection, amniocentesis, or chorionic villus sampling; see Chapter 115 ).

Table 98.3
Chromosomal Trisomies and Their Clinical Findings

SYNDROME INCIDENCE CLINICAL MANIFESTATIONS

Trisomy 13, 1/10,000 Cleft lip often midline; flexed fingers with postaxial polydactyly; ocular
Patau births hypotelorism, bulbous nose; low-set, malformed ears; microcephaly; cerebral
syndrome malformation, especially holoprosencephaly; microphthalmia, cardiac
malformations; scalp defects; hypoplastic or absent ribs; visceral and genital
anomalies
Early lethality in most cases, with a median survival of 12 days; ~80% die by 1
year; 10-year survival ~13%. Survivors have significant neurodevelopmental
delay.
Trisomy 18, 1/6,000 births Low birthweight, closed fists with index finger overlapping the 3rd digit and the
Edwards 5th digit overlapping the 4th, narrow hips with limited abduction, short sternum,
syndrome rocker-bottom feet, microcephaly, prominent occiput, micrognathia, cardiac and
renal malformations, intellectual disability
~88% of children die in the 1st year; 10-year survival ~10%. Survivors have
significant neurodevelopmental delay.
Trisomy 8, 1/20,000 Long face; high, prominent forehead; wide, upturned nose, thick, everted lower
mosaicism births lip; microretrognathia; low-set ears; high-arched, sometimes cleft, palate;
osteoarticular anomalies common (camptodactyly of 2nd-5th digits, small
patella); deep plantar and palmar creases; moderate intellectual disability

FIG. 98.9 Prehensile foot in a 1 mo old child with Down syndrome. (From
Wiedemann HR, Kunze J, Dibbern H: Atlas of clinical syndromes: a visual
guide to diagnosis, ed 3, St Louis, 1989, Mosby.)

Table 98.4
Clinical Features of Down Syndrome in the
Neonatal Period
Central Nervous System

Hypotonia*
Developmental delay
Poor Moro reflex*

Craniofacial

Brachycephaly with flat occiput

Flat face*
 Upward slanted palpebral fissures*
Epicanthal folds
Speckled irises (Brushfield spots)
Three fontanels
Delayed fontanel closure
Frontal sinus and midfacial hypoplasia
Mild microcephaly
Short, hard palate
Small nose, flat nasal bridge
Protruding tongue, open mouth
Small dysplastic ears*

Cardiovascular

Endocardial Cushing defects

Ventricular septal defect
Atrial septal defect
Patent ductus arteriosus
Aberrant subclavian artery
Pulmonary hypertension

Musculoskeletal

Joint hyperflexibility*
Short neck, redundant skin*
Short metacarpals and phalanges
Short 5th digit with clinodactyly*
Single transverse palmar creases*
Wide gap between 1st and 2nd toes
Pelvic dysplasia*
Short sternum
Two sternal manubrium ossification centers

Gastrointestinal

Duodenal atresia
 Annular pancreas
Tracheoesophageal fistula
Hirschsprung disease
Imperforate anus
Neonatal cholestasis

Cutaneous

Cutis marmorata

* Hall's criteria to aid in diagnosis.

Table 98.5
Additional Features of Down Syndrome That
Can Develop or Become Symptomatic With
Time
Neuropsychiatric

Developmental delay
Seizures
Autism spectrum disorders
Behavioral disorders (disruptive)
Depression
Alzheimer disease

Sensory

Congenital or acquired hearing loss

Serous otitis media
Refractive errors (myopia)
Congenital or acquired cataracts
Nystagmus
Strabismus
 Glaucoma
Blocked tear ducts

Cardiopulmonary

Acquired mitral, tricuspid, or aortic valve regurgitation

Endocarditis
Obstructive sleep apnea

Musculoskeletal

Atlantoaxial instability
Hip dysplasia
Slipped capital femoral epiphyses
Avascular hip necrosis
Recurrent joint dislocations (shoulder, knee, elbow, thumb)

Endocrine

Congenital or acquired hypothyroidism

Diabetes mellitus
Infertility
Obesity
Hyperthyroidism

Hematologic

Transient myeloproliferative syndrome

Acute lymphocytic leukemia
Acute myelogenous leukemia

Gastrointestinal

Celiac disease
Delayed tooth eruption
 Respiratory
Obstructed sleep apnea
Frequent infections (sinusitis, nasopharyngitis, pneumonia)

Cutaneous

Hyperkeratosis
Seborrhea
Xerosis
Perigenital folliculitis

Developmental delay is universal (Tables 98.6 and 98.7 and Fig. 98.10 ).
Cognitive impairment does not uniformly affect all areas of development. Social
development is often relatively spared, but autism spectrum disorder can occur.
Children with Down syndrome have considerable difficulty using expressive
language. Understanding the individual developmental strengths and challenges
is necessary to maximize the educational process. Persons with Down syndrome
often benefit from programs aimed at cognitive training, stimulation,
development, and education. Children with Down syndrome also benefit from
anticipatory guidance, which establishes the protocol for screening, evaluation,
and care for patients with genetic syndromes and chronic disorders (Table 98.8 ).
Up to 15% of children with Down syndrome have misalignment of the 1st
cervical vertebra (C1), which places them at risk for spinal cord injury with neck
hyperextension or extreme flexion. Special Olympics recommends sports
participation and training but requires x-ray examination (full extension and
flexion views) of the neck before participation in sports that may result in
hyperextension or radical flexion or pressure on the neck or upper spine. Such
sports include diving starts in swimming, butterfly stroke, diving, pentathlon,
high jump, equestrian sports, gymnastics, football, soccer, alpine skinning, and
warm-up exercises placing stress on the head and neck. If atlantoaxial instability
is diagnosed, Special Olympics will permit participation if the parents or
guardians request so and only after obtaining written certification from a
physician and acknowledgment of the risks by the parent or guardian.

Table 98.6
Developmental Milestones
 CHILDREN WITH DOWN SYNDROME UNAFFECTED CHILDREN
Milestone
Average (mo) Range (mo) Average (mo) Range (mo)
Smiling 2 1.5-3 1 1.5-3
Rolling over 6 2-12 5 2-10
Sitting 9 6-18 7 5-9
Crawling 11 7-21 8 6-11
Creeping 13 8-25 10 7-13
Standing 10 10-32 11 8-16
Walking 20 12-45 13 8-18
Talking, words 14 9-30 10 6-14
Talking, sentences 24 18-46 21 14-32
From Levine MD, Carey WB, Crocker AC, editors: Developmental-behavioral pediatrics, ed 2,
Philadelphia, 1992, Saunders.

Table 98.7
Self-Help Skills

DOWN SYNDROME CHILDREN UNAFFECTED CHILDREN

Skill
Average (mo) Range (mo) Average (mo) Range (mo)
EATING
Finger feeding 12 8-28 8 6-16
Using spoon/fork 20 12-40 13 8-20
TOILET TRAINING
Bladder 48 20-95 32 18-60
Bowel 42 28-90 29 16-48
DRESSING
Undressing 40 29-72 32 22-42
Putting clothes on 58 38-98 47 34-58
From Levine MD, Carey WB, Crocker AC, editors: Developmental-behavioral pediatrics, ed 2,
Philadelphia, 1992, Saunders.

FIG. 98.10 The area shaded in yellow denotes the range of intellectual
function of the majority of children with Down syndrome. (From Levine MD,
Carey WB, Crocker AC, editors: Developmental-behavioral pediatrics, ed 2,
Philadelphia, 1992, Saunders, p 226.)

Table 98.8
Health Supervision for Children With Down Syndrome

CONDITION TIME TO SCREEN COMMENT

Congenital heart Birth; by pediatric cardiologist 50% risk of congenital heart
disease Young adult for acquired valve disease disease; increased risk for
pulmonary hypertension
Strabismus, Birth or by 6 mo; by pediatric ophthalmologist Cataracts occur in 15%, refractive
cataracts, Check vision annually errors in 50%
nystagmus
Hearing Birth or by 3 mo with auditory brainstem response or Risk for congenital hearing loss
impairment or otoacoustic emission testing; check hearing q6mo up to 3 plus 50–70% risk of serous otitis
loss yr if tympanic membrane is not visualized; annually media
thereafter
Constipation Birth Increased risk for Hirschsprung
disease
Celiac disease At 2 yr or with symptoms Screen with IgA and tissue
transglutaminase antibodies
Hematologic At birth and in adolescence or if symptoms develop Increased risk for neonatal
disease polycythemia (18%), leukemoid
reaction, leukemia (<1%)
Hypothyroidism Birth; repeat at 6-12 mo and annually Congenital (1%) and acquired
(5%)
Growth and At each visit Discuss school placement options
development Use Down syndrome growth curves Proper diet to avoid obesity
Obstructive sleep Start at ~1 yr and at each visit Monitor for snoring, restless sleep
apnea
 Atlantoaxial At each visit by history and physical exam Special Olympics
subluxation or Radiographs at 3-5 yr or when planning to participate in recommendations are to screen for
instability contact sports high-risk sports, e.g., diving,
(incidence 10– Radiographs indicated wherever neurologic symptoms swimming, contact sports
30%) are present even if transient (neck pain, torticollis, gait
disturbances, weakness)
Many are asymptomatic
Gynecologic care Adolescent girls Menstruation and contraception
issues
Recurrent When present Check IgG subclass and IgA levels
infections
Psychiatric, At each visit Depression, anxiety, obsessive-
behavioral compulsive disorder, schizophrenia
disorders seem in 10–17%
Autism spectrum disorder in 5–
10%
Early-onset Alzheimer disease
IgA, Immunoglobulin A; IgG, immunoglobulin G.
Data from Committee on Genetics: Health supervision for children with Down syndrome,
Pediatrics 107:442–449, 2001; and Baum RA, Spader M, Nash PL, et al: Primary care of children
and adolescents with Down syndrome: an update, Curr Probl Pediatr Adolesc Health Care
38:235–268, 2008.

Compared with the general population, children with Down syndrome are at
increased risk for behavior problems; psychiatric comorbidity is an estimated
18–38% in this population. Common behavioral difficulties that occur in
children with Down syndrome include inattentiveness, stubbornness, and a need
for routine and sameness. Aggression and self-injurious behavior are less
common in this population than other children with similar degrees of
intellectual disability from other etiologies. All these behaviors can respond to
educational, behavioral, or pharmacologic interventions.
The life expectancy for children with Down syndrome is reduced and is
approximately 50-55 yr. Little prospective information about the secondary
medical problems of adults with Down syndrome is known. Retrospective
studies have shown premature aging and an increased risk of Alzheimer disease
in adults with Down syndrome. These studies have also shown unexpected
negative (protective) associations between Down syndrome and comorbidities.
Persons with Down syndrome have fewer-than-expected deaths caused by solid
tumors and ischemic heart disease. This same study reported increased risk of
adult deaths from congenital heart disease, seizures, and leukemia. In one large
study, leukemias accounted for 60% of all cancers in people with Down
syndrome and 97% of all cancers in children with Down syndrome. There was
decreased risk of solid tumors in all age-groups with Down syndrome, including
97% of the cases as a result of errors in meiosis. The majority of these occur in
maternal meiosis I (90%). Approximately 1% of persons with trisomy 21 are
mosaics, with some cells having 46 chromosomes, and another 4% have a
translocation that involves chromosome 21. The majority of translocations in
Down syndrome are fusions at the centromere between chromosomes 13, 14, 15,
21, and 22, known as robertsonian translocations. The translocations can be de
novo or inherited. Very rarely is Down syndrome diagnosed in a patient with
only a part of the long arm of chromosome 21 in triplicate (partial trisomy ).
Isochromosomes and ring chromosomes are other rarer causes of trisomy 21.
Down syndrome patients without a visible chromosome abnormality are the least
common. It is not possible to distinguish the phenotypes of persons with full
trisomy 21 and those with a translocation. Representative genes on chromosome
21 and their potential effects on development are noted in Table 98.9 . Patients
who are mosaic tend to have a milder phenotype.

Table 98.9
Genes Localized to Chromosome 21 That May Affect Brain
Development, Neuronal Loss, and Alzheimer-Type
Neuropathology

POSSIBLE
EFFECT IN
SYMBOL NAME FUNCTION
DOWN
SYNDROME
SIM2 Single-minded homolog 2 Brain development Required for synchronized cell division
and establishment of proper cell lineage
DYRK1A Dual-specificity tyrosine-(Y)- Brain development Expressed during neuroblast
phosphorylation regulated kinase proliferation
1A Believed important homolog in
regulating cell-cycle kinetics during
cell division
GART Phosphoribosylglycinamide Brain development Expressed during prenatal development
formyltransferase of the cerebellum
Phosphoribosylglycinamide
synthetase
Phosphoribosylaminoimidazole
synthetase
PCP4 Purkinje cell protein 4 Brain development Function unknown but found exclusively
in the brain and most abundantly in the
cerebellum
DSCAM Down syndrome cell adhesion Brain development Expressed in all molecule regions of the
molecule and possible brain and believed to have a role in
candidate gene for axonal outgrowth during development of
congenital heart the nervous system
 disease
GRIK1 Glutamate receptor, ionotropic Neuronal loss Function unknown, found in the cortex
kainite1 in fetal and early postnatal life and in
adult primates, most concentrated in
pyramidal cells in the cortex
APP Amyloid beta (A4) precursor Alzheimer type Seems to be involved in plasticity,
protein (protease nexin-II, neuropathy neurite outgrowth, and neuroprotection
Alzheimer disease)
S100B S100 calcium binding protein β Alzheimer type Stimulates glial formation
(neural) neuropathy
SOD1 Superoxide dismutase 1, soluble Accelerated aging? Scavenges free superoxide molecules in
(amyotrophic lateral sclerosis, the cell and might accelerate aging by
adult) producing hydrogen peroxide and
oxygen

Chromosome analysis is indicated in every person suspected of having Down

syndrome. If a translocation is identified, parental chromosome studies must be
performed to determine whether one of the parents is a translocation carrier,
which carries a high recurrence risk for having another affected child. That
parent might also have other family members at risk. Translocation (21;21)
carriers have a 100% recurrence risk for a chromosomally abnormal child, and
other robertsonian translocations, such as t(14;21), have a 5–7% recurrence risk
when transmitted by females. Genomic dosage imbalance contributes through
direct and indirect pathways to the Down syndrome phenotype and its
phenotypic variation.
Tables 98.10 and 98.11 provide more information on other aneuploidies and
partial autosomal aneuploidies (Figs. 98.11 to 98.14 ).

Table 98.10
Other Rare Aneuploidies and Partial Autosomal
Aneuploidies

DISORDER KARYOTYPE CLINICAL MANIFESTATIONS

Trisomy 8 47,XX/XY,+8 Growth and mental deficiency are variable.
The majority of patients are mosaics.
Deep palmar and plantar furrows are characteristic.
Joint contractures
Trisomy 9 47,XX/XY,+9 The majority of patients are mosaics.
Clinical features include craniofacial (high forehead, microphthalmia, low-
set malformed ears, bulbous nose) and skeletal (joint contractures)
malformations and heart defects (60%).
Trisomy 16 47,XX/XY,+16 The most commonly observed autosomal aneuploidy in spontaneous
abortion; the recurrence risk is negligible.
Tetrasomy 46,XX[12]/46,XX, Known as Pallister-Killian syndrome
12p +i(12p)[8] Sparse anterior scalp hair (more so temporal region), eyebrows, and
(mosaicism for an eyelashes; prominent forehead; chubby cheeks; long philtrum with thin
 isochromosome 12p) upper lip and cupid-bow configuration; polydactyly; streaks of hyper- and
hypopigmentation

Table 98.11
Findings That May Be Present in Trisomy 13 and Trisomy
18

TRISOMY 13 TRISOMY 18
HEAD AND FACE
Scalp defects (e.g., cutis aplasia) Small and premature appearance
Microphthalmia, corneal abnormalities Tight palpebral fissures
Cleft lip and palate in 60–80% of cases Narrow nose and hypoplastic nasal alae
Microcephaly Narrow bifrontal diameter
Microphthalmia Prominent occiput
Sloping forehead Micrognathia
Holoprosencephaly (arrhinencephaly) Cleft lip or palate
Capillary hemangiomas Microcephaly
Deafness
CHEST
Congenital heart disease (e.g., VSD, PDA, ASD) Congenital heart disease (e.g., VSD, PDA, ASD)
in 80% of cases Short sternum, small nipples
Thin posterior ribs (missing ribs)
EXTREMITIES
Overlapping of fingers and toes (clinodactyly) Limited hip abduction
Polydactyly Clinodactyly and overlapping fingers; index over
Hypoplastic nails, hyperconvex nails 3rd, 5th over 4th; closed fist
Rocker-bottom feet
Hypoplastic nails
GENERAL
Severe developmental delays and prenatal and Severe developmental delays and prenatal and
postnatal growth restriction postnatal growth restriction
Renal abnormalities Premature birth, polyhydramnios
Survival (see Table 98.3 ) Inguinal or abdominal hernias
Survival (see Table 98.3 )
ASD, Atrial septal defect; PDA, patent ductus arteriosus; VSD, ventricular septal defect.
From Behrman RE, Kliegman RM: Nelson essentials of pediatrics, ed 4, Philadelphia, 2002,
Saunders, p 142.
normal, but they are at increased risk for miscarriages, typically in paracentric
inversions, and chromosomally abnormal offspring in pericentric inversions.

Deletions and Duplications

Deletions involve loss of chromosome material and, depending on their location,
can be classified as terminal (at the end of chromosomes) or interstitial (within
the arms of a chromosome). They may be isolated or may occur along with a
duplication of another chromosome segment. The latter typically occurs in
unbalanced reciprocal chromosomal translocation secondary to abnormal
crossover or segregation in a translocation or inversion carrier.
A carrier of a deletion is monosomic for the genetic information of the
missing segment. Deletions are usually associated with intellectual disability and
malformations. The most commonly observed deletions in routine chromosome
preparations include 1p−, 4p−, 5p−, 9p−, 11p−, 13q−, 18p−, 18q−, and 21q−
(Table 98.12 and Fig. 98.16 ), all distal or terminal deletions of the short or the
long arms of chromosomes. Deletions may be observed in routine chromosome
preparations, and deletions and translocations larger than 5-10 Mbp are usually
visible microscopically.

Table 98.12

Common Deletions and Their Clinical Manifestations

DELETION CLINICAL ABNORMALITIES
4p− Wolf-Hirschhorn syndrome. The main features are a typical “Greek helmet” facies secondary to
ocular hypertelorism, prominent glabella, and frontal bossing; microcephaly, dolichocephaly,
hypoplasia of the orbits, ptosis, strabismus, nystagmus, bilateral epicanthic folds, cleft lip and
palate, beaked nose with prominent bridge, hypospadias, cardiac malformations, and intellectual
disability.
5p− Cri du chat syndrome. The main features are hypotonia, short stature, characteristic shrill cry in the
first few weeks of life (also called cat's cry syndrome), microcephaly with protruding metopic
suture, hypertelorism, bilateral epicanthic folds, high arched palate, wide and flat nasal bridge, and
intellectual disability.
9p− The main features are craniofacial dysmorphic features with trigonocephaly, slanted palpebral
fissures, discrete exophthalmos secondary to supraorbital hypoplasia, arched eyebrows, flat and
wide nasal bridge, short neck with low hairline, genital anomalies, long fingers and toes with extra
flexion creases, cardiac malformations, and intellectual disability.
13q− The main features are low birthweight, failure to thrive, microcephaly, and severe intellectual
disability. Facial features include high, wide nasal bridge; hypertelorism; ptosis; and micrognathia.
Ocular malformations are common (retinoblastoma). The hands have hypoplastic or absent thumbs
and syndactyly.
18p− A few patients (15%) are severely affected and have cephalic and ocular malformations:
holoprosencephaly, cleft lip and palate, ptosis, epicanthal folds, and varying degrees of intellectual
 disability. Most (80%) have only minor malformations and mild intellectual disability.
18q− The main features are growth deficiency and hypotonia with a “froglike” position with the legs
flexed, externally rotated, and in hyperabduction. The face is characteristic, with depressed midface
and apparent protrusion of the mandible, deep-set eyes, short upper lip, and everted lower lip
(“carplike” mouth); antihelix of the ears is very prominent. Varying degrees of intellectual
disability and belligerent personality are present. Myelination abnormalities occur in the central
nervous system.
 FIG. 98.16 A, Child with velocardiofacial syndrome (deletion 22q11.2). B,
Child with Prader-Willi syndrome (deletion 15q11-13). C, Child with
Angelman syndrome (deletion 15q11-13). D, Child with Williams syndrome
(deletion 7q11.23). (From Lin RL, Cherry AM, Bangs CD, et al: FISHing for
answers: the use of molecular cytogenetic techniques in adolescent
medicine practice. In Hyme HE, Greydanus D, editors: Genetic disorders in
adolescents: state of the art reviews. Adolescent medicine, Philadelphia,
2002, Hanley and Belfus, pp 305–313.)

High-resolution banding techniques, FISH, and molecular studies such as

aCGH can reveal deletions that are too small to be seen in ordinary or routine
chromosome spreads (see Fig. 98.7 ). Microdeletions involve loss of small
chromosome regions, the largest of which are detectable only with prophase
chromosome studies and molecular methods. For submicroscopic deletions, the
missing piece can only be detected using molecular methodologies such as
DNA-based studies (e.g., aCGH, FISH). The presence of extra genetic material
from the same chromosome is referred to as duplication . Duplications can also
be sporadic or result from abnormal segregation in translocation or inversion
carriers.
Microdeletions and microduplications usually involve regions that include
several genes, so the affected individuals can have a distinctive phenotype
depending on the number of genes involved. When such a deletion involves
more than a single gene, the condition is referred to as a contiguous gene
deletion syndrome (Table 98.13 ). With the advent of clinically available
aCGH, a large number of duplications, most of them microduplications, have
been uncovered. Many of those microduplication syndromes are the reciprocal
duplications of the known deletions or microdeletion counterparts and have
distinctive clinical features (Table 98.14 ).

Table 98.13

Microdeletion and Contiguous Gene Syndromes and Their Clinical Manifestations

DELETION SYNDROME CLINICAL MANIFESTATIONS
1p36 1p deletion Growth restriction, dysmorphic features with midface hypoplasia, straight
thin eyebrows, pointy chin, sensorineural hearing loss, progressive
cardiomyopathy, hypothyroidism, seizures, intellectual disability
5q35 Sotos (50% are Overgrowth, macrocephaly, prominent forehead, prominence of extraaxial
deletions of NSD1 fluid spaces on brain imaging, large hands and feet, hypotonia, clumsiness,
gene in Asians but mental disabilities
only 6% in whites)
6p25 Axenfeld-Rieger Axenfeld-Rieger malformation, hearing loss, congenital heart defects,
dental anomalies, developmental delays, facial dysmorphism
7q11.23 Williams Round face with full cheeks and lips, long philtrum, stellate pattern in iris,
strabismus, supravalvular aortic stenosis and other cardiac malformations,
varying degrees of intellectual disability, friendly personality
8p11 8p11 Kallmann syndrome type 2 (hypogonadotropic hypogonadism and
anosmia), spherocytosis (deletions of ankyrin 1), multiple congenital
anomalies, intellectual disability
8q24.1- Langer-Giedion or Sparse hair, multiple cone-shaped epiphyses, multiple cartilaginous
q24.13 trichorhinophalangeal exostoses, bulbous nasal tip, thickened alar cartilage, upturned nares,
type II prominent philtrum, large protruding ears, mild intellectual disability

9q22 Gorlin Multiple basal cell carcinomas, odontogenic keratocysts, palmoplantar pits,
calcification falx cerebri

9q34 9q34 deletion Distinct face with synophrys, anteverted nares, tented upper lip, protruding
tongue, midface hypoplasia, conotruncal heart defects, intellectual
disability
10p12-p13 DiGeorge type 2 Many of the DiGeorge type 1 and velocardiofacial type 1 features
(conotruncal defects, immunodeficiency, hypoparathyroidism, dysmorphic
features)
11p11.2 Potocki-Shaffer Multiple exostoses, parietal foramina, craniosynostosis, facial
dysmorphism, syndactyly, intellectual disability
11p13 WAGR Hypernephroma (W ilms tumor), a niridia, male g enital hypoplasia of
varying degrees, g onadoblastoma, long face, upward-slanting palpebral
fissures, ptosis, beaked nose, low-set poorly formed auricles, intellectual
disability (r etardation)
11q24.1- Jacobsen Growth restriction, intellectual disability, cardiac and digit anomalies,
11qter thrombocytopenia
15q11-q13 Prader-Willi Severe hypotonia and feeding difficulties at birth, voracious appetite and
(paternal) obesity in infancy, short stature (responsive to growth hormone), small
hands and feet, hypogonadism, intellectual disability
15q11-q13 Angelman Hypotonia, feeding difficulties, gastroesophageal reflux, fair hair and skin,
(maternal) midface hypoplasia, prognathism, seizures, tremors, ataxia, sleep
disturbances, inappropriate laughter, poor or absent speech, severe
intellectual disability
16p13.3 Rubinstein-Taybi Microcephaly, ptosis, beaked nose with low-lying philtrum, broad thumbs
and large toes, intellectual disability
17p11.2 Smith-Magenis Brachycephaly, midfacial hypoplasia, prognathism, myopia, cleft palate,
short stature, severe behavioral problems, intellectual disability
17p13.3 Miller-Dieker Microcephaly, lissencephaly, pachygyria, narrow forehead, hypoplastic
male external genitals, growth restriction, seizures, profound intellectual
disability
20p12 Alagille Bile duct paucity with cholestasis; heart defects, particularly pulmonary
artery stenosis; ocular abnormalities (posterior embryotoxon); skeletal
defects such as butterfly vertebrae; long nose
22q11.2 Velocardiofacial- Conotruncal cardiac anomalies, cleft palate, velopharyngeal incompetence,
DiGeorge hypoplasia or agenesis of thymus and parathyroid glands, hypocalcemia,
hypoplasia of auricle, learning disabilities, psychiatric disorders
22q13.3 Hypotonia, developmental delay, normal or accelerated growth, severe
deletion expressive language deficits, autistic behavior
Xp21.2- Duchenne muscular dystrophy, retinitis pigmentosa, adrenal hypoplasia,
p21.3 intellectual disability, glycerol kinase deficiency
Xp22.2- Ichthyosis, Kallmann syndrome, intellectual disability, chondrodysplasia
p22.3 punctata
Xp22.3 MLS M icrophthalmia, l inear s kin defects, poikiloderma, congenital heart
defects, seizures, intellectual disability
Table 98.14

Microduplications and Their Clinical Manifestations

DUPLICATION
DISEASE
CHROMOSOME CLINICAL FEATURES
REGION
REGION
1q21.1 Macrocephaly, DD, learning disabilities

3q29 Mild to moderate MR, microcephaly

7q11.23 Williams DD and severe expressive language disorder, autistic features,
syndrome subtle dysmorphisms
15q13.3 Prader- DD, MR, autistic features in duplications of maternal origin
Willi/Angelman
syndrome
15q24 Growth restriction, DD, microcephaly, digital anomalies,
hypospadias, connective tissue abnormalities
16p11.2 FTT, severe DD, short stature, GH deficiency, dysmorphic features
17p11.2 Potocki-Lupski Hypotonia, cardiovascular anomalies, FTT, DD, verbal apraxia,
syndrome autism, anxiety
17q21.31 Severe DD, microcephaly, short and broad digits, dysmorphic
features
22q11.2 Velocardiofacial- Cardiovascular defects, velopharyngeal insufficiency
DiGeorge
syndrome
Xq28 MECP2 gene In males: infantile hypotonia, immune deficiency, dysmorphic
(Rett syndrome) features, DD, speech delay, autistic behavior, regression in
childhood
DD, Developmental delay; ID, intellectual disability; FTT, failure to thrive; GH, growth hormone;
MR, mental retardation.

Subtelomeric regions are often involved in chromosome rearrangements that

cannot be visualized using routine cytogenetics. Telomeres, which are the distal
ends of the chromosomes, are gene-rich regions. The distal structure of the
telomeres is essentially common to all chromosomes, but proximal to these are
unique regions known as subtelomeres, which typically are involved in deletions
and other chromosome rearrangements. Small subtelomeric deletions,
duplications, or rearrangements (translocations, inversions) may be relatively
common in children with nonspecific intellectual disability and minor anomalies.
Subtelomeric rearrangements have been found in 3–7% of children with
moderate to severe intellectual disability and 0.5% of those with mild intellectual
disability and can be detected by aCGH studies.
Telomere mutations and length abnormalities have also been associated with
dyskeratosis congenita and other aplastic anemia syndromes, as well as
pulmonary or hepatic fibrosis. Both the subtelomeric rearrangements and the
microdeletion and microduplication syndromes are typically diagnosed by
molecular techniques such as aCGH and multiple ligation-dependent primer
amplification studies. Recent studies show that aCGH can detect 14–18% of
abnormalities in patients who previously had normal chromosome studies.

Insertions
Insertions occur when a piece of a chromosome broken at 2 points is
incorporated into a break in another part of a chromosome. A total of 3
breakpoints are then required, and they can occur between 2 or within 1
chromosome. A form of nonreciprocal translocation, insertions are rare. Insertion
carriers are at risk of having offspring with deletions or duplications of the
inserted segment.

Isochromosomes
Isochromosomes consist of 2 copies of the same chromosome arm joined
through a single centromere and forming mirror images of one another. The most
commonly reported autosomal isochromosomes tend to involve chromosomes
with small arms. Some of the more common chromosome arms involved in this
formation include 5p, 8p, 9p, 12p, 18p, and 18q. There is also a common
isochromosome abnormality seen in long arm of the X chromosome and
associated with Turner syndrome. Individuals who have 1 isochromosome X
within 46 chromosomes are monosomic for genes in the lost short arm and
trisomic for the genes present in the long arm of the X chromosome.

Marker and Ring Chromosomes

Marker chromosomes are rare and are usually chromosome fragments that are
too small to be identified by conventional cytogenetics; they usually occur in
addition to the normal 46 chromosomes. Most are sporadic (70%); mosaicism is
often (50%) noted because of the mitotic instability of the marker chromosome.
The incidence in newborn infants is 1 in 3,300, and the incidence in persons with
intellectual disability is 1 in 300. The associated phenotype ranges from normal
to severely abnormal, depending on the amount of chromosome material and
number of genes included in the fragment.
 Ring chromosomes, which are found for all human chromosomes, are rare. A
ring chromosome is formed when both ends of a chromosome are deleted and
the ends are then joined to form a ring. Depending on the amount of
chromosome material that is lacking or in excess (if the ring is in addition to the
normal chromosomes), a patient with a ring chromosome can appear normal or
nearly normal or can have intellectual disability and multiple congenital
anomalies.
Marker and ring chromosomes can be found in the cells of solid tumors of
children the cells of whose organs do not contain this additional chromosomal
material.

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Abnormalities of Chromosome Structure
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98.4
Sex Chromosome Aneuploidy
Carlos A. Bacino, Brendan Lee

About 1 in 400 males and 1 in 650 females have some form of sex chromosome
abnormality. Considered together, sex chromosome abnormalities are the most
common chromosome abnormalities seen in liveborn infants, children, and
adults. Sex chromosome abnormalities can be either structural or numerical and
can be present in all cells or in a mosaic form. Those affected with these
abnormalities might have few or no physical or developmental problems (Table
98.15 ).

Table 98.15
Sex Chromosome Abnormalities

APPROXIMATE
DISORDER KARYOTYPE
INCIDENCE
Klinefelter syndrome 47,XXY 1/580 males
48,XXXY 1/50,000-1/80,000 male births
Other (48,XXYY; 49,XXXYY;
mosaics)
XYY syndrome 47,XYY 1/800-1,000 males
Other X or Y chromosome 1/1,500 males
abnormalities
XX males 46,XX 1/20,000 males
Turner syndrome 45,X 1/2,500-1/5,000 females
Variants and mosaics
Trisomy X 47,XXX 1/1,000 females
48,XXXX and 49,XXXXX Rare
Other X chromosome abnormalities 1/3,000 females
XY females 46,XY 1/20,000 females

Turner Syndrome
Turner syndrome is a condition characterized by complete or partial monosomy
of the X chromosome and defined by a combination of phenotypic features
(Table 98.16 ). Half the patients with Turner syndrome have a 45,X chromosome
complement. The other half exhibit mosaicism and varied structural
abnormalities of the X or Y chromosome. Maternal age is not a predisposing
factor for children with 45,X. Turner syndrome occurs in approximately 1 in
5,000 female live births. In 75% of patients, the lost sex chromosome is of
paternal origin (whether an X or a Y). 45,X is one of the chromosome
abnormalities most often associated with spontaneous abortion. It has been
estimated that 95–99% of 45,X conceptions are miscarried.
Table 98.16
Signs Associated With Turner Syndrome
Short stature
Congenital lymphedema
Horseshoe kidneys
Patella dislocation
Increased carrying angle of elbow (cubitus valgus)
Madelung deformity (chondrodysplasia of distal radial epiphysis)
Congenital hip dislocation
Scoliosis
Widespread nipples
Shield chest
Redundant nuchal skin (in utero cystic hygroma)
Low posterior hairline
Coarctation of aorta
Bicuspid aortic valve
Cardiac conduction abnormalities
Hypoplastic left heart syndrome and other left-sided heart abnormalities
Gonadal dysgenesis (infertility, primary amenorrhea)
Gonadoblastoma (increased risk if Y chromosome material is present)
Learning disabilities (nonverbal perceptual motor and visuospatial skills)
(in 70%)
Developmental delay (in 10%)
Social awkwardness
Hypothyroidism (acquired in 15–30%)
Type 2 diabetes mellitus (insulin resistance)
 Strabismus
Cataracts
Red-green color blindness (as in males)
Recurrent otitis media
Sensorineural hearing loss
Inflammatory bowel disease
Celiac disease (increased incidence)

Clinical findings in the newborns can include small size for gestational age,
webbing of the neck, protruding ears, and lymphedema of the hands and feet,
although many newborns are phenotypically normal (Fig. 98.17 ). Older children
and adults have short stature and exhibit variable dysmorphic features.
Congenital heart defects (40%) and structural renal anomalies (60%) are
common. The most common heart defects are bicuspid aortic valves, coarctation
of the aorta, aortic stenosis, and mitral valve prolapse. The gonads are generally
streaks of fibrous tissue (gonadal dysgenesis ). There is primary amenorrhea
and lack of secondary sex characteristics. These children should receive regular
endocrinologic testing (see Chapter 604 ). Most patients tend to be of normal
intelligence, but intellectual disability is seen in up to 6% of affected children.
They are also at increased risk for behavioral problems and deficiencies in
spatial and motor perception. Guidelines for health supervision for children with
Turner syndrome are published by the American Academy of Pediatrics (AAP)
and include pubertal induction, as well as treatment with growth hormone and
oxandrolone.
look for Y chromosome mosaicism in all 45,X patients. If Y chromosome
material is identified, laparoscopic gonadectomy is recommended.
Noonan syndrome shares many clinical features with Turner syndrome and
was formerly called pseudo-Turner syndrome , although it is an autosomal
dominant disorder resulting from mutations in several genes involved in the
RAS-MAPK (mitogen-activated protein kinase) pathway. The most common of
these is PTPN11 (50%), which encodes a protein-tyrosine phosphatase (SHP-2)
on chromosome 12q24.1. Other genes include SOS1 in 10–13%, RAF1 in 3–
17%, RITI in 5%, KRAS <5%, BRAF <2%, MAP2K <2%, and NRAS (only few
reported families). Overlapping phenotypes are seen in LEOPARD (lentigines,
electrocardiographic abnormalities, ocular hypertelorism, pulmonary stenosis,
abnormalities of genitalia, retardation of growth, deafness) syndrome,
cardiofaciocutaneous (CFC) syndrome, and Costello syndrome; these are
Noonan-related disorders. Features common to Noonan syndrome include short
stature, low posterior hairline, shield chest, congenital heart disease, and a short
or webbed neck (Table 98.17 ). In contrast to Turner syndrome, Noonan
syndrome affects both sexes and has a different pattern of congenital heart
disease, typically involving right-sided lesions.
Table 98.17
Signs Associated With Noonan Syndrome
Short stature
Failure to thrive (best to use Noonan growth curve)
Tall forehead
Epicanthal folds
Ptosis
Blue-green irises
Hypertelorism
Low nasal bridge, upturned nose
Downward-slanting palpebral fissures
Myopia
Nystagmus
Low-set and posteriorly rotated auricles
Dental malocclusion
Low posterior hairline
Short, webbed neck (excessive nuchal skin), cystic hygroma
 Shield chest
Pectus carinatum superiorly
Scoliosis
Pigmented villonodular synovitis (polyarticular)
Cubitus valgus
Pulmonary valve stenosis (dysplastic valve)
Hypertrophic cardiomyopathy
Atrial septal defect, ventricular septal defect
Lymphedema
Nevi, lentigines, café au lait spots
Cryptorchidism
Small penis
Delayed puberty
Bleeding disorders, including thrombocytopenia and coagulation factor
deficiencies
Leukemia, myeloproliferative disorders, other malignancies
Cognitive delay (KRAS mutation)

Klinefelter Syndrome
Persons with Klinefelter syndrome are phenotypically male; this syndrome is the
most common cause of hypogonadism and infertility in males and the most
common sex chromosome aneuploidy in humans (see Chapter 601 ). Eighty
percent of children with Klinefelter syndrome have a male karyotype with an
extra chromosome X-47,XXY. The remaining 20% have multiple sex
chromosome aneuploidies (48,XXXY; 48,XXYY; 49,XXXXY), mosaicism
(46,XY/47,XXY), or structurally abnormal X chromosomes; the greater the
aneuploidy, the more severe the mental impairment and dysmorphism. Early
studies showed a birth prevalence of approximately 1 in 1,000 males, but more
recent studies suggest that the prevalence of 47,XXY appears has increased to
approximately 1 in 580 liveborn males; the reasons for this are still unknown but
hypothesized to be the result of environmental factors acting in spermatogenesis.
Errors in paternal nondisjunction in meiosis I account for half the cases.
Puberty commences at the normal age, but the testes remain small. Patients
develop secondary sex characters late, and 50% ultimately develop
gynecomastia. They have taller stature. Because many patients with Klinefelter
syndrome are phenotypically normal until puberty, the syndrome often goes
 PHENOTYPE
DISORDER Clinical and Imaging ONSET PENETRANCE
Cognitive or Behavioral
Signs
FULL MUTATION (>200 repeats)
FXS Developmental delay: Hypothalamic Neonate M 100%
mean IQ = 42 in M; IQ is dysfunction:
higher if significant macroorchidism,
residual FMRP is 40%*
produced (e.g., females Facial features,
and mosaic males or 60%,* large
unmethylated full cupped ears,
mutations) elongated face,
Autism 20–30% high arched palate
ADHD 80% Connective tissue
Anxiety 70–100% abnormalities:
mitral valve
prolapse, scoliosis,
joint laxity, flat
feet
Others: seizures
(20%), recurrent
otitis media
(60%), strabismus
(8–30%)
PREMUTATION (55-200 repeats)
Female reproductive POF (<40 yr) Adult/childhood F 20% †
symptoms Early menopause (<45 F 30% †
yr)
FXTAS Cognitive decline, dementia, Gait ataxia, intention >50 yr M 33% ‡
apathy, disinhibition, tremor, parkinsonism, F unknown
irritability, depression neuropathy, autonomic
dysfunction
Neurodevelopmental ADHD, autism, or Mild features of FXS Childhood 8% (1/13)*
disorder developmental delay
* Frequency of those signs in prepubertal boys; one third of boys with FXS are without classic

facial features. Macroorchidism is present in 90% of men.

† Maximum penetrance reported for allele size approximately 80-90 CGG repeats.

‡ Penetrance is correlated with age and repeat size.

ADHD, Attention-deficit/hyperactivity disorder; F, female; FMRP, fragile X mental retardation

protein; FXS, fragile X syndrome; FXTAS, fragile X–associated tremor/ataxia syndrome; M, male;
POF, premature ovarian failure.
From Jacquemont S, Hagerman RJ, Hagerman PJ, et al: Fragile-X syndrome and fragile X-
associated tremor/ataxia syndrome: two faces of FMRI, Lancet Neurol 6:45–55, 2007, Table 1.

Table 98.19 outlines therapy of the diverse neuropsychiatric manifestations

associated with fragile X syndrome. Inhibitors of mGluR (overexpressed in
fragile X) are undergoing clinical trials. In preliminary trials, minocycline
(lowers MMP-9) has resulted in short-term improvements in anxiety, mood, and
the clinical Global Impression Scale.

Table 98.19
Therapy for FMR1 -Related Disorders

FUTURE
DISORDER SYMPTOM THERAPY AND INTERVENTIONS POTENTIAL
THERAPY
FULL MUTATION
FXS* ADHD Stimulants mGluR5 antagonists
Anxiety, hyperarousal, SSRIs, atypical antipsychotics, occupational mGluR5 antagonists
aggressive outbursts therapy, behavioral therapy, counseling
Seizures Carbamazepine, valproic acid mGluR5 antagonists
Cognitive deficit Occupational therapy, speech therapy, special mGluR5 antagonists
education support
PREMUTATION
POF Premature ovarian failure Reproductive counseling, egg donation Cryopreservation of
ovarian tissue
Hormone replacement therapy
FXTAS † Intention tremor β-Blockers
Parkinsonism Carbidopa/levodopa
Cognitive decline, dementia Acetylcholinesterase inhibitors
Anxiety, apathy, Venlafaxine, SSRIs
disinhibition, irritability,
depression
Neuropathic pain Gabapentin
*
These data are based on a survey in 2 large referral centers. Drugs for anxiety were more
frequently prescribed than those for neurologic signs.
† There have been no controlled studies to assess drugs for FXTAS. These data were collected

through a questionnaire study (n = 56).

ADHD, Attention-deficit/hyperactivity disorder; FXS, fragile-X syndrome; FXTAS, fragile X–
associated tremor/ataxia syndrome; POF, premature ovarian failure; SSRIs, selective serotonin
reuptake inhibitors.
From Jacquemont S, Hagerman RJ, Hagerman PJ, et al: Fragile-X syndrome and fragile X-
associated tremor/ataxia syndrome: two faces of FMRI, Lancet Neurol 2006:45–55, 2007, Table 2.

Bibliography
Fragile Chromosome Sites
Abrams L, Cronister A, Brown WT, et al. Newborn, carrier, and
early childhood screening recommendations for fragile X.
 A classic example of imprinting disorder is seen in Prader-Willi syndrome and
Angelman syndrome, 2 very different clinical conditions. These syndromes are
usually associated with deletion of the same region in the proximal long arm of
chromosome 15. A deletion on the paternally derived chromosome causes
Prader-Willi syndrome, in which the maternally derived copy is still intact, but
some of the imprinted genes within this region normally remain silent. Prader-
Willi syndrome can be diagnosed clinically (Table 98.20 ) and confirmed with
genetic testing. Additional clinical features and issues of weight gain are noted
in Table 98.21 . The weight gain is difficult to control, but treatment with growth
hormone has resulted in improvements in height, lean body mass, decreased
adipose tissue, and improvement in cognitive function.

Table 98.20

Consensus Diagnostic Criteria for Prader-Willi Syndrome

MAJOR CRITERIA (1 point each) MINOR CRITERIA (1/2 point each)
1 Neonatal/infantile hypotonia Decreased fetal movement and infantile lethargy
2 Feeding problems and failure to thrive as an infant Typical behavior problems
3 Weight gain at 1-6 yr; obesity; hyperphagia Sleep apnea
4 Characteristic dysmorphic facial features Short stature for family by 15 yr
5 Small genitalia; pubertal delay and insufficiency Hypopigmentation for the family
6 Developmental delay/intellectual disability Small hands and feet for height
7 Narrow hands, straight ulnar border
8 Esotropia, myopia
9 Thick, viscous saliva
10 Speech articulation defects
11 Skin picking
Data from Cassidy SB, Schwartz S, Miller JL, Driscoll DJ: Prader-Willi syndrome, Genet Med
14(1):15, 2012, Table 2.

Table 98.21

Nutritional Phases in Prader-Willi Syndrome

PHASE MEDIAN AGES CLINICAL CHARACTERISTICS
0 Prenatal to birth Decreased fetal movements and lower birthweight than siblings
1a 0-9 mo Hypotonia with difficulty feeding and decreased appetite
1b 9-25 mo Improved feeding and appetite and growing appropriately
2a 2.1-4.5 yr Weight increasing without appetite increase or excess calories
2b 4.5-8 yr Increased appetite and calories, but can feel full
3 8 yr to adulthood Hyperphagic, rarely feels full
4 Adulthood Appetite is no longer insatiable
Modified from Miller JL, Lynn CH, Driscoll DC, et al. Nutritional phases in Prader-Willi syndrome.
Am J Med Genet A 155A:1040–1049, 2011.

A maternal deletion of the same region as in Prader-Willi syndrome causes

Angelman syndrome, leaving intact the paternal copy that in this case has genes
that are also normally silent. In other situations, UPD can lead to the same
diagnosis (Table 98.22 ). Many other disorders are associated with this type of
parent-of-origin effect, as in some cases of Beckwith-Wiedemann syndrome,
Russell-Silver syndrome, and neonatal diabetes.

Table 98.22

Molecular Mechanisms Causing Prader-Willi and Angelman Syndromes

PRADER-WILLI
ANGELMAN SYNDROME
SYNDROME
15q11-q13 deletion ~70% (paternal) ~70% (maternal)
Uniparental disomy ~30% (maternal) ~5% (paternal)
Single-gene mutation None detected E6-AP ubiquitin-protein ligase (11% of total but mostly in
familial cases)
Imprinting center 5% 1%
mutation
Unidentified <1% 10–15%
Data from Nicholls RD, Knepper JL: Genome organization, function and imprinting in Prader-Willi
and Angelman syndromes, Annu Rev Genomics Hum Genet 2:153–175, 2001; and Horsthemke
B, Buiting K: Imprinting defects on human chromosome 15, Cytogenet Genome Res 113:292–
299, 2006.

Bibliography
Uniparental Disomy and Imprinting
Al-Saleh S, Al-Naimi A, Hamilton J, et al. Longitudinal
evaluation of sleep-disordered breathing in children with
Prader-Willi syndrome during 2 years of growth hormone
therapy. J Pediatr . 2013;162:263–268.
Butler MG, Sturich J, Lee J, et al. Growth standards of infants
with Prader-Willi syndrome. J Pediatr . 2011;127:687–695.
Cassidy SB, Schwartz S, Miller JL, Driscoll DJ. Prader-Willi
syndrome. Genet Med . 2012;14:10–26.
Eggermann T. Russell-Silver syndrome. Am J Med Genet C
somatic mutations that can target various mediators of transcriptional regulation,
numerous therapeutic avenues have emerged that show promise. An interesting
noncancer example is the genetic condition called Kabuki syndrome , which is
caused by mutations in either a histone methyltransferase (KMT2D ) or a histone
demethylase (KDM6A ) gene, each of which has a role in creating accessible
chromatin to allow genes to be expressed appropriately (Fig. 100.3 and Table
100.1 ). With the idea that increasing the amount of histone acetylation could
help to compensate for the inappropriate histone methylation, mice with Kabuki
syndrome were placed on a ketogenic diet, which increases the amount of β-
hydroxybutyrate, an endogenous inhibitor of histone deacetylases. Mice on this
diet showed improved neurogenesis and memory, suggesting that such an
intervention in children with Kabuki syndrome may also have beneficial effects.

FIG. 100.3 Kabuki syndrome in 18 mo old boy. A, Long palpebral fissures and eversion
of lateral portion of lower eyelids. B, Prominent fingertip pads. (From Jones, KL, Jones
MC, Del Campo, M, editors: Smith's recognizable patterns of human malformation, ed 7,
Philadelphia, 2013, Elsevier, p 158.)

Table 100.1
Clinical Manifestations of Kabuki Syndrome
Facial

Long palpebral tissues and eversions of lateral third of lower eyelids

Ptosis
Broad, arched eyebrows with sparse hair on lateral third
Long eyelashes
Blue sclerae
Protuberant ears
Short nasal columella (depressed nasal tip)

Neurodevelopmental

Hypotonia
Developmental delay (IQ about 60; >80 in 10%)
Low birthweight
Postnatal growth deficiency
Microcephaly
Seizures
Autism

Extremity/Skeletal

Short, incurved 5th finger

Brachydactyly
Kyphosis
Joint hyperextensibility
Persistent fetal fingertip pads
Hypoplastic finger nails

Cardiovascular

Multiple forms of congenital heart disease

Other
 Nonimmune hydrops
Hypothyroidism
Precocious puberty
Delayed puberty
Lymphatic malformations
Feeding difficulties

Bibliography
Banka S, Lederer D, Benoit V, et al. Novel KDM6A (UTX)
mutations and a clinical and molecular review of the X-linked
Kabuki syndrome (KS2). Clin Genet . 2015;87:252–258.
Benjamin JS, Pilarowski GO, Carosso GA, et al. A ketogenic
diet rescues hippocampal memory defects in a mouse model
of Kabuki syndrome. Proc Natl Acad Sci USA .
2017;114(1):125–130.
Birney E, Smith GD, Greally JM. Epigenome-wide association
studies and the interpretation of disease–omics. PLoS Genet .
2016;12(6):e1006105.
Blewitt M, Whitelaw E. The use of mouse models to study
epigenetics. Cold Spring Harb Perspect Biol .
2013;5(11):a017939.
Chen F, Marquez H, Kim Y-K, et al. Prenatal retinoid deficiency
leads to airway hyperresponsiveness in adult mice. J Clin
Invest . 2014;124(2):801–811.
Dentici ML, Di Pede A, Lepri FR, et al. Kabuki syndrome:
clinical and molecular diagnosis in the first year of life. Arch
Dis Child . 2015;100:158–164.
Henikoff S, Greally JM. Epigenetics, cellular memory and gene
regulation. Curr Biol . 2016;26(14):R644–R648.
Janesick AS, Shioda T, Blumberg B. Transgenerational
inheritance of prenatal obesogen exposure. Mol Cell
Endocrinol . 2014;398(1–2):31–35.
Jirtle RL. The Agouti mouse: a biosensor for environmental
physical findings include dysmorphisms, organomegaly, neurologic impairment,
bone involvement, and dermatologic findings. Because many rare and novel
disorders are multisystemic, consultants play a critical role in every diagnostic
evaluation. Typical studies performed to address possible diagnoses are listed in
Table 101.1 ; neurodevelopmental or neurodegenerative phenotypes require even
more extensive studies (Table 101.2 ).

Table 101.1

Initial Studies to Generate New Diagnostic Hypotheses

TEST RELATED DISORDERS/DISORDER GROUPS
Electrolytes, lactate, pyruvate Energy metabolism defects, including mitochondrial disorders
Plasma amino acids Renal disorders, amino acid disorders
Urine organic acids Renal disorders, organic acid disorders, energy metabolism
disorders, vitamin deficiencies
Aldolase, creatine phosphokinase Muscle disorders
Carnitine (free, total, acyl, panel) Fatty acid oxidation disorders, carnitine metabolism disorders
Cerebrospinal fluid (CSF) analysis Neurotransmitter disorders, inborn errors of metabolism, select
disorders that may present only in the CSF
Brain MRI/magnetic resonance spectroscopy Structural and morphologic clues to disorders affecting central
nervous system
Mass spectrometry to detect N - and O -linked Congenital disorders of glycosylation
proteoglycan abnormalities
Lysosomal enzyme testing Lysosomal storage diseases
White cell and skin electron microscopy Lysosomal storage diseases; neuronal lipofuscinoses
Pathologic evaluation of affected tissues with Any
special stains, DNA hybridization
Echocardiogram, electrocardiogram Structural and functional abnormalities of the heart
Nerve conduction velocity, electromyogram Dysfunction of anterior horn cells, nerves, neuromuscular
junction, or muscle
Fibroblast cell line Any
Single nucleotide polymorphism, Any
exome/genome/karyotype
Erythrocyte sedimentation rate, C-reactive Inflammatory disorders
protein

Table 101.2
Diagnostic Evaluation of the Neurologically
Impaired Child
Consultations

Genetics/genetic counseling
Neurology
 Ophthalmology
Endocrinology
Immunology
Rheumatology
Dermatology
Cardiology
Neuropsychology
Nutrition
Rehabilitative medicine
Physical therapy
Occupational therapy
Speech therapy

Procedures

Swallow study for aspiration

Abdominal ultrasound (hepatosplenomegaly)
Skeletal survey (dysostosis)
Bone density scan (nonambulatory or growth failure patients)
Bone age
Electroencephalogram, evoked responses, electroretinogram (ERG)
Muscle biopsy for electron transport chain function, histology,
immunohistochemistry
Neuropsychometric testing
Nerve biopsy

Laboratory Evaluations

Complete blood count with differential and peripheral smear

Comprehensive metabolic panel
Prothrombin time/partial thromboplastin time (for anesthesia sedation)
Thyroid-stimulating hormone, thyroxine
Vitamins A and E, 1,25-dihydroxyvitamin D
Lactate, pyruvate
Ammonia
Amino acids (plasma and urine)
 Organic acids (urine)
Acylcarnitine profile
Total and free carnitine
Lysosomal enzyme analysis in leukocytes/fibroblasts
White blood cell coenzyme Q
Purines and pyrimidines (urine)
α-Glucosidase (plasma and urine)
Peroxisomal panel
Oxysterols
Methylmalonic acid and homocysteine (plasma)
Copper/ceruloplasmin
Transferrin isoelectric focusing
N - and O -glycans (plasma)
Oligosaccharides and free glycans (urine)
Glycosaminoglycans (urine)

Additional Testing if Clinically Indicated

Electron microscopy of white blood cell buffy coat for inclusion bodies
Electron microscopy of skin biopsy for evidence of storage
Stool for ova and parasites, occult blood, fecal fat, or fecal calprotectin
Autoimmune antibodies
Vaccine response titers
C3/C4
Quantitative immunoglobulins
T-cell subsets
Conjunctival or salivary gland biopsy

Research Specimens

Cerebrospinal fluid
Serum
Plasma
Skin biopsy for fibroblasts and/or melanocytes
Isolated DNA/RNA
Urine
Studies Under Sedation

3T MRI/magnetic resonance spectroscopy of brain (and spine if indicated)

Skin biopsy
Ophthalmologic exam
Brainstem auditory evoked response
Electroretinogram
Lumbar puncture for biopterin, neopterin, neurotransmitters, folate, and
inflammatory markers
Dental exam
Large blood draws
Catheterization for urine
Any part of the physical exam difficult to do in an awake child, including
dysmorphology measurements and genital and rectal exam
Electromyography and nerve conduction studies

An inpatient admission allows for close interaction among experts in different

fields, informs the evaluation of complex cases, and often leads to new disease
discovery. In the last situation, other family members require evaluation to
ascertain whether they are affected with the disorder.

Commercial Genetic Studies

Once phenotyping is complete, a list of candidate genetic disorders can be
compiled. Laboratory testing is available for an increasingly large number of
molecular disorders. Examples of genetic panels include those for X-linked
cognitive impairment, hereditary spastic paraplegia, spastic paraplegia and gait
disorders, spinocerebellar ataxias, dystonias, and mitochondrial disorders. Some
of these are expensive and may exceed the cost of exome sequencing . On the
other hand, exome and genome sequencing are not useful for detecting diseases
caused by many types of genetic disorder, including from DNA repeats. In
addition, exome sequencing may provide less certainty for excluding genetic
diseases than a disease-specific test panel.

Single Nucleotide Polymorphism Arrays

warrants a referral to genetics center for further evaluation.
Table 102.1
Disorders Recommended by the American
College of Medical Genetics Task Force for
Inclusion in Newborn Screening (“Primary
Disorders”)*
Disorders of Organic Acid Metabolism

Isovaleric acidemia
Glutaric aciduria type I
3-Hydroxy-3-methylglutaric aciduria
Multiple carboxylase deficiency
Methylmalonic acidemia (methylmalonyl-CoA mutase deficiency)
Methylmalonic acidemia (cbl A and cbl B defects)
Propionic acidemia
3-Methylcrotonyl-CoA carboxylase deficiency
β-Ketothiolase deficiency

Disorders of Fatty Acid Metabolism

Medium-chain acyl-CoA dehydrogenase deficiency

Very-long-chain acyl-CoA dehydrogenase deficiency
Long-chain 3-hydroxy-acyl-CoA dehydrogenase deficiency
Trifunctional protein deficiency
Carnitine uptake defect

Disorders of Amino Acid Metabolism

Phenylketonuria
Maple syrup urine disease
Homocystinuria
Citrullinemia type 1
Argininosuccinic acidemia
 Tyrosinemia type I

Hemoglobinopathies

Sickle cell anemia (hemoglobin SS disease)

Hemoglobin S/β-thalassemia
Hemoglobin S/C disease

Other Disorders

Congenital hypothyroidism
Biotinidase deficiency
Congenital adrenal hyperplasia
Galactosemia
Hearing loss
Cystic fibrosis
Severe combined immunodeficiency (SCID) †
Critical congenital heart disease †

cbl A, Cobalamin A defect; cbl B, cobalamin B defect; CoA, coenzyme A.

* As of November 2014, there is state-to-state variation in newborn screening; a

list of the disorders that are screened for by each state is available at http://genes-
r-us.uthscsa.edu/sites/genes-r-us/files/nbsdisorders.pdf .
† The inclusion of SCID and critical congenital heart disease received support of

the American College of Medical Genetics and Genomics.

Table 102.2
Secondary Conditions Recommended by
American College of Medical Genetics* Task
Force for Inclusion in Newborn Screening
Organic Acid Metabolism Disorders
 Methylmalonic acidemia (cbl C and cbl D defects)
Malonic acidemia
2-Methyl-3-hydroxybutyric aciduria
Isobutyryl-CoA dehydrogenase deficiency
2-Methylbutyryl-CoA dehydrogenase deficiency
3-Methylglutaconic aciduria

Fatty Acid Oxidation Disorders

Short-chain acyl-CoA dehydrogenase deficiency

Glutaric acidemia type 2
Medium/short-chain 3-hydroxy-acyl-CoA dehydrogenase deficiency
Medium-chain ketoacyl-CoA thiolase deficiency
Carnitine palmitoyltransferase IA deficiency
Carnitine palmitoyltransferase II deficiency
Carnitine:acylcarnitine translocase deficiency
Dienoyl-CoA reductase deficiency

Amino Acid Metabolism Disorders

Hyperphenylalaninemia, benign (not classic phenylketonuria)

Tyrosinemia type II
Tyrosinemia type III
Defects of biopterin cofactor biosynthesis
Defects of biopterin cofactor regeneration
Argininemia
Hypermethioninemia
Citrullinemia type II (citrin deficiency)

Hemoglobinopathies

Hemoglobin variants (including hemoglobin E)

Others
 Galactose epimerase deficiency
Galactokinase deficiency

cbl C, Cobalamin C defect; cbl D, cobalamin D defect; CoA, coenzyme A.

* The American College of Medical Genetics Newborn Screening Expert Group

(May 2006) recommended reporting, in addition to the primary disorders, 25

disorders (“secondary targets”) that can be detected through screening but that
do not meet the criteria for primary disorders
(https://www.acmg.net/resources/policies/nbs/NBS_Main_Report_01.pdf ).

Universal newborn screening may also identify mild forms of inherited

metabolic conditions, some of which may never cause clinical manifestations in
the lifetime of the individual. For example, short-chain acyl-CoA dehydrogenase
deficiency has been identified with unexpectedly high frequency in screening
programs using tandem mass spectrometry, but most of these children have
remained asymptomatic. This highlights the need for an ongoing evaluation of
metabolite cutoff values and approaches to confirmatory testing to maximize the
diagnostic yield and minimize potential psychosocial and economic implications
of such findings. Premature infants represent a special patient population in
whom the incidence of false-positive or false-negative test results can be
especially high.
With the advent of genetic therapy for spinal muscular atrophy (SMA) and
enzyme replacement therapy for some lysosomal storage diseases (e.g., Pompe
disease, Fabry disease, Gaucher disease, and mucopolysaccharidosis type 1),
pilot newborn screening programs have demonstrated initial success in
identifying SMA or lysosomal storage disorders, often before severe symptoms
develop.

Clinical Manifestations of Genetic

Metabolic Diseases
Physicians and other healthcare providers who care for children should
familiarize themselves with early manifestations of genetic metabolic disorders,
simultaneously in such infants. Lethargy, poor feeding, seizures, and coma may
also be seen in infants with hypoglycemia (Table 102.4 ) (see Chapters 111 and
127 ), hypocalcemia (Chapters 64 and 589 ), and hyperammonemia (Table 102.5
) (Chapter 103 ). Measurements of blood concentrations of glucose and calcium
and response to intravenous injection of glucose or calcium help establish these
diagnoses. Every organ system can be affected by metabolic disorders. However,
physical examination usually reveals nonspecific findings; most signs are related
to the central nervous system such as opisthotonus in the case of maple syrup
urine disease (MSUD). Hepatomegaly is a common finding in a variety of
inborn errors of metabolism (Table 102.6 ). Cardiomyopathy (Table 102.7 ),
dysmorphology (Table 102.8 ), and fetal hydrops (Table 102.9 ) are additional
potential manifestations of a metabolic disorder (Table 102.10 ). Occasionally, a
peculiar odor may offer an invaluable aid to the diagnosis (Table 102.11 ).

Table 102.3

Select Inborn Errors of Metabolism Associated With Neurologic and Laboratory

Manifestations in Neonates

DETERIORATION IN CONSCIOUSNESS
Metabolic Acidosis
Organic acidemias
Disorders of pyruvate metabolism
Fatty acid oxidation defects
Fructose-1,6-bisphosphatase deficiency
Glycogen storage diseases
Mitochondrial respiratory chain defects
Disorders of ketone metabolism
Hypoglycemia *
Fatty acid oxidation defects
Disorders of gluconeogenesis
Disorders of fructose and galactose metabolism
Glycogen storage diseases
Disorders of ketogenesis
Organic acidemias
Hyperinsulinemic hypoglycemias
Mitochondrial respiratory chain defects
Neonatal intrahepatic cholestasis caused by citrin deficiency
 Pyruvate carboxylase deficiency
Carbonic anhydrase VA deficiency
Hyperammonemia **
Urea cycle disorders
Organic acidemias
Fatty acid oxidation disorders
Disorders of pyruvate metabolism
GLUD1 -related hyperinsulinemic hypoglycemia
Carbonic anhydrase VA deficiency
SEIZURES AND HYPOTONIA
Antiquitin deficiency (pyridoxine-dependent epilepsy)
Pyridoxamine 5'-phosphate oxidase (PNPO) deficiency (pyridoxal phosphate-responsive epilepsy)
Folate metabolism disorders
Multiple carboxylase deficiency (holocarboxylase synthetase deficiency and biotinidase deficiency)
Urea cycle disorders
Organic acidemias
Fatty acid oxidation disorders
Disorders of creatine biosynthesis and transport
Disorders of neurotransmitter metabolism
Molybdenum cofactor deficiency and sulfite oxidase deficiency
Serine deficiency disorders
Glycine encephalopathy
Asparagine synthetase deficiency
Mitochondrial respiratory chain defects
Zellweger spectrum disorders
Congenital disorders of glycosylation
Purine and pyrimidine metabolism defects
NEONATAL APNEA
Glycine encephalopathy
Asparagine synthetase deficiency
Urea cycle disorders
Organic acidemias
Disorders of pyruvate metabolism
Fatty acid oxidation defects
Mitochondrial respiratory chain defects
*
Refer to Table 102.4 for more details on the metabolic disorders associated
with neonatal hypoglycemia.
**
Refer to Table 102.5 for more details on the differential diagnosis of neonatal
and infantile hyperammonemia.

Modified from El-Hattab AW: Inborn errors of metabolism, Clin Perinatol

42:413-439, 2015 (Box 1, p 415).

Table 102.4

Select Inborn Errors of Metabolism Associated With Neonatal Hypoglycemia

CATEGORY OF DISORDERS DISORDERS
Fatty acid oxidation disorders Carnitine-acylcarnitine translocase deficiency
Carnitine palmitoyltransferase Ia deficiency
Carnitine palmitoyltransferase II deficiency
Long-chain 3-hydroxyacyl-CoA dehydrogenase
deficiency/trifunctional protein deficiency
Medium-chain acyl-CoA dehydrogenase deficiency
Very-long-chain acyl-CoA dehydrogenase deficiency
Multiple acyl-CoA dehydrogenase deficiency
Disorders of gluconeogenesis Fructose-1,6-diphosphatase deficiency
Phosphoenolpyruvate carboxykinase deficiency
Disorders of fructose and Hereditary fructose intolerance
galactose metabolism Classic galactosemia
Glycogen storage diseases (GSD) GSD type Ia (glucose-6-phosphatase deficiency)
GSD type Ib (impaired glucose-6-phosphate exchanger)
GSD type III (glycogen debrancher enzyme deficiency)
GSD type VI (liver glycogen phosphorylase deficiency)
GSD type IX (phosphorylase kinase deficiencies)
Disorders of ketogenesis 3-Hydroxy-3-methylglutaryl-CoA lyase deficiency
Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency
Organic acidemias Propionic acidemia
Methylmalonic acidemia
Isovaleric acidemia
Maple syrup urine disease
Multiple carboxylase deficiency (holocarboxylase synthetase deficiency
and biotinidase deficiency)
Hyperinsulinemic hypoglycemia HADH -related disorder (3-alpha-hydroxyacyl-CoA dehydrogenase
deficiency)
GLUD1 -related disorder (hyperammonemia-hyperinsulinism syndrome,
HIHA)
Other Mitochondrial respiratory chain defects
Neonatal intrahepatic cholestasis caused by citrin deficiency
Pyruvate carboxylase deficiency
Carbonic anhydrase VA deficiency
Modified from Zinn AB: Inborn errors of metabolism. In Fanaroff & Martin's neonatal-perinatal
medicine: diseases of the fetus and infant, ed 10, vol 2, Philadelphia, 2015, Elsevier (Table 99.17,
p 1605).
Table 102.5

Differential Diagnosis of Hyperammonemia

INBORN ERRORS OF METABOLISM

Urea Cycle Enzyme Defects
N-acetylglutamate synthase (NAGS) deficiency
Carbamoyl phosphate synthetase 1 (CPS1) deficiency
Ornithine transcarbamylase (OTC) deficiency
Argininosuccinate synthetase (ASS) deficiency (citrullinemia type 1)
Argininosuccinate lyase (ASL) deficiency (argininosuccinic aciduria)
Arginase 1 deficiency
Transport and Synthesis Defects of Urea Cycle Intermediates
Hyperornithinemia-hyperammonemia-homocitrullinemia (HHH syndrome)
Citrullinemia type 2 caused by citrin deficiency
Lysinuric protein intolerance
Ornithine aminotransferase deficiency
Carbonic anhydrase VA deficiency
Organic Acidemias
Propionic acidemia
MUT -related methylmalonic acidemia and cobalamin metabolism disorders
Isovaleric acidemia
Fatty Acid Oxidation Disorders
Long-chain fatty acid oxidation defects
Systemic primary carnitine deficiency
Other
Pyruvate carboxylase deficiency
GLUD1 -related hyperinsulinemic hypoglycemia
Neonatal iron overload disorders (e.g. hereditary hemochromatoses)
ACQUIRED DISORDERS
Transient Hyperammonemia of the Newborn
Diseases of the Liver and Biliary Tract
Liver failure
Biliary atresia
Severe Systemic Neonatal Illness
Neonates sepsis
Heart failure
Medications
 Valproic acid
Cyclophosphamide
5-Pentanoic acid
Asparaginase
Other
Reye syndrome
ANATOMIC VARIANTS
Vascular bypass of the liver (e.g. a portosystemic anastomosis)
TECHNICAL
Inappropriate sample collection (e.g., capillary blood or prolonged placement of a tourniquet)
Sample not immediately analyzed

Modified from El-Hattab AW: Inborn errors of metabolism, Clin Perinatol

42:413-439, 2015 (Box 8, p 428).

Table 102.6

Select Metabolic Disorders Associated With Hepatic Dysfunction

CATEGORY OF DISORDERS DISORDERS
Disorders of amino acid metabolism Tyrosinemia type I
Citrullinemia type II caused by citrin deficiency
Disorders of methionine metabolism
Urea cycle disorders
Biliary tract disorders and disorder of bile See Chapter 383
acid synthesis
Disorders of fructose and galactose Hereditary fructose intolerance
metabolism Classic galactosemia
Epimerase deficiency galactosemia
Congenital disorders of glycosylation Multiple types
Fatty acid oxidation disorders Carnitine-acylcarnitine translocase deficiency
Carnitine palmitoyltransferase Ia deficiency
Carnitine palmitoyltransferase II deficiency
Long-chain 3-hydroxyacyl-CoA dehydrogenase
deficiency/trifunctional protein deficiency
Very-long-chain acyl-CoA dehydrogenase deficiency
Multiple acyl-CoA dehydrogenase deficiency
Glycogen storage disorders (GSD) GSD type III (glycogen debrancher enzyme deficiency)
GSD type IV (glycogen branching enzyme deficiency)
GSD type VI (liver glycogen phosphorylase deficiency)
Peroxisomal disorders Zellweger spectrum disorders
Disorders of peroxisomal β-oxidation
Mitochondrial respiratory chain (RC) Mitochondrial DNA (mtDNA) or nuclear DNA (nDNA) defects
defects Specific single nucleotide pathogenic variants in mtDNA
Large-scale mtDNA re-arrangements (Pearson syndrome)
 Disorders of mitochondrial translation (e.g., tRNAGlu )
Disorder of protein synthesis of RC complexes
Disorders affected the assembly or stabilization of RC complexes
(e.g., BCS1L )
Disorders of cofactor biosynthesis (e.g. coenzyme Q10)
Disorders of mitochondrial transport and dynamics
mtDNA depletion syndromes (e.g., DGUOK, MPV17, POLG,
SUCLG1 )
Lysosomal storage disorders Niemann-Pick disease type C
Other α1 -Antitrypsin deficiency

Modified from Zinn AB: Inborn errors of metabolism. In Fanaroff & Martin's neonatal-perinatal
medicine: diseases of the fetus and infant, ed 10, vol 2, Philadelphia, 2015, Elsevier (Table 99.5, p
1579).

Table 102.7

Select Metabolic Disorders Associated With Cardiomyopathy

CATEGORY OF
DISORDERS
DISORDERS
Organic acidemias Propionic acidemia
Cobalamin C deficiency
3-methylglutaconic acidurias (e.g., Barth syndrome and DCMA syndrome)
Lysosomal storage Sphingolipidoses (e.g., Fabry disease)
disorders Oligosaccharidoses and mucolipidoses (e.g., I-cell disease)
Mucopolysaccharidoses
Glycogen storage disorders GSD type II (Pompe disease)
(GSD) GSD type III (glycogen debrancher enzyme deficiency)
PRKAG2 -related disorders (includes lethal congenital glycogen storage disease
of heart)
Congenital disorders of Multiple types
glycosylation
Fatty acid oxidation Carnitine-acylcarnitine translocase deficiency
disorders Carnitine palmitoyltransferase II deficiency
Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency/trifunctional protein
deficiency
ACAD9 -related disorder (mitochondrial acyl-CoA dehydrogenase deficiency)
Multiple acyl-CoA dehydrogenase deficiency (includes glutaric aciduria type 2)
Very-long-chain acyl-CoA dehydrogenase deficiency
Systemic primary carnitine deficiency
Mitochondrial respiratory Mitochondrial DNA (mtDNA) or nuclear DNA (nDNA) defects
chain (RC) defects Specific single nucleotide pathogenic variants in mtDNA
Large-scale mtDNA deletions
Disorders of mitochondrial translation (e.g., tRNALeu )
Disorders of protein synthesis of RC complexes (e.g., MT-ATP6 , MT-ATP8 ,
NDUFS2, NDUFV2, SDHA, SCO2, COX10, COX15 )
Disorders affecting the assembly or stabilization of RC complexes (e.g.,
TMEM70 )
Disorders of cofactor biosynthesis (e.g. coenzyme Q10)
Disorders of mitochondrial transport and dynamics (e.g., SLC25A3 )
mtDNA depletion syndromes (e.g., SUCLG1 )
 Other Danon disease
Modified from Zinn AB: Inborn errors of metabolism. In Fanaroff & Martin's neonatal-perinatal
medicine: diseases of the fetus and infant, ed 10, vol 2, Philadelphia, 2015, Elsevier (Table 99.4, p
1576).

Table 102.8

Select Inborn Errors of Metabolism Associated With Dysmorphic Features

CATEGORY OF DISORDERS DISORDERS
Congenital disorders of N-Glycosylation disorders (e.g., PMM2-CDG and ALG3-CDG)
glycosylation O-Glycosylation disorders (e.g., Walker-Warburg syndrome)
Disorders of cholesterol Smith-Lemli-Opitz syndrome
biosynthesis Desmosterolosis
Lathosterolosis
EBP -related disorder (includes Conradi-Hunermann syndrome)
Lysosomal storage disorders Sphingolipidoses
Oligosaccharidoses and mucolipidoses
Mucopolysaccharidoses
Organic acidurias Multiple acyl-CoA dehydrogenase deficiency (includes glutaric aciduria
type 2)
Mevalonic aciduria*
Peroxisomal disorders Zellweger spectrum disorders
Disorders of peroxisomal β-oxidation
Other Pyruvate dehydrogenase complex deficiency
* Mevalonic aciduria has been classified as an organic acidemia based on the method used for its
diagnosis, but it can also be classified as a peroxisomal single-enzyme disorder or as a defect in
cholesterol biosynthesis because of its intracellular location and function, respectively.
Modified from Zinn AB: Inborn errors of metabolism. In Fanaroff & Martin's neonatal-perinatal
medicine: diseases of the fetus and infant, ed 10, vol 2, Philadelphia, 2015, Elsevier (Table 99.8, p
1583).

Table 102.9

Select Inborn Errors of Metabolism Associated With Hydrops Fetalis

Lysosomal storage disorders

Mucopolysaccharidoses types I, IVA, and VII
Sphingolipidoses (e.g., Gaucher disease, Farber disease, Niemann-Pick disease A, GM1 gangliosidosis, multiple
sulfatase deficiency)
Lipid storage diseases (Wolman and Niemann-Pick disease C)
Oligosaccharidoses (e.g., sialidosis type I)
Mucolipidoses (e.g., I-cell disease)
Zellweger spectrum disorders
Glycogen storage disease type IV
Congenital disorders of glycosylation
Mitochondrial respiratory chain defects
Transaldolase deficiency

Modified and adapted from El-Hattab AW: Inborn errors of metabolism, Clin
Perinatol 42:413-439, 2015 (Box 6, p 417).

Table 102.10

Pathognomonic Clinical Findings Associated With Inborn Errors of Metabolism

(Select Examples)
FINDINGS DISORDERS
Hepatomegaly Disorders of fructose and galactose metabolism (e.g., classic
galactosemia and hereditary fructose intolerance)
Glycogen storage diseases
Disorders of gluconeogenesis
Disorders of fatty acid oxidation and transport
Mitochondrial respiratory chain defects
Tyrosinemia type 1
Urea cycle disorders
Zellweger spectrum disorders
Niemann-Pick disease type C
Congenital disorders of glycosylation
Hepatosplenomegaly Mucopolysaccharidoses
Niemann-Pick disease types A, B, and C
Sphingolipidoses (e.g., GM1 gangliosidosis or Gaucher disease)
Wolman disease
Farber disease (acid ceramidase deficiency)
Macrocephaly Glutaric acidemia type 1
Canavan disease
Microcephaly Mitochondrial respiratory chain defects
Disorders of intracellular cobalamin metabolism (e.g., cbl C
deficiency)
Coarse facial features Mucopolysaccharidoses
Oligosaccharidoses and mucolipidoses (e.g., α-mannosidosis)
Sphingolipidoses (e.g., GM1 gangliosidosis)
Galactosialidosis
Macroglossia Glycogen storage disease type II (Pompe disease)
Mucopolysaccharidoses
Oligosaccharidoses and mucolipidoses
Sphingolipidoses
Galactosialidosis
Dystonia or extrapyramidal signs Gaucher disease type 2
Glutaric acidemia type 1
Methylmalonic acidemia
Propionic acidemia
 Krabbe disease
Crigler–Najjar syndrome
Disorders of neurotransmitter metabolism
Pyruvate dehydrogenase complex deficiency
Macular “cherry-red spot” GM1 gangliosidosis
Tay-Sachs disease (GM2 gangliosidosis)
Farber disease (acid ceramidase deficiency)
Galactosialidosis
Niemann-Pick disease type A
Sialidosis
Multiple sulfatase deficiency
“Bull eye” maculopathy cbl C deficiency (combined methylmalonic acidemia and homocystinuria,
type C)
Retinitis pigmentosa Mitochondrial respiratory chain defects
Peroxisomal disorders
Abetalipoproteinemia
Optic nerve atrophy or hypoplasia Pyruvate dehydrogenase complex deficiency
Mitochondrial respiratory chain defects
Peroxisomal disorders
Propionic acidemia
MUT -related methylmalonic acidemia and cobalamin metabolism
disorders
Corneal clouding or opacities Mucolipidoses
Mucopolysaccharidoses
Steroid sulfatase deficiency
Tyrosinemia type II
Cystinosis
Cataracts Disorders of galactose metabolism (e.g., classic galactosemia)
Congenital disorders of glycosylation
Mitochondrial respiratory chain (RC) defects
Peroxisomal disorders
Lowe oculocerebrorenal syndrome
Dislocated lens Cystathionine β-synthase deficiency
Molybdenum cofactor deficiency and sulfite oxidase deficiency
Skeletal dysplasias and dysostosis Oligosaccharidoses and mucolipidoses
multiplex Mucopolysaccharidoses
Sphingolipidoses
Galactosialidosis
Peroxisomal disorders
Disorders of cholesterol biosynthesis
Congenital disorders of glycosylation
Thick skin Oligosaccharidoses and mucolipidoses
Mucopolysaccharidoses
Sphingolipidoses
Desquamating, eczematous, or Acrodermatitis enteropathica
vesiculobullous skin lesions Essential amino acid deficiencies in organic acidemias
Hartnup disorder
Multiple carboxylase deficiency (holocarboxylase synthetase
deficiency and biotinidase deficiency)
Porphyrias
Ichthyosis Gaucher disease type 2
Steroid sulfatase deficiency
Refsum disease
ELOVL4 -related disorder
Serine deficiency disorders
 Alopecia Multiple carboxylase deficiency (holocarboxylase synthetase deficiency
and biotinidase deficiency)
Steely or kinky hair Menkes disease
Trichorrhexis nodosa Argininosuccinic aciduria (ASL deficiency)
Persistent diarrhea Glucose-galactose malabsorption
Congenital lactase deficiency
Congenital chloride diarrhea
Sucrase-isomaltase deficiency
Acrodermatitis enteropathica
Abetalipoproteinemia
Congenital folate malabsorption
Wolman disease
Lysinuric protein intolerance
Classic galactosemia
Modified from Cederbaum S: Introduction to metabolic and biochemical genetic diseases. In
Gleason CA, Juul SE, editors: Avery's diseases of the newborn, ed 10, Philadelphia, 2018,
Elsevier (Table 21.1, p 227).

Table 102.11

Inborn Errors of Amino Acid Metabolism Associated With Peculiar Odor

INBORN ERROR OF METABOLISM URINE ODOR
Isovaleric acidemia Sweaty feet, acrid
Glutaric acidemia (type II)
Maple syrup urine disease Maple syrup, burnt sugar
Multiple carboxylase deficiency Cat urine
3-Methylcrotonyl-CoA carboxylase deficiency
3-Hydroxy-3-methylglutaric aciduria
Phenylketonuria Mousey or musty
Trimethylaminuria Rotten fish
Dimethylglycine dehydrogenase deficiency
Tyrosinemia type 1 Boiled cabbage, rancid butter
Hypermethioninemia Boiled cabbage
Cystinuria Sulfur
Tyrosinemia type I
Hawkinsinuria “Swimming pool”
Oasthouse urine disease Hops-like

In an increasing number of patients, a metabolic condition may be recognized

months or years after birth. This is more typical in patients carrying milder
autosomal recessive pathogenic variants, in mitochondrial disorders, in females
affected by X-linked recessive conditions, and specific metabolic conditions that
usually present later in life. Clinical manifestations, such as intellectual
disability, motor deficits, developmental regression, seizures, psychosis,
cardiomyopathy, myopathy, organomegaly, and recurrent emesis, in patients
beyond the neonatal period should suggest an inherited metabolic disease (Table
102.12 ). There may be an episodic or intermittent pattern, with episodes of
acute clinical manifestations separated by periods of seemingly disease-free
states. The episodes are usually triggered by stress or nonspecific catabolic stress
such as an infection. The child may die during one of these acute attacks. An
inborn error of metabolism should be considered in any child with 1 or more of
the following manifestations: unexplained developmental delay; intellectual
disability; developmental regression; motor deficits or adventitious movements
(e.g., dystonia, choreoathetosis, ataxia); seizures; catatonia; unusual odor
(particularly during an acute illness); intermittent episodes of unexplained
vomiting, acidosis, mental deterioration, psychosis, or coma; hepatomegaly;
renal stones; renal dysfunction, especially Fanconi syndrome or renal tubular
acidosis; muscle weakness; and cardiomyopathy (Table 102.12 ).

Table 102.12

Clinical Findings That Should Prompt a Metabolic Workup

Family history Sibling(s) who died from unexplained causes or exhibit overlapping symptoms
Ethnic groups with high prevalence of metabolic disorders
Consanguinity
Perinatal Intrauterine growth retardation, sepsis-like presentation in the neonatal period, nonimmune fetal
history hydrops
Growth Postnatal failure to thrive, microcephaly, macrocephaly, short stature
Central and Progressive encephalopathy, lethargy, coma, intractable seizures, developmental delay,
peripheral developmental regression, intellectual disability, autism spectrum disorder, hypotonia, spasticity,
nervous dystonia, strokes, ataxia, psychosis, intracranial calcifications, white matter disease, peripheral
systems neuropathy
Respiratory Hyperventilation, apnea
system
Cardiovascular Cardiac failure with or without cardiomyopathy, arrhythmia
system
Musculoskeletal Rhabdomyolysis, myopathy
system Osteopenia, early-onset osteoporosis, skeletal dysplasia, epiphyseal abnormalities, bone
crises
Eye Retinitis pigmentosa, macular dystrophy, cataracts, corneal opacities, nystagmus, cherry-red
spot
Hearing Sensorineural hearing loss
Gastrointestinal Hepatomegaly, splenomegaly, liver failure, Reye syndrome, cholestasis, cirrhosis, chronic
system diarrhea, vomiting, acute pancreatitis
Kidney Renal dysfunction, renal stones
Hematological Anemia, leukopenia, thrombocytopenia, pancytopenia, hemolytic-uremic syndrome
system
Skin Hair abnormality, alopecia, lipodystrophy, recalcitrant eczema

Diagnosis usually requires a variety of specific laboratory studies. Plasma

amino acid analysis, plasma acylcarnitine profile, total and free carnitine profile,
and urine organic acid assay, while not exhaustive in their diagnostic scope, are
useful as initial screening tests to evaluate for a suspected inborn error of
metabolism. Measurements of plasma ammonia, lactate, bicarbonate, and pH are
readily available in hospitals and very helpful initially in differentiating major
causes of genetic metabolic disorders (Table 102.13 ; see Fig. 102.1 ). Elevation
of blood ammonia is usually caused by defects of urea cycle enzymes, organic
acidemias, and disorders of fatty acid oxidation. Infants with elevated blood
ammonia levels from urea cycle defects tend to have normal serum pH and
bicarbonate values; without measurement of blood ammonia, they may remain
undiagnosed and succumb to their disease. In organic acidemias, elevated
plasma ammonia is accompanied by severe acidosis caused by accumulation of
organic acids, ketone bodies, and lactate in body fluids.
Table 102.13
Laboratory Findings That Should Prompt a
Metabolic Workup

Hyperammonemia
Metabolic acidosis
Lactic acidosis
Ketosis
Hypoglycemia
Liver dysfunction
Pancytopenia

When blood ammonia, pH, and bicarbonate values are normal, other
aminoacidopathies (e.g. hyperglycinemia) or galactosemia should be considered.
Galactosemic infants may also manifest cataracts, hepatomegaly, ascites, and
jaundice.

Treatment
The majority of patients with genetic disorders of metabolism respond to one or
more of the following treatments:

1. Special diets play an important role in the treatment of affected children.

 The diagnosis is confirmed by finding massive excretion of homogentisic acid
on urine organic acid testing. Tyrosine levels are normal. The enzyme is
expressed only in the liver and kidneys.
Treatment of the arthritis is symptomatic. Nitisinone efficiently reduces
homogentisic acid production in alkaptonuria. If presymptomatic individuals are
detected, treatment with nitisinone, combined with a phenylalanine- and
tyrosine-restricted diet, seems reasonable, although no experience is available
regarding long-term efficacy.
The gene for homogentisate 1,2-dioxygenase (HGD) maps to chromosome
3q13.3. Alkaptonuria is most common in the Dominican Republic and Slovakia.

Tyrosine Hydroxylase Deficiency

See Chapter 103.11 .

Albinism
See also Chapters 640 and 672 .
Albinism is caused by deficiency of melanin , the main pigment of the skin
and eye (Table 103.1 ). Melanin is synthesized by melanocytes from tyrosine in a
membrane-bound intracellular organelle, the melanosome. Melanocytes
originate from the embryonic neural crest and migrate to the skin, eyes (choroid
and iris), hair follicles, and inner ear. The melanin in the eye is confined to the
iris stromal and retinal pigment epithelia, whereas in skin and hair follicles, it is
secreted into the epidermis and hair shaft. Albinism can be caused by
deficiencies of melanin synthesis, by some hereditary defects of melanosomes,
or by disorders of melanocyte migration. Neither the biosynthetic pathway of
melanin nor many facets of melanocyte cell biology are completely elucidated
(see Fig. 103.2 ). The end products are 2 pigments: pheomelanin, which is a
yellow-red pigment, and eumelanin, a brown-black pigment.

Table 103.1
Classification of Major Causes of Albinism

TYPE GENE CHROMOSOME

OCULOCUTANEOUS ALBINISM (OCA)
OCA1 (tyrosinase deficient) TYR 11q14-q21
 OCA1A (severe deficiency) TYR 11q14-q21
OCA1B (mild deficiency)* TYR 11q14-q21
OCA2 (tyrosinase positive) † OCA2 15q12-q13
OCA3 (Rufous, red OCA) TYRP1 ‡ 9p23
OCA4 SLC45A2 5p13.3
Hermansky-Pudlak syndrome HPS1-9 Different chromosomes
Chédiak-Higashi syndrome LYST 1q42.1
OCULAR ALBINISM (OA)
OA1 (Nettleship-Falls type) OA Xp22.3
LOCALIZED ALBINISM
Piebaldism KIT 4q12
Waardenburg syndrome (WS1-WS4) See text See text
* This includes Amish, minimal pigment, yellow albinism, and platinum and temperature-sensitive

variants.
† Includes brown OCA.

‡ Tyrosinase-related protein 1.

Clinically, primary albinism can be generalized or localized. Primary

generalized albinism can be ocular or oculocutaneous. Some syndromes feature
albinism in association with platelet, immunologic, or neurologic dysfunction. In
generalized oculocutaneous albinism, hypopigmentation can be either complete
or partial. Individuals with complete albinism do not develop either generalized
(tanning) or localized (pigmented nevi) skin pigmentation.
The diagnosis of albinism is usually evident, but for some white children
whose families are particularly light-skinned, normal variation may be a
diagnostic consideration. Unlike patients with albinism, normal fair-skinned
children progressively develop pigmentation with age, do not exhibit the eye
manifestations of albinism, and have pigmentary development similar to other
family members. The clinical diagnosis of oculocutaneous albinism, as opposed
to other types of cutaneous hypopigmentation, requires the presence of
characteristic eye findings.
The ocular manifestations of albinism include hypopigmentation of iris and
retina with foveal hypoplasia, along with reduced visual acuity, refractive errors,
nystagmus, alternating strabismus, and iris transillumination (diffuse reddish hue
of iris produced during ophthalmoscopic or slit-lamp examination of eye). There
is also an abnormality in routing of the optic fibers at the chiasm. Unlike in
pigmented individuals, in patients with albinism the majority of the nerve fibers
from the temporal side of the retina cross to the contralateral hemisphere of the
brain. This results in lack of binocular (stereoscopic) vision and depth perception
and in repeated switching of vision from eye to eye, causing alternating
strabismus. This abnormality also causes a characteristic pattern of visual
promptly. Secondary carnitine deficiency, seen in up to 50% of patients, can be
corrected with L -carnitine supplementation. For symptomatic patients, some
centers recommend keeping protein intake at the recommended dietary
allowance in conjunction with the oral administration of L -carnitine and the
proactive management of catabolic states. Normal growth and development are
expected in most patients.
3-MCC deficiency is an autosomal recessive condition. The gene for α-
subunit (MCCC1) is located on chromosome 3q27.1, and that for the β-subunit
(MCCC2) is mapped to chromosome 5q13.2. Pathogenic variants in either of
these genes result in the enzyme deficiency with overlapping clinical features.

3-Methylglutaconic Acidurias
The 3-methylglutaconic acidurias are a heterogeneous group of metabolic
disorders characterized by excessive excretion of 3-methylglutaconic acid in the
urine (Table 103.2 ). Other metabolites found in 3-methylglutaconic aciduria
patients may include 3-methylglutaric acid and 3-hydroxyisovaleric acid.
Current classification distinguishes primary and secondary forms. Primary 3-
methylglutaconic aciduria is caused by the deficiency of mitochondrial 3-
methylglutaconyl-CoA hydratase (see Fig. 103.4 ), formerly 3-methylglutaconic
aciduria type I . Secondary 3-methylglutaconic aciduria can be further classified
based on the underlying mechanism (e.g., defective phospholipid remodeling vs
dysfunction of mitochondrial membrane) or the known molecular cause. Known
secondary 3-methylglutaconic aciduria includes TAZ -related syndrome (Barth
syndrome ), OPA3 -related 3-methylglutaconic aciduria (Costeff syndrome ),
SERAC1 -related syndrome (MEGDEL syndrome ), TMEM70 -related
syndrome, and DNAJC19 -related syndrome (DCMA syndrome ).

Table 103.2
3-Methylglutaconic Acidurias

GENE PREVIOUS DISEASE CLINICAL

GROUP DISORDER
(CHROMOSOME) CLASSIFICATION MECHANISM DESCRIPTION
Primary 3- 3- AUH (9q22.31) Type I Enzyme Depending on age,
methylglutaconic Methylglutaconyl- deficiency in variable presentation
aciduria CoA hydratase the leucine is seen ranging from
deficiency degradation younger
pathway asymptomatic
patients to older
 patients with
progressive
leukoencephalopathy
Secondary 3- Barth syndrome TAZ (Xq28) Type II Defective X-linked inheritance,
methylglutaconic phospholipid cardiomyopathy,
acidurias remodeling endocardial
fibroelastosis,
proximal myopathy,
failure to thrive,
neutropenia,
dysmorphic findings
Costeff syndrome OPA3 (19q13.32) Type III Mitochondrial Progressive optic
membrane nerve atrophy,
dysfunction chorea, spastic
paraparesis,
cognitive
impairment
MEGDEL SERAC1 (6q25.3) Type IV Defective Progressive
syndrome phospholipid deafness, dystonia,
remodeling spasticity, basal
ganglia changes
TMEM70 -related TMEM70 (8q21.11) Type IV Mitochondrial Developmental
disorder membrane delay, failure to
dysfunction thrive, metabolic
decompensations,
microcephaly,
cardiomyopathy,
dysmorphic findings
3- Unknown Type IV Unknown Variable presentation
Methylglutaconic
aciduria, not
otherwise
specified
DCMA syndrome DNAJC19 (3q26.33) Type V Mitochondrial Cardiomyopathy,
membrane ataxia, optic nerve
dysfunction atrophy, failure to
thrive

Significant and persistent 3-methylglutaconic aciduria with negative

molecular evaluation for known genetic causes represents a heterogeneous group
called 3-methylglutaconic aciduria not otherwise specified awaiting further
molecular characterization. Primary and secondary 3-methylglutaconic aciduria
should be distinguished from mild and transient urinary elevations of 3-
methylglutaconic acid seen in patients affected by other metabolic disorders,
such as mitochondrial disorders of diverse etiology.

3-Methylglutaconyl-CoA Hydratase Deficiency

Two main clinical forms of 3-methylglutaconyl-CoA hydratase deficiency have
been described (see Fig. 103.4 ). In the childhood form, nonspecific
 SLC6A3
dopamine-serotonin vesicular transporter disease
vesicular monoamine transporter deficiency
SLC18A2
vesicular monoamine transporter 2
VMAT2
hyperprolinemia

Neurotransmitters are chemical substances released from the axonal end of

excited neurons at the synaptic junctions; they mediate initiation and
amplification or inhibition of neural impulses. A number of amino acids and
their metabolites comprise the bulk of neurotransmitters. Pathogenic variants in
genes responsible for the synthesis, transport, or degradation of these substances
may cause conditions that manifest neurologic and/or psychiatric abnormalities
(Table 103.3 ). Previously, children affected by disorders of neurotransmitters
have been given syndromic diagnoses such as cerebral palsy, epilepsy,
parkinsonism, dystonia, or autism. Diagnosis, in most cases, requires specialized
laboratory studies of the cerebrospinal fluid (CSF), because some of the
neurotransmitters generated in the central nervous system (CNS), dopamine and
serotonin, do not cross the blood-brain barrier, and their abnormal concentrations
are not detected in the serum or urine. A growing number of these conditions are
being identified; diseases once thought to be rare are now diagnosed with
increasing frequency.

Table 103.3
Genetic Disorders of Neurotransmitters in Children

TRANSMITTER SYNTHESIS DEFECTS DEGRADATION DEFECTS

MONOAMINES
Dopamine TH deficiency MAO deficiency
Serotonin and dopamine AADC deficiency MAO deficiency
BH4 deficiency
With and without
hyperphenylalaninemia
Norepinephrine DβH deficiency MAO deficiency
GABA ? GABA transaminase
deficiency
GHB aciduria
Histamine HDC deficiency ?
TRANSPORTER PROTEINS
 Dopamine transporter DAT deficiency ?
Vesicular monoamine VMAT2 deficiency ?
transporter
AMINO ACIDS
Proline ? Hyperprolinemia
Serine 3-PGD, PSAT, PSPH deficiencies ?
Glycine 3-PDG, PSAT deficiencies NKH
AADC, Aromatic L -amino acid decarboxylase; BH4 , tetrahydrobiopterin; DAT, dopamine
transporter; DβH, dopamine β-hydroxylase; GABA, γ-aminobutyric acid; GHB, γ-hydroxybutyric
acid; HDC, histidine decarboxylase; hyperphe, hyperphenylalaninemia; MAO, monoamine
oxidase; NKH, nonketotic hyperglycinemia; 3-PGD, 3-phosphoglycerate dehydrogenase; PSAT,
phosphoserine aminotransferase; PSPH, 3-Phosphoserine Phosphatase Deficiency; TH, tyrosine
hydroxylase; VMAT2, vesicular monoamine transporter 2.

Tyrosine Hydroxylase Deficiency

(Infantile Parkinsonism, Autosomal
Recessive Dopa-Responsive Dystonia,
Autosomal Recessive Segawa
Syndrome)
Tyrosine hydroxylase catalyzes the formation of L -dopa from tyrosine.
Deficiency of this enzyme results in deficiencies of dopamine and
norepinephrine (see Fig. 103.2 ). The differential diagnosis includes a wide
range of inherited dystonias, including autosomal dominant dystonia caused by
GTP cyclohydrolase 1 deficiency.
Clinical manifestations range from mild to very severe. In general, 2
phenotypes have been recognized. In the mild form (dopa-responsive dystonia,
or type A ), symptoms of unilateral limb dystonia causing gait incoordination
and postural tremor occur in childhood and worsen with age if the condition
remains untreated. Diurnal variation of symptoms (worse at the end of the day)
may be present. Cognitive development is usually normal.
In the severe form of tyrosine hydroxylase deficiency (infantile parkinsonism,
infantile encephalopathy, or type B ), the clinical manifestations occur at birth or
shortly thereafter and include microcephaly, developmental delay, involuntary
movements of the limbs with spasticity, dystonia, ptosis, expressionless face,
oculogyric crises (upward eye-rolling movements), and autonomic dysfunction
(temperature instability, excessive sweating, hypoglycemia, salivation, tremor,
Inborn Errors of Metabolism Causing
Hyperammonemia
Deficiencies of the urea cycle enzymes
Carbamyl phosphate synthetase 1
Ornithine transcarbamylase
Argininosuccinate synthetase
Argininosuccinate lyase
Arginase 1
N -acetylglutamate synthetase
Organic acidemias
Propionic acidemia
Methylmalonic acidemia
Isovaleric acidemia
β-Ketothiolase deficiency
Multiple carboxylase deficiencies
Medium-chain fatty acid acyl-CoA dehydrogenase deficiency
Glutaric acidemia type I
3-Hydroxy-3-methylglutaric aciduria
Lysinuric protein intolerance
Hyperammonemia-hyperornithinemia-homocitrullinemia syndrome
Transient hyperammonemia of the newborn
Congenital hyperinsulinism with hyperammonemia

Clinical Manifestations of
Hyperammonemia
In the neonatal period , symptoms and signs are mostly related to brain
dysfunction and are similar regardless of the cause of the hyperammonemia. The
affected infant appears normal at birth but becomes symptomatic following the
introduction of dietary protein. Refusal to eat, vomiting, tachypnea, and lethargy
can quickly progress to a deep coma. Seizures are common. Physical
examination may reveal hepatomegaly in addition to obtundation.
Hyperammonemia can trigger increased intracranial pressure that may be
manifested by a bulging fontanelle and dilated pupils.
Treatment of Acute Hyperammonemia
Clinical outcome depends mainly on the severity and the duration of
hyperammonemia. Serious neurologic sequelae are likely in newborns with
severe elevations in blood ammonia (>300 µmol/L) for more than 12 hr. Thus,
acute hyperammonemia should be treated promptly and vigorously. The goal of
therapy is to lower the concentration of ammonia. This is accomplished by (1)
removal of ammonia from the body in a form other than urea and (2) minimizing
endogenous protein breakdown and favoring endogenous protein synthesis by
providing adequate calories and essential amino acids (Table 103.5 ). Fluid,
electrolytes, glucose (10–15%), and lipids (1-2 g/kg/24 hr) should be infused
intravenously, together with minimal amounts of protein (0.25 g/kg/24 hr),
preferably including essential amino acids. Oral feeding with a low-protein
formula (0.5-1.0 g/kg/24 hr) through a nasogastric tube should be started as soon
as sufficient improvement is seen.
Table 103.5
Treatment of Acute Hyperammonemia in an
Infant

1. Provide adequate calories, fluid, and electrolytes intravenously (10%

glucose, NaCl* and intravenous lipids 1 g/kg/24 hr). Add minimal
amounts of protein preferably as a mixture of essential amino acids (0.25
g/kg/24 hr) during the 1st 24 hr of therapy.
2. Give priming doses of the following compounds:
(To be added to 20 mL/kg of 10% glucose and infused within 1-2 hr)
• Sodium benzoate 250 mg/kg †
• Sodium phenylacetate 250 mg/kg †
• Arginine hydrochloride 200-600 mg/kg as a 10% solution
3. Continue infusion of sodium benzoate † (250-500 mg/kg/24 hr), sodium
phenylacetate † (250-500 mg/kg/24 hr), and arginine (200-600 mg/kg/24
hr ‡ ) following the above priming doses. These compounds should be
added to the daily intravenous fluid.
4. Initiate peritoneal dialysis or hemodialysis if above treatment fails to
produce an appreciable decrease in plasma ammonia.
* The concentration of sodium chloride should be calculated to be 0.45–0.9%,

including the amount of the sodium in the drugs.

† Sodium from these drugs should be included as part of the daily sodium

requirement.
‡ The higher dose is recommended in the treatment of patients with citrullinemia

and argininosuccinic aciduria. Arginine is not recommended in patients with

arginase deficiency and in those whose hyperammonemia is secondary to
organic acidemia. Sodium benzoate and sodium phenylacetate should be used
with caution in patients with organic acidemias.

Because the kidneys clear ammonia poorly, its removal from the body must be
expedited by formation of compounds with a high renal clearance. An important
advance in the treatment of hyperammonemia has been the introduction of
acylation therapy by using an exogenous organic acid that is acylated
endogenously with nonessential amino acids to form a nontoxic compound with
high renal clearance. The main organic acids used for this purpose are sodium
salts of benzoic acid and phenylacetic acid. Benzoate forms hippurate with
endogenous glycine in the liver (see Fig. 103.12 ). Each mole of benzoate
removes 1 mole of ammonia as glycine. Phenylacetate conjugates with
glutamine to form phenylacetylglutamine, which is readily excreted in the urine.
One mole of phenylacetate removes 2 moles of ammonia as glutamine from the
body (see Fig. 103.12 ). Sodium phenylbutyrate, metabolized to phenylacetate, is
the primary oral formulation. For intravenous (IV) use, a combined formulation
of benzoate and phenylacetate (Ammonul) is commercially available.
Another valuable therapeutic adjunct is IV infusion of arginine , which is
effective in all patients (except those with arginase deficiency). Arginine
administration supplies the urea cycle with ornithine (see Fig. 103.12 ). In
patients with citrullinemia, 1 mole of arginine reacts with 1 mole of ammonia (as
carbamoyl phosphate) to form citrulline. In patients with argininosuccinic
acidemia, 2 moles of ammonia (as carbamoyl phosphate and aspartate) react
with arginine to form argininosuccinic acid. Citrulline and argininosuccinate are
less toxic than ammonia and more readily excreted by the kidneys. In patients
with CPS1 or OTC deficiencies arginine administration is indicated because this
amino acid is not produced in sufficient amounts to enable endogenous protein
synthesis. For enteral therapy, patients with OTC deficiency benefit from
during periods of reduced caloric intake caused by gastrointestinal illness or
increased energy expenditure during febrile illness. Under these conditions, the
body switches from using predominantly carbohydrate to predominantly fat as
its major fuel. Fatty acids are also important fuels for exercising skeletal muscle
and are the preferred substrate for normal cardiac metabolism. In these tissues,
fatty acids are completely oxidized to carbon dioxide and water. The end
products of hepatic fatty acid oxidation are the ketone bodies β-hydroxybutyrate
and acetoacetate. These cannot be oxidized by the liver but are exported to serve
as important fuels in peripheral tissues, particularly the brain, where ketone
bodies can partially substitute for glucose during periods of fasting.
Genetic defects have been identified in almost all the known steps in the fatty
acid oxidation pathway; all are recessively inherited (Table 104.1 ).

Table 104.1
Mitochondrial Fatty Acid Oxidation Disorders—Clinical and
Biochemical Features

ENZYME
GENE CLINICAL PHENOTYPE LABORATORY FINDINGS
DEFICIENCY
Carnitine OCTN2 Cardiomyopathy, skeletal myopathy, liver ↓ Total and free carnitine,
transporter SLC22A5 disease, sudden death, endocardial normal acylcarnitines,
fibroelastosis, prenatal and newborn acylglycine, and organic acids
screening diagnosis reported
Long-chain fatty FATP1-6 Rare, acute liver failure in childhood ↓ intracellular C14 -C18 fatty
acid transporter requiring liver transplantation acids, ↓ fatty acid oxidation
Carnitine CPT-IA Liver failure, renal tubulopathy, and sudden Normal or ↑ free carnitine,
palmitoyl death. Prenatal and newborn screening normal acylcarnitines,
transferase-I diagnosis reported, maternal preeclampsia, acylglycine, and organic acids
HELLP syndrome association described in a
few patients.
Carnitine CACT Chronic progressive liver failure, persistent ↑ Normal or ↓ free carnitine,
acylcarnitine SLC25A20 NH3 , hypertrophic cardiomyopathy. abnormal acylcarnitine profile
translocase Newborn screening diagnosis reported.
Carnitine CPT-II Early and late onset types. Liver failure, Normal or ↓ free carnitine,
palmitoyl encephalopathy, skeletal myopathy, abnormal acylcarnitine profile
transferase-II cardiomyopathy, renal cystic changes,
newborn screening diagnosis reported. Adult
form with acute rhabdomyolysis,
myoglobinuria.
Short-chain acyl- SCAD Clinical phenotype unclear. Many individuals Normal or ↓ free carnitine,
CoA ACADS appear to be normal. Others have a variety of elevated urine ethylmalonic
dehydrogenase inconsistent signs and symptoms. Subset may acid, inconsistently abnormal
have severe manifestations of unclear acylcarnitine profile
relationship to biochemical defects. Newborn
screening diagnosis reported; significance
 being questioned.
Medium-chain MCAD Hypoglycemia, hepatic encephalopathy, Normal or ↓ free carnitine, ↑
acyl-CoA ACADM sudden death. Newborn screening diagnosis plasma acylglycine, plasma C6
dehydrogenase possible, maternal preeclampsia, HELLP -C10 free fatty acids, ↑ C8 -C10
syndrome association described rarely, acyl-carnitine
possible long Qt interval.
Very long-chain VLCAD Dilated cardiomyopathy, arrhythmias, Normal or ↓ free carnitine, ↑
acyl-CoA ACADVL hypoglycemia, and hepatic steatosis. Late- plasma C14:1 , C14
dehydrogenase onset, stress-induced rhabdomyolysis, acylcarnitine, ↑ plasma C10 -
episodic myopathy. Prenatal and newborn C16 free fatty acids
screening diagnosis possible.
ETF ETF-DH Nonketotic fasting hypoglycemia, congenital Normal or ↓ free carnitine,
dehydrogenase* anomalies, milder forms of liver disease, increased ratio of acyl:free
cardiomyopathy, and skeletal myopathy. carnitine, ↑ acylcarnitine,
Newborn screening diagnosis reported. urine organic acid and
acylglycines
ETF-α* α-ETF Nonketotic fasting hypoglycemia, congenital Normal or ↓ free carnitine,
anomalies, liver disease, cardiomyopathy, increased ratio of acyl:free
and skeletal myopathy also described. carnitine, ↑ acylcarnitine,
Newborn screening diagnosis reported. urine organic acid and
acylglycines
ETF-β* β-ETF Fasting hypoglycemia, congenital anomalies, Normal or ↓ free carnitine,
liver disease, cardiomyopathy, and skeletal increased ratio of acyl:free
myopathy also described. Newborn screening carnitine, ↑ acylcarnitine,
diagnosis reported. urine organic acid and
acylglycines
Short-chain L -3- SCHAD Hyperinsulinemic hypoglycemia, Normal or ↓ free carnitine,
hydroxyacyl- HAD1 cardiomyopathy, myopathy. Newborn elevated free fatty acids,
CoA screening diagnosis reported. inconsistently abnormal urine
dehydrogenase organic acid, ↑ 3-OH glutarate,
↑ plasma C4 -OH acylcarnitine
Long-chain L -3- LCHAD Newborn screening diagnosis reported, Normal or ↓ free carnitine,
hydroxyacyl- HADH-A maternal preeclampsia, HELLP syndrome, increased ratio of acyl:free
CoA and AFLP association described frequently. carnitine, ↑ free fatty acids, ↑
dehydrogenase See also MTP below for clinical C16 -OH and C18 -OH
manifestations. carnitines
MTP HADH-A, Severe cardiac and skeletal myopathy, Normal or ↓ free carnitine,
HADH-B hypoglycemia, acidosis, hyper NH3 , sudden increased ratio of acyl:free
death, elevated liver enzymes, retinopathy. carnitine, ↑ free fatty acids, ↑
Maternal preeclampsia, HELLP syndrome, C16 -OH and C18 -OH
and AFLP association described frequently. carnitines
Long-chain 3- LKAT Severe neonatal presentation, hypoglycemia, Normal or ↓ free carnitine,
ketoacyl-CoA HADH-B acidosis, ↑ creatine kinase, cardiomyopathy, increased ratio of acyl:free
thiolase neuropathy, and early death carnitine, ↑ free fatty acids, ↑
2-trans , 4-cis -
decadienoylcarnitine
Short-chain 2,3- ECHS1 Leigh disease, lactic acidosis, seizures, cystic Abnormal organic acids, 2-
enoyl-CoA degeneration of white matter, microcephaly, methacrylglycine, 2-methyl-
hydratase metabolic acidosis, extrapyramidal dystonia, 2,3 dihydroxybutyrate, also S-
dilated cardiomyopathy (2-carboxypropyl)cysteine, S-
(2-carboxyethyl) cysteamine.
Acylcarnitine shows ↑ C4OH
(inconsistently).
2,4-Dienoyl-CoA DECR1 Only 1 patient described, hypotonia in the Normal or ↓ free carnitine, ↑
reductase newborn, mainly severe skeletal myopathy acyl:free carnitine ratio,
 and respiratory failure. Hypoglycemia rare. normal urine organic acids and
acylglycines
HMG CoA HMGCS2 Hypoketosis and hypoglycemia, rarely ↑ total plasma fatty acids,
synthetase myopathy enzyme studies in biopsied
liver may be diagnostic,
genetic testing preferred
HMG CoA lyase HMGCL Hypoketosis and hypoglycemia, rarely Normal free carnitine, ↑ C5 -
myopathy OH, and methylglutaryl-
carnitine, enzymes studies in
fibroblasts may be diagnostic
Monocarboxylate SLC16A1 Severe fasting induced ketoacidosis, rarely Profound ketoacidosis; no
transporter 1 hypoglycemia specific biomarkers yet
(MCT1) identified
*
Also known as glutaric acidemia type II or multiple acyl-CoA dehydrogenase defect (MADD).
AFLP, Acute fatty liver of pregnancy; CoA, coenzyme A; ETF, electron transport flavoprotein;
HELLP, hemolysis, elevated liver enzymes, low platelets; MTP, mitochondrial trifunctional protein;
NH3 , ammonia.
From Shekhawat PS, Matern D, Strauss AW: Fetal fatty oxidation disorders, their effect on
maternal health and neonatal outcome: impact of expanded newborn screening on their diagnosis
and management, Pediatr Res 57:78R–84R, 2005.

Clinical manifestations characteristically involve tissues with a high β-

oxidation flux, including liver, skeletal, and cardiac muscle. The most common
presentation is an acute episode of life-threatening coma, hepatic
encephalopathy, and hypoglycemia induced by a period of fasting resulting from
defective hepatic ketogenesis. Other manifestations may include chronic
cardiomyopathy and muscle weakness or exercise-induced acute
rhabdomyolysis. The fatty acid oxidation defects can often be asymptomatic
during periods when there is no fasting stress or increased energy demand.
Acutely presenting disease may be misdiagnosed as Reye syndrome or, if fatal,
as sudden unexpected infant death . Fatty acid oxidation disorders are easily
overlooked because the only specific clue to the diagnosis may be the finding of
inappropriately low concentrations of plasma or urinary ketones in an infant who
has hypoglycemia, unless specialized metabolic testing is performed. Genetic
defects in ketone body utilization may also be overlooked because ketonemia is
an expected finding with fasting hypoglycemia. In some circumstances, clinical
manifestations appear to arise from toxic effects of fatty acid metabolites rather
than inadequate energy production. These circumstances include certain long-
chain fatty acid oxidation disorders (deficiencies of long-chain 3-hydroxyacyl
dehydrogenase [LCHAD ], carnitine palmitoyltransferase-IA [CPT-IA ], or
mitochondrial trifunctional protein [MTP ; also known as TFP]) in which the
presence of a homozygous affected fetus increases the risk of a life-threatening
involves a complex series of reactions that involves at least 23 distinct proteins.
These proteins, referred to as peroxins, are encoded by PEX genes.

Table 104.2
Classification of Peroxisomal Disorders

PEROXISOMAL BIOGENESIS DISORDERS SINGLE-ENZYME DEFECTS

Zellweger spectrum disorder X-linked adrenoleukodystrophy
Zellweger syndrome Acyl-CoA oxidase deficiency
Neonatal adrenoleukodystrophy (ALD) Bifunctional enzyme deficiency
Infantile Refsum disease 2-Methylacyl-CoA racemase
Rhizomelic chondrodysplasia punctata (RCDP) and other PEX7 deficiency
conditions DHAP acyltransferase deficiency
Alkyl-DHAP synthase deficiency
Adult Refsum disease

Epidemiology
Except for X-linked adrenoleukodystrophy (ALD) , all the peroxisomal
disorders listed in Table 104.2 are autosomal recessive diseases . ALD is the
most common peroxisomal disorder, with an estimated incidence of 1 in 17,000
live births. The combined incidence of the other peroxisomal disorders is
estimated to be 1 in 50,000 live births, although with broader newborn screening
it is expected that the actual incidences of all of the disorders of very-long-chain
fatty acids will be more accurately established.

Pathology
Absence or reduction in the number of peroxisomes is pathognomonic for
disorders of peroxisome biogenesis. In most disorders, membranous sacs contain
peroxisomal integral membrane proteins, which lack the normal complement of
matrix proteins; these are peroxisome “ghosts.” Pathologic changes are observed
in most organs and include profound and characteristic defects in neuronal
migration, micronodular cirrhosis of the liver, renal cysts, chondrodysplasia
punctata, sensorineural hearing loss, retinopathy, congenital heart disease, and
dysmorphic features.

Pathogenesis
All pathologic changes likely are secondary to the peroxisome defect. Multiple
peroxisomal enzymes fail to function in the PBDs (Table 104.3 ). The enzymes
that are diminished or absent are synthesized but are degraded abnormally fast
because they may be unprotected outside the peroxisome. It is not clear how
defective peroxisome functions lead to the widespread pathologic
manifestations.
Table 104.3
Abnormal Laboratory Findings Common to
Zellweger Spectrum Disorders
Peroxisomes absent to reduced in number
Catalase in cytosol
Deficient synthesis and reduced tissue levels of plasmalogens
Defective oxidation and abnormal accumulation of very-long-chain fatty
acids
Deficient oxidation and age-dependent accumulation of phytanic acid
Defects in certain steps of bile acid formation and accumulation of bile
acid intermediates
Defects in oxidation and accumulation of L -pipecolic acid
Increased urinary excretion of dicarboxylic acids

Mutations in 12 different PEX genes have been identified in PBDs. The

pattern and severity of pathologic features vary with the nature of the import
defects and the degree of import impairment. These gene defects lead to
disorders that were named before their relationship to the peroxisome was
recognized, namely, Zellweger syndrome, neonatal ALD, infantile Refsum
disease, and rhizomelic chondrodysplasia punctata (RCDP ). The first 3
disorders are considered to form a clinical continuum , with Zellweger syndrome
the most severe, infantile Refsum disease the least severe, and neonatal ALD
intermediate. They can be caused by mutations in any of the 11 genes involved
in peroxisome assembly. The specific gene defects cannot be distinguished by
clinical features. The clinical severity varies with the degree to which protein
import is impaired. Mutations that abolish import completely are often
associated with the Zellweger syndrome phenotype, whereas a missense
mutation, in which some degree of import function is retained, leads to the

FIG. 104.3 Zellweger syndrome. Three affected neonates. Note the hypotonia, high
forehead with shallow supraorbital ridges, anteverted nares, and mild micrognathia, as
well as the talipes equinovarus and contractures at the knees. (From Shaheen R, Al-
Dirbashi OY, Al-Hassnan ZN, et al: Clinical, biochemical and molecular characterization
of peroxisomal diseases in Arabs, Clin Genet 79(1):60–70, 2011.)

Table 104.4
Main Clinical Abnormalities in Zellweger Syndrome

PATIENTS IN WHOM THE FEATURE WAS PRESENT

ABNORMAL FEATURE
Number %
High forehead 58 97
Flat occiput 13 81
Large fontanelle(s), wide sutures 55 96
 Shallow orbital ridges 33 100
Low/broad nasal bridge 23 100
Epicanthus 33 92
High-arched palate 35 95
External ear deformity 39 97
Micrognathia 18 100
Redundant skin fold of neck 13 100
Brushfield spots 5 83
Cataract/cloudy cornea 30 86
Glaucoma 7 58
Abnormal retinal pigmentation 6 40
Optic disc pallor 17 74
Severe hypotonia 94 99
Abnormal Moro response 26 100
Hyporeflexia or areflexia 56 98
Poor sucking 74 96
Gavage feeding 26 100
Epileptic seizures 56 92
Psychomotor retardation 45 100
Impaired hearing 9 40
Nystagmus 30 81
From Heymans HAS: Cerebro-hepato-renal (Zellweger) syndrome: clinical and biochemical
consequences of peroxisomal dysfunctions, Thesis, University of Amsterdam, 1984.

Patients with neonatal ALD show fewer, less prominent craniofacial features.
Neonatal seizures occur frequently. Some degree of psychomotor developmental
delay is present; function remains in the range of severe intellectual disability,
and development may regress after 3-5 yr of age, probably from a progressive
leukodystrophy. Hepatomegaly, impaired liver function, pigmentary
degeneration of the retina, and severely impaired hearing are invariably present.
Adrenocortical function is usually impaired and may require adrenal hormone
replacement. Chondrodysplasia punctata and renal cysts are absent.
Patients with infantile Refsum disease have survived to adulthood. They can
walk, although gait may be ataxic and broad based. Cognitive function is
generally impaired, but accurate assessment is limited, usually by the presence
of both vision and hearing impairment. Almost all have some degree of
sensorineural hearing loss and pigmentary degeneration of the retina. They have
moderately dysmorphic features that may include epicanthal folds, a flat nose
bridge, and low-set ears. Early hypotonia and hepatomegaly with impaired
function are common. Levels of plasma cholesterol and high-density and low-
density lipoprotein are often moderately reduced. Chondrodysplasia punctata
and renal cortical cysts are absent. Postmortem study in infantile Refsum disease
reveals micronodular liver cirrhosis and small, hypoplastic adrenals. The brain
shows no malformations, except for severe hypoplasia of the cerebellar granule
are normal, but plasma phytanic acid levels are increased and red blood cell
(RBC) plasmalogen levels are reduced. In other peroxisomal disorders, the
biochemical abnormalities are still more restricted. Therefore, a panel of tests is
recommended and includes plasma levels of VLCFAs and phytanic, pristanic,
and pipecolic acids and RBC levels of plasmalogens. Tandem mass spectrometry
techniques also permit convenient quantitation of bile acids in plasma and urine.
This panel of tests can be performed on very small amounts of venous blood and
permits detection of most peroxisomal disorders. Furthermore, normal results
make the presence of the typical peroxisomal disorder unlikely. Biochemical
findings combined with the clinical presentation are often sufficient to arrive at a
clinical diagnosis. Methods using dried blood spots of filter paper have been
developed and are being incorporated into newborn screening assays.

Table 104.5
Diagnostic Biochemical Abnormalities in Peroxisomal
Disorders

DISORDER VLCFA PHYTANIC ACID PRISTANIC ACID PLASMALOGENS

ZSD ↑↑ ↑* ↑* ↓
RCDP Nl ↑ Nl ↓↓
ALD ↑ Nl Nl Nl
ACoX ↑ Nl Nl Nl
Bifunctional enzyme deficiency ↑ ↑ ↑ Nl
AMACR Nl ↑ ↑ Nl
Refsum disease Nl ↑ ↑ Nl
* Phytanic acid and pristanic acid accumulation is age dependent, and normal (Nl) levels may be

seen in infants and young children.

VLCFA, Very-long-chain fatty acids; ZSD, Zellweger spectrum disorder; RCDP, rhizomelic
chondroplasia punctata; ALD, adrenoleukodystrophy; ACoX, acyl-CoA oxidase deficiency;
AMACR, 2-methylacyl-CoA racemase deficiency.

The next step in diagnosis is generally to proceed to molecular DNA

diagnosis, and many clinical laboratories provide a peroxisomal panel using
next-generation technology. In some circumstances the diagnosis has been
revealed through whole exome sequencing and the pathogenic nature of the
alteration then confirmed through biochemical means.
Definition of the molecular defect in the proband is essential for carrier
detection and speeds prenatal diagnosis . Characterization of the mutation may
be of prognostic value in patients with PEX1 defects. This defect is present in
approximately 60% of PBD patients, and about half the PEX1 defects have the
C-II, and C-III are small peptides important in triglyceride metabolism. Loss of
function and disruptive mutations of the APOC3 gene are associated with low
levels of triglycerides and a reduced risk of ischemic CHD. Likewise, apoE ,
which is present in VLDL, HDL, chylomicrons, and chylomicron remnants,
plays an important role in the clearance of triglycerides.

Table 104.6
Characteristics of the Major Lipoproteins

COMPOSITION
SIZE DENSITY
LIPOPROTEIN SOURCE Protein Lipid
(nm) (g/mL) Apolipoproteins
(%) (%)
Chylomicrons Intestine 80- <0.95 1-2 98-99 C-I, C-II, C-III, E, A-I, A-
1,200 II, A-IV, B-48
Chylomicron Chylomicrons 40-150 <1.0006 6-8 92-94 B-48, E
remnants
VLDL Liver, intestine 30-80 0.95-1.006 7-10 90-93 B-100, C-I, C-II, C-III
IDL VLDL 25-35 1.006-1.019 11 89 B-100, E
LDL VLDL 18-25 1.019-1.063 21 79 B-100
HDL Liver, intestine VLDL, 5-20 1.125-1.210 32-57 43-68 A-I, A-II, A-IV C-I, C-II,
chylomicrons C-III D, E
HDL, High-density lipoproteins; IDL, intermediate-density lipoproteins; LDL, low-density
lipoproteins; VLDL, very-low-density lipoproteins.

Transport of Exogenous (Dietary) Lipids

All dietary fat except medium-chain triglycerides is efficiently carried into the
circulation by way of lymphatic drainage from the intestinal mucosa.
Triglyceride and cholesteryl esters combine with apoA and apoB-48 in the
intestinal mucosa to form chylomicrons, which are carried into the peripheral
circulation via the lymphatic system. HDL particles contribute apoC-II to the
chylomicrons, required for the activation of lipoprotein lipase (LPL) within the
capillary endothelium of adipose, heart, and skeletal muscle tissue. Free fatty
acids are oxidized, esterified for storage as triglycerides, or released into the
circulation bound to albumin for transport to the liver. After hydrolysis of the
triglyceride core from the chylomicron, apoC particles are recirculated back to
HDL. The subsequent contribution of apoE from HDL to the remnant
chylomicron facilitates binding of the particle to hepatic LDL receptor (LDL-R).
Within the hepatocyte, the chylomicron remnant may be incorporated into
membranes, resecreted as lipoprotein back into the circulation, or secreted as
Because hepatic secretion of lipid particles into the bile is the only mechanism
by which cholesterol can be removed from the body, transport of excess
cholesterol from the peripheral cells is a vitally important function of HDL. HDL
is heavily laden with apoA-I–containing lipoproteins, which is nonatherogenic,
in contrast to B lipoproteins. Cholesterol-poor nascent HDL particles secreted by
the liver and small intestine are esterified to more mature HDL-2 particles by the
action of the enzyme lecithin-cholesterol acyltransferase (LCAT ), which
facilitates movement of chylomicrons and VLDL into the HDL core. HDL-2
may transfer cholesteryl esters back to apoB lipoproteins mediated by
cholesteryl ester transfer protein (CETP), or the cholesterol-rich particle may be
removed from the plasma by endocytosis, completing reverse cholesterol
transport. Low HDL may be genetic (deficiency of apoA-I) or secondary to
increased plasma triglyceride.
LCAT deficiency results in diminished maturation of HDL particles, affecting
their ability to do reverse cholesterol transport. This reduces its protective effect
on atherosclerosis. There are rare reports, however, of less-than-expected
severity of atherosclerosis despite low HDL secondary to LCAT deficiency,
suggesting that the relationship may, for unknown reasons, be variable.

Hyperlipoproteinemias
Hypercholesterolemia
See Table 104.7 .

Table 104.7
Hyperlipoproteinemias

LIPOPROTEINS ESTIMATED
DISORDER CLINICAL FINDINGS GENETICS
ELEVATED INCIDENCE
Familial hypercholesterolemia LDL Tendon xanthomas, CHD AD 1 in 500
Familial defective ApoB-100 LDL Tendon xanthomas, CHD AD 1 in 1,000
Autosomal recessive LDL Tendon xanthomas, CHD AR <1 in
hypercholesterolemia 1,000,000
Sitosterolemia LDL Tendon xanthomas, CHD AR <1 in
1,000,000
Polygenic LDL CHD 1 in 30?
hypercholesterolemia
Familial combined LDL, TG CHD AD 1 in 200
hyperlipidemia
 Familial LDL, TG Tuberoeruptive xanthomas, AD 1 in 10,000
dysbetalipoproteinemia peripheral vascular disease
Familial chylomicronemia TG ↑↑ Eruptive xanthomas, AR 1 in 1,000,000
(Frederickson type I) hepatosplenomegaly,
pancreatitis
Familial hypertriglyceridemia TG ↑ ±CHD AD 1 in 500
(Frederickson type IV)
Familial hypertriglyceridemia TG ↑↑ Xanthomas ± CHD AD —
(Frederickson type V)
Familial hepatic lipase VLDL CHD AR <1 in
deficiency 1,000,000
AD, Autosomal dominant; AR, autosomal recessive; CHD, coronary heart disease; LDL, low-
density lipoproteins, TG, triglycerides; VLDL, very-low-density lipoproteins.

Familial Hypercholesterolemia
Familial hypercholesterolemia (FH) is a monogenic autosomal co-dominant
disorder characterized by strikingly elevated LDL cholesterol (LDL-C),
premature cardiovascular disease (CVD), and tendon xanthomas. In the past, FH
referred to defects of LDL-R activity. The etiology of this lipoprotein
abnormality also includes defects in the genes for apoB (as well as PCSK-9). Of
the almost 1200 mutations described, some result in failure of synthesis of the
LDL-R (receptor negative), and others cause defective binding or release at the
lipoprotein-receptor interface. Receptor-negative mutations result in more severe
phenotypes than receptor-defective mutations.

Homozygous Familial Hypercholesterolemia

FH homozygotes inherit 2 abnormal LDL receptor genes, resulting in markedly
elevated plasma cholesterol levels ranging between 500 and 1,200 mg/dL.
Triglyceride levels are normal to mildly elevated, and HDL levels may be
slightly decreased. The condition occurs in 1 in 500,000 persons. Receptor-
negative patients have <2% normal LDL-R activity, whereas those who are
receptor defective may have as much as 25% normal activity and a better
prognosis.
The prognosis is poor regardless of the specific LDL-R aberration. Severe
atherosclerosis involving the aortic root and coronary arteries is present by early
to middle childhood. These children usually present with xanthomas , which
may cause thickening of the Achilles tendon or extensor tendons of the hands, or
cutaneous lesions on the hands, elbows, knees, or buttocks (Figs. 104.10 to
104.12 ). Corneal arcus may be present. Family history is informative because
premature heart disease is strongly prevalent among relatives of both parents.
risk of CHD in individuals with FH can be up to 20 times greater than in the
general population.
Plasma levels of LDL-C do not allow unequivocal diagnosis of FH
heterozygotes, but values are generally twice normal for age because of 1 absent
or dysfunctional allele. The U.S. MED-PED (Make Early Diagnosis–Prevent
Early Death) Program has formulated diagnostic criteria. Similar criteria with
minor variations exist in the United Kingdom (Simon Broome criteria) and
Holland (Dutch Lipid Clinic Network criteria). Within well-defined FH families,
the diagnosis is reliably established according to LDL cutoff points. More
stringent criteria are required to establish the diagnosis in previously
undiagnosed families, requiring strong evidence of an autosomal inheritance
pattern and higher LDL cutoff points. At a total cholesterol level of 310 mg/dL,
only 4% of adults in the general population would have FH, whereas 95% of
adults who were first-degree relatives of known cases would have the disease.
The mathematical probability of FH in MED-PED, verified by molecular
genetics, is derived from a U.S. population cohort and may not be applicable to
other countries.
Very high cholesterol levels in children should prompt extensive screening of
adult first- and second-degree relatives (“reverse cascade” cholesterol
screening). In the general population, a child younger than age 18 yr with total
plasma cholesterol of 270 mg/dL and/or LDL-C of 200 mg/dL has an 88%
chance of having FH (Table 104.8 ). Formal clinical diagnosis of FH is based on
the presence of 2 or more family members having elevated LDL-C levels (the
95th percentile LDL-C level cutoff points for children vary with age and are
lower than for adults; see Table 104.9 ). Thus the criteria for probable FH in a
child whose first-degree relative has known FH require only modest elevation of
total cholesterol to 220 mg/dL (LDL-C 160 mg/dL; Table 104.8 ). The challenge
of childhood FH diagnosis is heightened by the lack of clinical stigmata such as
xanthomata that are employed in the Simon Broome and Dutch Lipid Clinic
Network schema and highlights the shift toward genetic diagnosis.

Table 104.8
Percentage of Youths Younger than Age 18 Yr Expected to
Have Familial Hypercholesterolemia (FH) According to
Cholesterol Levels and Closest Relative With FH
 PERCENTAGE WITH FH AT THAT LEVEL
TOTAL CHOL (mg/dL) LDL CHOL (mg/dL) Degree of Relative
General Population
First Second Third
180 122 7.2 2.4 0.9 0.01
190 130 13.5 5.0 2.2 0.03
200 138 26.4 10.7 4.9 0.07
210 147 48.1 23.6 11.7 0.19
220 155 73.1 47.5 27.9 0.54
230 164 90.0 75.0 56.2 1.8
240 172 97.1 93.7 82.8 6.3
250 181 99.3 97.6 95.3 22.2
260 190 99.9 99.5 99.0 57.6
270 200 100.0 99.9 99.8 88.0
280 210 100.0 100.0 100.0 97.8
290 220 100.0 100.0 100.0 99.6
300 230 100.0 100.0 100.0 99.9
310 240 100.0 100.0 100.0 100.0
Chol, Cholesterol; LDL, low-density lipoprotein.
From Williams RR, Hunt SC, Schumacher MC, et al: Diagnosing heterozygous familial
hypercholesterolemia using new practical criteria validated by molecular genetics, Am J Cardiol
72:171–176, 1993.

Table 104.9
Plasma Cholesterol and Triglyceride Levels in Childhood
and Adolescence: Means and Percentiles

TOTAL TRIGLYCERIDE TOTAL CHOLESTEROL LDL CHOLESTEROL HDL CHOLESTEROL

(mg/dL) (mg/dL) (mg/dL) (mg/dL)*
5th Mean 75th 90th 95th 5th Mean 75th 90th 95th 5th Mean 75th 90th 95th 5th 10th 25th
Cord 14 34 — — 84 42 68 — — 103 17 29 — — 50 13 —
1-4 YR
Male 29 56 68 85 99 114 155 170 190 203 — — — — — — —
Female 34 64 74 95 112 112 156 173 188 200 — — — — — — —
5-9 YR
Male 28 52 58 70 85 125 155 168 183 189 63 93 103 117 129 38 42
Female 32 64 74 103 126 131 164 176 190 197 68 100 115 125 140 36 38
10-14 YR
Male 33 63 74 94 111 124 160 173 188 202 64 97 109 122 132 37 40
Female 39 72 85 104 120 125 160 171 191 205 68 97 110 126 136 37 40
15-19 YR
Male 38 78 88 125 143 118 153 168 183 191 62 94 109 123 130 30 34
Female 36 73 85 112 126 118 159 176 198 207 59 96 111 29 137 35 38
* Note that different percentiles are listed for high-density lipoprotein (HDL) cholesterol. LDL, Low-
density lipoprotein.
Data for cord blood from Strong W: Atherosclerosis: its pediatric roots. In Kaplan N, Stamler J,
editors: Prevention of coronary heart disease , Philadelphia, 1983, Saunders. Data for children 1-
Table 104.10
Secondary Causes of Hyperlipidemia
Hypercholesterolemia

Hypothyroidism
Nephrotic syndrome
Cholestasis
Anorexia nervosa
Drugs: progesterone, thiazides, carbamazepine (Tegretol), cyclosporine

Hypertriglyceridemia

Obesity
Type 2 diabetes
Alcohol
Renal failure
Sepsis
Stress
Cushing syndrome
Pregnancy
Hepatitis
AIDS, protease inhibitors
Drugs: anabolic steroids, β-blockers, estrogen, thiazides

Reduced High-Density Lipoprotein

Smoking
Obesity
Type 2 diabetes
Malnutrition
Drugs: β-blockers, anabolic steroids

Treatment of hypertriglyceridemia in children rarely requires medication

unless levels >1,000 mg/dL persist after dietary restriction of fats, sugars, and
Familial Hypobetalipoproteinemia
Familial homozygous hypobetalipoproteinemia is associated with symptoms
very similar to those of abetalipoproteinemia, but the inheritance pattern is
autosomal co-dominant. The disease is caused by mutations in the gene encoding
apoB-100 synthesis. It is distinguishable from abetalipoproteinemia in that
heterozygous parents of probands have plasma LDL-C and apoB levels less than
half normal. There are no symptoms or sequelae associated with the
heterozygous condition.
The selective inability to secrete apoB-48 from the small intestine results in a
condition resembling abetalipoproteinemia or homozygous
hypobetalipoproteinemia. Sometimes referred to as Anderson disease , the
failure of chylomicron absorption causes steatorrhea and fat-soluble vitamin
deficiency. The blood level of apoB-100, derived from normal hepatocyte
secretion, is normal in this condition.

Smith-Lemli-Opitz Syndrome
Patients with Smith-Lemli-Opitz syndrome (SLOS ) often have multiple
congenital anomalies and developmental delay caused by low plasma cholesterol
and accumulated precursors (Tables 104.11 and 104.12 ) (see Chapter 606.2 ).
Family pedigree analysis has revealed its autosomal recessive inheritance
pattern. Mutations in the DHCR7 (7-dehydrocholesterol-Δ7 reductase) gene
result in deficiency of the microsomal enzyme DHCR7, which is necessary to
complete the final step in cholesterol synthesis. It is not known why defects in
cholesterol synthesis result in congenital malformations, but since cholesterol is
a major component of myelin and a contributor to signal transduction in the
developing nervous system, neurodevelopment is severely impaired. The
incidence of SLOS is estimated to be 1 in 20,000-60,000 births among whites,
with a somewhat higher frequency in Hispanics and lower incidence in
individuals of African descent.
Table 104.11
Major Clinical Characteristics of Smith-
Lemli-Opitz Syndrome: Frequent Anomalies
(>50% of Patients)
Craniofacial
 Microcephaly
Blepharoptosis
Anteverted nares
Retromicrognathia
Low-set, posteriorly rotated ears
Midline cleft palate
Broad maxillary alveolar ridges
Cataracts (<50%)

Skeletal Anomalies

Syndactyly of toes II/III

Postaxial polydactyly (<50%)
Equinovarus deformity (<50%)

Genital Anomalies

Hypospadias
Cryptorchidism
Sexual ambiguity (<50%)

Development

Prenatal and postnatal growth retardation

Feeding problems
Mental impairment
Behavioral abnormalities

From Haas D, Kelley RI, Hoffmann GF: Inherited disorders of cholesterol

biosynthesis, Neuropediatrics 32:113–122, 2001.
Table 104.12
Characteristic Malformations of Internal
Organs in Severely Affected Smith-Lemli-
Opitz Patients
Central Nervous System

Frontal lobe hypoplasia

Enlarged ventricles
Agenesis of corpus callosum
Cerebellar hypoplasia
Holoprosencephaly

Cardiovascular

Atrioventricular canal
Secundum atrial septal defect
Patent ductus arteriosus
Membranous ventricular septal defect

Urinary Tract

Renal hypoplasia or aplasia

Renal cortical cysts
Hydronephrosis
Ureteral duplication

Gastrointestinal

Hirschsprung disease
Pyloric stenosis
Refractory dysmotility
Cholestatic and noncholestatic progressive liver disease

Pulmonary

Pulmonary hypoplasia
Abnormal lobation
Endocrine

Adrenal insufficiency

From Haas D, Kelley RI, Hoffmann GF: Inherited disorders of cholesterol

biosynthesis, Neuropediatrics 32:113–122, 2001.

Spontaneous abortion of SLOS fetuses may occur. Type II SLOS often leads
to death by the end of the neonatal period. Survival is unlikely when the plasma
cholesterol level is <20 mg/dL. Laboratory measurement should be performed
by gas chromatography, because standard techniques for lipoprotein assay
include measurement of cholesterol precursors, which may yield a false-positive
result. Milder cases may not present until late childhood. Phenotypic variance
ranges from microcephaly, cardiac and brain malformation, and multiorgan
system failure to only subtle dysmorphic features and mild developmental delay.
Treatment includes supplemental dietary cholesterol (egg yolk) and HMG-CoA
reductase inhibition to prevent the synthesis of toxic precursors proximal to the
enzymatic block.

Disorders of Intracellular Cholesterol

Metabolism
Cerebrotendinous Xanthomatosis
This autosomal recessive disorder presents clinically in late adolescence with
tendon xanthomas, cataracts, and progressive neurodegeneration. It is caused by
tissue accumulation of bile acid intermediates shunted into cholestanol, resulting
from mutations in the gene for sterol 27-hydroxylase. This enzyme is necessary
for normal mitochondrial synthesis of bile acids in the liver. Early treatment with
chenodeoxycholic acid reduces cholesterol levels and prevents the development
of symptoms.

Wolman Disease and Cholesterol Ester Storage Disease

These autosomal recessive disorders are caused by lack of lysosomal acid lipase.
After LDL cholesterol is incorporated into the cell by endocytosis, it is delivered
to lysosomes, where it is hydrolyzed by lysosomal lipase. Failure of hydrolysis
complex rather than simple carbohydrates is emphasized.
If followed, these dietary recommendations will provide adequate calories for
optimal growth and development without promoting obesity. Compliance on the
part of children and their caregivers is challenging. Children learn eating habits
from their parents. Successful adoption of a healthier lifestyle is much more
likely to occur if meals and snacks in the home are applicable to the entire
family rather than an individual child. A regular time for meals together as a
family is desirable. Grandparents and other nonparental caregivers sometimes
need to be reminded not to indulge the child who is on a restricted diet.
Additionally, the rise in obesity is prompting some school districts to restrict
sweetened drink availability and offer more nutritious cafeteria selections.
Changes in physical activity habits are also an important part of the initial
lifestyle modification. The National Association for Sport and Physical
Education recommends that children should accumulate at least 60 min of age-
appropriate physical activity on most days of the week. Extended periods (≥2 hr)
of daytime inactivity are discouraged, as is >2 hr of television and other forms of
screen time.

Pharmacologic Therapy.
See Tables 104.13 and 104.14 .

Table 104.13
Drugs Used for the Treatment of Hyperlipidemia

DRUG MECHANISM OF ACTION INDICATION STARTING DOSE

HMG-CoA reductase inhibitors ↓ Cholesterol and VLDL Elevated LDL 5-80 mg every night at
(statins) synthesis bedtime
↑ Hepatic LDL receptors
Bile acid sequestrants: ↑ Bile and excretion Elevated LDL
Cholestyramine 4-32 g daily
Colestipol 5-40 g daily
Nicotinic acid ↓ Hepatic VLDL synthesis Elevated LDL 100-2,000 mg 3 times
daily
Elevated TG
Fibric acid derivatives: ↑ LPL Elevated TG 600 mg twice daily
Gemfibrozil ↓ VLDL
Fish oils ↓ VLDL production Elevated TG 3-10 g daily
Cholesterol absorption inhibitors:
Ezetimibe ↓ Intestinal absorption Elevated LDL 10 mg daily
cholesterol
LDL, Low-density lipoprotein(s); LPL, lipoprotein lipase; TG, triglycerides; VLDL, very-low-density
lipoprotein.

Table 104.14
Adverse Effects of Cholesterol-Lowering
Drugs
Statins

Myalgia, myositis, transaminase elevations, hepatic dysfunction, increased

risk of diabetes mellitus
Rare: Rhabdomyolysis, hemorrhagic stroke

Ezetimibe

Diarrhea, arthralgia, rhabdomyolysis, hepatitis, pancreatitis,

thrombocytopenia

Pcsk9 Inhibitors

Nasopharyngitis, upper respiratory tract infection, influenza, back pain,

injection site reactions, rash, allergic skin reactions, cognitive effects,
antidrug antibodies

Bile Acid Sequestrants

Constipation, heartburn, nausea, eructation, bloating

Adverse effects are more common with colestipol and cholestyramine and
may diminish over time.

Fibric Acid Derivatives

Gastrointestinal (GI) disturbances, cholelithiasis, hepatitis, myositis

Niacin
 Skin flushing, pruritus, GI disturbances, blurred vision, fatigue, glucose
intolerance, hyperuricemia, hepatic toxicity, exacerbation of peptic ulcers
Adverse effects, especially flushing, occur more frequently with
immediate-release products.
Rare: Dry eyes, hyperpigmentation

Fish Oil

Eructation, dyspepsia, unpleasant aftertaste

From The Medical Letter: Lipid-lowering drugs, Med Lett 58:133-140, 2016
(Table 2, p 136).

Pharmacologic therapy with cholesterol-lowering medication is the

cornerstone of therapy for children who fail to respond to 6 mo of rigorous
lifestyle modification. Drug therapy should be considered when 1 of the
following conditions are met (also shown in Fig. 104.14 ):

◆ LDL cholesterol remains >190 mg/dL

◆ LDL cholesterol remains >160 mg/dL with
presence of 1 high-level risk factor and/or at least 2
moderate-level risk factors
◆ LDL cholesterol remains >130 mg/dL with
presence of at least 2 high-level risk factors, 1 high-
level risk factor, and at least 2 moderate-level risk
factors, or evidence of coronary artery disease (CAD)
HMG-CoA reductase inhibitors, also known as “statins” are remarkably
effective in lowering LDL cholesterol levels and reducing plaque inflammation,
thereby reducing the likelihood of a sudden coronary event in an at-risk adult
within weeks of starting the medication. As a class, they work by blocking the
intrahepatic biosynthesis of cholesterol, thereby stimulating the production of
more LDL receptors on the cell surface and facilitating the uptake of LDL-C
 Multiple sulfatase deficiency
Krabbe disease

The lysosomal lipid storage diseases are diverse disorders, each caused by an
inherited deficiency of a specific lysosomal hydrolase leading to the
intralysosomal accumulation of the enzyme's particular substrate (Tables 104.15
and 104.16 ). Except for Wolman disease and cholesterol ester storage disease,
the lipid substrates share a common structure that includes a ceramide backbone
(2-N -acylsphingosine) from which the various sphingolipids are derived by
substitution of hexoses, phosphorylcholine, or 1 or more sialic acid residues on
the terminal hydroxyl group of the ceramide molecule. The pathway of
sphingolipid metabolism in nervous tissue (Fig. 104.15 ) and in visceral organs
(Fig. 104.16 ) is known; each catabolic step, with the exception of the catabolism
of lactosylceramide, has a genetically determined metabolic defect and a
resultant disease. Because sphingolipids are essential components of all cell
membranes, the inability to degrade these substances and their subsequent
accumulation results in the physiologic and morphologic alterations and
characteristic clinical manifestations of the lipid storage disorders (Table 104.15
). Progressive lysosomal accumulation of glycosphingolipids in the CNS leads to
neurodegeneration, whereas storage in visceral cells can lead to organomegaly,
skeletal abnormalities, pulmonary infiltration, and other manifestations. The
storage of a substrate in a specific tissue depends on its normal distribution in the
body.

Table 104.15
Clinical Findings in Lysosomal Storage Diseases

COARSE
FACIAL
HYDROPS
NOMENCLATURE ENZYME DEFECT FEATURES HEPATOSPLENOMEGALY
FETALIS
DYSOSTOSIS
MULTIPLEX
MUCOLIPIDOSES
Mucolipidoses II, I-cell N - (+) ++ +
disease Acetylglucosaminylphosphotransferase
Mucolipidosis III, N - − + (+)
pseudo-Hurler Acetylglucosaminylphosphotransferase
Mucolipidosis IV Unknown − − +
SPHINGOLIPIDOSES
Fabry disease α-Galactosidase − − −
Farber disease Acid ceramidase − − (+)
 Galactosialidosis β-Galactosidase and sialidase (+) ++ ++
GM1 gangliosidosis β-Galactosidase (+) ++ +
GM2 gangliosidosis β-Hexosaminidases A and B − − (+)
(Tay-Sachs, Sandhoff
disease)
Gaucher type I Glucocerebrosidase − − ++
Gaucher type II Glucocerebrosidase (+) − ++
Gaucher type III Glucocerebrosidase (+) − +
Niemann-Pick type A Acid Sphingomyelinase (+) − ++
Niemann-Pick type B Acid Sphingomyelinase − − ++
Metachromatic Arylsulfatase A − − −
leukodystrophy
Krabbe disease β-Galactocerebrosidase − − −
LIPID STORAGE DISORDERS
Niemann-Pick type C Intracellular cholesterol transport − − (+)
Wolman disease Lysosomal acid lipase (+) − +
Ceroid lipofuscinosis, Palmitoyl-protein thioesterase (CLN1) − − −
infantile (Santavuori-
Haltia)
Ceroid lipofuscinosis, Pepstatin-insensitive peptidase − − −
late infantile (Jansky- (CLN2); variants in Finland (CLN5),
Bielschowsky) Turkey (CLN7), and Italy (CLN6)
Ceroid lipofuscinosis, CLN3, membrane protein − − −
juvenile (Spielmeyer-
Vogt)
Ceroid lipofuscinosis, CLN4, probably heterogeneous (+) − −
adult (Kufs, Parry)
OLIGOSACCHARIDOSES
Aspartylglucosaminuria Aspartylglucosylaminase − + (+)
Fucosidosis α-Fucosidase − ++ (+)
α-Mannosidosis α-Mannosidase − ++ +
β-Mannosidosis β-Mannosidase − + (+)
Schindler disease α-N -Acetylgalactosaminidase − − −
Sialidosis I Sialidase (+) − −
Sialidosis II Sialidase (+) ++ +
++, Prominent; +, often present; (+), inconstant or occurring later in the disease course; –, not
present.
Modified from Hoffmann GF, Nyhan WL, Zschoke J, et al: Storage disorders in inherited metabolic
diseases , Philadelphia, 2002, Lippincott Williams & Wilkins, pp 346–351.

Table 104.16
Lysosomal Storage Disorders in the Newborn Period:
Genetic and Clinical Characteristics of Neonatal
Presentation

NEUROLOGIC DISTINCTIVE EYE

DISORDER ONSET FACIES DEFECT
FINDINGS FEATURES FINDINGS
Niemann–Pick A Early Frontal Difficulty Brownish- Cherry-red Sphingomyelinase
disease infancy bossing feeding, apathy, yellow skin, spot (50%) deficiency
deafness, xanthomas
blindness,
hypotonia
Niemann–Pick C Birth–3 Normal Developmental – – Abnormal
disease months delay, vertical cholesterol
gaze paralysis, esterification
hypotonia, later
spasticity

Gaucher disease type 2 In utero– Normal Poor suck and Congenital – Glucocerebrosidase
6 months swallow, weak ichthyosis, deficiency
cry, squint, collodion skin
trismus,
strabismus,
opsoclonus,
hypertonic, later
flaccidity
Krabbe disease 3–6 Normal Irritability, tonic Increased CSF Optic Galactocerebrosidase
months spasms with light protein level atrophy deficiency
or noise
stimulation,
seizures,
hypertonia, later
flaccidity
GM1 gangliosidosis Birth Coarse Poor suck, weak Gingival Cherry-red β-Galactosidase
cry, lethargy, hypertrophy, spot (50%) deficiency
exaggerated edema, rashes
startle, blindness,
hypotonia, later
spasticity
Farber disease type I 2 weeks– Normal Progressive Joint swelling Grayish Lysosomal acid
4 months psychomotor with nodules, opacification ceramidase
impairment, hoarseness, lung surrounding
seizures, disease, retina in
decreased contractures, some
reflexes, fever, patients,
hypotonia granulomas, subtle
dysphagia, cherry-red
vomiting, spot
increased CSF
protein level

Farber disease types II Birth–9 Normal — Joint swelling Normal —

and III months with nodules, macula,
(≤20 hoarseness corneal
months) opacities
Farber disease type IV Birth Normal Nodules not Corneal — —
(neonatal) consistent opacities (1/3)
findings
Congenital sialidosis In utero– Cognitive, Intellectual Neonatal Corneal Neuraminidase
birth edema impairment, ascites, inguinal clouding deficiency
hypotonia hernias, renal
disease
 Galactosialidosis In utero– Coarse Intellectual Ascites, edema, Cherry-red Absence of a
birth impairment, inguinal spot, corneal protective protein
occasional hernias, renal clouding that safeguards
deafness, disease, neuraminidase and
hypotonia telangiectasias β-galactosidase from
premature
degradation
Wolman disease First Normal Cognitive Vomiting, — Lysosomal acid
weeks of deterioration diarrhea, lipase deficiency
life steatorrhea,
abdominal
distention,
failure to thrive,
anemia, adrenal
calcifications
Infantile sialic acid In utero– Coarse, Intellectual Ascites, anemia, — Defective transport
storage disease birth dysmorphic impairment, diarrhea, failure of sialic acid out of
hypotonia to thrive the lysosome
I-cell disease In utero– Coarse Intellectual Gingival Corneal Lysosomal enzymes
birth impairment, hyperplasia, clouding lack mannose 6-
deafness restricted joint phosphate
mobility, recognition marker
hernias and fail to enter the
lysosome
(phosphotransferase
deficiency, 3-subunit
complex [α2 β2 γ2])
Mucolipidosis type IV Birth–3 Normal Intellectual — Severe Unknown; some
months impairment, corneal patients with partial
hypotonia clouding, deficiency of
retinal ganglioside sialidase
degeneration,
blindness
Mucopolysaccharidosis In utero– Variable Mild to severe Hernias Variable β-Glucuronidase
type VII childhood coarseness intellectual corneal deficiency
impairment clouding
Modified from Thomas JA, Lam C, Berry GT: Lysosomal storage, peroxisomal, and glycosylation
disorders and Smith-Lemli-Opitz syndrome presenting in the neonate. In Gleason CA, Juul SE,
editors: Avery's diseases of the newborn, ed 10, Philadelphia, 2018, Elsevier, Table 23.1.

FIG. 104.19 Typical angiokeratomas. Angiokeratomas are quite large and easily
recognizable, but if only a few lesions exist or they are restricted only to the genitalia or
umbilical regions, they can be easily missed. (From Zarate VA, Hopkin RJ: Fabry's
disease, Lancet 372:1427, 2008.)

Pain is the most debilitating symptom in childhood and adolescence. Fabry

crises, lasting from hours to several days, consist of agonizing, burning pain in
the hands, feet, and proximal extremities and are usually associated with
exercise, fatigue, fever, or a combination of these factors. These painful
acroparesthesias usually become less frequent in the 3rd and 4th decades,
although in some men these may become more frequent and severe. Attacks of
abdominal or flank pain may simulate appendicitis or renal colic. Pain may
suggest other diagnoses (Table 104.17 ).
Table 104.17
Common Misdiagnoses for Fabry Disease
Growing pains Polyphyria Erythromelalgia
Chronic overlapping Guillain-Barre syndrome Meniere disease
pain syndrome Hereditary neuropathy Coronary heart disease
Irritable bowel Uremic neuropathy Complex regional pain
syndrome Diabetic neuropathy syndromes
Malingering Polyneuropathy Multiple sclerosis
Systemic lupus C1 esterase deficiency Osler disease
erythematous TNF receptor-associated periodic syndrome (TRAPS) Appendicitis
Rheumatic fever Joint and recurrent fever syndromes (juvenile idiopathic Metabolic bone disease
Fibromyalgia arthritis, familial Mediterranean fever) (rickets, uremia, scurvy)
Dermatomyositis
Raynaud
phenomenon
Raynaud syndrome
 phosphatase; Pb, inactive phosphorylase; PbKa, active phosphorylase b kinase; PbKb,
inactive phosphorylase b kinase; UDP, uridine diphosphate. (Adapted from Beaudet AR:
Glycogen storage disease. In Harrison TR, Isselbacher KJ, editors: Harrison's
principles of internal medicine, ed 13, New York, 1994, McGraw-Hill. Reproduced with
permission of The McGraw-Hill Companies.)

Defects in glycogen metabolism typically cause an accumulation of glycogen

in the tissues, thus the name glycogen storage disease (Table 105.1 ). Defects in
gluconeogenesis or the glycolytic pathway, including galactose and fructose
metabolism, do not result in an accumulation of glycogen (Table 105.1 ). The
defects in pyruvate metabolism in the pathway of the conversion of pyruvate to
carbon dioxide and water via mitochondrial oxidative phosphorylation are more
often associated with lactic acidosis and some tissue glycogen accumulation.

Table 105.1
Features of the Disorders of Carbohydrate Metabolism

DISORDERS BASIC DEFECTS CLINICAL PRESENTATION COMMENTS

LIVER GLYCOGENOSES
Type/Common Name
Ia/Von Gierke Glucose-6- Growth retardation, hepatomegaly, Common, severe
phosphatase hypoglycemia; elevated blood hypoglycemia
lactate, cholesterol, triglyceride, and Adulthood: hepatic
uric acid levels adenomas and
carcinoma, osteoporosis,
pulmonary hypertension,
and renal failure
Ib Glucose-6-phosphate Same as type Ia, with additional 10% of type Ia
translocase findings of neutropenia, periodontal
disease, inflammatory bowel disease
IIIa/Cori or Forbes Liver and muscle Childhood: hepatomegaly, Common, intermediate
debrancher growth retardation, muscle severity of hypoglycemia
deficiency (amylo- weakness, hypoglycemia, Muscle weakness may
1,6-glucosidase) hyperlipidemia, elevated progress to need for
transaminase levels ambulation assistance
Adult form: muscle atrophy and such as wheelchair.
weakness, peripheral
neuropathy, liver cirrhosis and
failure, risk for hepatocellular
carcinoma
IIIb Liver debrancher Liver symptoms same as in type 15% of type III
deficiency; normal IIIa; no muscle symptoms
muscle enzyme
activity

IV/Andersen Branching enzyme Childhood: failure to thrive, Rare neuromuscular variants

hypotonia, hepatomegaly, exist
splenomegaly, progressive
cirrhosis (death usually before
 5th yr), elevated transaminase
levels; a subset does not have
progression of liver disease
Adult form: isolated myopathy,
central and peripheral nervous
system involvement
VI/Hers Liver phosphorylase Hepatomegaly, typically mild Often underdiagnosed, severe
hypoglycemia, hyperlipidemia, and presentation also known
ketosis
IX/phosphorylase Common, X-linked, typically
kinase (PhK) less severe than autosomal
deficiency forms; clinical variability
within and between subtypes;
severe cases being
recognized across different
subtypes
IX (PHKA2 variant) Liver PhK Hypoglycemia, hyperketosis X-linked
hepatomegaly, chronic liver disease,
hyperlipidemia, elevated liver
enzymes, growth retardation
IX (PHKB variant) Liver and muscle Hepatomegaly, growth retardation Autosomal recessive
PhK
IX (PHKG2 variant) Liver PhK More severe than IXa; marked Autosomal recessive
hepatomegaly, recurrent
hypoglycemia, liver cirrhosis
Glycogen synthase Glycogen synthase Early morning drowsiness and Decreased liver glycogen
deficiency fatigue, fasting hypoglycemia, and store
ketosis, no hepatomegaly
XI/Fanconi-Bickel Glucose transporter 2 Failure to thrive, rickets, GLUT-2 expressed in liver,
syndrome (GLUT-2) hepatorenomegaly, proximal renal kidney, pancreas, and
tubular dysfunction, impaired intestine
glucose and galactose utilization
MUSCLE GLYCOGENOSES
Type/Common Name
IX (PHKA1 variant) Muscle PhK Exercise intolerance, cramps, X-linked or autosomal
myalgia, myoglobinuria; no recessive
hepatomegaly
II/Pompe infantile Acid α-glucosidase Cardiomegaly, hypotonia, Common, cardiorespiratory
(acid maltase) hepatomegaly; onset: birth to 6 mo failure leading to death by
age 1-2 yr; minimal to no
residual enzyme activity
II/Late-onset Pompe Acid α-glucosidase
Myopathy, variable Residual enzyme activity
(juvenile and adult) (acid maltase) cardiomyopathy, respiratory
insufficiency; onset: childhood to
adulthood
Danon disease Lysosome-associated Hypertrophic cardiomyopathy, heart Rare, X-linked
membrane protein 2 failure
(LAMP2)
PRKAG2 deficiency Adenosine Hypertrophic cardiomyopathy. Autosomal dominant
monophosphate Congenital fetal form is rapidly
(AMP)–activated fatal; myopathy, myalgia, seizures
protein kinase γ
V/McArdle Myophosphorylase Exercise intolerance, muscle Common, male
cramps, myoglobinuria, “second predominance
 wind” phenomenon
VII/Tarui Phosphofructokinase Exercise intolerance, muscle Prevalent in Japanese and
cramps, compensatory hemolytic Ashkenazi Jews
anemia, myoglobinuria
Late-onset Glycogenin-1 Adult-onset proximal muscle Autosomal recessive, rare
polyglucosan body weakness, nervous system
myopathy involvement uncommon
Phosphoglycerate Phosphoglycerate As with type V Rare, X-linked
kinase deficiency kinase
Phosphoglycerate M subunit of As with type V Rare, majority of patients are
mutase deficiency phosphoglycerate African American
mutase
Lactate M subunit of lactate As with type V Rare
dehydrogenase dehydrogenase
deficiency
GALACTOSE DISORDERS
Galactosemia with Galactose-1- Vomiting, hepatomegaly, cataracts, Black patients tend to have
transferase phosphate aminoaciduria, failure to thrive milder symptoms
deficiency uridyltransferase
Galactokinase Galactokinase Cataracts Benign
deficiency
Generalized uridine Uridine diphosphate Similar to transferase deficiency A benign variant also exists
diphosphate galactose-4- with additional findings of
galactose-4- epimerase hypotonia and nerve deafness
epimerase deficiency
FRUCTOSE DISORDERS
Essential fructosuria Fructokinase Urine reducing substance Benign
Fructose-1-phosphate Acute: vomiting, sweating, lethargy
aldolase
Hereditary fructose Chronic: failure to thrive, hepatic Prognosis good with fructose
intolerance failure restriction
DISORDERS OF GLUCONEOGENESIS
Fructose-1,6- Fructose-1,6- Episodic hypoglycemia, apnea, Good prognosis, avoid
diphosphatase diphosphatase acidosis fasting
deficiency
Phosphoenolpyruvate Phosphoenolpyruvate Hypoglycemia, hepatomegaly, Rare
carboxykinase carboxykinase hypotonia, failure to thrive
deficiency
DISORDERS OF PYRUVATE METABOLISM
Pyruvate Pyruvate Severe fatal neonatal to mild late Most commonly caused by
dehydrogenase dehydrogenase onset, lactic acidosis, psychomotor E1α subunit, defect X-linked
complex defect retardation, failure to thrive
Pyruvate carboxylase Pyruvate carboxylase Same as above Rare, autosomal recessive
deficiency
Respiratory chain Complexes I-V, Heterogeneous with multisystem Mitochondrial inheritance
defects (oxidative many mitochondrial involvement
phosphorylation DNA mutations
disease)
DISORDERS IN PENTOSE METABOLISM
Pentosuria L -Xylulose reductase Urine-reducing substance Benign
Transaldolase Transaldolase Liver cirrhosis and failure, Autosomal recessive
deficiency cardiomyopathy

Ribose-5-phosphate Ribose-5-phosphate Progressive leukoencephalopathy

 isomerase deficiency isomerase and peripheral neuropathy

105.1
Glycogen Storage Diseases
Priya S. Kishnani, Yuan-Tsong Chen

Keywords
glycogen
liver glycogen
hepatomegaly
myopathy
hypoglycemia
ketosis
enzyme replacement therapy

The disorders of glycogen metabolism, the glycogen storage diseases (GSDs ),

result from deficiencies of various enzymes or transport proteins in the pathways
of glycogen metabolism (see Fig. 105.1 ). Glycogen found in these disorders is
abnormal in quantity, quality, or both. GSDs are categorized by numerical type
in accordance with the chronological order in which these enzymatic defects
were identified. This numerical classification is still widely used, at least up to
number VII. The GSDs can also be classified by organ involvement into liver
and muscle glycogenoses (see Table 105.1 ).
There are more than 12 forms of GSDs. Glucose-6-phosphatase deficiency
(type I), lysosomal acid α-glucosidase deficiency (type II), debrancher
deficiency (type III), and liver phosphorylase kinase deficiency (type IX) are the
most common of those that typically present in early childhood;
myophosphorylase deficiency (type V, McArdle disease) is the most common in
adolescents and adults. The cumulative frequency of all forms of GSD is
 FIG. 105.4 Enzymatic reactions of carbohydrate metabolism, deficiencies
of which can give rise to lactic acidosis, pyruvate elevations, or
hypoglycemia. The pyruvate dehydrogenase complex comprises, in
addition to E1 , E2 , and E3 , an extra lipoate-containing protein (not
shown), called protein X, and pyruvate dehydrogenase phosphatase.

Table 105.2
Causes of Type B Lactic Acidosis
Type B1—Underlying Diseases

Renal failure
Hepatic failure
Diabetes mellitus
Malignancy
Systemic inflammatory response syndrome
Human immunodeficiency virus

Type B2—Drugs and Toxins

Acetaminophen
Alcohols—ethanol, methanol, diethylene glycol, isopropanol, and
propylene glycol
Antiretroviral nucleoside analogs—zidovudine, didanosine, and lamivudine
β-Adrenergic agonists—epinephrine, ritodrine, and terbutaline
Biguanides—phenformin and metformin
 Cocaine, methamphetamine
Cyanogenic compounds—cyanide, aliphatic nitriles, and nitroprusside
Diethyl ether
Fluorouracil
Halothane
Iron
Isoniazid
Linezolid
Nalidixic acid
Niacin
Propopol
Salicylates
Strychnine
Sugars and sugar alcohols—fructose, sorbitol, and xylitol
Sulfasalazine
Total parenteral nutrition
Valproic acid
Vitamin deficiencies—thiamine and biotin

Type B3—Inborn Errors of Metabolism

Glucose-6-phosphatase deficiency (von Gierke disease)

Fructose-1,6-diphosphatase deficiency
Phosphoenolpyruvate carboxykinase deficiency
Pyruvate carboxylase deficiency
Pyruvate dehydrogenase complex (PDHC) deficiency
Krebs cycle defects
Methylmalonic aciduria and other organic acidemias
Kearns-Sayre syndrome
Pearson syndrome
Barth syndrome
Mitochondrial DNA depletion syndromes
Nuclear DNA respiratory chain defects
Mitochondrial DNA respiratory defects
Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes
(MELAS)
Myoclonic epilepsy with ragged red fibers (MERRF)
Clinical and Genetic Heterogeneity of Disorders Related to
Mutations in Mitochondrial DNA*
LARGE DELETIONS MUTATION IN
SYMPTOMS, MUTATION IN MUTATION IN
IN MITOCHONDRIAL RIBOSOMAL
SIGNS, AND TRANSFER RNA MESSENGER RNA
DNA RNA
FINDINGS
KSS PEO PS MERRF MELAS AID NARP MILS LHON
CENTRAL NERVOUS SYSTEM
Seizures − − − +++ + − − + −
Ataxia + − − + + + ± −
Myoclonus − − − + ± − − − −
Psychomotor − − − − − − − + −
retardation
Psychomotor + − − ± + − − − −
regression
Hemiparesis and − − − − +++ − − − −
hemianopia
Cortical blindness − − − − + − − − −
Migraine-like − − − − + − − − −
headaches
Dystonia − − − − + − − + ±
PERIPHERAL NERVOUS SYSTEM
Peripheral ± − − ± ± − + − −
neuropathy
MUSCLE
Weakness and + +++ − + + − + + −
exercise intolerance
Ophthalmoplegia + + ± − − − − − −
Ptosis + − − − − − − −
EYE
Pigmentary + − − − − − + ± −
retinopathy
Optic atrophy − − − − − − ± ±
BLOOD
Sideroblastic anemia ± − + − − − − − −
ENDOCRINE SYSTEM
Diabetes mellitus ± − − − ± − − − −
Short stature + − − + + − − − −
Hypoparathyroidism ± − − − − − − − −
HEART
Conduction disorder + − − − ± − − − ±
Cardiomyopathy ± − − − ± + − ± −
GASTROINTESTINAL SYSTEM
Exocrine pancreatic ± − + − − − − − −
dysfunction
Intestinal − − − − + − − − −
pseudoobstruction
EAR, NOSE, AND THROAT
Sensorineural ± − − + + + ± − −
hearing loss
KIDNEY
 Fanconi syndrome − ± − ± − − − −
LABORATORY FINDINGS
Lactic acidosis + ± + + + ± ± ± −
Ragged-red fibers on + + ± + + − − − −
muscle biopsy
MODE OF INHERITANCE
Maternal − − − + + − + + +
Sporadic + + + − − − − − −
* Characteristic constellations of symptoms and signs are in bold .

+, Presence of a symptom, sign, or finding; −, absence of a symptom, sign, or finding; ±, possible

presence of a symptom, sign, or finding; AID, aminoglycoside-induced deafness; KSS, Kearns-
Sayre syndrome; LHON, Leber hereditary optic neuropathy; MELAS, mitochondrial
encephalomyopathy, lactic acidosis, and stroke-like episodes; MERRF, myoclonic epilepsy with
ragged-red fibers; MILS, maternally inherited Leigh syndrome; NARP, neuropathy, ataxia, and
retinitis pigmentosa; PEO, progressive external ophthalmoplegia; PS, Pearson syndrome.
From DiMauro S, Schon EA: Mitochondrial respiratory-chain diseases, N Engl J Med 348:2656–
2668, 2003. Copyright 2003 Massachusetts Medical Society. All rights reserved.

Diagnosis requires demonstration of abnormalities of oxidative

phosphorylation enzyme complex activities in tissues or of mitochondrial DNA
or a nuclear gene coding for mitochondrial functions, or both (Fig. 105.6 ).
Muscle histology, including EM, can detect ragged red fibers and other
abnormalities typical of mitochondrial myopathies. Analysis of oxidative
phosphorylation complexes I-IV from intact mitochondria isolated from fresh
skeletal muscle is the most sensitive assay for mitochondrial disorders; however,
electron transport chain testing of flash-frozen muscle provides an alternative
approach when fresh muscle testing is not available. Next-generation sequencing
of mitochondrial DNA and panels of nuclear genes provides a noninvasive
alternative to diagnosis. Specific criteria may assist in making a diagnosis (Table
105.4 ). Table 105.5 lists clues to the diagnosis of mitochondrial diseases.
 FIG. 105.6 Mutations in the human mitochondrial genome that are known to cause
disease. Disorders that are frequently or prominently associated with mutations in a
particular gene are shown in bold . Diseases caused by mutations that impair
mitochondrial protein synthesis are shown in blue. Diseases caused by mutations in
protein-coding genes are shown in red. ECM, Encephalomyopathy; FBSN, familial
bilateral striatal necrosis; LHON, Leber hereditary optic neuropathy; LS, Leigh
syndrome; MELAS, mitochondrial encephalomyopathy, lactic acidosis, and stroke-like
episodes; MERRF, myoclonic epilepsy with ragged red fibers; MILS, maternally
inherited Leigh syndrome; NARP, neuropathy, ataxia, and retinitis pigmentosa; PEO,
progressive external ophthalmoplegia; PPK, palmoplantar keratoderma; SIDS, sudden
infant death syndrome. (From DiMauro S, Schon EA: Mitochondrial respiratory-chain
diseases, N Engl J Med 348:2656–2668, 2003. Copyright 2003 Massachusetts Medical
Society. All rights reserved.)

Table 105.4
Mitochondrial Disease Criteria (Simplified Version for
Bedside Use)*
 I. CLINICAL SIGNS AND SYMPTOMS, 1
POINT/SYMPTOM (max. 4 points)
A. Muscular B. CNS C. Multisystem
II. Metabolic/Imaging III. Morphology
Presentation (max. 2 Presentation (max. Disease (max. 3
Studies (max. 4 points) (max. 4 points)
points) 2 points) points)
Ophthalmoplegia † Developmental Hematology Elevated lactate † Ragged red/blue
delay fibers ‡
Facies myopathica Loss of skills GI tract Elevated L/P ratio COX-negative
fibers ‡
Exercise intolerance Stroke-like episode Endocrine/growth Elevated alanine † Reduced COX
staining ‡
Muscle weakness Migraine Heart Elevated CSF lactate † Reduced SDH
staining
Rhabdomyolysis Seizures Kidney Elevated CSF protein SDH positive
blood vessels †
Abnormal EMG Myoclonus Vision Elevated CSF alanine † Abnormal
mitochondria/EM
†
Cortical blindness Hearing Urinary TA excretion †
Pyramidal signs Neuropathy Ethylmalonic aciduria
Extrapyramidal Recurrent/familial Stroke-like picture/MRI
signs
Brainstem Leigh syndrome/MRI †
involvement
Elevated lactate/MRS
* Score 1: mitochondrial disorder unlikely; score 2 to 4: possible mitochondrial disorder; score 5 to

7: probable mitochondrial disorder; score 8 to 12: definite mitochondrial disorder.

† This specific symptom scores 2 points.

‡
This symptom in a higher percentage scores 4 points.
GI, gastrointestinal; L/P, lactate/pyruvate; COX, cytochrome C oxidase; SDH, succinate
dehydrogenase; EM, electron microscopy; EMG, electromyography; TA, tricarbon acid.
From Morava E, van den Heuvel L, Hol F, et al: Mitochondrial disease criteria – diagnostic
applications in children. Neurology 67:1823-1826, 2006, p 1824.

Table 105.5
Clues to the Diagnosis of Mitochondrial
Disease
Neurologic

Cerebral stroke-like lesions in a nonvascular pattern

Basal ganglia disease
Encephalopathy: recurrent or with low/moderate dosing of valproate
 Neurodegeneration
Epilepsia partialis continua
Myoclonus
Ataxia
MRI findings consistent with Leigh disease
Characteristic MRS peaks
Lactate peak at 1.3 ppm TE (time to echo) at 35 and 135
Succinate peak at 2.4 ppm

Cardiovascular

Hypertrophic cardiomyopathy with rhythm disturbance

Unexplained heart block in a child
Cardiomyopathy with lactic acidosis (>5 mM)
Dilated cardiomyopathy with muscle weakness
Wolff-Parkinson-White arrhythmia

Ophthalmologic

Retinal degeneration with signs of night blindness, color vision deficits,

decreased visual acuity, or pigmentary retinopathy
Ophthalmoplegia/paresis
Fluctuating, dysconjugate eye movements
Ptosis
Sudden- or insidious-onset optic neuropathy/atrophy

Gastroenterologic

Unexplained or valproate-induced liver failure

Severe dysmotility
Pseudoobstructive episodes

Other

A newborn, infant, or young child with unexplained hypotonia, weakness,

 failure to thrive, and a metabolic acidosis (particularly lactic acidosis)
Exercise intolerance that is not in proportion to weakness
Hypersensitivity to general anesthesia
Episodes of acute rhabdomyolysis
Elevated GDF-15 level

MRI, Magnetic resonance imaging, MRS, magnetic resonance spectroscopy;

GDF, growth and differentiation factor.

From Haas RH, Parikh S, Falk MJ, et al: Mitochondrial disease: a practical
approach for primary care physicians, Pediatrics 120:1326–1333, 2007 (Table 1,
p 1327).

The majority of mitochondrial disorders are caused by nuclear genes involved

in mitochondrial function, and >300 genes have been included in nuclear gene
panels for mitochondrial disorder diagnosis. However, pathogenic variants can
be identified in 50% or fewer of patients diagnosed clinically with a
mitochondrial disorder. An important consideration is that many genetic and
multifactorial conditions have been associated with defects in 1 or more of the 4
complexes assayed in mitochondrial oxidative phosphorylation testing. These
latter conditions feature so-called secondary mitochondrial dysfunction, because
the conditions are not considered to be mitochondrial disorders per se.
Treatment remains largely symptomatic and does not significantly alter the
outcome of disease. Some patients appear to respond to cofactor supplements,
typically coenzyme Q10 ± L -carnitine at pharmacologic doses. The addition of
creatine monohydrate and α-lipoic acid supplementation may add a significant
benefit. EPI-743 is a parobenzoquinone like agent that has protective activity
against oxidative injury; it is a promising agent in the treatment of mitochondrial
disorders, including Leigh syndrome.

Leigh Disease (Subacute Necrotizing

Encephalomyelopathy)
Leigh disease is a heterogeneous neurologic disease characterized by
demyelination, gliosis, necrosis, relative neuronal sparing, and capillary
proliferation in specific brain regions (see Chapter 616.2 ). Patients with Leigh
 FIG. 105.9 Patients with phosphomannomutase-2 deficiency (PMM2-CDG) and
recognizable clinical features. A, Inverted nipples. B and C, Abnormal fat distribution. D,
Muscle atrophy caused by peripheral neuropathy after puberty. E, Characteristic facial
features with strabismus, short nose, anteverted nares, long philtrum, and large ears. F,
MRI of brain with T1-weighted sagittal image showing cerebellar vermis hypoplasia
(arrow) and brain atrophy.

Table 105.6
Clinical and Laboratory Features in Common Congenital
Disorders of Glycosylation (CDGs), with Clinically
Recognizable Phenotype and Abnormal Glycosylation,
Detectable by Serum Transferrin Isoform Analysis (TIEF)

OTHER
DEFECTIVE MOST FREQUENT SUGGESTIVE LABORATORY
BIOCHEMICAL
GENE CLINICAL FEATURES FEATURES ABNORMALITIES
ANOMALIES
PMM2 Strabismus, nystagmus, Inverted nipples Elevated serum Type 1 serum
smooth philtrum, large ears, and/or abnormal fat transaminases, TIEF, decreased
vomiting, diarrhea, FTT, axial pads, stroke-like hypoalbuminemia, PMM activity in
hypotonia, cerebellar vermis episodes decreased factor IX, leukocytes and
hypoplasia, ataxia, XI and AT activity, fibroblasts
psychomotor disability, low serum
 seizures, spasticity, ceruloplasmin and
neuropathy, pigmentary TBG levels
retinitis
PMI Cholestasis, hepatomegaly, Hyperinsulinism, Elevated Type 1 serum
feeding difficulties, recurrent protein losing transaminases, TIEF, decreased
vomiting, chronic diarrhea, enteropathy hypoalbuminemia, PMI activity in
ascites, recurrent thrombosis, Normal hypoglycemia, leukocytes and
gastrointestinal bleeding intelligence and decreased factor IX, fibroblasts
absence of XI, and AT-III
neurologic activity
features
ALG6 Hypotonia, muscle weakness, (Distal limb Elevated serum Type 1 serum
seizures, ataxia, intellectual malformations) transaminases; TIEF, abnormal
disability, behavioral hypoalbuminemia; LLO results in
abnormalities decreased factor IX, fibroblasts
XI, and AT activity;
low serum IgG level
DPAGT1 Microcephaly, brain Congenital Decreased AT, Type 1 serum
malformations, hypotonia, myasthenia protein C, and protein TIEF
severe psychomotor disability, phenotype S activity; increased
seizures, spasticity, proximal In multisystem creatine kinase;
weakness, failure to thrive, phenotype: hypoalbuminemia;
joint contractures cataract normal creatine
kinase in myasthenia
SRD5A3 Developmental delay, Congenital cataract, Low anticoagulation Type 1 serum
hypotonia, ataxia, cerebellar retinal and iridic factors (AT, protein TIEF but reported
vermis hypoplasia, intellectual coloboma, glaucoma, C, and protein S false-negative
disability, speech delay, visual optic nerve dysplasia, activity), increased TIEF
loss ichthyosis serum transaminases
ATP6V0A2 Generalized cutis laxa, Cobblestone-like Mild coagulation Type 2 serum
hypotonia, strabismus, brain dysgenesis abnormalities, TIEF but
characteristic facial features, increased serum reported
joint laxity, seizures, motor transaminase levels false-negative
ATP6V1A and and language developmental Cardiovascular Mild coagulation TIEF
ATP6V1E1 delay, spontaneous anomalies abnormalities and Abnormal
improvement of cutis laxa by increased serum apoC-III IEF,
aging transaminase levels, characteristic
hypercholesterolemia MALDI TOF
profile
(Note
abnormal
skin
histology)
PGM1 Pierre Robin sequence, Cleft palate, Hypoglycemia, Mixed type 1/ 2
cholestasis, short stature, hyperinsulinism, increased serum serum TIEF,
dilated cardiomyopathy, normal intelligence transaminase levels, decreased
decreased AT fibroblast PGM1
activity
MAN1B1 Developmental delay, speech Obesity, autistic Increased serum Type 2 serum
delay, intellectual disability, features, inverted transaminase levels, TIEF, abnormal
muscle weakness nipples, characteristic low AT apoC-III IEF,
face diagnostic
MALDI TOF
profile
TMEM199 Cholestasis, hepatomegaly, Normal intelligence Decreased serum Type 2 serum
 CCDC115 liver steatosis, liver fibrosis, Hepatomegaly ceruloplasmin, TIEF, abnormal
ATP6AP1 and liver failure, spontaneous Immune deficiency increased serum apoC-III IEF,
ATP6AP2 bleedings, motor transaminase levels, characteristic
developmental delay hypercholesterolemia, MALDI TOF
high AP profile
SLC39A8 Seizures, hypsarrhythmia, Dwarfism, Decreased serum Type 2 serum
hypotonia, developmental and craniosynostosis, manganese, high TIEF, abnormal
speech delay, FTT rhizomelia, Leigh serum transaminases, apoC-III,
disease abnormal coagulation characteristic
MALDI TOF
profile
AP, Alkaline phosphatase; AT, antithrombin; apoC-III: apolipoprotein C-III; FTT, failure to thrive;
LLO, lipid-linked oligosaccharides; MALDI-TOF, matrix-assisted laser desorption/ionization time of
flight; TBG, thyroxine-binding globulin; TIEF, transferrin isoelectric focusing.

There are also congenital disorders of deglycosylation , including known

lysosomal disorders and a severe neurologic condition caused by defective N -
glycanase function (NGLY1 defect).
Laboratory evaluations in most N -linked CDGs rely on a primary screening
method called serum transferrin isoelectric focusing (TIEF) . Transferrin
isoforms, which are hyposialylated (missing terminal sialic acid residues), show
different cathodal shifts depending on either missing glycan chains or truncated
glycans. A type 1 pattern suggests an early metabolic defect in the cytosolic-
ER–related glycan synthesis and assembly. A type 2 pattern suggests Golgi-
related glycan-processing defects (Fig. 105.10 ).
report family members related through their maternal lineage (both males and
females may be affected, but only affected individuals will be connected through
the female germline), with a range of functional problems in different organs,
such as migraines, fatigue, exercise intolerance, stroke, diabetes mellitus, thyroid
dysfunction, irritable bowel spectrum, mood disorder, or vision and hearing
problems. Inherited X-linked disorders typically present with symptoms only, or
more severely, in males related through unaffected or minimally affected
females. Autosomal recessive disorders are common in pediatric mitochondrial
disease, particularly in consanguineous pedigrees, where a rare variant in the
general population becomes enriched and passed down through both maternal
and paternal lineages to become homozygous in the affected proband and also
affect multiple individuals in a given generation without having affected
individuals in earlier generations. Autosomal dominant variants may occur de
novo or are passed on from either parent to their child, although many disorders
may have reduced penetrance, which may make the genetic disorder appear to
skip a generation. Identifying a likely inheritance pattern through pedigree
analysis can inform accurate interpretation of large-scale genetic diagnostic
evaluations, such as multigene sequencing and deletion/duplication analysis
panels and exome or genome sequencing. Establishing a correct genetic
diagnosis for mitochondrial disease in an affected individual is essential to
enable reliable recurrence risk counseling and testing options in a given family,
whether in a future pregnancy by chorionic villus sampling (CVS, typically
performed at 10-12 weeks’ gestation) or amniocentesis (typically performed at
16-20 weeks’ gestation) or in the in vitro fertilization (IVF) setting with
preimplantation genetic diagnosis (PGD) for a specific disease-causing variant.

Table 106.1
Major Molecular Categories of Mitochondrial Genes

CAUSAL DISEASE
COMPONENT GENE MUTATION EFFECTS
GENOME EXAMPLES
Electron Nuclear or Decreased functioning of electron transport chain complex Complex I
transport chain mtDNA deficiency
enzyme subunits Complex II
deficiency
Electron Nuclear Decreased assembly of electron transport chain enzyme Complex III
transport chain complex deficiency
assembly factors Complex IV
deficiency
Complex V
 deficiency
Electron Nuclear Decreased functioning of electron transport chain Coenzyme Q10
transport chain deficiency
cofactors Iron sulfur
cluster defect
Lipoyltransferase
deficiency
mtDNA Nuclear or Decreased translation of protein-coding mitochondrial Combined oxidative
translation mtDNA DNA genes leading to decreased functioning of electron phosphorylation
transport chain enzymes complexes deficiency
mtDNA Nuclear Increased errors in mitochondrial DNA leading to increased Mitochondrial
maintenance presence of point mutations and deletions, resulting in DNA depletion
decreased translation of electron transport chain subunits syndromes
Mitochondrial
DNA multiple
deletion
disorders
Mitochondrial Nuclear Increased mtDNA point mutations and deletions; clumped OPA1 -related
membrane and fragmented mitochondria conditions
fission and MFN2 -related
fusion conditions
From McCormick EM, Muraresku CC, Falk MJ: Mitochondrial genomics: a complex field now
coming of age. Curr Genet Med Rep 6:52–61, 2018 (Table 1, p. 57).

Special mention is warranted to consider the unique aspects of maternal

inheritance that typify mtDNA disorders. More than 300 disease-causing
mtDNA variants have been identified, with extensive variation in disease
manifestations and features. Most disease-causing variants are present in only a
portion of an individual's mtDNA genomes, a concept known as heteroplasmy .
For heteroplasmic mtDNA variants, the precise mutation level (percent) can vary
between an individual's different tissues and can change over time, with
symptom severity corresponding to different threshold mutation levels that can
be difficult to define and that typically vary between organs. An individual's
mtDNA genome background set of fixed sequence variants, known as a
haplogroup , can also influence the penetrance or severity of a mtDNA disease.
When a novel or rare mtDNA variant is identified in a given individual, it may
be useful to use highly sensitive sequencing methods to test the levels of that
mutation (which may be accurate to detect 1% mutation levels) in their different
tissues (blood, urine, buccal, skin cells, muscle), as well as tissues from their
mother or maternal relatives, to accurately determine whether it may be causal of
disease in that family. Research-based functional testing may also be necessary
to characterize fully the effects of a newly recognized mtDNA variant. When it
is not known whether an mtDNA variant is maternally inherited or occurs de
novo, the recurrence risk to future offspring of their asymptomatic parent is
empirically estimated at 1 in 25 (4%), although the empirical recurrence risk
Recognition Pattern of Mucopolysaccharidoses

MUCOPOLYSACCHARIDOSIS (MPS) TYPE

MANIFESTATIONS
I-H I-S II III IV VI VII
Intellectual disability + − ± + − − ±
Coarse facial features + (+) + + − + ±
Corneal clouding + + − − (+) + ±
Visceromegaly + (+) + (+) − + +
Short stature + (+) + − + + +
Joint contractures + + + − − + +
Dysostosis multiplex + (+) + (+) + + +
Leucocyte inclusions + (+) + + − + +
Mucopolysacchariduria + + + + + + +
I-H, Hurler syndrome; I-S, Scheie syndrome; II, Hunter syndrome; III, Sanfilippo syndrome; IV,
Morquio syndrome; VI, Maroteaux-Lamy syndrome; VII, Sly syndrome.
+, Presence of manifestation, −, absence of manifestation; ±, possible presence of manifestation;
(+), mild manifestation.

FIG. 107.2 Patients with various types of mucopolysaccharidoses. MPS-I: Hurler

syndrome, age 3 yr; MPS-II: Hunter syndrome, 12 yr; MPS-III: Sanfilippo syndrome, 4 yr;
MPS-IV: Morquio syndrome, 10 yr; MPS-VI: Maroteaux-Lamy syndrome, 15 yr.

Table 107.2
Mucopolysaccharidoses: Clinical, Molecular, and
Biochemical Aspects
 MAIN
MPS GENE DEFECTIVE
EPONYM INHERITANCE CLINICAL ASSAY
TYPE CHROMOSOME ENZYME
FEATURES
I-H (Pfaundler-) AR IDUA Severe Hurler α-L -iduronidase L, F,
Hurler 4p16.3 phenotype, mental Ac, Cv
deficiency, corneal
clouding, death
usually before age
14 yr
I-S Scheie AR IDUA Stiff joints, α-L -iduronidase L, F,
4p16.4 corneal clouding, Ac, Cv
aortic valve
disease, normal
intelligence,
survive to
adulthood
I-HS Hurler-Scheie AR IDUA Phenotype α-L -iduronidase L, F,
4p16.4 intermediate Ac, Cv
between I-H and
I-S
II Hunter XLR IDS Severe Iduronate sulfate S, F,
Xq27.3-28 course: sulfatase Af, Ac,
similar to I-H Cv
but clear
corneas
Mild course:
less
pronounced
features, later
manifestation,
survival to
adulthood
with mild or
without
mental
deficiency
IIIA Sanfilippo A AR SGSH Behavioral Heparan-S- L, F,
17q25.3 problems, sulfamidase Ac, Cv
sleeping
IIIB Sanfilippo B AR NAGLU N -Acetyl-α-D - S, F,
disorder,
17q21 aggression, glucosaminidase Ac, Cv
IIIC Sanfilippo C AR HGSNAT progressive Acetyl-CoA- F, Ac
8p11.21 dementia, glucosaminide N -
mild acetyltransferase
IIID Sanfilippo D AR GNS dysmorphism, N - F, Ac
12q14 coarse hair, Acetylglucosamine–
clear corneas 6-sulfate sulfatase
Survival to
adulthood
possible
IVA Morquio A AR GALNS Short-trunk N - L, F,
16q24.3 dwarfism, fine Acetylgalactosamine- Ac
corneal opacities, 6-sulfate sulfatase
 characteristic bone
dysplasia; final
height <125 cm
IVB Morquio B AR GLB1 Same as IVA, but β-Galactosidase L, F,
3p21.33 milder; adult Ac, Cv
height >120 cm
VI Maroteaux- AR ARSB Hurler phenotype N - L, F,
Lamy 5q11-q13 with marked Acetylgalactosamine- Ac
corneal clouding α-4-sulfate sulfatase
but normal (arylsulfatase B)
intelligence; mild,
moderate, and
severe expression
in different
families
VII Sly AR GUSB Varying from fetal β-Glucuronidase S, F,
7q21.11 hydrops to mild Ac, Cv
dysmorphism;
dense inclusions
in granulocytes
IX Hyaluronidase AR HYAL1 Periarticular Hyaluronidase 1 S
deficiency 3p21.3 masses, no Hurler
phenotype
MPSPS MPS plus AR VPS33A Mild Hurler No lysosomal
syndrome phenotype, enzyme deficiency
cognitive
deficiency,
organomegaly,
skeletal dysplasia,
pancytopenia,
renal
insufficiency,
optic atrophy,
early death
AR, Autosomal recessive; XLR, X-linked recessive; L, Leukocytes; S, serum; F, cultured
fibroblasts; Ac, cultured amniotic cells; Af, amniotic fluid; Cv, chorionic villus sampling; MIM,
Mendelian Inheritance in Man Catalogue.

Mucopolysaccharidoses are autosomal recessive disorders, with the exception

of Hunter disease (Hunter syndrome), which is X-linked recessive. Their birth
prevalence varies between 1.2 per 100,000 births (United States) and 16.9 per
100,000 births (Saudi Arabia). In the United States the most common subtype is
MPS-III, followed by MPS-I and MPS-II.

Disease Entities
Mucopolysaccharidosis I
Mucopolysaccharidosis I (MPS-I) is caused by mutations of the IUA gene on
chromosome 4p16.3 encoding α-L -iduronidase. Mutation analysis has revealed 2
major alleles, W402X and Q70X, which account for more than half the MPS-I
alleles in the white population. The mutations that introduce stop codons with
ensuing absence of functional enzyme (null alleles), and in homozygosity or
compound heterozygosity, give rise to Hurler syndrome. Other mutations occur
in only one or a few individuals.
Deficiency of α-L -iduronidase results in a wide range of clinical involvement,
from severe Hurler syndrome to mild Scheie syndrome, which are ends of a
broad clinical spectrum. Homozygous nonsense mutations result in severe forms
of MPS-I, whereas missense mutations are more likely to preserve some residual
enzyme activity associated with a milder form of the syndrome.

Hurler Syndrome
The Hurler form of MPS-I (MPS I-H ) is a severe, progressive disorder with
involvement of multiple organs and tissues that results in premature death,
usually by 10 yr of age. An infant with Hurler syndrome appears normal at birth,
but inguinal hernias and failed neonatal hearing tests may be early signs.
Diagnosis is usually made at 6-24 mo, with evidence of hepatosplenomegaly,
coarse facial features, corneal clouding, large tongue, enlarged head
circumference, joint stiffness, short stature, and skeletal dysplasia. Acute
cardiomyopathy has been found in some infants <1 yr. Most patients have
recurrent upper respiratory tract and ear infections, noisy breathing, and
persistent copious nasal discharge. Valvular heart disease, notably with
incompetence of the mitral and aortic valves, regularly develops, and narrowing
of the coronary arteries occurs. Obstructive airway disease, especially during
sleep, may necessitate tracheotomy. Obstructive airway disease, respiratory
infection, and cardiac complications are the common causes of death (Table
107.3 ).

Table 107.3

Analysis of Symptom Frequency in Patients With MPS-I ≤2 Yr of Age

SYMPTOMS/COMPLICATIONS PERCENTAGE OF PATIENTS WITH SYMPTOM
Coarse facies 98
Valvular disease 95

Corneal clouding 90
Hepatomegaly 84
 Upper airway obstruction → OSA 82
Kyphosis gibbus 75
Joint contractures 72
Hernia 70
Dysostosis multiplex 70
Cognitive impairment 60
Enlarged tongue 60
Splenomegaly 60
Eustachian tube obstruction → otitis media 55
Hip dysplasia 42
Genu valgum 38
Reactive airway disease 37
Scoliosis 35
Carpal tunnel syndrome 25
Pes cavus 18
Glaucoma 10
Heart failure 3
Cor pulmonale 2
OSA, Obstructive sleep apnea.
From Clarke LA, Atherton AM, Burton BK, et al: Mucopolysaccharidosis type I newborn screening:
best practices for diagnosis and management, J Pediatr 182:363–370, 2017 (Table 1, p 364).

Most children with Hurler syndrome acquire only limited language skills
because of intellectual disability, combined conductive and neurosensory hearing
loss, and an enlarged tongue. Progressive ventricular enlargement with increased
intracranial pressure caused by communicating hydrocephalus also occurs.
Corneal clouding, glaucoma, and retinal degeneration are common. Radiographs
show a characteristic skeletal dysplasia known as dysostosis multiplex (Figs.
107.3 and 107.4 ). The earliest radiographic signs are thick ribs and ovoid
vertebral bodies. Skeletal abnormalities (in addition to those shown in the
figures) include enlarged, coarsely trabeculated diaphyses of the long bones with
irregular metaphyses and epiphyses. With disease progression, macrocephaly
develops with thickened calvarium, premature closure of lambdoid and sagittal
sutures, shallow orbits, enlarged J -shaped sella, and abnormal spacing of teeth
with dentigerous cysts.
Treatment
Hematopoietic stem cell transplantation has resulted in significant clinical
improvement of somatic disease in patients with MPS I, II, and VI (Table 107.4
). Clinical effects are increased life expectancy with resolution or improvement
of growth, hepatosplenomegaly, joint stiffness, facial appearance, skin changes,
obstructive sleep apnea, heart disease, communicating hydrocephalus, and
hearing loss. Enzyme activity in serum and urinary GAG excretion normalize.
This is true for MPS I-H, II, and III. Patients with MPS-I who have undergone
transplantation before 9 mo of age may show normal cognitive development.
Transplantation before 24 mo and with a baseline mental development index >70
have improved long-term outcome. Transplantation does not significantly
improve the neuropsychological outcome of MPS patients with impaired
cognition at transplantation. Early transplantation in the MPS-II patient may
have the same effect. Transplantation in the MPS-VI patient stabilizes or
improves cardiac manifestations, posture, and joint mobility. Stem cell
transplantation does not correct skeletal or ocular anomalies.

Table 107.4
Therapies Aimed at Proximate Causes of
Mucopolysaccharidoses

HEMATOPOIETIC ENZYME
MPS
STEM CELL REPLACEMENT REMARKS
TYPE
TRANSPLANTATION THERAPY
I Yes Laronidase Developmental trajectory dependent on time of
(Aldurazyme) transplantation. Little effect on connective tissue
II Yes Idursulfase manifestations. Enzyme replacement immediately after
(Elaprase) diagnosis.
III No No Experimental intrathecal application of recombinant
heparin-N -sulfatase in MPS-IIIA.
IV Yes Elosulfase Improved daily activities. No effect on growth or skeletal
(Vimizim) dysplasia.

VI Yes Galsulfase Improved daily activities. Improved growth. No effect on

(Naglazyme) skeletal dysplasia.
VII Yes rhGUS Phase 3 study by Ultragenyx, 2016. Limited experience
because of rarity of condition.

Enzyme replacement therapy (ERT) using recombinant α-L -iduronidase has

been approved for patients with MPS-I (Table 107.4 ). It reduces organomegaly
and ameliorates rate of growth, improves joint mobility, and reduces the number
of episodes of sleep apnea and urinary GAG excretion. The enzyme does not
cross the blood-brain barrier and does not prevent deterioration of
neurocognitive function. Consequently, ERT is appropriate for patients with mild
CNS involvement or to stabilize extraneural manifestations in young patients
before stem cell transplantation. Recombinant iduronate-2-sulfatase is the
treatment of choice for MPS-II to ameliorate nonneural manifestations. ERT
with recombinant human GALNS improves physical endurance, respiratory
function, and daily living activity of patients with MPS-IV. Similar effects
produce recombinant N -acetylgalactosamine-4-sulfatase in patients with MPS-
VI.
Symptomatic therapy focuses on respiratory and cardiovascular
complications, hearing loss, carpal tunnel syndrome, spinal cord compression,
hydrocephalus, and other problems (Table 107.5 ). The multisystem involvement
and progressive nature of MPS syndromes usually requires the complex care
provided by medical centers.

Table 107.5
Symptomatic Management of Mucopolysaccharidoses

PREDOMINANTLY
PROBLEM MANAGEMENT
IN
NEUROLOGIC
Hydrocephalus MPS I, II, VI, VII Funduscopy, CT scan
Chronic headaches All Ventriculoperitoneal shunting
Behavioral MPS-III Behavioral medication, sometimes
disturbance CT scan, ventriculoperitoneal shunting
Disturbed sleep– MPS-III Melatonin
wake cycle
Seizures MPS I, II, III EEG, anticonvulsants
Atlantoaxial MPS IV Cervical MRI, upper cervical fusion
instability
Spinal cord All Laminectomy, dural excision
compression
OPHTHALMOLOGIC
Corneal opacity MPS I, VI, VII Corneal transplant

Glaucoma MPS I, VI, VII Medication, surgery

Retinal MPS I, II Night-light
degeneration
EARS, AIRWAYS
Recurrent otitis MPS I, II, VI, VII Ventilating tubes
media
Impaired hearing All except MPS-IV Audiometry, hearing aids
Obstruction All except MPS-III Adenotomy, tonsillectomy, bronchodilator therapy, CPAP at night,
 laser excision of tracheal lesions, tracheotomy
CARDIAC
Cardiac valve MPS I, II, VI, VII Endocarditis prevention, valve replacement
disease
Coronary MPS I, II, VI, VII Medical therapy
insufficiency
Arrhythmias MPS I, II, VI, VII Antiarrhythmic medication, pacemaker
ORAL, GASTROINTESTINAL
Hypertrophic gums, MPS I, II, VI, VII Dental care
poor teeth
Chronic diarrhea MPS-II Diet modification, loperamide
MUSCULOSKELETAL
Joint stiffness All except MPS IV Physical therapy
Weakness All Physical therapy, wheelchair
Gross long-bone All Corrective osteotomies
malalignment
Carpal tunnel MPS I, II, VI, VII Electromyography, surgical decompression
syndrome
ANESTHESIA All except III Avoid atlantoaxial dislocation; use angulated video intubation
laryngoscope and small endotracheal tubes.
CT, Computed tomography; CPAP, continuous positive airway pressure; EEG,
electroencephalogram; MRI, magnetic resonance imaging.

Bibliography
Burton BK, Jego V, Mikl J, et al. Survival in idursulfase-treated
and untreated patients with mucopolysaccharidosis type II:
data from the Hunter Outcome survey (HOS). J Inherit Metab
Dis . 2017;40:867–874.
Clarke LA. Mucopolysaccharidosis type I. Pagon RA, Adam
MP, Ardinger HH, et al. Gene reviews (internet) . 2016
[Seattle].
Clarke LA, Atherton AM, Burton BK, et al.
Mucopolysaccharidosis type I newborn screening: best
practices for diagnosis and management. J Pediatr .
2017;182:363–370.
Dvorakova L, Vlaskova H, Sarjlija A, et al. Genotype-
phenotype correlation in 44 Czech, Slovak, Croatian and
Serbian patients with mucopolysaccharidosis type II. Clin
Genet . 2017;91:787–796.

FIG. 109.3 Unrelated 7 yr old female and 10 yr old male with progeria.
Appearance is remarkably similar between patients. (Photograph courtesy
of The Progeria Research Foundation)

Table 109.1
Features of Hutchinson-Gilford Progeria Syndrome and
Other Disorders With Overlapping Features

HUTCHINSON-
WIEDEMANN- ROTHMUND-
GILFORD WERNER COCKAYNE RESTRICTIVE
RAUTENSTRAUCH THOMPSON
PROGERIA SYNDROME SYNDROME DERMOPATHY
SYNDROME SYNDROME
SYNDROME
Causative LMNA Unknown WRN , LMNA CSA RECQL4 ZMPSTE24,
gene(s) (ERCC8) LMNA
CSB
(ERCC6)
Inheritance Autosomal Unknown, likely Recessive Recessive Recessive Recessive
Dominant recessive
Onset Infancy Newborn Young adult Newborn/infancy Infancy Newborn
Growth Postnatal Intrauterine Onset after Postnatal Postnatal Intrauterine
retardation puberty
Hair loss + Total + Scalp patchy + Scalp, − + Diffuse + Diffuse
sparse,
graying
Skin + + + + + +
abnormalities
Subcutaneous + + + + − −
 fat loss
Skin + Rarely − + − − −
calcification
Short stature + + + + + +
Coxa valga + − − − − −
Acroosteolysis + + + − − −
Mandibular + + − − − +
dysplasia
Osteopenia + Mild + + − + +
Vasculopathy + − + + − −
Heart failure + − + − − −
Strokes + − − − − −
Insulin + − + Rarely − − −
Resistance
Diabetes − − + − − −
Hypogonadism + − + + + −
Dental + + + + + +
abnormality
Voice + − + − − −
abnormality
Hearing loss + − − + − −
Joint + − − − − +
contractures
Hyperkeratosis − − + − + −
Cataracts − − + + + −
Tumor − − + − + −
predisposition
Intellectual − + − + − −
disability
Neurologic − + + Mild + − −
disorder
Adapted from Hegele RA: Drawing the line in Progeria syndromes, Lancet 362;416–417, 2003.

Treatment and Prognosis

Children with progeria develop a severe premature form of atherosclerosis. Prior
to death, cardiac decline with left-sided hypertrophy, valvular insufficiency, and
pulmonary edema develop; neurovascular decline with transient ischemic attacks
(TIAs), strokes, and occasionally seizures can result in significant morbidity.
Death occurs generally between ages 5 and 20 yr, with a median life span of 14.5
yr, resulting from heart failure, sometimes with superimposed respiratory
infection (approximately 80%); from head injury or trauma, including subdural
hematoma (approximately 15%); and rarely from stroke (1–3%) or
complications from anesthesia during surgery (1–3%).
Growth hormone , 0.05 mg/kg/day subcutaneously, has resulted in increased
rate of weight gain and overall size, but still well below that seen in normal
 (dashed arrow) .

Altered activity of each enzyme in the pathway has been associated with a
specific type of porphyria (Table 110.1 ). The first enzyme, ALA synthase
(ALAS), occurs in 2 forms. An erythroid specific form, ALAS2, is deficient in
X-linked sideroblastic anemia, as a result of mutations of the ALAS2 gene on
chromosome Xp11.2. Gain-of-function mutations of ALAS2 caused by deletions
in the last exon cause X-linked protoporphyria (XLP ), which is phenotypically
identical to erythropoietic protoporphyria.

Table 110.1
The Human Porphyrias: Mutations, Time of Presentation,
and Tissue- and Symptom-Based Classifications

Classification*
DISEASE ENZYME INHERITANCE PRESENTATION

H E A/N C
X-Linked δ-Aminolevulinate X-linked Childhood X X
protoporphyria (XLP) synthase 2 (ALAS2)
δ-Aminolevulinic acid δ-Aminolevulinic Autosomal recessive Mostly post X X* X
dehydratase porphyria acid dehydratase puberty
(ADP) (ALAD)
Acute intermittent Porphobilinogen Autosomal dominant Post puberty X X
porphyria (AIP) deaminase (PBGD)
Homozygous AIP Homozygous dominant Childhood X X X
Congenital Uroporphyrinogen Autosomal recessive In utero or infancy X X
erythropoietic III synthase (UROS)
porphyria (CEP)
Porphyria cutanea tarda Uroporphyrinogen Sporadic Adults X X
(PCT) type 1 decarboxylase
(UROD)
PCT type 2 † Autosomal dominant Adults X X
PCT type 3 Unknown Adults X X
Hepatoerythropoietic Homozygous dominant Childhood X X* X
porphyria (HEP)
Hereditary Coproporphyrinogen Autosomal dominant Post puberty X X X
coproporphyria (HCP) oxidase (CPOX)
Homozygous HCP Homozygous dominant Childhood X X X X
Variegate porphyria Protoporphyrinogen Autosomal dominant Post puberty X X X
(VP) oxidase (PPOX)
Homozygous VP Homozygous dominant Childhood X X X X
Erythropoietic Ferrochelatase Autosomal recessive (most Childhood X X
protoporphyria (EPP) (FECH) commonly heteroallelic
with hypomorphic allele)
Features
PRESENTING EXACERBATING MOST IMPORTANT
TREATMENT
SYMPTOMS FACTORS SCREENING TESTS
Acute Neurologic, adult Drugs (mostly P450 Urinary Hemin, glucose
intermittent onset inducers), progesterone, porphobilinogen
porphyria dietary restriction
Porphyria Skin blistering and Iron, alcohol, smoking, Plasma (or urine) Phlebotomy, low-
cutanea tarda fragility (chronic), estrogens, hepatitis C, porphyrins dose
adult onset HIV, halogenated hydroxychloroquine
hydrocarbons
Erythropoietic Phototoxic pain and Total erythrocyte Sun protection
protoporphyria swelling (mostly protoporphyrin with
acute), childhood metal-free and zinc
onset protoporphyrin

First-Line Laboratory Diagnostic Testing

A few sensitive and specific first-line laboratory tests should be obtained
whenever symptoms or signs suggest the diagnosis of porphyria. If a first-line or
screening test is significantly abnormal, more comprehensive testing should
follow to establish the type of porphyria. Overuse of lab tests for screening can
lead to unnecessary expense and even delay in diagnosis. In patients who present
with a past diagnosis of porphyria, lab reports that were the basis for the original
diagnosis must be reviewed, and if these were inadequate, further testing
considered.
Acute porphyria should be suspected in patients with neurovisceral symptoms
such as abdominal pain after puberty, when initial clinical evaluation does not
suggest another cause. Urinary PBG and total porphyrins should be measured.
Urinary PBG is virtually always increased during acute attacks of AIP, HCP, and
VP and is not substantially increased in any other medical conditions. Therefore
this measurement is both sensitive and specific. Results from spot (single void)
urine specimens are highly informative because very substantial increases are
expected during acute attacks of porphyria. A 24 hr collection can unnecessarily
delay diagnosis. The same spot urine specimen should be saved for quantitative
determination of PBG and total porphyrins (both expressed relative to creatinine)
to confirm the qualitative PBG result. ALA is often measured as well, but is
usually less elevated than PBG in AIP, HCP, and VP. In ALA dehydratase
porphyria, urinary ALA and porphyrins, but not PBG, are greatly elevated.
Urinary porphyrins may remain increased longer than porphyrin precursors in
some cases of HCP and VP. Measurement of urinary porphyrins alone should be
hepatic ALAS1 is less effective.
It is not proved, however, that hepatic PBGD remains constant at
approximately 50% of normal activity during exacerbations and remission of
AIP, as in erythrocytes. An early report suggested that the enzyme activity is
considerably less than half-normal in the liver during an acute attack. Hepatic
PBGD activity might be reduced further once AIP becomes activated if, as
suggested, excess PBG interferes with assembly of the dipyrromethane cofactor
for this enzyme. It also seems likely that currently unknown genetic factors play
a contributing role in, for example, patients who continue to have attacks even
when known precipitants are avoided.
AIP is almost always latent before puberty and becomes active mostly in adult
women, which suggests that endocrine factors, and especially adult levels of
female steroid hormones, are important for clinical expression. Premenstrual
attacks are probably the result of endogenous progesterone. Acute porphyrias are
sometimes exacerbated by exogenous steroids, including oral contraceptive
preparations containing progestins. Surprisingly, pregnancy is usually well
tolerated, suggesting that beneficial metabolic changes may ameliorate the
effects of high levels of progesterone.
Drugs that are unsafe in acute porphyrias (Table 110.3 ) include those having
the capacity to induce hepatic ALAS1, which is closely associated with
induction of CYPs. Some chemicals (e.g., griseofulvin) can increase heme
turnover by promoting the destruction of specific CYPs to form an inhibitor
(e.g., N -methyl protoporphyrin) of ferrochelatase (FECH, the final enzyme in
the pathway). Sulfonamide antibiotics are harmful but apparently not inducers of
hepatic heme synthesis. Ethanol and other alcohols are inducers of ALAS1 and
some CYPs.

Table 110.3

Drugs Regarded as Unsafe and Safe in Acute Porphyrias

UNSAFE SAFE
Barbiturates (all) Narcotic analgesics
Sulfonamide antibiotics* Aspirin
Meprobamate* (also mebutamate,* tybutamate* ) Acetaminophen (paracetamol)
Carisoprodol* Phenothiazines
Glutethimide* Penicillin and derivatives
Methyprylon Streptomycin
Ethchlorvynol* Glucocorticoids
Mephenytoin Bromides
Phenytoin* Insulin
 Succinimides Atropine
Carbamazepine* Cimetidine
Clonazepam ‡ Ranitidine †
Primidone* Acetazolamide
Valproic acid* Allopurinol
Pyrazolones (aminopyrine, antipyrine) Amiloride
Griseofulvin* Bethanidine
Ergots Bumetanide
Metoclopramide* ‡ Coumarins
Rifampin* Fluoxetine
Pyrazinamide* ‡ Gabapentin
Diclofenac* ‡ Gentamicin
Fluconazole* Guanethidine
Oral contraceptives Ofloxacin
Progesterone and synthetic progestins* Propranolol
Danazol* Succinylcholine

Alcohol Tetracycline
ACEIs (especially enalapril) ‡
Spironolactone
CCBs (especially nifedipine) ‡
Ketoconazole
Ketamine*
*
Porphyria has been listed as a contraindication, warning, precaution, or adverse effect in U.S.
labeling for these drugs. Estrogens are also listed as harmful in porphyria but have been
implicated as harmful in acute porphyrias, mostly based only on experience with estrogen-
progestin combinations. Although estrogens can exacerbate porphyria cutanea tarda, there is little
evidence they are harmful in the acute porphyrias.
† Porphyria has been listed as a precaution in U.S. labeling for this drug. However, this drug is

regarded as safe by other sources.

‡ These drugs have been classified as probably safe by some sources, but this is controversial,

and they should be avoided.

This partial listing does not include all available information about drug safety in acute porphyrias.
Other sources should be consulted for drugs not listed here.
ACEIs, Angiotensin-converting enzyme inhibitors; CCBs, calcium channel blockers.

Nutritional factors , principally reduced intake of calories and carbohydrates,

as may occur with illness or attempts to lose weight, can increase porphyrin
precursor excretion and induce attacks of porphyria. Increased carbohydrate
intake may ameliorate attacks. Hepatic ALAS1 is modulated by the peroxisome
proliferator-activated receptor-γ coactivator-1α, which is an important link
between nutritional status and exacerbations of acute porphyria.
Other factors have been implicated. Chemicals in cigarette smoke, such as
polycyclic aromatic hydrocarbons, can induce hepatic CYPs and heme synthesis.
A survey of AIP patients found an association between smoking and repeated
porphyric attacks. Attacks may result from metabolic stress and impaired
nutrition associated with major illness, infection, or surgery. Clinical
observations suggest an additive effect of multiple predisposing factors,
including drugs, endogenous hormones, nutritional factors, and smoking, are
common.

Neurologic Mechanisms
The mechanism of neural damage in acute porphyrias is poorly understood. The
most favored hypothesis at present is that 1 or more heme precursors, or perhaps
a derivative, are neurotoxic. Increased ALA in AIP, HCP, VP, ADP, plumbism,
and hereditary tyrosinemia type 1, which have similar neurologic manifestations,
suggests that this substance or a derivative may be neuropathic. Porphyrins
derived from ALA after its uptake into cells may have toxic potential. ALA can
also interact with γ-aminobutyric acid (GABA) receptors. Severe AIP greatly
improves after allogeneic liver transplantation. This experience and the
demonstration that recipients of AIP livers develop porphyria support the
hypothesis that heme precursors from the liver cause the neurologic
manifestations.

Epidemiology
AIP occurs in all races and is the most common acute porphyria, with an
estimated prevalence in most countries of 5 in 100,000. In Sweden, prevalence
was estimated to be 7.7 in 100,000, including latent cases with normal porphyrin
precursors. A much higher prevalence of 60-100 in 100,000 in northern Sweden
is the result of a founder effect. The combined prevalence of AIP and VP in
Finland is approximately 3.4 in 100,000. A survey of chronic psychiatric patients
in the United States using an erythrocyte PBGD determination found a high
prevalence (210 in 100,000) of PBGD deficiency, but a study in Mexico found a
similar prevalence in psychiatric patients and controls. Population screening by
erythrocyte PBGD activity or DNA analysis revealed a prevalence of 200
heterozygotes per 100,000 people in Finland, and 1 in approximately 1,675 (60
in 100,000) in France. Studies using exomic/genomic databases show that the
estimated frequency of pathogenic mutations in the HMBS gene is 0.00056 (56
in 100,000) suggesting that the penetrance of this disorder may be as low as 1%,
and that carriers of PBGD mutations that can cause AIP are much more common
than previously believed.

Clinical Manifestations
Neurovisceral manifestations of acute porphyrias may appear any time after
puberty, but rarely before (Table 110.4 ). Symptomatic childhood cases have
been reported, but most were not adequately documented biochemically and
confirmed by genetic testing. Abdominal pain is the most common presenting
symptom in such cases, but seizures are common and may precede the diagnosis
of AIP. Other manifestations reported in children include peripheral neuropathy,
myalgias, hypertension, irritability, lethargy, and behavioral abnormalities. A
population-based study in Sweden indicated that symptoms suggestive of
porphyria may occur in heterozygotes during childhood, even, in contrast to
adults, when urinary porphyria precursors are not elevated. This study did not
compare the frequency of such nonspecific symptoms in a control group of
children. Very rare cases of homozygous AIP present differently, with severe
neurologic manifestations early in childhood.

Table 110.4
Common Presenting Symptoms and Signs of Acute
Porphyria

SYMPTOMS FREQUENCY
COMMENT
AND SIGNS (%)
GASTROINTESTINAL
Abdominal 85–95 Usually unremitting (for hours or longer) and poorly localized but can be
pain cramping.
Vomiting 43–88 Neurologic in origin and rarely accompanied by peritoneal signs, fever, or
leukocytosis.
Constipation 48–84 Nausea and vomiting often accompany abdominal pain. May be accompanied by
bladder paresis.
Diarrhea 5–12
NEUROLOGIC
Pain in 50–70 Pain may begin in the chest or back and move to the abdomen. Extremity pain
extremities, chest, neck, or head indicates involvement of sensory nerves; objective sensory
back loss reported in 10–40% of cases.
Paresis 42–68 May occur early or late during a severe attack. Muscle weakness usually begins
proximally rather than distally and more often in the upper than lower
extremities.
Respiratory 9–20 Preceded by progressive peripheral motor neuropathy and paresis.
paralysis
Mental 40–58 May range from minor behavioral changes to agitation, confusion,
 symptoms hallucinations, and depression.
Convulsions 10–20 A central neurologic manifestation of porphyria or caused by hyponatremia,
which often results from syndrome of inappropriate antidiuretic hormone
secretion or sodium depletion.
CARDIOVASCULAR
Tachycardia 64–85 May warrant treatment to control rate, if symptomatic
Systemic 36–55 May require treatment during acute attacks, and sometimes becomes chronic.
arterial
hypertension
From Anderson KE, Bloomer JR, Bonkovsky HL, et al: Desnick recommendations for the
diagnosis and treatment of the acute porphyrias, Ann Intern Med 142(6):439–450, 2005.

Acute attacks in adults are characterized by a constellation of nonspecific

symptoms, which may become severe and life threatening. Abdominal pain
occurs in 85–95% of AIP patients; is usually severe, steady, and poorly
localized, but is sometimes cramping; and accompanied by signs of ileus,
including abdominal distention and decreased bowel sounds. Nausea, vomiting,
and constipation are common, but increased bowel sounds and diarrhea may
occur. Bladder dysfunction may cause hesitancy and dysuria. Tachycardia , the
most common physical sign, occurs in up to 80% of attacks. This is often
accompanied by hypertension , restlessness, coarse or fine tremors, and excess
sweating, which are attributed to sympathetic overactivity and increased
catecholamines. Other common manifestations include mental symptoms; pain
in the extremities, head, neck, or chest; muscle weakness; and sensory loss.
Because all these manifestations are neurologic rather than inflammatory, there
is little or no abdominal tenderness, fever, or leukocytosis.
Porphyric neuropathy is primarily motor and appears to result from axonal
degeneration rather than demyelinization. Sensory involvement is indicated by
pain in the extremities, which may be described as muscle or bone pain, and by
numbness, paresthesias, and dysesthesias. Paresis may occur early in an attack
but is more often a late manifestation in an attack that is not recognized and
adequately treated. Rarely, severe neuropathy develops when there is little or no
abdominal pain. Motor weakness most commonly begins in the proximal
muscles of the upper extremities and then progresses to the lower extremities
and the periphery. It is usually symmetric, but occasionally asymmetric or focal.
Initially, tendon reflexes may be little affected or hyperactive and become
decreased or absent. Cranial nerves, most often X and VII, may be affected, and
blindness from involvement of the optic nerves or occipital lobes has been
reported. More common central nervous system (CNS) manifestations include
seizures, anxiety, insomnia, depression, disorientation, hallucinations, and
paranoia. Seizures may result from hyponatremia, porphyria itself, or an
Manifestations of Hypoglycemia in Childhood
Features Associated With Activation of Autonomic Nervous
System and Epinephrine Release*

Anxiety †
Perspiration †
Palpitation (tachycardia) †
Pallor ‡
Tremulousness ‡
Weakness
Hunger
Nausea
Emesis

Features Associated With Cerebral Glucopenia

Headache †
Mental confusion †
Visual disturbances (↓ acuity, diplopia) †
Organic personality changes †
Inability to concentrate †
Dysarthria
Staring
Paresthesias
Dizziness
Amnesia
Ataxia, incoordination
Refusal to feed ‡
Somnolence, lethargy ‡
Seizures ‡
Coma
Stroke, hemiplegia, aphasia
Decerebrate or decorticate posture
* Some of these features will be attenuated if the patient is receiving β-

adrenergic blocking agents.

† Common.

‡ Most common manifestations in the newborn.

Many neonates have asymptomatic (chemical) hypoglycemia. The incidence

of symptomatic hypoglycemia is highest in small-for-gestational-age (SGA)
infants (Fig. 111.1 ). The exact incidence of symptomatic hypoglycemia has
been difficult to establish because many of the symptoms in neonates occur
together with other conditions, such as infections, especially sepsis and
meningitis; CNS anomalies, hemorrhage, or edema; hypocalcemia and
hypomagnesemia; asphyxia; drug withdrawal; apnea of prematurity; congenital
heart disease; or polycythemia.

FIG. 111.1 Incidence of hypoglycemia by birthweight, gestational age, and intrauterine
growth. (From Lubchenco LO, Bard H: Incidence of hypoglycemia in newborn infants
classified by birthweight and gestational age, Pediatrics 47:831–838, 1971.)

The onset of symptoms in neonates varies from a few hours to a week after
birth. In approximate order of frequency, symptoms include jitteriness or
tremors, apathy, episodes of cyanosis, seizures, intermittent apneic spells or
tachypnea, weak or high-pitched cry, limpness or lethargy, difficulty feeding
(latching on), and eye rolling. Episodes of sweating, sudden pallor, hypothermia,
and cardiac arrest and failure may also occur. Frequently, a clustering of episodic
symptoms may be noted. Because these clinical manifestations may result from
various causes, it is critical to measure serum glucose levels and determine
whether symptoms disappear with the administration of sufficient glucose to
raise the blood glucose to normal levels; if they do not, other diagnoses must be
considered.

Classification of Hypoglycemia in Infants

and Children
Classification is based on knowledge of the control of glucose homeostasis in
infants and children (Table 111.2 ).
Table 111.2
Classification of Hypoglycemia in Infants and
Children
Neonatal Transitional (Adaptive) Hypoglycemia
Associated With Inadequate Substrate or Immature Enzyme Function in
Otherwise Normal Neonates

Prematurity
Small for gestational age
Normal newborn

Transient Neonatal Hyperinsulinism

Infant of diabetic mother

Small for gestational age
Discordant twin
Birth asphyxia
Infant of toxemic mother
Neonatal, Infantile, or Childhood Persistent Hypoglycemia
Hyperinsulinism

Recessive KATP channel HI

Recessive HADH (hydroxyl acyl-CoA dehydrogenase) mutation HI
Recessive UCP2 (mitochondrial uncoupling protein 2) mutation HI
Focal KATP channel HI
Dominant KATP channel HI
Atypical congenital hyperinsulinemia (no mutations in ABCC8 or KCN11
genes)
Dominant glucokinase HI
Dominant glutamate dehydrogenase HI (hyperinsulinism-
hyperammonemia syndrome)
Dominant mutations in HNF-4A and HNF-1A (hepatocyte nuclear factors
4α and 1α) HI with monogenic diabetes of youth later in life
Dominant mutation in SLC16A1 (the pyruvate transporter)—exercise-
induced hypoglycemia
Activating mutations in the calcium channel CACNA1D (permit calcium
influx and thus unregulated insulin secretion)
Acquired or familial islet adenoma associated with mutations in MEN1
gene
Beckwith-Wiedemann syndrome
Kabuki syndrome
Insulin administration (Munchausen syndrome by proxy)
Oral sulfonylurea drugs
Congenital disorders of glycosylation

Counter-Regulatory Hormone Deficiency

Panhypopituitarism
Isolated growth hormone deficiency
Adrenocorticotropic hormone deficiency
Addison disease (including congenital adrenal hypoplasia, adrenal
leukodystrophy, triple A syndrome, ACTH receptor deficiency, and
autoimmune disease complex)
Epinephrine deficiency
Glycogenolysis and Gluconeogenesis Disorders

Glucose-6-phosphatase deficiency (GSD Ia)

Glucose-6-phosphate translocase deficiency (GSD Ib)
Amylo-1,6-glucosidase (debranching enzyme) deficiency (GSD III)
Liver phosphorylase deficiency (GSD VI)
Phosphorylase kinase deficiency (GSD IX)
Glycogen synthetase deficiency (GSD 0)
Fructose-1,6-diphosphatase deficiency
Pyruvate carboxylase deficiency
Galactosemia
Hereditary fructose intolerance

Lipolysis Disorders
Fatty Acid Oxidation Disorders

Carnitine transporter deficiency (primary carnitine deficiency)

Carnitine palmitoyltransferase-1 deficiency
Carnitine translocase deficiency
Carnitine palmitoyltransferase-2 deficiency
Secondary carnitine deficiencies
Very-long-, long-, medium-, short-chain acyl-CoA dehydrogenase
deficiency

Other Etiologies
Substrate-Limited Causes

Ketotic hypoglycemia
Poisoning—drugs
Salicylates
Alcohol
Oral hypoglycemic agents
Insulin
Propranolol
Pentamidine
Quinine
 Disopyramide
Ackee fruit (unripe)—hypoglycin
Litchi – associated toxin (toxic hypoglycemic syndrome).
Vacor (rat poison)
Trimethoprim-sulfamethoxazole (with renal failure)
L -Asparaginase and other antileukemic drugs

Liver Disease

Reye syndrome
Hepatitis
Cirrhosis
Hepatoma

Amino Acid and Organic Acid Disorders

Maple syrup urine disease

Propionic acidemia
Methylmalonic acidemia
Tyrosinosis
Glutaric aciduria
3-Hydroxy-3-methylglutaric aciduria

Systemic Disorders

Sepsis
Carcinoma/sarcoma (secreting—insulin-like growth factor II)
Heart failure
Malnutrition
Malabsorption
Antiinsulin receptor antibodies
Antiinsulin antibodies
Neonatal hyperviscosity
Renal failure
Diarrhea
Burns
 Shock
Chiari malformation
Postsurgical complication
Pseudohypoglycemia (leukocytosis, polycythemia)
Excessive insulin therapy of insulin-dependent diabetes mellitus
Factitious disorder
Nissen fundoplication (dumping syndrome)
Falciparum malaria

GSD, Glycogen storage disease; HI, hyperinsulinemia; KATP , regulated

potassium channel.

Neonatal, Transient, Small-for-Gestational-Age,

and Premature Infants
The estimated incidence of symptomatic hypoglycemia in newborns is 1-3 in
1,000 live births. This incidence is increased several fold in certain high-risk
neonatal groups (see Table 111.2 and Fig. 111.1 ). Premature and SGA infants
are vulnerable to the development of hypoglycemia. The factors responsible for
the high frequency of hypoglycemia in this group, as well as in other groups
outlined in Table 111.2 , are related to the inadequate stores of liver glycogen,
muscle protein, and body fat needed to sustain the substrates required to meet
energy needs. These infants are small by virtue of prematurity or impaired
placental transfer of nutrients. Their enzyme systems for gluconeogenesis may
not be fully developed. Transient hyperinsulinism responsive to diazoxide has
also been reported as contributing to hypoglycemia in asphyxiated, SGA, and
premature newborn infants. This form of hyperinsulinism, associated with
perinatal asphyxia, intrauterine growth restriction, maternal toxemia, and other
perinatal stressors, is probably the most common cause of hyperinsulinemic
hypoglycemia in neonates and may be quite severe. In most patients the
condition resolves quickly, but it may persist to 7 mo of life or longer.
In contrast to deficiency of substrates or enzymes, the hormonal system
appears to be functioning normally at birth in most low-risk neonates. Despite
hypoglycemia, plasma concentrations of alanine, lactate, and pyruvate are
higher, implying their diminished rate of utilization as substrates for
gluconeogenesis. Infusion of alanine elicits further glucagon secretion but causes
Hypoglycemia in Infants and Children: Clinical and
Laboratory Features
AGE AT DIAGNOSIS GLUCOSE* INSULIN FASTING TIME TO
GROUP
(mo) (mg/dL) (µU/mL) HYPOGLYCEMIA (hr)
Hyperinsulinemia (N = 12)
Mean 7.4 23.1 22.4 2.1 †
SEM 2.0 2.7 3.2 0.6
Nonhyperinsulinemia (N = 16)
Mean 41.8 36.1 5.8 18.2
SEM 7.3 2.4 0.9 2.9
* In hypoglycemia caused by hyperinsulinism β-hydroxybutyrate and free fatty acids are low
compared with normal at same duration of fasting.
† Milder forms of hyperinsulinism may require up to 18 hr of fasting to provoke hypoglycemia.

SEM, Standard error of mean.

Adapted from Antunes JD, Geffner ME, Lippe BM, et al: Childhood hypoglycemia: differentiating
hyperinsulinemic from nonhyperinsulinemic causes, J Pediatr 116:105–108, 1990.

Table 111.4
Correlation of Clinical Features With Molecular Defects in
Persistent Hyperinsulinemic Hypoglycemia in Infancy

FAMILY MOLECULAR
TYPE MACROSOMIA HYPOGLYCEMIA/HYPERINSULINEMIA
HISTORY DEFECTS

Sporadic Present at birth Moderate/severe in 1st days to weeks of life Negative ? SUR1 /KIR 6.2
mutations not always
identified in diffuse
hyperplasia
Autosomal Present at birth Severe in 1st days to weeks of life Positive SUR /KIR 6.2
recessive

Autosomal Unusual Moderate onset usually >6 mo of age Positive Glucokinase

dominant (activating)
Some cases gene
unknown

Autosomal Unusual Moderate onset usually >6 mo of age Positive Glutamate

dominant dehydrogenase
(activating)
Beckwith- Present at birth Moderate, spontaneously resolves >6 mo of Negative Duplicating/imprinting
Wiedemann age in chromosome
syndrome 11p15.1

Congenital Not usual Moderate/onset >3 mo of age Negative Phosphomannose

disorders of isomerase deficiency
glycosylation

Table 111.5
Analysis of Critical Blood Sample During
Hypoglycemia and 30 Min After Glucagon*
Substrates

Glucose
Free fatty acids
Ketones
Lactate
Uric acid
Ammonia

Hormones

Insulin
Cortisol
 Growth hormone
Thyroxine, thyroid-stimulating hormone
Insulin-like growth factor binding protein-1 †

* Glucagon 0.5 mg with maximum of 1 mg IV or IM.

† Measure once only before or after glucagon administration. Rise in glucose of

≥40 mg/dL after glucagon given at the time of hypoglycemia strongly suggests a
hyperinsulinemic state with adequate hepatic glycogen stores and intact
glycogenolytic enzymes. If ammonia is elevated to 100-200 µM, consider
activating mutation of glutamate dehydrogenase.
Table 111.6
Criteria for Diagnosing Hyperinsulinism
Based on “Critical” Samples (Drawn at a
Time of Fasting Hypoglycemia: Plasma
Glucose <50 mg/dL)

1. Hyperinsulinemia (plasma insulin >2 µU/mL)*

2. Hypofatty acidemia (plasma free fatty acids <1.5 mmol/L)
3. Hypoketonemia (plasma β-hydroxybutyrate <2.0 mmol/L)
4. Inappropriate glycemic response to glucagon, 1 mg IV (change in glucose
>40 mg/dL)

* Depends on sensitivity of insulin assay.

From Stanley CA, Thomson PS, Finegold DN, et al: Hypoglycemia in infants
and neonates. In Sperling MA, editor: Pediatric endocrinology , ed 2,
Philadelphia, 2002, Saunders, pp 135–159.
Table 111.7
Diagnosis of Acute Hypoglycemia in Infants
and Children
Acute Symptoms Present

1. Obtain blood sample before and 30 min after glucagon administration.

2. Obtain urine as soon as possible. Examine for ketones; if not present and
hypoglycemia confirmed, suspect hyperinsulinemia or fatty acid
oxidation defect; if present, suspect ketotic, hormone deficiency, inborn
error of glycogen metabolism, or defective gluconeogenesis.
3. Measure glucose in the original blood sample. If hypoglycemia is
confirmed, proceed with substrate-hormone measurement as in Table
111.5 .
4. If glycemic increment after glucagon exceeds 40 mg/dL above basal,
suspect hyperinsulinemia.
5. If insulin level at time of confirmed hypoglycemia is >5 µU/mL, suspect
endogenous hyperinsulinemia; if >100 µU/mL, suspect factitious
hyperinsulinemia (exogenous insulin injection). Admit to hospital for
supervised fast.
6. If cortisol is <10 µg/dL or growth hormone is <5 ng/mL, or both, suspect
adrenal insufficiency or pituitary disease, or both. Admit to hospital for
hormonal testing and neuroimaging.

History Suggestive: Acute Symptoms Not Present

1. Careful history for relation of symptoms to time and type of food intake,
considering age of patient. Exclude possibility of alcohol or drug
ingestion. Assess possibility of insulin injection, salt craving, growth
velocity, or intracranial pathology.
2. Careful examination for hepatomegaly (glycogen storage disease; defect
in gluconeogenesis); pigmentation (adrenal failure); stature and
neurologic status (pituitary disease).
3. Admit to hospital for provocative testing:
a. 24 hr fast under careful observation; when symptoms provoked,
proceed with steps 1-4 as when acute symptoms present.
b. Pituitary-adrenal function using arginine-insulin stimulation test if
indicated.
4. Consider molecular diagnostic test before liver biopsy for histologic and
enzyme determinations.
 5. Oral glucose tolerance test (1.75 g/kg; max 75 g) if reactive hypoglycemia
suspected (e.g., dumping syndrome).

The measurement of serum IGFBP-1 concentration may help diagnose

hyperinsulinism. The secretion of IGFBP-1 is acutely inhibited by insulin action;
IGFBP-1 concentrations are low during hyperinsulinism-induced hypoglycemia.
In patients with spontaneous or fasting-induced hypoglycemia with a low insulin
level (ketotic hypoglycemia, normal fasting), IGFBP-1 concentrations are
significantly higher.
The differential diagnosis of endogenous hyperinsulinism includes diffuse β-
cell hyperplasia or focal β-cell microadenoma . The distinction between these
2 major entities is important because the diffuse hyperplasia, if unresponsive to
medical therapy, requires near-total pancreatectomy, despite which
hypoglycemia may persist or diabetes mellitus may ensue later. Some, but not
all, affected infants may respond to sirolimus. By contrast, focal adenomas
diagnosed preoperatively or intraoperatively permit localized curative resection
with subsequent normal glucose metabolism. Approximately 50% of the
autosomal recessive or sporadic forms of neonatal/infantile hyperinsulinism are
caused by focal microadenomas, which may be distinguished from the diffuse
form by the pattern of insulin response to selective insulin secretagogues infused
into an arterial branch supplying the pancreas, with sampling by the hepatic vein.
However, these invasive and technically difficult procedures have been largely
abandoned in favor of positron emission tomography (PET) using 18-fluoro-L -
dopa. This technique can distinguish the diffuse form (uniform fluorescence
throughout the pancreas) from the focal form (focal uptake of 18-fluoro-L -dopa
and localized fluorescence) with an extremely high degree of reliability, success,
specificity, and sensitivity (see Fig. 111.3 ).
Insulin-secreting macroadenomas are rare in childhood and may be
diagnosed preoperatively by CT or MRI. The plasma levels of insulin alone,
however, cannot distinguish the aforementioned entities. The diffuse or
microadenomatous forms of islet cell hyperplasia represent a variety of genetic
defects responsible for abnormalities in the endocrine pancreas, characterized by
autonomous insulin secretion that is not appropriately reduced when blood
glucose declines spontaneously or in response to provocative maneuvers such as
fasting (see Tables 111.4 , 111.7 , and 111.8 ). Clinical, biochemical, and
molecular genetic approaches permit classification of congenital
hyperinsulinism, formerly termed nesidioblastosis, into distinct entities.
disorders (Table 113.1 ). Persistently small fontanels suggest microcephaly,
craniosynostosis, congenital hyperthyroidism, or wormian bones; presence of a
3rd fontanel suggests trisomy 21 but is seen in preterm infants. Soft areas
(craniotabes ) are occasionally found in the parietal bones at the vertex near the
sagittal suture; they are more common in preterm infants and in infants who
have been exposed to uterine compression. Although such soft areas are usually
insignificant, their possible pathologic cause should be investigated if they
persist. Soft areas in the occipital region suggest the irregular calcification and
wormian bone formation associated with osteogenesis imperfecta, cleidocranial
dysostosis, lacunar skull, cretinism, and occasionally Down syndrome.

Table 113.1
Disorders Associated with a Large Anterior Fontanel
Hypothyroidism
Achondroplasia
Apert syndrome
Cleidocranial dysostosis
Congenital rubella syndrome
Hallermann-Streiff syndrome
Hydrocephaly
Hypophosphatasia
Intrauterine growth restriction
Kenny syndrome
Osteogenesis imperfecta
Prematurity
Pyknodysostosis
Russell-Silver syndrome
Trisomies 13, 18, and 21
Vitamin D deficiency rickets

Atrophic or alopecic scalp areas may represent aplasia cutis congenita ,

which may be sporadic, or autosomal dominant, or associated with trisomy 13,
chromosome 4 deletion, or Johanson-Blizzard syndrome. Deformational
plagiocephaly may be the result of in utero positioning forces on the skull and
manifests as an asymmetric skull and face with ear malalignment (see Chapter
610 ). It is associated with torticollis and vertex positioning. Depression of the
skull (indentation, fracture, Ping-Pong ball deformity) is usually of prenatal
onset and a result of prolonged focal pressure by the maternal pelvic bone.

Face
of discharge.

Table 113.4
Criteria for Discharge of Healthy Term Newborns*
GENERAL
Normal vital signs including respiratory rate <60 breaths/min; axillary temperature 36.5°C-37.4°C (97.7°-99.3°F)
in open crib
Physical examination reveals no abnormalities requiring continued hospitalization
Regular urination; stool × 1
At least 2 uneventful, successful feedings
No excessive bleeding 2 hr after circumcision
LABORATORY AND OTHER SCREENS
Maternal syphilis, hepatitis B surface antigen, and HIV status
Newborn hepatitis B vaccine administered or appointment for vaccination confirmed
Maternal tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis, adsorbed (Tdap) vaccination
Maternal influenza vaccination during flu season
Evaluation and monitoring for sepsis based on maternal risk factors including GBS colonization
Umbilical or newborn direct Coombs test and blood type if clinically indicated
Expanded newborn metabolic screening
Hearing screening
Screening for hypoglycemia based on infant risk factors
Pulse oximetry screening
Screening for hyperbilirubinemia, with management and follow-up as recommended based on level of jaundice
SOCIAL
Evidence of parental knowledge, ability, and confidence to care for the baby at home:
Feeding
Normal stool and urine output
Cord, skin, and genital care
Recognition of illness (jaundice, poor feeding, lethargy, fever, etc.)
Infant safety (car seat, supine sleep position, etc.)
Availability of family and physician support (physician follow-up)
Assessment of family, environmental, and social risk factors:
Substance abuse
History of child abuse
Domestic violence
Mental illness
Teen mother
Homelessness
Barriers to follow-up
Source of continuing medical care is identified.
* Refers to infants born between 37 and 42 wk of gestation after uncomplicated pregnancy, labor,

and delivery.
From American Academy of Pediatrics Committee on Fetus and Newborn: Hospital stay for
healthy term newborn infants, Pediatrics 135:948–953, 2015.

Bibliography
 Additional practices that encourage successful breastfeeding include
antepartum education and encouragement, immediate postpartum mother–infant
contact with suckling, demand feeding, inclusion of maternal partners in
breastfeeding education, and support from experienced women. Nursing at first
for least 5 min at each breast is reasonable, allows a baby to obtain most of the
available breast contents, and provides effective stimulation for increasing the
milk supply. Nursing episodes should then be extended according to the comfort
and desire of the mother and infant. A confident and relaxed mother, supported
by an encouraging home and hospital environment, is likely to nurse well. The
Baby-Friendly Hospital Initiative , a global effort sponsored by WHO and the
UN Children's Fund to promote breastfeeding, recommends 10 steps to
successful breastfeeding (Table 113.5 ). When instituted together as a complete
bundle, these practices can improve multiple outcomes, including breastfeeding
initiation, duration of exclusive breastfeeding, and duration of overall
breastfeeding. In the United States, however, the vast majority of newborns are
still not delivered in Baby-Friendly hospitals that have implemented all 10 steps.
Educating mothers during pregnancy and showing mothers how to breastfeed are
the most widely implemented strategies, while establishment of written
breastfeeding policies, restriction of formula access, and establishment of
breastfeeding support groups after discharge are among the most challenging to
implement.

Table 113.5
Ten Steps to Successful Breastfeeding
Every facility providing maternity services and care for newborn infants should accomplish the following:
1. Have a written feeding policy that is routinely communicated to staff and patients, comply with WHO
restrictions on marketing of breast milk substitutes, and establish ongoing monitoring and data-management
systems.
2. Ensure that staff have sufficient knowledge, competence, and skills to support breastfeeding.
3. Discuss the importance and management of breastfeeding with pregnant women and their families.
4. Facilitate immediate and uninterrupted skin-to-skin contact and help initiate breastfeeding as soon as
possible after birth.
5. Support mothers to initiate and maintain breastfeeding and manage common difficulties.
6. Give newborn infants no food or drink other than breast milk unless medically indicated.
7. Practice rooming-in (allow mothers and infants to remain together) 24 hr a day.
8. Support mothers to recognize and respond to their infants' feeding cues.
9. Counsel mothers on the use and risks of feeding bottles, teats, and pacifiers.
10. Coordinate discharge to ensure timely access to ongoing support and care.
Adapted from Guideline: Protecting, promoting and supporting breastfeeding in facilities providing
maternity and newborn services. Geneva, 2017, World Health Organization.
Table 113.6
Drugs of Abuse and Adverse Infant Effects
CONTRAINDICATED
Amphetamines
Antineoplastic agents
Bromocriptine
Chloramphenicol
Clozapine
Cocaine
Cyclophosphamide
Doxorubicin
Ecstasy (MDMA)
Ergots
Gold salts
Heroin
Immunosuppressants
Methamphetamine
Phencyclidine (PCP)
Radiopharmaceuticals
Thiouracil
USE WITH CAUTION
Alcohol
Amiodarone
Anthraquinones (laxatives)
Aspirin (salicylates)
Atropine
β-Adrenergic blocking agents
Benzodiazepines
Birth control pills
Bromides
Cascara
Codeine
Dicumarol
Dihydrotachysterol
Domperidone
Estrogens
Hydrocodone
Lithium
Marijuana
Metoclopramide
Meperidine
Oxycodone
Phenobarbital*
Primidone
Reserpine
Salicylazosulfapyridine (sulfasalazine)
* Watch for sedation.

Contraindications to Breastfeeding
Medical contraindications to breastfeeding in the United States include infants
with galactosemia, maple syrup urine disease, and phenylketonuria. Maternal
conditions that contraindicate breastfeeding include infection with human T-cell
lymphotropic virus types 1 and 2, active tuberculosis (until appropriately treated
≥2 wk and not considered contagious), herpesvirus infection on breast, use of or
dependence on certain illicit drugs, and maternal treatment with some
radioactive compounds (Table 113.7 ). Because clean water and affordable
replacement feeding are available in the United States, it is recommended that
HIV-infected mothers not breastfeed their infants regardless of maternal viral
load and antiretroviral therapy. However, in resource-limited countries where
diarrhea and pneumonia are significant causes of infant and child mortality,
breastfeeding may not be contraindicated for HIV-positive mothers receiving
antiretroviral therapy. Donor human milk, particularly that purchased online,
may be contaminated with potential pathogens. Contamination is much less of a
concern with pasteurized human milk obtained from a milk bank.

Table 113.7
Summary of Infectious Agents Detected in Milk and
Newborn Disease

BREAST MILK
DETECTED MATERNAL INFECTION
REPORTED AS CAUSE
INFECTIOUS AGENT IN BREAST CONTRAINDICATION TO
OF NEWBORN
MILK? BREASTFEEDING?
DISEASE?
BACTERIA
Mastitis/Staphylococcus aureus Yes No No, unless breast abscess
present
Mycobacterium tuberculosis :
Active disease Yes No Yes, because of aerosol spread,
or tuberculosis mastitis
Purified protein derivative skin No No No
test result positive, chest
radiograph findings negative
Escherichia coli , other gram- Yes, stored Yes, stored —
negative rods
Group B streptococci Yes Yes No*
Listeria monocytogenes Yes Yes No*
Coxiella burnetii Yes Yes No*
Syphilis No No No †
VIRUSES
HIV Yes Yes Yes, developed countries
Cytomegalovirus:
Term infant Yes Yes No
 Preterm infant Yes Yes Evaluate on an individual basis
Hepatitis B virus Yes, surface No No, developed countries ‡
antigen
Hepatitis C virus Yes No No §
Hepatitis E virus Yes No No
Human T-cell leukemia virus Yes Yes Yes, developed countries
(HTLV)-1
HTLV-2 Yes Uncertain Yes, developed countries
Herpes simplex virus Yes Yes No, unless breast vesicles
present
Rubella
Wild type Yes Yes, rare No
Vaccine Yes No No
Varicella-zoster virus Yes No No, cover active lesions ¶
Epstein-Barr virus Yes No No
Human herpesvirus (HHV)-6 No No No
HHV-7 Yes No No
West Nile virus Possible Possible Unknown
Zika virus Yes No No
PARASITES
Toxoplasma gondii Yes Yes, 1 case No
* Provided that the mother and child are taking appropriate antibiotics.

†
Treat mother and child if active disease.
‡ Immunize and immune globulin at birth.

§ Provided that the mother is HIV seronegative. Mothers should be counseled that breast milk

transmission of hepatitis C virus has not been documented, but is theoretically possible.
¶ Provide appropriate antivaricella therapy or prophylaxis to newborn.

Adapted from Jones CA: Maternal transmission of infectious pathogens in breast milk, J Paediatr
Child Health 37:576–582, 2001.

Bibliography
American Academy of Pediatrics, Committee on Pediatric
AIDS. Infant feeding and transmission of human
immunodeficiency virus in the United States. Pediatrics .
2013;131:391–396.
American Academy of Pediatrics, Section on Breastfeeding.
Breastfeeding and the use of human milk. Pediatrics .
2012;129:e827–e841.
Becker GE, Remmington S, Remmington T. Early additional
food and fluids for healthy breastfed full-term infants.
C H A P T E R 11 4

High-Risk Pregnancies
Kristen R. Suhrie, Sammy M. Tabbah

The care of high-risk pregnancies should be coordinated with an experienced

maternal-fetal medicine specialist.
In general, high-risk pregnancies are those that increase the likelihood of
maternal complications, miscarriage, fetal death, preterm delivery, intrauterine
growth restriction (IUGR), poor cardiopulmonary or metabolic transitioning at
birth, fetal or neonatal disease, congenital malformations, or intellectual
impairment and other handicaps (Table 114.1 ).There is no accepted
comprehensive definition of what constitutes a high-risk pregnancy , therefore,
specific epidemiologic data regarding the incidence/prevalence cannot be
reliably reported. Some factors, such as ingestion of a teratogenic drug in the
first trimester, are causally related to the risk, while others, such as
polyhydramnios, are associations that alert a physician to determine the etiology
and avoid the inherent risks associated with excessive amniotic fluid. Although
assessing antepartum risk is important in reducing perinatal mortality and
morbidity, some pregnancies become high risk only during labor and delivery;
therefore careful monitoring is critical throughout the intrapartum course.

Table 114.1
Factors Associated With High-Risk Pregnancy
ECONOMIC
Poverty
Unemployment
Uninsured, underinsured
Poor access to prenatal care
CULTURAL/BEHAVIORAL
Low educational status
Poor healthcare attitudes
No care or inadequate prenatal care
Cigarette, alcohol, or illicit drug use
Age <20 or >40 yr
Unmarried
Short interpregnancy interval (<18 mo between pregnancies)
Lack of support group (husband, family, religion)
Stress (physical, psychologic)
Black race (preterm birth rates are 48% higher than for other women)
BIOLOGIC/GENETIC
Previous low-birthweight or preterm infant
Low weight for height
Poor weight gain during pregnancy
Short stature
Poor nutrition
Consanguinity
Intergenerational effects
Low maternal birthweight
Maternal obesity
Hereditary diseases (inborn error of metabolism)
REPRODUCTIVE
Previous cesarean birth
Previous infertility
Conception by reproductive technology
Prolonged gestation (>40 wk)
Prolonged labor
Previous infant with cerebral palsy, intellectual impairment, birth trauma, or congenital anomalies
Abnormal lie (breech)
Multiple gestations
Premature rupture of membranes
Infection (systemic, amniotic, extra-amniotic, cervical)
Preeclampsia or eclampsia
Uterine bleeding (abruptio placentae, placenta previa)
Parity (0 or >5 previous deliveries)
Uterine or cervical anomalies
Fetal disease
Abnormal fetal growth
Idiopathic premature labor
Iatrogenic prematurity
High or low levels of maternal serum α-fetoprotein
MEDICAL
Diabetes mellitus
Hypertension
Congenital heart disease
Autoimmune disease
Sickle cell anemia
Intercurrent surgery or trauma
Sexually transmitted infection
Maternal hypercoagulable states
Exposure to prescription medications
TORCH (toxoplasmosis, other agents, rubella, cytomegalovirus, herpes simplex) infection

Identifying high-risk pregnancies is important not only because it is the first


FIG. 114.1 Natural birth prevalence of Down syndrome according to maternal age.
(From Wald NJ, Leck I: Antenatal and neonatal screening, ed 2, Oxford, 2000, Oxford
University Press.)

Maternal illness (Table 114.2 ), multiple pregnancies (particularly those

involving monochorionic twins), infections (Table 114.3 ), and certain drugs (see
Chapter 115.4 ) increase the risk for the fetus. The use of assisted reproductive
technology (e.g., ovulation induction, in vitro fertilization, intracytoplasmic
sperm injection) increases the risk of prematurity, perinatal mortality, infant
morbidity, low and very-low birthweight, imprinting disorders, and cerebral
palsy. These risks are largely because of the increase in multiple gestations with
such technology and the association with prematurity . The risks for birth defects
are also increased with assisted reproductive technology, in part because of
epigenetic effects on gene expression.

Table 114.2
Maternal Conditions Affecting the Fetus or Neonate

DISORDER EFFECT(S) MECHANISM(S)

Assisted reproductive Beckwith-Wiedemann, Silver-Russel, Altered imprinting
technology Angelman syndromes
Autoantibody against Neural tube defects Blockage of cellular uptake of folate
folate receptors
Cervical neoplasia Preterm premature rupture of Associated with loop electrosurgical excision
membranes, preterm birth procedure or cone therapy
 Cholestasis Preterm delivery, intrauterine fetal Unknown, possibly bile acid–induced fetal
demise arrhythmia
Cyanotic heart disease IUGR Low fetal oxygen delivery
Diabetes mellitus:
Mild LGA, hypoglycemia Fetal hyperglycemia: produces
hyperinsulinemia; insulin promotes growth
Severe Growth restriction Vascular disease, placental insufficiency
Drug addiction IUGR, neonatal withdrawal Direct drug effect plus poor nutrition
Endemic goiter Hypothyroidism Iodine deficiency
Graves' disease Transient neonatal thyrotoxicosis Transplacental passage of IgG thyroid-
stimulating antibody
Herpes gestationis Bullous rash, intrauterine fetal demise Autoantibody similar to that in bullous
(noninfectious) pemphigoid
Hyperparathyroidism Neonatal hypocalcemia Maternal calcium crosses to fetus and
suppresses fetal parathyroid gland
Hypertension IUGR, intrauterine fetal demise Placental insufficiency, fetal hypoxia
Idiopathic Thrombocytopenia Nonspecific maternal platelet antibodies cross
thrombocytopenic placenta
purpura
Isoimmune Neutropenia or thrombocytopenia Specific antifetus neutrophil or platelet
neutropenia or antibody crosses placenta after sensitization of
thrombocytopenia mother
Malignant melanoma Placental or fetal tumor Placental metastasis
Myasthenia gravis Transient neonatal myasthenia IgG antibody to acetylcholine receptor crosses
placenta
Myotonic dystrophy Neonatal myotonic dystrophy, Genetic anticipation
congenital contractures, respiratory
insufficiency
NMDAR antibody Cortical dysplasia Transplacental antibody
encephalitis
Obesity LGA or IUGR, hypoglycemia Unknown, similarities to diabetes
Phenylketonuria Microcephaly, retardation Elevated fetal phenylalanine values
Poor nutrition IUGR, adult insulin resistance Reduced fetal nutrients, nutritional
programming
Preeclampsia, IUGR, thrombocytopenia, neutropenia, Uteroplacental insufficiency, fetal hypoxia,
eclampsia fetal demise vasoconstriction
Renal transplantation IUGR Uteroplacental insufficiency
Rhesus or other blood Fetal anemia, hypoalbuminemia, IgG crosses placenta and is directed to fetal
group sensitization hydrops, neonatal jaundice cells with antigen
Sickle cell anemia Preterm birth, IUGR, stillbirth Placental insufficiency via maternal sickling,
producing fetal hypoxia
Systemic lupus Congenital heart block, rash, anemia, Antibody directed to fetal heart, red and white
erythematosus thrombocytopenia, neutropenia blood cells, and platelets
IgG, Immunoglobulin G; LGA, large for gestational age; NMDAR, antibody to N -methyl-D -
aspartate receptor; IUGR, intrauterine growth restriction.

Table 114.3
Maternal Infections Affecting the Fetus or Newborn

INFECTION MODE(S) OF NEONATAL OUTCOME

 TRANSMISSION
BACTERIA
Group B Ascending cervical Sepsis, pneumonia
streptococcus
Escherichia coli Ascending cervical Sepsis, pneumonia
Listeria Transplacental Sepsis, pneumonia
monocytogenes
Mycoplasma Ascending cervical Pneumonia
hominis
Chlamydia Vaginal passage Conjunctivitis, pneumonia
trachomatis
Syphilis Transplacental, vaginal Congenital syphilis
passage
Neisseria Vaginal passage Ophthalmia (conjunctivitis), sepsis, meningitis
gonorrhoeae
Mycobacterium Transplacental Prematurity, fetal demise, congenital tuberculosis
tuberculosis
VIRUS
Rubella Transplacental Congenital rubella
Cytomegalovirus Transplacental, breast milk Congenital cytomegalovirus or asymptomatic
(rare)
HIV Transplacental, vaginal Congenital or acquired immunodeficiency syndrome
passage, breast milk
Hepatitis B Vaginal passage, Neonatal hepatitis, chronic hepatitis B surface antigen carrier
transplacental, breast milk state
Hepatitis C Transplacental and vaginal Rarely neonatal hepatitis, ~5% chronic carrier state possible
passage
Herpes simplex Intrapartum exposure Neonatal herpes simplex virus
type 2 or 1 Neonatal encephalitis; disseminated viremia, or cutaneous
infection
Varicella-zoster Transplacental:
Early Congenital anomalies
Late Neonatal varicella
Parvovirus Transplacental Fetal anemia, hydrops
Coxsackievirus B Fecal-oral Myocarditis, meningitis, hepatitis
Rubeola Transplacental Abortion, fetal measles
West Nile Transplacental (rare) Uncertain, possible rash, encephalitis
Possible perinatal
Zika Transplacental Congenital microcephaly, intracranial calcifications, brain
abnormalities, retinal lesions
Chikungunya Transplacental (rare), Neonatal encephalitis
perinatal
Dengue Transplacental, perinatal Neonatal sepsis-like symptoms
PARASITES
Toxoplasmosis Transplacental Congenital toxoplasmosis
Malaria Transplacental Abortion, prematurity, intrauterine growth restriction
FUNGI
Candida Ascending, cervical Sepsis, pneumonia, rash

Preterm birth is common in high-risk pregnancies (see Chapter 117 ).

Factors associated with prematurity (see Table 114.1 ) include multiple
gestations as well as biologic markers such as cervical shortening, genital
Table 114.4
Conditions Associated With Disorders of Amniotic Fluid
Volume
OLIGOHYDRAMNIOS
Amniotic fluid leak/rupture of membranes
Intrauterine growth restriction
Fetal anomalies (particularly GU abnormalities)
Twin-twin transfusion (donor)
Fetal akinesia syndrome
Prune-belly syndrome
Pulmonary hypoplasia
Amnion nodosum
Indomethacin
Angiotensin-converting enzyme inhibitors or receptor antagonists
POLYHYDRAMNIOS
Congenital Anomalies
CNS abnormalities
Tracheoesophageal fistula
Intestinal atresia
Spina bifida
Cleft lip or palate
Cystic adenomatoid lung malformation
Diaphragmatic hernia
Syndromes
Achondroplasia
Klippel-Feil
Trisomy 18
Trisomy 21
TORCH*
Hydrops fetalis
Multiple congenital anomalies
Bartter
Other
Diabetes mellitus
Twin-twin transfusion (recipient)
Fetal anemia
Fetal heart failure
Polyuric renal disease (congenital nephrotic syndrome)
Neuromuscular diseases
Nonimmune hydrops
Chylothorax
Teratoma
Idiopathic
* Toxoplasmosis, other agents, rubella, cytomegalovirus, and herpes simplex.

CNS, Central nervous system; GU, genitourinary.

Oligohydramnios is associated with congenital anomalies; IUGR; severe


FIG. 115.5 Abnormal umbilical artery Doppler in which the diastolic
component shows flow in a reverse direction. This finding occurs in severe
intrauterine hypoxia and intrauterine growth restriction. (From Trudinger C:
Doppler US assessment of blood flow. In Creasy RK, Resnik R, editors:
Maternal-fetal medicine: principles and practice, ed 5, Philadelphia, 2004,
Saunders.)

Table 115.1
Fetal Diagnosis and Assessment

METHOD COMMENT(S) AND INDICATION(S)

IMAGING
Ultrasound (real-time) Biometry (growth), anomaly detection, number of fetuses, sites of calcification
Biophysical profile
Amniotic fluid volume, hydrops
Ultrasound (Doppler) Velocimetry (blood flow velocity)
Detection of increased vascular resistance in the umbilical artery secondary to
placental insufficiency
Detection of fetal anemia (MCA Doppler)
MRI Defining of lesions before fetal surgery
Better delineation of fetal CNS anatomy
FLUID ANALYSIS
Amniocentesis Karyotype or microarray (cytogenetics), biochemical enzyme analysis, molecular
genetic DNA diagnosis, or α-fetoprotein determination
Bacterial culture, pathogen antigen, or genome detection (PCR)
Cordocentesis Detection of blood type, anemia, hemoglobinopathies, thrombocytopenia,
(percutaneous umbilical polycythemia, acidosis, hypoxia, thrombocytopenia, IgM antibody response to
blood sampling) infection
Rapid karyotyping and molecular DNA genetic diagnosis
Fetal therapy (see Table 115.5 )
FETAL TISSUE ANALYSIS
Chorionic villus biopsy Cytogenetic and molecular DNA analysis, enzyme assays
Circulating fetal DNA Noninvasive molecular DNA genetic analysis including microarray analysis and
chromosome number (screening method)
MATERNAL SERUM α-FETOPROTEIN CONCENTRATION
Elevated Twins, neural tube defects (anencephaly, spina bifida), intestinal atresia, hepatitis,
 nephrosis, fetal demise, incorrect gestational age
Reduced Trisomies, aneuploidy
MATERNAL CERVIX
Fetal fibronectin Indicates possible risk of preterm birth
Transvaginal cervical length Short length suggests possible risk of preterm birth
Bacterial culture Identifies risk of neonatal infection (group B streptococcus, Neisseria gonorrhoeae,
Chlamydia trachomatis )
Amniotic fluid Determination of premature rupture of membranes (PROM)
ANTEPARTUM BIOPHYSICAL MONITORING
Nonstress test Fetal distress; hypoxia
Biophysical profile and Fetal distress; hypoxia
modified biophysical profile
Intrapartum fetal heart rate See Fig. 115.6
monitoring

The most common noninvasive tests are the nonstress test (NST ) and the
biophysical profile (BPP ). The NST monitors the presence of fetal heart rate
(FHR ) accelerations that follow fetal movement. A reactive (normal) NST
result demonstrates 2 FHR accelerations of at least 15 beats/min above the
baseline FHR lasting 15 sec during 20 min of monitoring. A nonreactive NST
result suggests possible fetal compromise and requires further assessment with a
BPP. Although the NST has a low false-negative rate, it does have a high false-
positive rate, which is often remedied by the BPP. The full BPP assesses fetal
breathing, body movement, tone, NST, and amniotic fluid volume. It effectively
combines acute and chronic indicators of fetal well-being, which improves the
predictive value of abnormal testing (Table 115.2 ). A score of 2 or 0 is given for
each observation. A total score of 8-10 is reassuring; a score of 6 is equivocal,
and retesting should be done in 12-24 hr; and a score of 4 or less warrants
immediate evaluation and possible delivery. The BPP has good negative
predictive value. The modified BPP consists of the combination of an US
estimate of amniotic fluid volume (the amniotic fluid index) and the NST. When
results of both are normal, fetal compromise is very unlikely. Signs of
progressive compromise seen on Doppler US include reduced, absent, or
reversed diastolic waveform velocity in the fetal aorta or umbilical artery (see
Fig. 115.5 and Table 115.1 ). The umbilical vein and ductus venosus waveforms
are also used to assess the degree of fetal compromise. Fetuses at highest risk of
stillbirth often have combinations of abnormalities, such as growth restriction,
oligohydramnios, reversed diastolic Doppler umbilical artery blood flow
velocity, and a low BPP.

Table 115.2

Biophysical Profile Scoring: Technique and Interpretation

Biophysical Profile Scoring: Technique and Interpretation
BIOPHYSICAL
NORMAL SCORE (2) ABNORMAL SCORE (0)
VARIABLE
Fetal breathing At least 1 episode of FBM of at least 30 Absence of FBM or no episode ≥30 sec in 30 min
movements sec duration in 30 min observation
(FBMs)
Gross body At least 3 discrete body/limb 2 or fewer episodes of body/limb movements in 30
movement movements in 30 min (episodes of min
active continuous movement considered
a single movement)
Fetal tone At least 1 episode of active Either slow extension with return to partial flexion or
extension with return to flexion of movement of limb in full extension or absence of
fetal limb(s) or trunk fetal movement with the hand held in complete or
Opening and closing of hand partial deflection
considered evidence of normal tone
Reactive fetal At least 2 episodes of FHR acceleration Less than 2 episodes of acceleration of FHR or
heart rate (FHR) of ≥15 beats/min and at least 15 sec in acceleration of <15 beats/min in 30 min
duration associated with fetal
movement in 30 min
Quantitative At least 1 pocket of AF that measures at Either no AF pockets or a pocket <2 cm in 2
amniotic fluid least 2 cm in 2 perpendicular planes perpendicular planes
(AF) volume*
* Modification of the criteria for reduced amniotic fluid from <1 cm to <2 cm would seem

reasonable. Ultrasound is used for biophysical assessment of the fetus.

From Creasy RK, Resnik R, Iams JD, editors: Maternal-fetal medicine: principles and practice, ed
5, Philadelphia, 2004, Saunders.

Fetal compromise during labor may be detected by monitoring the FHR,

uterine pressure, and fetal scalp blood pH (Fig. 115.6 ). Continuous fetal heart
rate monitoring detects abnormal cardiac patterns by instruments that compute
the beat-to-beat FHR from a fetal electrocardiographic signal. Signals are
derived either from an electrode attached to the fetal presenting part, from an
ultrasonic transducer placed on the maternal abdominal wall to detect continuous
ultrasonic waves reflected from the contractions of the fetal heart, or from a
phonotransducer placed on the mother's abdomen. Uterine contractions are
recorded from an intrauterine pressure catheter or from an external
tocotransducer applied to the maternal abdominal wall overlying the uterus. FHR
patterns show various characteristics, some of which suggest fetal compromise.
The baseline FHR is determined over 10 min devoid of accelerations or
decelerations. Over the course of pregnancy, the normal baseline FHR gradually
decreases from approximately 155 beats/min in early pregnancy to 135
beats/min at term. The normal range throughout pregnancy is 110-160 beats/min.
Tachycardia (>160 beats/min) is associated with early fetal hypoxia, maternal
fever, maternal hyperthyroidism, maternal β-sympathomimetic drug or atropine
minimal variability, if amplitude range is ≤5 beats/min; moderate variability, if
amplitude range is 6-25 beats/min; and marked variability, if amplitude range is
>25 beats/min. Variability may be decreased or lost with fetal hypoxemia or the
placental transfer of drugs such as atropine, diazepam, promethazine,
magnesium sulfate, and most sedative and narcotic agents. Prematurity, the sleep
state, and fetal tachycardia may also diminish beat-to-beat variability.
Accelerations or decelerations of the FHR in response to or independent of
uterine contractions may also be monitored (see Fig. 115.6 ). An acceleration is
an abrupt increase in FHR of ≥15 beats/min in ≥15 sec. The presence of
accelerations or moderate variability reliably predicts the absence of fetal
metabolic acidemia. However, their absence does not reliably predict fetal
acidemia or hypoxemia. Early decelerations are a physiologic vagal response to
uterine contractions, with resultant fetal head compression, and represent a
repetitive pattern of gradual decrease and return of the FHR that is coincidental
with the uterine contraction (Table 115.3 ). Variable decelerations are
associated with umbilical cord compression and are characterized by a V or U
shaped pattern, are abrupt in onset and resolution, and may occur with or without
uterine contractions.

Table 115.3
Characteristics of Decelerations of Fetal Heart Rate (FHR)
LATE DECELERATION
Visually apparent, usually symmetric gradual decrease and return of the FHR associated with a uterine
contraction.
A gradual FHR decrease is defined as duration of ≥30 sec from the onset to the nadir of the FHR.
The decrease in FHR is calculated from the onset to the nadir of the deceleration.
The deceleration is delayed in timing, with the nadir of the deceleration occurring after the peak of the
contraction.
In most cases, the onset, nadir, and recovery of the deceleration occur after the beginning, peak, and ending of the
contraction, respectively.
EARLY DECELERATION
Visually apparent, usually symmetric gradual decrease and return of the FHR associated with a uterine
contraction.
A gradual FHR decrease is defined as duration of ≥30 sec from the onset to the FHR nadir.
The decrease in FHR is calculated from the onset to the nadir of the deceleration.
The nadir of the deceleration occurs at the same time as the peak of the contraction.
In most cases, the onset, nadir, and recovery of the deceleration are coincident with the beginning, peak, and
ending of the contraction, respectively.
VARIABLE DECELERATION
Visually apparent, abrupt decrease in FHR.
An abrupt FHR decrease is defined as duration <30 sec from the onset of the deceleration to the beginning of the
FHR nadir of the deceleration.
The decrease in FHR is calculated from the onset to the nadir of the deceleration.
 The decrease in FHR is ≥15 beats/min, lasting ≥15 sec, and <2 min in duration.
When variable decelerations are associated with uterine contractions, their onset, depth, and duration commonly
vary with successive uterine contractions.
From Macones GA, Hankins GDV, Spong CY, et al: The 2008 National Institute of Child Health
and Human Development workshop report on electronic fetal monitoring: update on definitions,
interpretation, and research guidelines, Obstet Gynecol 112:661–666, 2008.

Late decelerations are associated with fetal hypoxemia and are characterized
by onset after a uterine contraction is well established and persists into the
interval following resolution of the contraction. The late deceleration pattern is
usually associated with maternal hypotension or excessive uterine activity, but it
may be a response to any maternal, placental, umbilical cord, or fetal factor that
limits effective oxygenation of the fetus. The significance of late decelerations
varies according to the underlying clinical context. They are most likely to be
associated with true fetal hypoxemia/acidemia when they are recurrent and occur
in conjunction with decreased or absent variability. Late decelerations represent
a compensatory, chemoreceptor-mediated response to fetal hypoxemia. The
transient decrease in FHR serves to increase ventricular preload during the peak
of hypoxemia (i.e., at the crest of a uterine contraction). If fetal acidemia
progresses, late decelerations may become less pronounced or absent, indicating
severe hypoxic depression of myocardial function. Prompt delivery is indicated
if late decelerations are unresponsive to oxygen supplementation, hydration,
discontinuation of labor stimulation, and position changes. Approximately 10–
15% of term fetuses have terminal (just before delivery) FHR decelerations that
are usually benign if they last <10 min before delivery.
A 3-tier system has been developed by a panel of experts for interpretation of
FHR tracings (Table 115.4 ). Category I tracings are normal and are strongly
predictive of normal fetal acid-base status at the time of the observation.
Category II tracings are not predictive of abnormal fetal status, but there is
insufficient evidence to categorize them as category I or III; therefore further
evaluation, surveillance, and reevaluation are indicated. Category III tracings
are abnormal and predictive of abnormal fetal acid-base status at the time of
observation. Category III tracings require prompt evaluation and efforts to
resolve expeditiously the abnormal FHR as previously discussed for late
decelerations.

Table 115.4
Three-Tier Fetal Heart Rate (FHR) Interpretation System
 CATEGORY I
Category I FHR tracings include all the following:
• Baseline rate: 110-160 beats/min
• Baseline FHR variability: moderate
• Late or variable decelerations: absent
• Early decelerations: present or absent
• Accelerations: present or absent
CATEGORY II
Category II FHR tracings include all FHR tracings not categorized as category I or category III. Category II
tracings may represent an appreciable fraction of those encountered in clinical care. Examples of category II
FHR tracings include any of the following:
Baseline Rate
• Bradycardia not accompanied by absence of baseline variability
• Tachycardia
Baseline FHR Variability
• Minimal baseline variability
• Absence of baseline variability not accompanied by recurrent decelerations
• Marked baseline variability
Accelerations
• Absence of induced accelerations after fetal stimulation
Periodic or Episodic Decelerations
• Recurrent variable decelerations accompanied by minimal or moderate baseline variability
• Prolonged deceleration, ≥2 min but <10 min
• Recurrent late decelerations with moderate baseline variability
• Variable decelerations with other characteristics, such as slow return to baseline, “overshoots,” and “shoulders”
CATEGORY III
Category III FHR tracings include either:
• Absence of baseline FHR variability
or
Any of the following:
• Recurrent late decelerations
• Recurrent variable decelerations
• Bradycardia
• Sinusoidal pattern
Adapted from Macones GA, Hankins GDV, Spong CY, et al: The 2008 National Institute of Child
Health and Human Development workshop report on electronic fetal monitoring: update on
definitions, interpretation, and research guidelines, Obstet Gynecol 112:661–666, 2008.

Umbilical cord blood samples obtained at delivery are useful to document

fetal acid-base status. Although the exact cord blood pH value that defines
significant fetal acidemia is unknown, an umbilical artery pH <7.0 has been
associated with greater need for resuscitation and a higher incidence of
respiratory, gastrointestinal, cardiovascular, and neurologic complications.
Nonetheless, in many cases, even when a low pH is detected, newborn infants
are neurologically normal.

Bibliography
for drugs that are contraindicated in pregnancy on the basis of animal and human
evidence and for which the risk exceeds the benefits.
The use of medications or herbal remedies during pregnancy is potentially
harmful to the fetus. Consumption of medications occurs during the majority of
pregnancies. The average mother has taken 4 drugs other than vitamins or iron
during pregnancy. Almost 40% of pregnant women receive a drug for which
human safety during pregnancy has not been established (category C pregnancy
risk). Moreover, many women are exposed to potential reproductive toxins, such
as occupational, environmental, or household chemicals, including solvents,
pesticides, and hair products. The effects of drugs taken by the mother vary
considerably, especially in relation to the time in pregnancy when they are taken
and the fetal genotype for drug-metabolizing enzymes.
Miscarriage or congenital malformations result from the maternal ingestion
of teratogenic drugs during the period of organogenesis. Maternal medications
taken later, particularly during the last few weeks of gestation or during labor,
tend to affect the function of specific organs or enzyme systems, and these
adversely affect the neonate rather than the fetus (Tables 115.5 and 115.6 ). The
effects of drugs may be evident immediately in the delivery room or later in the
neonatal period, or they may be delayed even longer. The administration of
diethylstilbestrol during pregnancy, for instance, increased the risk for vaginal
adenocarcinoma in female offspring in the 2nd or 3rd decade of life.

Table 115.5

Agents Acting on Pregnant Women That May Adversely Affect the Structure or
Function of the Fetus and Newborn
DRUG EFFECT ON FETUS
Accutane (isotretinoin) Facial-ear anomalies, heart disease, CNS anomalies
Alcohol Congenital cardiac, CNS, limb anomalies; IUGR; developmental delay;
attention deficits; autism
Aminopterin Abortion, malformations
Amphetamines Congenital heart disease, IUGR, withdrawal
ACE inhibitors, angiotensin Oligohydramnios, IUGR, renal failure, Potter-like syndrome
receptor antagonists
Azathioprine Abortion
Busulfan (Myleran) Stunted growth; corneal opacities; cleft palate; hypoplasia of ovaries, thyroid,
and parathyroids
Carbamazepine Spina bifida, possible neurodevelopmental delay
Carbimazole Scalp defects, choanal atresia, esophageal atresia, developmental delay
Carbon monoxide Cerebral atrophy, microcephaly, seizures
Chloroquine Deafness
Chorionic villus sampling Probably no effect, possibly limb reduction
 Cigarette smoking LBW for gestational age
Cocaine/crack Microcephaly, LBW, IUGR, behavioral disturbances
Cyclophosphamide Multiple malformations
Danazol Virilization
17α-Ethinyl testosterone Masculinization of female fetus
(Progestoral)
Hyperthermia Spina bifida
Infliximab Possible increased risk of live vaccine associated disease in infant; neutropenia
Lithium Ebstein anomaly, macrosomia
Lopinavir-ritonavir Transient adrenal dysfunction
6-Mercaptopurine Abortion
Methyl mercury Minamata disease, microcephaly, deafness, blindness, mental retardation
Methyltestosterone Masculinization of female fetus
Misoprostol Arthrogryposis, cranial neuropathies (Möbius syndrome), equinovarus
Mycophenolate mofetil Craniofacial, limb, cardiovascular, CNS anomalies
Norethindrone Masculinization of female fetus
Penicillamine Cutis laxa syndrome
Phenytoin Congenital anomalies, IUGR, neuroblastoma, bleeding (vitamin K deficiency)
Polychlorinated biphenyls Skin discoloration—thickening, desquamation, LBW, acne, developmental
delay
Prednisone Oral clefts
Progesterone Masculinization of female fetus
Quinine Abortion, thrombocytopenia, deafness
Selective serotonin reuptake Small increased risk of congenital anomalies, persistent pulmonary hypertension
inhibitors of newborn
Statins IUGR, limb deficiencies, VACTERAL
Stilbestrol (diethylstilbestrol Vaginal adenocarcinoma in adolescence
[DES])
Streptomycin Deafness
Tetracycline Retarded skeletal growth, pigmentation of teeth, hypoplasia of enamel, cataract,
limb malformations
Thalidomide Phocomelia, deafness, other malformations
Toluene (solvent abuse) Craniofacial abnormalities, prematurity, withdrawal symptoms, hypertonia
Topiramate Cleft lip
Trimethadione and Abortion, multiple malformations, mental retardation
paramethadione
Valproate CNS (spina bifida), facial and cardiac anomalies, limb defects, impaired
neurologic function, autism spectrum disorder
Vitamin D Supravalvular aortic stenosis, hypercalcemia
Warfarin (Coumadin) Fetal bleeding and death, hypoplastic nasal structures
ACE, Angiotensin-converting enzyme; CNS, central nervous system; IUGR, intrauterine growth
restriction; LBW, low birthweight; VACTERAL, vertebral, anal, cardiac, tracheoesophageal fistula,
renal, arterial, limb.

Table 115.6
Agents Acting on Pregnant Women That May Adversely
Affect the Newborn Infant*
Acebutolol—IUGR, hypotension, bradycardia
 Acetazolamide—metabolic acidosis
Amiodarone—bradycardia, hypothyroidism
Anesthetic agents (volatile)—CNS depression
Adrenal corticosteroids—adrenocortical failure (rare)
Ammonium chloride—acidosis (clinically inapparent)
Aspirin—neonatal bleeding, prolonged gestation
Atenolol—IUGR, hypoglycemia
Baclofen—withdrawal
Blue cohosh herbal tea—neonatal heart failure
Bromides—rash, CNS depression, IUGR
Captopril, enalapril—transient anuric renal failure, oligohydramnios
Caudal-paracervical anesthesia with mepivacaine (accidental introduction of anesthetic into scalp of baby)—
bradypnea, apnea, bradycardia, convulsions
Cholinergic agents (edrophonium, pyridostigmine)—transient muscle weakness
CNS depressants (narcotics, barbiturates, benzodiazepines) during labor—CNS depression, hypotonia
Cephalothin—positive direct Coombs test reaction
Dexamethasone—periventricular leukomalacia
Fluoxetine and other SSRIs—transient neonatal withdrawal, hypertonicity, minor anomalies, preterm birth,
prolonged QT interval
Haloperidol—withdrawal
Hexamethonium bromide—paralytic ileus
Ibuprofen—oligohydramnios, pulmonary hypertension
Imipramine—withdrawal
Indomethacin—oliguria, oligohydramnios, intestinal perforation, pulmonary hypertension
Intravenous fluids during labor (e.g., salt-free solutions)—electrolyte disturbances, hyponatremia, hypoglycemia
Iodide (radioactive)—goiter
Iodides—goiter
Lead—reduced intellectual function
Magnesium sulfate—respiratory depression, meconium plug, hypotonia
Methimazole—goiter, hypothyroidism
Morphine and its derivatives (addiction)—withdrawal symptoms (poor feeding, vomiting, diarrhea, restlessness,
yawning and stretching, dyspnea and cyanosis, fever and sweating, pallor, tremors, convulsions)
Naphthalene—hemolytic anemia (in G6PD-deficient infants)
Nitrofurantoin—hemolytic anemia (in G6PD-deficient infants)
Oxytocin—hyperbilirubinemia, hyponatremia
Phenobarbital—bleeding diathesis (vitamin K deficiency), possible long-term reduction in IQ, sedation
Primaquine—hemolytic anemia (in G6PD-deficient infants)
Propranolol—hypoglycemia, bradycardia, apnea
Propylthiouracil—goiter, hypothyroidism
Pyridoxine—seizures
Reserpine—drowsiness, nasal congestion, poor temperature stability
Sulfonamides—interfere with protein binding of bilirubin; kernicterus at low levels of serum bilirubin, hemolysis
with G6PD deficiency
Sulfonylurea agents—refractory hypoglycemia
Sympathomimetic (tocolytic β-agonist) agents—tachycardia
Thiazides—neonatal thrombocytopenia (rare)
Tumor necrosis factor blocking agents—neutropenia, possible increased risk of infection during 1st yr of life
Valproate—developmental delay
Zolpidem (Ambien)—low birthweight
* See also Table 115.5 .

CNS, Central nervous system; G6PD, glucose-6-phosphate dehydrogenase; IUGR, intrauterine

growth restriction; SSRI, selective serotonin reuptake inhibitor.

Often the risk of controlling maternal disease must be balanced with the risk
 FIG. 115.7 Assessment of fetal anatomy. A, Overall view of the uterus at 24 wk showing
a longitudinal section of the fetus and an anterior placenta. B, Transverse section at the
level of the lateral ventricle at 18 wk showing (on the right ) prominent anterior horns of
the lateral ventricles on either side of the midline echo of the falx. C, Cross section of
the umbilical cord showing that the lumen of the umbilical vein is much wider than that
of the 2 umbilical arteries. D, Four-chambered view of the heart at 18 wk with equal-
sized atria. E(i), Normal male genitals near term. E(ii), Hydrocele outlining a testicle
within the scrotum projecting into a normal-size pocket of amniotic fluid at 38 wk.
Approximately 2% of male infants after birth have clinical evidence of a hydrocele that
is often bilateral, not to be confused with subcutaneous edema occurring during
vaginal breech birth. F, Section of a thigh near term showing thick subcutaneous tissue
(4.6 mm between markers ) above the femur of a fetus with macrosomia. G, Fetal face
viewed from below, showing (from right to left ) the nose, alveolar margin, and chin at
20 wk. (From Special investigative procedures. In Beischer NA, Mackay EV, Colditz PB,
editors: Obstetrics and the newborn, ed 3, Philadelphia, 1997, Saunders.)

Table 115.7
Significance of Fetal Ultrasonographic Anatomic Findings

PRENATAL DIFFERENTIAL POSTNATAL

DEFINITION SIGNIFICANCE
OBSERVATION DIAGNOSIS EVALUATION
Dilated cerebral Ventriculomegaly Hydrocephalus Transient isolated Serial head
ventricles ≥10 mm Hydranencephaly ventriculomegaly US or MRI
Dandy-Walker cyst is common and Evaluate for
Agenesis of corpus usually benign. extracranial
callosum Persistent or anomalies.
Volume loss progressive
ventriculomegaly
is more worrisome.
Identify associated
cranial and
extracranial
anomalies.
Choroid plexus Size ~10 Abnormal karyotype Often isolated, Head US
cysts mm: (trisomy 18, 21) benign; resolves by Examine for
unilateral or Increased risk if AMA 24-28 wk. extracranial
bilateral Fetus should be anomalies;
1–3% examined for other karyotype if
incidence organ anomalies; if indicated.
 additional
anomalies present,
amniocentesis
should be
performed for
karyotype.
Nuchal fold ≥6 mm at 15-20 Cystic hygroma trisomy ~50% of affected Evaluate for
thickening wk 21, 18 fetuses have multiple organ
Turner syndrome (XO) chromosome malformations;
Other genetic syndromes abnormalities. karyotype if
Normal (~25%) Amniocentesis for indicated.
karyotype needed.
Dilated renal Pyelectasis Normal variant Often Repeat
pelvis ≥4 to 10 mm Uteropelvic junction “physiologic” and ultrasonography
0.6–1% obstruction transient on day 5 and at 1
incidence Vesicoureteral reflux Reflux is common. mo; voiding
Posterior ureteral valves If dilation is >10 cystourethrogram,
Entopic ureterocele mm or associated prophylactic
Large-volume with caliectasis, antibiotics
nonobstruction pathologic cause
should be
considered.
If large bladder
present, posterior
urethral valves and
megacystis–
microcolon
hypoperistalsis
syndrome should
be considered.
Echogenic bowel 0.6% incidence CF, meconium peritonitis, Often normal Sweat
trisomy 21 or 18, other Consider CF, chloride and
chromosomal abnormalities aneuploidy, and DNA testing
cytomegalovirus, TORCH. Karyotype
toxoplasmosis, GI Surgery for
obstruction, intrauterine obstruction
bleeding (fetal swallowing of Evaluation
blood) for TORCH
Stomach Small or absent Upper GI obstruction Must also consider Chromosomes;
appearance or with double (esophageal atresia) neurologic kidney, ureter,
bubble Double bubble signifies disorders that and bladder
duodenal atresia reduce swallowing. radiograph if
Aneuploidy >30% with double indicated; upper
Polyhydramnios bubble have GI series;
Stomach in chest trisomy 21. neurologic
signifies diaphragmatic evaluation
hernia
CF, Cystic fibrosis; CMV, cytomegalovirus; GI, gastrointestinal; TORCH, toxoplasmosis, other
agents, rubella, CMV, herpes simplex syndrome; US, ultrasound.

Real-time US also facilitates performance of needle-guided procedures (i.e.

cordocentesis) and the BPP by imaging fetal breathing, body movements, tone,
and amniotic fluid volume (see Table 115.2 ). Doppler velocimetry assesses fetal
arterial blood flow (vascular resistance) (see Figs. 115.4 and 115.5 ). Fetal MRI
is used to better define abnormalities detected on US and to help with
prognostication (see Fig. 115.1 ).
Amniocentesis , the transabdominal withdrawal of amniotic fluid during
pregnancy for diagnostic purposes (see Table 115.1 ), is a common obstetric
procedure. It is frequently performed to evaluate for infection. It is also done for
genetic indications, usually between the 15th and 20th wk of gestation, with
results available as soon as 24-48 hr for fluorescence in situ hybridization
(FISH) testing and 2-3 wk for microarray testing. The most common indication
for genetic amniocentesis is advanced maternal age ; the risk for chromosome
abnormality at term at age 21 yr is 1 : 525, vs 1 : 6 at age 49 yr. ACOG
recommends that all pregnant women be offered amniocentesis to evaluate
further for an underlying genetic condition such as Down syndrome. Analysis of
amniotic fluid may also help in identifying NTDs (elevation of α-fetoprotein
[AFP] and presence of acetylcholinesterase). Additionally, families with a
known genetic syndrome may be offered prenatal genetic testing from amniotic
fluid or amniocytes obtained via amniocentesis or CVS.
Chorionic villus sampling (CVS) is performed in the first trimester, either
transvaginally or transabdominally. The sample obtained is placental in origin,
which can sometimes be problematic because aneuploidy may be present in the
placenta and not the fetus, a condition known as confined placental mosaicism ,
which can give a false-positive rate as high as 3%. Furthermore, CVS may be
associated with a slightly higher risk of fetal loss than amniocentesis.
Amniocentesis can be carried out with little discomfort to the mother.
Procedure-related complications are relatively rare, and many can be avoided by
using a US-guided approach. These risks include direct damage to the fetus,
placental puncture and bleeding with secondary damage to the fetus, stimulation
of uterine contraction and premature labor, chorioamnionitis, maternal
sensitization to fetal blood, and pregnancy loss. Best available data indicate that
the pregnancy loss rate associated with amniocentesis is 1 : 500-900 procedures.
Amniocentesis is not recommended before 14 wk of gestation because this has
been associated with a higher risk of pregnancy loss, ruptured membranes, and
clubfoot.
Cordocentesis , or percutaneous umbilical blood sampling (PUBS), is used to
diagnose fetal hematologic abnormalities, genetic disorders, infections, and fetal
acidosis (see Table 115.1 ). Under direct US visualization, a long needle is
passed into the umbilical vein at its entrance to the placenta or in a free loop of
cord. Transfusion or administration of drugs can be performed through the
umbilical vein (Table 115.8 ). The predominant indication for this procedure is
for confirmation of fetal anemia (in Rh isoimmunization) or thrombocytopenia
(NAIT), with subsequent transfusion of packed red blood cells or platelets into
the umbilical venous circulation.

Table 115.8
Fetal Therapy

DISORDER POSSIBLE TREATMENT

HEMATOLOGIC
Anemia with hydrops (erythroblastosis Cordocentesis of umbilical vein with packed red blood cell transfusion
fetalis)
Isoimmune thrombocytopenia Umbilical vein platelet transfusion, maternal IVIG
Autoimmune thrombocytopenia (ITP) Maternal steroids and IVIG
METABOLIC/ENDOCRINE
Maternal phenylketonuria (PKU) Phenylalanine restriction
Fetal galactosemia Galactose-free diet (?)
Multiple carboxylase deficiency Biotin if responsive
Methylmalonic acidemia Vitamin B12 if responsive
21-Hydroxylase deficiency Dexamethasone if female fetus
Maternal diabetes mellitus Tight insulin control during pregnancy, labor, and delivery
Fetal goiter Maternal hyperthyroidism—maternal propylthiouracil
Fetal hypothyroidism—intraamniotic thyroxine
Bartter syndrome Maternal indomethacin may prevent nephrocalcinosis and postnatal
sodium losses
FETAL DISTRESS
Hypoxia Maternal oxygen, position changes
Intrauterine growth restriction Improve macronutrients and micronutrients if deficient, smoking
cessation, treatment of maternal disease, antenatal fetal surveillance
Oligohydramnios, premature rupture of Antenatal fetal surveillance
membranes with variable deceleration Approach dependent on etiology
Amnioinfusion (intrapartum)
Polyhydramnios Antenatal fetal surveillance
Approach dependent on etiology
Amnioreduction if indicated,
Supraventricular tachycardia Maternal digoxin,* flecainide, procainamide, amiodarone, quinidine
Lupus anticoagulant Maternal aspirin and heparin
Meconium-stained fluid Amnioinfusion
Congenital heart block Dexamethasone, pacemaker (with hydrops)
Premature labor Magnesium sulfate, nifedipine, indomethacin with antenatal
corticosteroids (betamethasone)
RESPIRATORY
Pulmonary immaturity Betamethasone
Bilateral chylothorax—pleural effusions Thoracentesis, pleuroamniotic shunt
CONGENITAL ABNORMALITIES †
Neural tube defects Folate, vitamins (prevention); fetal surgery ‡
 Posterior urethral valves, urethral atresia Percutaneous vesicoamniotic shunt
(lower urinary tract obstruction)
Cystic adenomatoid malformation (with Pleuroamniotic shunt or resection ‡
hydrops)
Fetal neck masses Secure an airway with EXIT procedure ‡
INFECTIOUS DISEASE
Group B streptococcus colonization Ampicillin, penicillin
Chorioamnionitis Antibiotics and delivery
Toxoplasmosis Spiramycin, pyrimethamine, sulfadiazine, folic acid
Syphilis Penicillin
Tuberculosis Antituberculosis drugs
Lyme disease Penicillin, ceftriaxone
Parvovirus Intrauterine red blood cell transfusion for hydrops, severe anemia
Chlamydia trachomatis Azithromycin
HIV-AIDS Maternal and neonatal antiretroviral therapy (see Chapter 302 )
Cytomegalovirus No approved prenatal treatments
OTHER
Nonimmune hydrops (anemia) Umbilical vein packed red blood cell transfusion
Narcotic abstinence (withdrawal) Maternal methadone maintenance
Sacrococcygeal teratoma (with hydrops) In utero resection or catheter-directed vessel obliteration
Cardiac rhabdomyoma Maternal sirolimus
Intrapericardial teratoma Fetal surgery
CRISPR-Cas9 gene editing Proof of concept in previable in vitro fertilized human embryos
Twin-twin transfusion syndrome Repeated amniocentesis, yttrium-aluminum-garnet (YAG) laser
photocoagulation of shared vessels
Twin reversed arterial perfusion (TRAP) Cord occlusion, radiofrequency ablation
syndrome
Multifetal gestation Selective reduction
Neonatal hemochromatosis Maternal IVIG
Aortic stenosis In utero valvuloplasty
* Drug of choice (may require percutaneous umbilical cord sampling and umbilical vein
administration if hydrops is present). Most drug therapy is given to the mother, with subsequent
placental passage to the fetus.
† Detailed fetal ultrasonography is needed to detect other anomalies; karyotype is also indicated.

‡ EXIT permits surgery and other procedures.

EXIT, Ex utero intrapartum treatment; IVIG, intravenous immune globulin; (?), possible but not
proved efficacy.

Aneuploidy screening is offered to pregnant women in the first trimester or at

midgestation to evaluate the risk for common aneuploidies such as Down
syndrome (trisomy 21), trisomy 18, trisomy 13, and congenital malformations
(e.g., abdominal wall or neural tube defects) known to cause elevations of
various markers. A combination of these biochemical markers (including AFP,
inhibin A, estriol, pregnancy-associated plasma protein A, β–human chorionic
gonadotropin [hCG]) and US increases the positive predictive value (PPV) of
these screening tests. Fetal DNA in maternal plasma and fetal cells circulating in
maternal blood are potential noninvasive sources of material for prenatal genetic
C H A P T E R 11 6

Fetal Intervention and Surgery

Paul S. Kingma

Numerous diagnoses have been evaluated for the possibility of fetal intervention
(Tables 116.1 and 116.2 ). Some have proved beneficial to the developing infant,
some have been abandoned, and some are still under investigation.

Table 116.1
Fetal Diagnoses Evaluated and Treated in Fetal Centers
Amniotic band syndrome (ABS)
Anomalies in monochorionic twins
Aortic stenosis
Arachnoid cyst
Bladder exstrophy
Bladder outlet obstruction
Bronchopulmonary sequestration (BPS)
Cervical teratoma
Cloaca
Cloaca exstrophy
Complete heart block
Congenital pulmonary airway malformation (CPAM)
Congenital diaphragmatic hernia (CDH)
Congenital high airway obstruction syndrome (CHAOS)
EXIT to airway procedure for CHAOS
Conjoined twins
Dandy-Walker malformation
Duodenal atresia
Encephalocele
Enteric duplicational atresia
Esophageal atresia
Gastroschisis
Hydrocephalus
Hydronephrosis
Hypoplastic left heart syndrome (HLHS)
Imperforate anus
Intraabdominal cyst
Lymphangioma
 Mediastinal teratoma
Myelomeningocele, spina bifida
Neuroblastoma
Obstructive uropathy
Omphalocele
Pentalogy of Cantrell
Pericardial teratoma
Pleural effusions
Pulmonary agenesis
Pulmonary atresia with intact ventricular septum
Sacrococcygeal teratoma (SCT)
Twin reversed arterial perfusion (TRAP) sequence
Twin-twin transfusion syndrome (TTTS)
Vein of Galen aneurysm
EXIT, Ex utero intrapartum treatment.

Table 116.2
Indications and Rationales for in Utero Surgery on the
Fetus, Placenta, Cord, or Membranes

RATIONALE FOR IN UTERO

FETAL SURGERY PATHOPHYSIOLOGY
INTERVENTION
SURGERY ON THE FETUS
1. Congenital Pulmonary hypoplasia and anatomic substrate Reversal of pulmonary hypoplasia and
diaphragmatic hernia for pulmonary hypertension reduced degree of pulmonary
hypertension; repair of actual defect
delayed until after birth
2. Lower urinary tract Progressive renal damage due to Prevention of renal failure and
obstruction obstructive uropathy pulmonary hypoplasia by anatomic
Pulmonary hypoplasia due to correction or urinary deviation
oligohydramnios
3. Sacrococcygeal High-output cardiac failure due to AV Reduction of functional impact of
teratoma shunting and/or bleeding tumor by ablation of tumor or
Direct anatomic effects of the tumoral (part of) its vasculature
mass Reduction of anatomic effects by
Polyhydramnios-related preterm labor drainage of cysts or bladder
Amnioreduction preventing
obstetric complications
4. Thoracic space- Pulmonary hypoplasia (space-occupying Creation of space for lung
occupying lesions mass) development
Hydrops due to impaired venous return Reversal of the process of cardiac
(mediastinal compression) failure
5. Neural tube defects Damage to exposed neural tube Prevention of exposure of the spinal
Chronic CSF leak, leading to Arnold- cord to amniotic fluid; restoration of
Chiari malformation and hydrocephalus CSF pressure correcting Arnold-Chiari
malformation
6. Cardiac malformations Critical lesions causing irreversible Reversal of process by anatomic
hypoplasia or damage to developing heart correction of restrictive pathology
SURGERY ON THE PLACENTA, CORD, OR MEMBRANES
7. Chorioangioma High-output cardiac failure due to AV Reversal of process of cardiac failure
 shunting and hydrops fetoplacentalis by
Effects of polyhydramnios ablation or reduction of flow
8. Amniotic bands Progressive constrictions causing irreversible Prevention of amniotic band syndrome
neurologic or vascular damage leading to deformities and function
loss
9. Abnormal Intertwin transfusion leading to Arrest of intertwin transfusion;
monochorionic oligopolyhydramnios sequence, prevention/reversal of cardiac
twinning: twin-to-twin hemodynamic changes; preterm labor, failure and/or neurologic damage,
transfusion; fetus and rupture of membranes; in utero including at in utero death;
acardiacus, and damage to brain, heart, or other organs prolongation of gestation
discordant anomalies In utero fetal death may cause damage to Selective fetocide to arrest
co-twin. parasitic relationship, to prevent
Cardiac failure of pump twin and consequences of in utero fetal
consequences of polyhydramnios death, and to avoid termination of
Serious anomaly raising the question of entire pregnancy
termination of pregnancy
Selective fetocide
AV, Arteriovenous; CSF, cerebrospinal fluid.
From Deprest J, Hodges R, Gratacos E, Lewi L: Invasive fetal therapy. In Creasy RK, Resnick R,
Iams JD, et al, editors: Creasy & Resnik's maternal-fetal medicine, ed 7, Philadelphia, 2014,
Elsevier (Table 35-1).

Fetal Therapy Ethics

With the development of advanced fetal ultrasound (US), fetal MRI, and fetal
echocardiography, the ability to accurately diagnose fetal disease has improved
substantially over the past 3 decades. There have also been advances in maternal
anesthesia and tocolysis, reduction in maternal morbidity, development of fetal
surgery–specific equipment, improved clinical expertise of the fetal care team,
and construction of state–of-the-art fetal treatment centers. Fetal surgery remains
controversial, however, and every discussion of fetal surgery must include a
careful consideration of the ethical conflicts inherit to these procedures.
Unlike most surgical procedures, fetal surgery must consider 2 patients
simultaneously, balancing the potential risks and benefits to the fetus with those
to the mother during the current and future pregnancies. The International Fetal
Medicine and Surgery Society (IFMSS) established a consensus statement on
fetal surgery, as follows:

1. A fetal surgery candidate should be a singleton with no other

abnormalities observed on level II ultrasound, karyotype (by
amniocentesis), α-fetoprotein (AFP) level or viral cultures.
2. The disease process must not be so severe that the fetus cannot be saved
 extremities. Images of the limbs of a fetus with amniotic band sequence show multiple
amniotic bands (short arrows, A and B ), amputation of fingers and toes (long arrows, A
and B ), and a fixed deformity of the hand at the wrist (arrowhead, B ). C and D, Effects
on the thorax and abdomen of the same fetus as in A and B. Sagittal image (C) shows a
thoracoabdominal wall defect (arrows) with a large amount of herniated abdominal and
thoracic contents (black H) outside the body. White H, Head. D, Axial image of the fetal
abdomen (A) confirms the presence of a large ventral abdominal hernia (H), in the
setting of amniotic bands (arrow). E to G, Effects on craniofacial structures in a different
fetus. E, Coronal image of face shows multiple amniotic bands (short arrows) and
nonvisualization of the calvarium. This results in a craniofacial appearance that
resembles anencephaly (long arrow). F, A large encephalocele (black arrow) is seen
above the level of the orbits (long white arrow) in a different scan plane. An amniotic
band (short white arrow) is also seen. G, Coronal image of anterior portion of face
shows facial clefts (black arrows) due to amniotic bands. Short white arrow, Amniotic
band; long white arrow, orbits. H, Band constricting the ankle, leading to deformational
defects. I, Pseudosyndactyly, amputation and disruption of finger morphogenesis. (A-G,
From Hertzberg BS, Middleton WD: Ultrasound: the requisites, ed 3, Philadelphia, 2016,
Elsevier, Fig 19-22; H and I, From Jones KL, Smith DW, Hall BD, et al. A pattern of
craniofacial and limb defects secondary to aberrant tissue bands. J Pediatr 84:90–
95:1974.)

Fetal Centers
The value of fetal centers extends beyond fetal surgery. Often, families will
present to a fetal center with a newly discovered diagnosis and little
understanding of what the diagnosis means for their baby. Prenatal counseling
by the fetal team can provide comfort to the family by helping them understand
the diagnosis and treatment options and by developing a management plan that
may include fetal surgery. Some plans may call for enhanced monitoring of the
fetus and mother, followed by complex deliveries involving multidisciplinary
delivery teams and specialized equipment, as required for EXIT to ECMO, EXIT
to airway, EXIT to tumor resection, delivery to cardiac catheterization, and
procedures on placental support. Other plans may focus on postnatal therapy.
Not all severely affected fetuses have available therapies in utero or after
birth. In these lethal situations, fetal care planning will provide support for the
family and a plan for delivery room or nursery palliative care (Table 116.3 ) (see
Chapter 7 ).

Table 116.3
Selection of Patients for Fetal Repair

LEVEL OF CERTAINTY DIAGNOSIS

DIAGNOSTIC CERTAINTY/PROGNOSTIC CERTAINTY
Genetic problems Trisomy 13, 15, or 18
Triploidy
 Central nervous system abnormalities Anencephaly/acrania
Holoprosencephaly
Large encephaloceles
Heart problems Acardia
Inoperable heart anomalies
Kidney problems Potter syndrome/renal agenesis
Multicystic/dysplastic kidneys
Polycystic kidney disease
DIAGNOSTIC UNCERTAINTY/PROGNOSTIC CERTAINTY
Genetic problems Thanatophoric dwarfism or lethal forms of osteogenesis imperfecta
Early oligo/anhydramnios and pulmonary Potter syndrome with unknown etiology
hypoplasia
Central nervous system abnormalities Hydranencephaly
Congenital severe hydrocephalus with absent or minimal brain
growth
Prematurity <23 wk gestation
PROGNOSTIC UNCERTAINTY/BEST INTEREST
Genetic problems Errors of metabolism that are expected to be lethal even with
available therapy
Mid oligo/anhydramnios Renal failure requiring dialysis
Central nervous system abnormalities Complex or severe cases of meningomyelocele
Neurodegenerative diseases, such as spinal muscular atrophy
Heart problems Some cases of hypoplastic left heart syndrome
Pentalogy of Cantrell (ectopia cordis)
Other structural anomalies Some cases of giant omphalocele
Severe congenital diaphragmatic hernia with hypoplastic lungs
Idiopathic nonimmune hydrops
Inoperable conjoined twins
Multiple severe anomalies
Prematurity 23-24 wk gestation
From Leuthner SR: Fetal palliative care, Clin Perinatol 31:649–665, 2004 (Table 1, p 652).

Bibliography
Adzick NS. Management of fetal lung lesions. Clin Perinatol .
2009;36(2):363–376.
Adzick NS, Thom EA, Spong CY, et al. A randomized trial of
prenatal versus postnatal repair of myelomeningocele. N Engl
J Med . 2011;364(11):993–1004.
Al-Maary J, Eastwood MP, Russo FM, et al. Fetal tracheal
occlusion for severe pulmonary hypoplasia in isolated
congenital diaphragmatic hernia: a systematic review and
meta-analysis of survival. Ann Surg . 2016;264(6):929–933.
Antiel RM, Flake AW. Responsible surgical innovation and
C H A P T E R 11 7

The High-Risk Infant

Jennifer M. Brady, Maria E. Barnes-Davis, Brenda B. Poindexter

The term high-risk infant designates an infant at greater risk for neonatal
morbidity and mortality; many factors can contribute to an infant being high risk
(Table 117.1 ). High-risk infants are categorized into 4 main groups: the preterm
infant, infants with special health care needs or dependence on technology,
infants at risk because of family issues, and infants with anticipated early death.

Table 117.1
Factors in Considering Infants as High Risk for Morbidity
or Mortality in the Neonatal Period
MATERNAL DEMOGRAPHIC/SOCIAL FACTORS
Maternal age <16 yr or >40 yr
Illicit drug, alcohol, cigarette use
Poverty
Unmarried
Emotional or physical stress
MATERNAL MEDICAL HISTORY
Genetic disorders
Diabetes mellitus
Hypertension
Asymptomatic bacteriuria
Rheumatologic illness (systemic lupus erythematosus)
Immune-mediated diseases (IgG crossing placenta)
Long-term medication (see Chapters 115.4 and 115.5 )
PREVIOUS PREGNANCY
Intrauterine fetal demise
Neonatal death
Prematurity
Intrauterine growth restriction
Congenital malformation
Incompetent cervix
Blood group sensitization, neonatal jaundice
Neonatal thrombocytopenia
Hydrops
 Inborn errors of metabolism
PRESENT PREGNANCY
Vaginal bleeding (abruptio placentae, placenta previa)
Sexually transmitted infections (colonization: herpes simplex, group B streptococcus, chlamydia, syphilis,
hepatitis B, HIV)
Multiple gestation
Preeclampsia
Premature rupture of membranes
Short interpregnancy time
Poly-/oligohydramnios
Acute medical or surgical illness
Inadequate prenatal care
Familial or acquired hypercoagulable states
Abnormal fetal ultrasonographic findings
Treatment of infertility
LABOR AND DELIVERY
Premature labor (<37 wk)
Postdates pregnancy (≥42 wk)
Fetal distress
Immature lecithin/sphingomyelin ratio; absence of phosphatidylglycerol
Breech presentation
Meconium-stained fluid
Nuchal cord
Cesarean delivery
Forceps delivery
Apgar score <4 at 5 min
NEONATE
Birthweight <2,500 g or >4,000 g
Birth <37 wk or ≥42 wk of gestation
Small or large for gestational age
Respiratory distress, cyanosis
Congenital malformation
Pallor, plethora, petechiae

All high-risk infants require closer evaluation and/or treatment by experienced

physicians and nurses. This often starts at delivery and continues through a
neonatal intensive care unit (NICU) stay (see Chapter 121 ). Regionalized care
for infants is based on the acuity of care that can be provided at hospitals with
different levels of care and whether transport should be undertaken (see Chapter
118 ). It is important to note that additional care does not stop at time of NICU
discharge, and that many high-risk infants also benefit from additional resources
and follow-up after discharge from the hospital (see Chapter 117.5 ).
Approximately 15 million infants are born preterm (before 37 wk gestational
age) each year worldwide, accounting for approximately 1 in every 10 babies
born, and the overwhelming majority of high-risk infants. The World Health
Organization (WHO) defines infants born before 28 wk gestational age as
extremely preterm infants, infants born between 28 and wk as very preterm,
and infants born between 32 and weeks as moderate to late preterm infants.

FIG. 117.4 Representation of first-trimester risk assessment for the development of
discordant growth, twin-twin transfusion syndrome (TTTS), or intrauterine demise.
Discordant amniotic fluid in the first trimester generally corresponded with deepest
vertical pockets ≤3 cm in one sac and ≥6.5 cm in the other. Discordance in crown-rump
length (CRL) was present if the difference was ≥12 mm. (From Lewi L, Gucciardo L, Van
Mieghem T, et al: Monochorionic diamniotic twin pregnancies: natural history and risk
stratification, Fetal Diagn Ther 27:121–133, 2010.)

Table 117.2
Characteristic Changes in Monochorionic Twins With
Uncompensated Placental Arteriovenous Shunts

TWIN ON:
Arterial Side—Donor Venous Side—Recipient
Prematurity Prematurity
Oligohydramnios Polyhydramnios
Small premature Hydrops
Malnourished Large premature
Pale Well nourished
Anemic Plethoric
Hypovolemic Polycythemic
Hypoglycemic Hypervolemic
Microcardia Cardiac hypertrophy
Glomeruli small or normal Myocardial dysfunction
Arterioles thin walled Tricuspid valve regurgitation
Right ventricular outflow obstruction
Glomeruli large
 Arterioles thick walled

FIG. 117.5 Color-dye-stained twin-to-twin transfusion syndrome placenta that was
treated using the Solomon technique. Blue and green dye used to stain the arteries, and
pink and yellow dye used to stain the veins. After identification and coagulation of each
individual anastomosis, the complete vascular equator is coagulated from one
placental margin to the other. (From Slaghekke F, Lopriore E, Lewi L, et al: Fetoscopic
laser coagulation of the vascular equator versus selective coagulation for twin-to-twin
transfusion syndrome: an open-label randomized controlled trial, Lancet 383:2144–
2150, 2014, Fig 3.)

Diagnosis
A prenatal diagnosis of pregnancy with twins is suggested by a uterine size that
is greater than that expected for gestational age, auscultation of 2 fetal hearts,
and elevated maternal serum α-fetoprotein (AFP) or human chorionic
gonadotropin (hCG) levels. It is confirmed by ultrasonography. Physical
examination of twins is necessary but not sufficient to determine zygosity of
twins. In the event that congenital anomalies are present or there are transfusion
or transplantation considerations, genetic testing of zygosity should be
performed. While noninvasive prenatal testing (NIPT) is becoming more
common, the results should be interpreted with caution in multiple-gestation
pregnancies until more findings are better established.
or early preterm.

FIG. 117.6 Preterm birth rates in the United States in 2007, 2014, 2015, and 2016
(provisional). There was a recent rise in preterm birth rate from 2014 to 2016. Preterm
birth rate further divided into early preterm birth (birth <32 wk) and late preterm birth

(birth at wk). (From Hamilton BE, Martin JA, Osterman MJK, et al: Births:
provisional data for 2016, Vital Statistics Rapid Release 2017; 1–21, Fig 4.)

Etiology
Despite the frequency of preterm birth, it is often difficult to determine a specific
cause. The etiology of preterm birth is multifactorial and involves complex
interactions between fetal, placental, uterine, and maternal factors. In the setting
of maternal or fetal conditions that prompt early delivery, as well as placental
and uterine pathology, causes of preterm birth can sometimes be identified
(Table 117.3 ).

Table 117.3
Identifiable Risk Factors for Preterm Birth
FETAL
Fetal distress
Multiple gestation
Erythroblastosis
 Nonimmune hydrops
PLACENTAL
Placental dysfunction
Placenta previa
Placental abruption
UTERINE
Bicornuate uterus
Incompetent cervix (premature dilation)
MATERNAL
Previous preterm birth
Preeclampsia
Black race
Chronic medical illness (cyanotic heart disease, renal disease, thyroid disease)
Short interpregnancy interval
Infection (Listeria monocytogenes, group B streptococcus, urinary tract infection, bacterial vaginosis,
chorioamnionitis)
Obesity
Drug abuse (cocaine)
Young or advanced maternal age
OTHER
Premature rupture of membranes
Polyhydramnios
Iatrogenic
Assisted reproductive technology
Trauma

However, most preterm births are spontaneous without an identifiable cause.

Older maternal age, poorer maternal health, history of previous preterm delivery,
short interpregnancy interval, and lower socioeconomic status (SES) have all
been associated with preterm birth. Racial disparities also exist, which seem to
persist when taking into account SES. Large population studies have also found
associations between maternal genetics and preterm birth. Gestational duration
and actual preterm birth have been noted with genetic variants in the maternal
genome. Many of these genes have roles in regulation of the estrogen receptor,
uterine development, maternal nutrition, or vascular reactivity. In addition, cell
free RNA transcripts in maternal blood may also be of value in predicting
preterm birth.

Assessment of Gestational Age

With insufficient prenatal care or discrepancies between birthweight and
predicted gestational age at birth, it is often helpful to be able to assess infants at
birth for an estimated gestational age. Examination and assessment is needed to
distinguish SGA and IUGR infants from preterm infants. Compared with a
premature infant of appropriate weight, an infant with IUGR has a reduced
Immaturity of Drug Metabolism
Great care must be taken when prescribing and dosing medications for
premature infants (Table 117.4 ). Renal clearance of almost all substances
excreted in the urine is diminished in newborn infants, and to even a greater
extent in premature infants. The glomerular filtration rate rises with increasing
gestational age; therefore, drug dosing recommendations vary with age. For
drugs primarily excreted by the kidneys, longer intervals between dosages are
often needed with increasing degree of prematurity. Drugs that are detoxified in
the liver or require chemical conjugation before renal excretion should also be
given with caution and in doses smaller than usual.

Table 117.4

Potential Adverse Reactions to Drugs Administered to Premature Infants

DRUG REACTION(S)
Oxygen Retinopathy of prematurity, bronchopulmonary dysplasia
Sulfisoxazole Kernicterus
Chloramphenicol Gray baby syndrome—shock, bone marrow suppression
Vitamin K analogs Jaundice
Novobiocin Jaundice
Hexachlorophene Encephalopathy
Benzyl alcohol Acidosis, collapse, intraventricular bleeding
Intravenous vitamin E Ascites, shock
Phenolic detergents Jaundice
NaHCO3 Intraventricular hemorrhage
Amphotericin Anuric renal failure, hypokalemia, hypomagnesemia
Reserpine Nasal stuffiness
Indomethacin Oliguria, hyponatremia, intestinal perforation
Cisapride Prolonged QTc interval
Tetracycline Enamel hypoplasia
Tolazoline Hypotension, gastrointestinal bleeding
Calcium salts Subcutaneous necrosis
Aminoglycosides Deafness, renal toxicity
Enteric gentamicin Resistant bacteria
Prostaglandins Seizures, diarrhea, apnea, hyperostosis, pyloric stenosis
Phenobarbital Altered state, drowsiness
Morphine Hypotension, urine retention, withdrawal
Pancuronium Edema, hypovolemia, hypotension, tachycardia, vecuronium contractions,
prolonged hypotonia
Iodine antiseptics Hypothyroidism, goiter
Fentanyl Seizures, chest wall rigidity, withdrawal
Dexamethasone Gastrointestinal bleeding, hypertension, infection, hyperglycemia,
cardiomyopathy, reduced growth
Furosemide Deafness, hyponatremia, hypokalemia, hypochloremia, nephrocalcinosis, biliary
stones
 Heparin (not low-dose Bleeding, intraventricular hemorrhage, thrombocytopenia
prophylactic use)
Erythromycin Pyloric stenosis

Many drugs apparently safe for adults on the basis of toxicity studies may be
harmful to newborns, especially premature infants. Oxygen and a number of
drugs have proved toxic to premature infants in amounts not harmful to term
infants. Thus, administering any drug, particularly in high doses, that has not
undergone pharmacologic testing in premature infants should be undertaken
carefully after risks have been weighed against benefits.

Morbidity and Mortality

Rates of neonatal morbidity and mortality are high in extremely preterm infants,
and risks increase with decreasing gestational age and lower birthweight (Table
117.5 ). Data on extremely preterm infants born between 2003 and 2007 found
that 42% of VLBW infants developed BPD, 12% developed ROP requiring
treatment, 11% NEC, 36% late-onset sepsis, 16% grade III or IV
intraventricular hemorrhage (IVH) , and 3% periventricular leukomalacia
(PVL) . Morality increased with lower gestational age, with a 94% mortality in
infants born at 22 wk and 8% mortality at 28 wk. As a whole, the group of
extremely preterm infants had a 28% mortality rate, with 37% surviving without
a significant neonatal morbidity.

Table 117.5
Neonatal Morbidities Associated With Prematurity
RESPIRATORY
Respiratory distress syndrome (hyaline membrane disease)
Bronchopulmonary dysplasia*
Pneumothorax, pneumomediastinum; interstitial emphysema
Congenital pneumonia
Apnea
CARDIOVASCULAR
Patent ductus arteriosus
Hypotension
Bradycardia (with apnea)
HEMATOLOGIC
Anemia (early or late onset)
GASTROINTESTINAL
Poor gastrointestinal function—poor motility
Necrotizing enterocolitis*
 Hyperbilirubinemia—direct and indirect
Spontaneous gastrointestinal isolated perforation
METABOLIC-ENDOCRINE
Hypocalcemia
Hypoglycemia
Hyperglycemia
Metabolic acidosis
Hypothermia
Euthyroid but low thyroxine status
Osteopenia
CENTRAL NERVOUS SYSTEM
Intraventricular hemorrhage*
Periventricular leukomalacia*
Seizures
Retinopathy of prematurity*
Deafness
Hypotonia
RENAL
Hyponatremia
Hypernatremia
Hyperkalemia
Renal tubular acidosis
Renal glycosuria
Edema
OTHER
Infections* (congenital, perinatal, nosocomial: bacterial, viral, fungal, protozoal)
* Major neonatal morbidities.

Another study found that morbidity and mortality among VLBW infants
decreased between 2000 and 2009. This study was limited to live-born infants
with birthweight of 500-1500 g. For infants born in 2009, this study found a
12.4% mortality rate; 28% of infants developed BPD, 7% severe ROP, 5% NEC,
15% late-onset sepsis, 6% grade III or IV IVH, and 3% PVL; 51% survived
without significant neonatal morbidity.
Outcomes may be slightly improving with time; survival among infants born
22-24 wk gestation increased from 30% in 2000–2003 to 36% in 2008–2011.
The percentage surviving without neurodevelopmental impairment increased
from 16% to 20% over this same period. However, extreme prematurity is still
associated with significant risk of both mortality and major neonatal morbidities.
For infants who survive to discharge, prematurity, as well as neonatal
morbidities, put them at increased risk for developmental delays and impairment
as they age (see Chapter 117.5 ).

Bibliography
Adams M, Bassler D, Bucher HU, et al. Variability of very low
 IUGR is associated with medical conditions that interfere with the circulation
and efficiency of the placenta, with the development or growth of the fetus, or
with the general health and nutrition of the mother (Table 117.6 ). Many factors
are common to both prematurely born and LBW infants with IUGR. IUGR is
associated with decreased insulin production or insulin-like growth factor (IGF)
action at the receptor level. Infants with IGF-1 receptor defects, pancreatic
hypoplasia, or transient neonatal diabetes have IUGR. Genetic mutations
affecting the glucose-sensing mechanisms of the pancreatic islet cells result in
decreased insulin release (loss of function of the glucose-sensing glucokinase
gene) and give rise to IUGR.

Table 117.6
Factors Often Associated With Intrauterine Growth
Restriction
FETAL
Chromosomal disorders
Chronic fetal infections (cytomegalic inclusion disease, congenital rubella, syphilis)
Congenital anomalies—syndrome complexes
Irradiation
Multiple gestation
Pancreatic hypoplasia
Insulin deficiency (production or action of insulin)
Insulin-like growth factor type I deficiency
PLACENTAL
Decreased placental weight, cellularity, or both
Decrease in surface area
Villous placentitis (bacterial, viral, parasitic)
Infarction
Tumor (chorioangioma, hydatidiform mole)
Placental separation
Twin transfusion syndrome
MATERNAL/PATERNAL
Toxemia
Hypertension or renal disease, or both
Hypoxemia (high altitude, cyanotic cardiac or pulmonary disease)
Malnutrition (micronutrient or macronutrient deficiencies)
Chronic illness
Sickle cell anemia
Drugs (narcotics, alcohol, cigarettes, cocaine, antimetabolites)
IGF2 mutation (paternal)

IUGR may be a normal fetal response to nutritional or oxygen deprivation;

therefore the issue is not the IUGR but rather the ongoing risk of fetal
malnutrition or hypoxia. IUGR is often classified as reduced growth that is
symmetric (head circumference, length, and weight equally affected) or
asymmetric (with relative sparing of head growth). Symmetric IUGR often has
an earlier onset in the first trimester of pregnancy and is associated with diseases
that seriously affect fetal cell number, such as conditions with chromosomal,
genetic, malformation, teratogenic, infectious, or severe maternal hypertensive
etiologies. It is important to assess gestational age carefully in infants suspected
to have symmetric IUGR because incorrect overestimation of gestational age
may lead to the diagnosis of symmetric IUGR. Asymmetric IUGR is often of
late onset in the 2nd half of pregnancy, demonstrates preservation of Doppler
waveform velocity to the carotid vessels, and is associated with poor maternal
nutrition or with late onset or exacerbation of maternal vascular disease
(preeclampsia, chronic hypertension).
Table 117.7 lists common problems of infants with IUGR. In addition, in both
preterm and term infants, SGA has been shown to be associated with an
increased risk of neurodevelopmental impairment.

Table 117.7

Problems of Infants Small for Gestational Age or With Intrauterine Growth

Restriction*
PROBLEM PATHOGENESIS
Intrauterine fetal demise Hypoxia, acidosis, infection, lethal anomaly
Perinatal asphyxia ↓ Uteroplacental perfusion during labor ± chronic fetal hypoxia-acidosis;
meconium aspiration syndrome
Hypoglycemia ↓ Tissue glycogen stores, ↓ gluconeogenesis, hyperinsulinism, ↑ glucose needs of
hypoxia, hypothermia, large brain
Polycythemia-hyperviscosity Fetal hypoxia with ↑ erythropoietin production
Reduced oxygen Hypoxia, hypoglycemia, starvation effect, poor subcutaneous fat stores
consumption/hypothermia
Dysmorphology Syndrome anomalads, chromosomal-genetic disorders, oligohydramnios-induced
deformation, TORCH †
* Other problems include pulmonary hemorrhage and those common to the gestational age–
related risks of prematurity if born at <37 wk.
† Toxoplasmosis, other agents, rubella, cytomegalovirus, herpes simplex infection.

↓, Decreased; ↑, increased.

Large-for-Gestational-Age Infants
Infants with birthweight >90th percentile for gestational age are called large for
 early intervention
Individuals with Disabilities Act
neonatal follow-up program

Discharge From the Hospital

Numerous criteria need to be met before a high-risk infant is ready for discharge
from the hospital (Table 117.8 ). Before discharge, infants should be taking most
or all nutrition by nipple, either bottle or breast. Some medically fragile infants
may be discharged home while receiving gavage feedings after the parents have
received appropriate training and education. Growth should be occurring at
steady increments, with a goal weight gain of approximately 30 g/day.
Temperature should be stable and normal in an open crib. Infants should have
had no recent episodes of apnea or bradycardia requiring intervention for at least
5-7 days prior to discharge. Stable infants recovering from BPD may be
discharged on a regimen of home oxygen given by nasal cannula as long as
careful follow-up is arranged with home pulse oximetry monitoring and
outpatient visits. All infants with birthweight <1,500 g or gestational age <30 wk
at birth should undergo an eye examination to screen for ROP. If born preterm,
hemoglobin or hematocrit should be determined to evaluate for possible anemia
of prematurity. Every infant should have a hearing test before discharge. Routine
vaccinations should be given based on chronological age before discharge. In
addition, palivizumab (Synagis) should be given to eligible infants during
respiratory syncytial virus (RSV) season immediately before discharge for
prophylaxis against RSV, with continued monthly doses arranged as an
outpatient as appropriate.

Table 117.8
Readiness for Discharge of High-Risk Infants Criteria
Resolution of acute life-threatening illnesses
Ongoing follow-up for chronic but stable problems:
Bronchopulmonary dysplasia
Intraventricular hemorrhage
Necrotizing enterocolitis after surgery or recovery
Ventricular septal defect, other cardiac lesions
Anemia
Retinopathy of prematurity
Hearing problems
 Apnea
Cholestasis
Stable temperature regulation
Gain of weight with enteral feedings:
Breastfeeding
Bottle feeding
Gastric tube feeding
Free of significant apnea
Appropriate immunizations and planning for respiratory syncytial virus prophylaxis if indicated
Hearing screenings
Ophthalmologic examination if <30 wk of gestation or <1,500 g at birth
Parental knowledge, skill, and confidence documented in:
Administration of medications (diuretics, methylxanthines, aerosols, etc.)
Use of oxygen, apnea monitors, oximeters
Nutritional support:
Timing
Volume
Mixing concentrated formulas
Recognition of illness and deterioration
Basic cardiopulmonary resuscitation
Infant safety
Scheduling of referrals:
Primary care provider
Neonatal follow-up clinic
Occupational therapy/physical therapy
Imaging (head ultrasound)
Assessment of and solution to social risks
Data from American Academy of Pediatrics, American College of Obstetricians: Guidelines for
perinatal care, ed 7, Elk Grove Village, IL, 2013, American Academy of Pediatrics.

If all major medical problems have resolved and the home setting is adequate,
premature infants may then be discharged when their weight approaches 1,800-
2,000 g, they are >34-35 wk PMA, and all the above criteria are met. Parental
education, close follow-up, and healthcare provider accessibility are all essential
for early discharge protocols. Ideally, the primary caregivers for the infant have a
chance to provide infant care in the hospital with nursing supervision and help
before discharge home. All high-risk infants should follow-up with their primary
care provider within a few days of discharge.

Postdischarge Follow-Up
Medical Follow-Up
Even after discharge from the hospital, high-risk infants need very close medical
follow-up. They continued to be at increased risk for poor weight gain and
failure to thrive. In the setting of viral illness, premature infants are at increased
risk for significant respiratory distress. Infants who are sent home on oxygen
need very close medical follow-up with frequent visits and assessments, often
with pulmonology. Table 117.9 lists common sequelae of prematurity.

Table 117.9

Sequelae of Prematurity
IMMEDIATE LATE
Hypoxia, Intellectual disability, spastic diplegia, microcephaly, seizures, poor school performance
ischemia
Intraventricular Intellectual disability, spasticity, seizures, post hemorrhagic hydrocephalus
hemorrhage
Sensorineural Hearing and visual impairment, retinopathy of prematurity, strabismus, myopia
injury
Respiratory Bronchopulmonary dysplasia, pulmonary hypertension, bronchospasm, malnutrition, subglottic
failure stenosis
Necrotizing Short-bowel syndrome, malabsorption, malnutrition
enterocolitis
Cholestatic Cirrhosis, hepatic failure, malnutrition
liver disease
Nutrient Osteopenia, fractures, anemia, growth failure
deficiency
Social stress Child abuse or neglect, failure to thrive, divorce
Other sequelae Sudden infant death syndrome, infections, inguinal hernia, cutaneous scars (chest tube, patent
ductus arteriosus ligation, intravenous infiltration), gastroesophageal reflux, hypertension,
craniosynostosis, cholelithiasis, nephrocalcinosis, cutaneous hemangiomas

Medically complex infants can go home with a multitude of subspecialty

appointments to help manage existing morbidities secondary to prematurity. For
example, cardiology for management of a patent ductus arteriosus or pulmonary
hypertension, pulmonary for BPD, nephrology for hypertension, ophthalmology
for ROP, neurosurgery for hydrocephalus, and neurology for history of seizures.
The extensive follow-up requirements can be overwhelming and daunting for
families. It is very important that these infants have a primary care provider who
serves as their “medical home” to help coordinate and assimilate the care from
all these providers for families.

Developmental Follow-Up
It is well known that premature infants are at greater risk for developmental
delays than their term counterparts; the more preterm, the greater the risk of
delay. In addition, certain postnatal morbidities (severe BPD, grade III or IV
intraventricular hemorrhage, severe ROP) are associated with significantly
increased risk of developmental delays. It is very important that preterm infants
Table 119.1

Common Life-Threatening Congenital Anomalies

ANOMALY MANIFESTATIONS
Choanal atresia Respiratory distress in delivery room; nasogastric tube cannot be
passed through nares.
Suspect CHARGE (coloboma of eye, heart anomaly, choanal atresia,
retardation, genital and ear anomalies) syndrome.
Pierre Robin syndrome, Stickler Micrognathia, cleft palate, airway obstruction
syndrome
Diaphragmatic hernia Scaphoid abdomen, bowel sounds present in chest, respiratory distress
Tracheoesophageal fistula Polyhydramnios, aspiration pneumonia, excessive salivation;
nasogastric tube cannot be placed in stomach.
Suspect VATER (vertebral defects, imperforate anus,
tracheoesophageal fistula, radial and renal dysplasia) syndrome.
Intestinal obstruction: volvulus, Polyhydramnios, bile-stained emesis, abdominal distention
duodenal atresia, ileal atresia Suspect trisomy 21, cystic fibrosis, or cocaine use.
Gastroschisis, omphalocele Polyhydramnios, intestinal obstruction
Renal agenesis, Potter syndrome Oligohydramnios, anuria, pulmonary hypoplasia, pneumothorax
Neural tube defects: anencephalus, Polyhydramnios, elevated α-fetoprotein, decreased fetal activity
meningomyelocele
Ductus-dependent congenital heart Cyanosis, hypotension, murmur
disease

Cyanosis
Central cyanosis generates a broad differential diagnosis encompassing
respiratory, cardiac, CNS, infectious, hematologic, and metabolic etiologies
(Table 119.2 ). Typically, 5 g/dL of deoxyhemoglobin must be present in the
blood for central cyanosis to be clinically apparent. If respiratory insufficiency is
caused by pulmonary conditions, respirations tend to be rapid with increased
work of breathing. If caused by CNS depression, respirations tend to be irregular
and weak and are often slow. Cyanosis unaccompanied by obvious signs of
respiratory difficulty suggests cyanotic congenital heart disease or
methemoglobinemia. Cyanosis resulting from congenital heart disease may,
however, be difficult to distinguish clinically from cyanosis caused by
respiratory disease. Episodes of cyanosis may also be the initial sign of
hypoglycemia, bacteremia, meningitis, shock, or pulmonary hypertension.
Peripheral acrocyanosis is common in neonates and thought to represent
peripheral venous congestion associated with immature control of peripheral
vascular tone. It does not usually warrant concern unless poor perfusion is
suspected.
Table 119.2
Differential Diagnosis of Cyanosis in the Newborn
CENTRAL OR PERIPHERAL NERVOUS SYSTEM HYPOVENTILATION
Birth asphyxia
Intracranial hypertension, hemorrhage
Oversedation (direct or through maternal route)
Diaphragm palsy
Neuromuscular diseases
Seizures
RESPIRATORY DISEASE
Airway
Choanal atresia/stenosis
Pierre Robin syndrome
Intrinsic airway obstruction (laryngeal/bronchial/tracheal stenosis)
Extrinsic airway obstruction (bronchogenic cyst, duplication cyst, vascular compression)
Lung
Respiratory distress syndrome
Transient tachypnea
Meconium aspiration
Pneumonia (sepsis)
Pneumothorax
Congenital diaphragmatic hernia
Pulmonary hypoplasia
CARDIAC RIGHT-TO-LEFT SHUNT
Abnormal Connections (Pulmonary Blood Flow Normal or Increased)
Transposition of great vessels
Total anomalous pulmonary venous return
Truncus arteriosus
Hypoplastic left heart syndrome
Single ventricle or tricuspid atresia with large ventricular septal defect but without pulmonic stenosis
Obstructed Pulmonary Blood Flow (Pulmonary Blood Flow Decreased)
Pulmonic atresia with intact ventricular septum
Tetralogy of Fallot
Critical pulmonic stenosis with patent foramen ovale or atrial septal defect
Tricuspid atresia
Single ventricle with pulmonic stenosis
Ebstein malformation of tricuspid valve
Persistent fetal circulation (persistent pulmonary hypertension of newborn)
METHEMOGLOBINEMIA
Congenital (hemoglobin M, methemoglobin reductase deficiency)
Acquired (nitrates, nitrites)
Inadequate ambient O2 or less O2 delivered than expected (rare)
Disconnection of O2 supply to nasal cannula, head hood
Connection of air, rather than O2 , to a mechanical ventilator
SPURIOUS/ARTIFACTUAL
Oximeter artifact (poor contact between probe and skin, poor pulse searching)
Arterial blood gas artifact (contamination with venous blood)
OTHER
Hypoglycemia
Adrenogenital syndrome
Polycythemia
Blood loss
hepatitis, congenital atresia of the bile ducts, inspissated bile syndrome after
erythroblastosis fetalis, syphilis, herpes simplex other congenital infections, or
other conditions (see Chapter 123.3 ).

Pain
Pain in neonates may be unrecognized and/or undertreated. The intensive care of
neonates may involve several painful procedures, including blood sampling
(heelstick, venous or arterial puncture), endotracheal intubation and suctioning,
mechanical ventilation, and insertion of chest tubes and intravascular catheters.
Pain in neonates results in obvious distress and acute physiologic stress
responses, which may have developmental implications for pain in later life.
Moreover, knowing that infants may experience pain contributes to parental
stress.
Pain and discomfort are potentially avoidable problems during the treatment
of sick infants. The most common causes of painful stimuli include circumcision
pain and that associated with phlebotomy for metabolic screening tests. Oral
sucrose solutions are well tolerated by most infants and have proven efficacy for
procedural pain. For NICU infants, the most frequently used drugs are
intermittent or continuous doses of opioids (morphine, fentanyl) and
benzodiazepines (midazolam, lorazepam). Although the long-term effects of
opioids and sedatives are not well established, the first concern should be the
treatment and/or prevention of acute pain. Continuous opiate infusions should be
used with caution. Some minor but painful procedures performed in well
neonates can be managed with oral sucrose solutions (Table 119.3 ).

Table 119.3
Pain in the Neonate: General Considerations
• Pain in newborns is often unrecognized and/or undertreated.
• If a procedure is painful in adults, it should be considered painful in newborns.
• Healthcare institutions should develop and implement patient care policies to assess, prevent, and manage pain
in neonates.
• Pharmacologic agents with known pharmacokinetic and pharmacodynamic properties and demonstrated efficacy
in neonates should be used. Agents known to compromise cardiorespiratory function should be administered
only by persons experienced in neonatal airway management and in settings with the capacity for continuous
monitoring.
• Educational programs to increase the skills of healthcare professionals in the assessment and management of
stress and pain in neonates should be provided.
• Further research is needed to develop and validate neonatal pain assessment tools that are useful in the clinical
 setting; to determine optimal behavioral and pharmacologic interventions; and to study long-term effects of pain
and pain management.
Data from American Academy of Pediatrics Committee on Fetus and Newborn, Committee on
Drugs, Section on Anesthesiology, Section on Surgery; Canadian Paediatric Society, Fetus and
Newborn Committee: Prevention and management of pain and stress in the neonate, Pediatrics
105:454–461, 2000; and from Anand KJS; International Evidence-Based Group for Neonatal Pain:
Consensus statement for the prevention and management of pain in the newborn, Arch Pediatr
Adolesc Med 155:173–180, 2001.

119.1
Hyperthermia
Elizabeth Enlow, James M. Greenberg

Serious infection (pneumonia, bacteremia, meningitis, and viral infections,

particularly herpes simplex or enteroviruses) may cause fever and must be
considered, although such infections often occur without provoking a febrile
response in newborn infants (see Chapters 201 and 202 ). Providers should
consider evaluation for bacterial infection in infants <28 days old with a rectal
temperature ≥38°C (100.5°F), including blood culture, urine culture, and lumbar
puncture (LP), although stepwise approaches to identify low-risk patients and
limiting LP to a subset of higher-risk infants are gaining favor. Fever
immediately after birth may be caused by radiant warmers, maternal fever, or
maternal epidural analgesia. Fever may also be caused by elevated
environmental temperatures because of weather, overheated nurseries,
incubators, or radiant warmers, or excessive clothing. It has also been attributed
to dehydration, although dehydration fever is a diagnosis of exclusion in
newborn infants.

Bibliography
Velasco R, Gomez B, Hernandez-Bou S, et al. Validation of a
predictive model for identifying febrile young infants with
cerebellar injury and may be more predictive of adverse long-term outcome.

Prognosis
The degree of IVH and presence of PVL are strongly linked to survival and
neurodevelopmental impairment (Tables 120.1 and 120.2 ). For infants with
birthweight <1,000 g, the incidence of severe neurologic impairment (defined as
Bayley Scales of Infant Development II mental developmental index <70,
psychomotor development index <70, cerebral palsy, blindness, or deafness)
after IVH is highest with grade IV hemorrhage and lower birthweight. PVL,
cystic PVL, and progressive hydrocephalus requiring shunt insertion are each
independently associated with a poorer prognosis (Table 120.3 ). Current data
suggest that outcomes for infants with grade III/IV intraventricular hemorrhage
may be improving, with rates of cerebral palsy and neurodevelopmental
impairment closer to 30–40% at age 2 yr.

Table 120.1
Short-Term Outcome of Germinal Matrix–Intraventricular
Hemorrhage as a Function of Severity of Hemorrhage and
Birthweight*

DEATHS IN FIRST 14 DAYSc PVD (SURVIVORS >14 DAYS)

SEVERITY OF
HEMORRHAGE <750 g (n = 751-1500 g (n = <750 g (n = 751-1500 g (n =
75) 173) 56) 165)
Grade I 3/24 (12) 0/80 (0) 1/21 (5) 3/80 (4)
Grade II 5/21 (24) 1/44 (2) 1/16 (6) 6/43 (14)
Grade III 6/19 (32) 2/26 (8) 10/13 (77) 18/24 (75)
Grade III and apparent PHI 5/11 (45) 5/23 (22) 5/6 (83) 12/18 (66)
* Values are n (%). Deaths occurring later in the neonatal period are not shown; the total mortality

rates (early and late deaths) are approximately 50–100% greater for each grade of hemorrhage
and birthweight than those shown in the table for early deaths alone.
PHI, Periventricular hemorrhagic infarction; PVD, progressive ventricular dilation.
Data from Murphy BP, Inder TE, Rooks V, Taylor GA, et al. Posthemorrhagic ventricular dilatation
in the premature infant: natural history and predictors of outcome, Arch Dis Child Fetal Neonatal
Ed 87:F37–F41, 2002.
Adapted from Inder TE, Perlman JM, Volpe JJ: Preterm intraventricular
hemorrhage/posthemorrhagic hydrocephalus. In Volpe's neurology of the newborn, ed 6,
Philadelphia, 2018, Elsevier (Table 24-15).
Table 120.2

Long-Term Outcome: Neurologic Sequelae in Survivors With Germinal Matrix–

Intraventricular Hemorrhage as a Function of Severity of Hemorrhage*

SEVERITY OF HEMORRHAGEb INCIDENCE OF DEFINITE NEUROLOGIC SEQUELAE † (%)

Grade I 15
Grade II 25
Grade III 50
Grade III and apparent PVI 75
*
Data are derived from reports published since 2002 and include personal published and
unpublished cases. Mean values (to nearest 5%); considerable variability among studies was
apparent, especially for the severe lesions.
† Definite neurologic sequelae included principally cerebral palsy or mental retardation, or both.

PVI, Periventricular hemorrhagic infarction.

Adapted From Inder TE, Perlman JM, Volpe JJ: Preterm intraventricular
hemorrhage/posthemorrhagic hydrocephalus. In Volpe's neurology of the newborn, ed 6,
Philadelphia, 2018, Elsevier (Table 24-16).

Table 120.3

Ultrasonographic (US) Diagnosis of Periventricular Leukomalacia

TEMPORAL
US APPEARANCE NEUROPATHOLOGIC CORRELATION
FEATURES
Echogenic foci, bilateral, posterior > 1st wk Necrosis with congestion and/or hemorrhage
anterior (size >1 cm)
Echolucent foci (“cysts”) 1-3 wk Cyst formation secondary to tissue dissolution
(size >3 mm)
Ventricular enlargement, often with ≥2-3 mo Deficient myelin formation; gliosis, often
disappearance of “cysts” with collapse of cyst
From Neil JJ, Volpe JJ: Encephalopathy of prematurity: clinical-neurological features, diagnosis,
imaging, prognosis, therapy. In Volpe's neurology of the newborn, ed 6, Philadelphia, 2018,
Elsevier (Table 16-6).

Most infants with IVH and acute ventricular distention do not have PHH .
Only 10–15% of LBW neonates with IVH develop PHH, which may initially
present without clinical signs (enlarging head circumference, lethargy, a bulging
fontanel or widely split sutures, apnea, and bradycardia). In infants in whom
symptomatic hydrocephalus develops, clinical signs may be delayed 2-4 wk
despite progressive ventricular distention and compression and thinning of the
cerebral cortex. Many infants with PHH have spontaneous regression; only 3–
5% of VLBW infants with PHH ultimately require shunt insertion. Those infants
infants with severe fetal acidosis (pH <6.7) (90% death/impairment) and a base
deficit >25 mmol/L (72% mortality). Multiorgan failure and insult can occur
(Table 120.4 ).

Table 120.4

Multiorgan Systemic Effects of Asphyxia

SYSTEM EFFECTS
Central nervous Hypoxic-ischemic encephalopathy, infarction, intracranial hemorrhage, seizures, cerebral edema,
hypotonia, hypertonia
Cardiovascular Myocardial ischemia, poor contractility, cardiac stunning, tricuspid insufficiency, hypotension
Pulmonary Pulmonary hypertension, pulmonary hemorrhage, respiratory distress syndrome
Renal Acute tubular or cortical necrosis
Adrenal Adrenal hemorrhage
Gastrointestinal Perforation, ulceration with hemorrhage, necrosis
Metabolic Inappropriate secretion of antidiuretic hormone, hyponatremia, hypoglycemia, hypocalcemia,
myoglobinuria
Integumentary Subcutaneous fat necrosis
Hematologic Disseminated intravascular coagulation

Etiology
Most neonatal encephalopathy and seizure, in the absence of major congenital
malformations or metabolic or genetic syndromes, appear to be caused by
perinatal events. Brain MRI or autopsy findings in full-term neonates with
encephalopathy demonstrate that 80% have acute injuries, <1% have prenatal
injuries, and 3% have non–hypoxic-ischemic diagnoses. Fetal hypoxia may be
caused by various disorders in the mother, including: (1) inadequate oxygenation
of maternal blood from hypoventilation during anesthesia, cyanotic heart
disease, respiratory failure, or carbon monoxide poisoning; (2) low maternal
blood pressure from acute blood loss, spinal anesthesia, or compression of the
vena cava and aorta by the gravid uterus; (3) inadequate relaxation of the uterus
to permit placental filling as a result of uterine tetany caused by the
administration of excessive oxytocin; (4) premature separation of the placenta;
(5) impedance to the circulation of blood through the umbilical cord as a result
of compression or knotting of the cord; and (6) placental insufficiency from
maternal infections, exposures, diabetes, toxemia or postmaturity.
Placental insufficiency often remains undetected on clinical assessment.
Intrauterine growth restriction may develop in chronically hypoxic fetuses
without the traditional signs of fetal distress. Doppler umbilical waveform
velocimetry (demonstrating increased fetal vascular resistance) and
cordocentesis (demonstrating fetal hypoxia and lactic acidosis) identify a
chronically hypoxic infant (see Chapter 115 ). Uterine contractions may further
reduce umbilical oxygenation, depressing the fetal cardiovascular system and
CNS and resulting in low Apgar scores and respiratory depression at birth.
After birth, hypoxia may be caused by (1) failure of oxygenation as a result of
severe forms of cyanotic congenital heart disease or severe pulmonary disease;
(2) severe anemia (severe hemorrhage, hemolytic disease); (3) shock severe
enough to interfere with the transport of oxygen to vital organs from
overwhelming sepsis, massive blood loss, and intracranial or adrenal
hemorrhage; or (4) failure to breathe after birth because of in utero CNS injury
or drug-induced suppression.

Pathophysiology and Pathology

The topography of cerebral injury typically correlates with areas of decreased
cerebral blood flow and areas of relatively higher metabolic demand, although
regional vulnerabilities are impacted by gestational age and severity of insult
(Table 120.5 ). After an episode of hypoxia and ischemia, anaerobic metabolism
occurs and generates increased amounts of lactate and inorganic phosphates.
Excitatory and toxic amino acids, particularly glutamate, accumulate in the
damaged tissue. prompting overactivation of N -methyl-D -aspartate (NMDA),
amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA), and kainate
receptors. This receptor overactivation increases cellular permeability to sodium
and calcium ions. Because of inadequate intracellular energy, normal sodium and
calcium homeostasis is lost, and intracellular accumulation of these ions results
in cytotoxic edema and neuronal death. Intracellular calcium accumulation may
also result in apoptotic cell death. Concurrent with the excitotoxic cascade, there
is also increased production of damaging free radicals and nitric oxide in these
tissues. The initial circulatory response of the fetus is increased shunting through
the ductus venosus, ductus arteriosus, and foramen ovale, with transient
maintenance of perfusion of the brain, heart, and adrenals in preference to the
lungs, liver, kidneys, and intestine. Thus, serum laboratory evidence of injury to
these organs may be present in more severe cases.

Table 120.5
Topography of Brain Injury in Term Infants With Hypoxic-
Ischemic Encephalopathy and Clinical Correlates
AREA OF LONG-TERM
LOCATION OF INJURY CLINICAL CORRELATES
INJURY SEQUELAE
Selective Entire neuraxis, deep cortical area, Stupor or coma Cognitive delay
neuronal brainstem and pontosubicular Seizures Cerebral palsy
necrosis Hypotonia Dystonia
Oculomotor abnormalities Seizure disorder
Suck/swallow abnormalities Ataxia
Bulbar and
pseudobulbar palsy
Parasagittal Cortex and subcortical white Proximal-limb weakness Spastic
injury matter Upper extremities affected > quadriparesis
Parasagittal regions, especially lower extremities Cognitive delay
posterior Visual and auditory
processing difficulty
Focal Cortex and subcortical white Unilateral findings Hemiparesis
ischemic matter Seizures common and Seizures
necrosis Vascular injury (usually middle typically focal Cognitive delays
cerebral artery distribution)
Periventricular Injury to motor tracts, especially Bilateral and symmetric Spastic diplegia
injury lower extremity weakness in lower
extremities
More common in preterm
infants
Adapted from Volpe JJ, editor: Neurology of the newborn , ed 4, Philadelphia, 2001, Saunders.

The pathology of hypoxia-ischemia outside the CNS depends on the affected

organ and the severity of the injury. Early congestion, fluid leak from increased
capillary permeability, and endothelial cell swelling may lead to signs of
coagulation necrosis and cell death. Congestion and petechiae are seen in the
pericardium, pleura, thymus, heart, adrenals, and meninges. Prolonged
intrauterine hypoxia may result in inadequate perfusion of the periventricular
white matter, resulting in PVL. Pulmonary arteriole smooth muscle hyperplasia
may develop, which predisposes the infant to pulmonary hypertension (see
Chapter 122.9 ). If fetal distress produces gasping, amniotic fluid contents
(meconium, squames, lanugo) may be aspirated into the trachea or lungs with
subsequent complications, including pulmonary hypertension and
pneumothoraces.

Clinical Manifestations
Intrauterine growth restriction with increased vascular resistance may be an
indication of chronic fetal hypoxia before the peripartum period. During labor,
the fetal heart rate slows and beat-to-beat variability declines. Continuous heart
rate recording may reveal a variable or late deceleration pattern (see Chapter 115
, Fig. 115.4 ). Particularly in infants near term, these signs should lead to the
administration of high concentrations of oxygen to the mother and consideration
of immediate delivery to avoid fetal death and CNS damage.
At delivery, the presence of meconium-stained amniotic fluid indicates that
fetal distress may have occurred. At birth, affected infants may have neurologic
impairment and may fail to breathe spontaneously. Pallor, cyanosis, apnea, a
slow heart rate, and unresponsiveness to stimulation are also nonspecific initial
signs of potential HIE. During the ensuing hours, infants may be hypotonic, may
change from a hypotonic to a hypertonic state, or their tone may appear normal
(Tables 120.6 and 120.7 ). Cerebral edema may develop during the next 24 hr
and result in profound brainstem depression. During this time, seizure activity
may occur; it may be severe and refractory to typical doses of anticonvulsants.
Although most often a result of the HIE, seizures in asphyxiated newborns may
also be caused by vascular events (hemorrhage, arterial ischemic stroke, or sinus
venous thrombosis), metabolic derangements (hypocalcemia, hypoglycemia),
CNS infection, and cerebral dysgenesis or genetic disorders (nonketotic
hyperglycinemia, vitamin-dependent epilepsies, channelopathies). Conditions
that result in neuromuscular weakness and poor respiratory effort may also result
secondarily in neonatal hypoxic brain injury and seizure. Such conditions might
include congenital myopathies, congenital myotonic dystrophy, or spinal
muscular atrophy.

Table 120.6
Poor Predictive Variables for Death/Disability After
Hypoxic-Ischemic Encephalopathy
• Low (0–3) 10 min Apgar score
• Need for CPR in the delivery room
• Delayed onset (≥20 min) of spontaneous breathing
• Severe neurologic signs (coma, hypotonia, hypertonia)
• Seizures onset ≤12 hr or difficult to treat
• Severe, prolonged (~7 days) EEG findings including burst suppression pattern
• Prominent MRI basal ganglia/thalamic lesions
• Oliguria/anuria >24 hr
• Abnormal neurologic exam ≥14 days
Table 120.7
Hypoxic-Ischemic Encephalopathy in Term Infants

SIGNS STAGE 1 STAGE 2 STAGE 3

Level of consciousness Hyperalert Lethargic Stuporous, coma
Muscle tone Normal Hypotonic Flaccid
Posture Normal Flexion Decerebrate
Tendon reflexes/clonus Hyperactive Hyperactive Absent
Myoclonus Present Present Absent
Moro reflex Strong Weak Absent
Pupils Mydriasis Miosis Unequal, poor light
reflex
Seizures None Common Decerebration
Electroencephalographic Normal Low voltage changing to Burst suppression to
findings seizure activity isoelectric
Duration <24 hr if progresses; otherwise, 24 hr to 14 days Days to weeks
may remain normal
Outcome Good Variable Death, severe deficits
Adapted from Sarnat HB, Sarnat MS: Neonatal encephalopathy following fetal distress: a clinical
and electroencephalographic study, Arch Neurol 33:696–705, 1976.Copyright 1976, American
Medical Association.

In addition to CNS dysfunction, systemic organ dysfunction is noted in up to

80% of affected neonates. Myocardial dysfunction and cardiogenic shock,
persistent pulmonary hypertension, RDS, gastrointestinal perforation, and acute
kidney and liver injury are associated with perinatal asphyxia secondary to
inadequate perfusion (see Table 120.4 ).
The severity of neonatal encephalopathy depends on the duration and timing
of injury. A clinical grading score first proposed by Sarnat continues to be a
useful tool. Symptoms develop over days, making it important to perform serial
neurologic examinations (see Tables 120.6 and 120.7 ). During the initial hours
after an insult, infants have a depressed level of consciousness. Periodic
breathing with apnea or bradycardia is present, but cranial nerve functions are
often spared, with intact pupillary response and spontaneous eye movement.
Seizures are common with extensive injury. Hypotonia is also common as an
early manifestation of HIE, but it should be distinguished from other causes by
history and serial examination.

Diagnosis
MRI is the most sensitive imaging modality for detecting hypoxic brain injury in
 FIG. 120.8 MR images of focal ischemic cerebral injury. MRI was performed on the 3rd
postnatal day. A, Axial T2-weighted mage shows a lesion in the distribution of the main
branch of the left middle cerebral artery. B, Diffusion-weighted image demonstrates the
lesion more strikingly. (From Volpe JJ, editor: Neurology of the newborn , ed 5,
Philadelphia, 2008, Saunders/Elsevier, p 422.)

Table 120.8
Major Aspects of MRI in Diagnosis of Hypoxic-Ischemic
Encephalopathy in the Term Infant
MAJOR CONVENTIONAL MR FINDINGS IN 1ST WEEK
Cerebral cortical gray-white differentiation lost (on T1W or T2W)
Cerebral cortical high signal (T1W and FLAIR), especially in parasagittal perirolandic cortex
Basal ganglia/thalamus, high signal (T1W and FLAIR), usually associated with the cerebral cortical changes but
possibly alone with increased signal in brainstem tegmentum in cases of acute severe insult
Parasagittal cerebral cortex, subcortical white matter, high signal (T1W and FLAIR)
Periventricular white matter, decreased signal (T1W) or increased signal (T2W)
Posterior limb of internal capsule, decreased signal (T1W or FLAIR)
Cerebrum in a vascular distribution, decreased signal (T1W), but much better visualized as decreased diffusion
(increased signal) on diffusion-weighted MRI
Diffusion-weighted MRI more sensitive than conventional MRI, especially in 1st days after birth, when former
shows decreased diffusion (increased signal) in injured areas
FLAIR, Fluid-attenuated inversion recovery; MRI, magnetic resonance imaging; T1W and T2W,
T1- and T2-weighted images.
From Volpe JJ, editor: Neurology of the newborn, ed 5, Philadelphia, 2008, Elsevier (Table 9-16).

Amplitude-integrated electroencephalography (aEEG) may help to

determine which infants are at highest risk for developmental sequelae of
neonatal brain injury (Tables 120.9 and 120.10 ). The aEEG background voltage
ranges, signal patterns, and rates of normalization, as assessed at various points
in the 1st hours and days of life, can provide valuable prognostic information,
with positive predictive value of 85% and negative predictive value of 91–96%
for infants who will have adverse neurodevelopmental outcome. Unfortunately,
even with recent improvements in technology, aEEG still has difficulty detecting
seizures, particularly those that are brief or originate far from the electrodes.
Sensitivity of aEEG for seizure detection, when used by a typical reader, is
<50%. For this reason, conventional EEG montage with concurrent video of the
patient are preferred for seizure monitoring.

Table 120.9
Value of Electroencephalography in Assessment of
Asphyxiated Term Infants
Detection of severe abnormalities (i.e., CLV, FT, BSP) in 1st hours of life has a positive predictive value of an
unfavorable outcome of 80–90%.
Severe abnormalities may improve within 24 hr (~50% of BSP and 10% of CLV/FT).
Rapid recovery of severe abnormalities is associated with a favorable outcome in 60% of cases.
The combination of early neonatal neurologic examination and early aEEG enhances the positive predictive value
and specificity.
aEEG, Amplitude-integrated encephalography; BSP, burst-suppression pattern; CLV, continuous
low voltage; FT, flat trace.
From Inder TE, Volpe JJ: Hypoxic-ischemic injury in the term infant: clinical-neurological features,
diagnosis, imaging, prognosis, therapy. In Volpe's neurology of the newborn, ed 6, Philadelphia,
2018, Elsevier (Table 20-28).

Table 120.10
Electroencephalographic Patterns of Prognostic
Significance in Asphyxiated Term Infants*
ASSOCIATED WITH FAVORABLE OUTCOME
Mild depression (or less) on day 1
Normal background by day 7
ASSOCIATED WITH UNFAVORABLE OUTCOME
Predominant interburst interval >20 sec on any day
Burst-suppression pattern on any day
Isoelectric tracing on any day
Mild (or greater) depression after day 12
* Associations with favorable or unfavorable outcome are generally ≥90%, but the clinical context
must be considered.
collapse may follow the negative airway pressures generated during inspiration,
or it may result from incoordination of the tongue and other upper airway
muscles involved in maintaining airway patency. Central apnea, which is
caused by decreased central nervous system (CNS) stimuli to respiratory
muscles, results in both airflow and chest wall motion being absent. Gestational
age is the most important determinant of respiratory control, with the frequency
of central apnea being inversely related to gestational age. The immaturity of the
brainstem respiratory centers is manifest by an attenuated response to CO2 and a
paradoxical response to hypoxia that results in central apnea rather than
hyperventilation. Mixed apnea is most often observed in apnea of prematurity
(50–75% of cases), with obstructive apnea preceding central apnea. Short
episodes of apnea are usually central, whereas prolonged ones are often mixed.
Apnea depends on the sleep state; its frequency increases during active (rapid
eye movement) sleep.
Although apnea is usually observed in preterm infants as a result of immature
respiratory control or an associated illness, apnea in term infants is uncommon,
often associated with serious pathology, and demands prompt diagnostic
evaluation. Apnea accompanies many primary diseases that affect neonates
(Table 122.1 ). These disorders produce apnea by direct depression of CNS
control of respiration (hypoglycemia, meningitis, drugs, intracranial hemorrhage,
seizures), disturbances in oxygen delivery (shock, sepsis, anemia), or ventilation
defects (obstruction of the airway, pneumonia, muscle weakness).The term
neonate with apnea should receive continuous cardiorespiratory monitoring
while performing an assessment for bacterial or viral sepsis/meningitis,
intracranial hemorrhage, seizures, and airway instability. Supportive care and
close monitoring are essential while the underlying etiology is ascertained and
appropriately treated.

Table 122.1

Potential Causes of Neonatal Apnea and Bradycardia

Central nervous Intraventricular hemorrhage, drugs, seizures, hypoxic injury, herniation, neuromuscular
system disorders, Leigh syndrome, brainstem infarction or anomalies (e.g., olivopontocerebellar
atrophy), spinal cord injury after general anesthesia
Respiratory Pneumonia, obstructive airway lesions, upper airway collapse, atelectasis, extreme prematurity,
laryngeal reflex, phrenic nerve paralysis, pneumothorax, hypoxia
Infectious Sepsis, meningitis (bacterial, fungal, viral), respiratory syncytial virus, pertussis
Gastrointestinal Oral feeding, bowel movement, necrotizing enterocolitis, intestinal perforation
Metabolic ↓ Glucose, ↓ calcium, ↓/↑ sodium, ↑ ammonia, ↑ organic acids, ↑ ambient temperature,
 hypothermia
Cardiovascular Hypotension, hypertension, heart failure, anemia, hypovolemia, vagal tone
Other Immaturity of respiratory center, sleep state
Sudden unexpected postnatal collapse

Apnea of Prematurity
Apnea of prematurity results from immature respiratory control, most frequently
occurs in infants <34 wk of gestational age (GA), and occurs in the absence of
identifiable predisposing diseases. The incidence of idiopathic apnea of
prematurity varies inversely with GA. Apnea of prematurity is almost universal
in infants born at <28 wk GA, and the incidence rapidly decreases from 85% of
infants <30 wk GA to 20% of infants <34 wk GA. The onset of apnea of
prematurity can be during the initial days to weeks of age but is often delayed if
there is RDS or other causes of respiratory distress. In premature infants without
respiratory disease, apneic episodes can occur throughout the 1st 7 postnatal
days with equal frequency.
Apnea in preterm infants is defined as cessation of breathing for ≥20 sec or for
any duration if accompanied by cyanosis and bradycardia (<80-100 beats/min).
The incidence of associated bradycardia increases with the length of the
preceding apnea and correlates with the severity of hypoxia. Short apnea
episodes (10 sec) are rarely associated with bradycardia, whereas longer
episodes (>20 sec) have a higher incidence of bradycardia. Bradycardia follows
the apnea by 1-2 sec in >95% of cases and is most often sinus, but on occasion it
can be nodal. Vagal responses and rarely heart block are causes of bradycardia
without apnea. Short, self-resolving oxygen desaturation episodes noted with
continuous monitoring are normal in neonates, and treatment is not necessary.
Preterm infants born at <35 wk GA are at risk for apnea of prematurity and
therefore should receive cardiorespiratory monitoring. Apnea that occurs in the
absence of other clinical signs of illness in the 1st 2 wk in a preterm infant is
likely apnea of prematurity, and therefore additional evaluation for other
etiologies is often unwarranted. However, the onset of apnea in a previously well
preterm neonate after the 2nd wk of life (or, as previously, in a term infant at any
time) is a critical event that may be associated with serious underlying
pathology. Prompt investigation for medication side effects, metabolic
derangements, structural CNS anomalies, intracranial hemorrhage, seizures, or
sepsis/meningitis is warranted.
reliable and correlated with discharge home on oxygen, length of hospital stay,
and hospital readmissions in the 1st yr of life. The risk of neurodevelopmental
impairment and pulmonary morbidity and the severity of BPD are directly
correlated.

Table 122.2
Definition of Bronchopulmonary Dysplasia (BPD):
Diagnostic Criteria*

GESTATIONAL AGE
<32 Wk ≥32 Wk
Time point 36 wk PMA or discharge home, whichever >28 days but <56 days postnatal age or
of comes first discharge home, whichever comes first
assessment Treatment with >21% oxygen for at least Treatment with >21% oxygen for at least 28
28 days plus : days plus :
Mild BPD Breathing room air at 36 wk PMA or discharge Breathing room air by 56 days postnatal age or
home, whichever comes first discharge home, whichever comes first
Moderate Need † for <30% oxygen at 36 wk PMA or Need † for <30% oxygen at 56 days postnatal age
BPD discharge home, whichever comes first or discharge home, whichever comes first
Severe Need † for ≥30% oxygen and/or positive Need † for ≥30% oxygen and/or positive pressure
BPD pressure (PPV or NCPAP) at 36 wk PMA or (PPV or NCPAP) at 56 days postnatal age or
discharge home, whichever comes first discharge home, whichever comes first
* BPD usually develops in neonates being treated with oxygen and PPV for respiratory failure,
most frequently respiratory distress syndrome (RDS). Persistence of the clinical features of
respiratory disease (tachypnea, retractions, crackles) is considered common to the broad
description of BPD and has not been included in the diagnostic criteria describing the severity of
BPD. Infants treated with >21% oxygen and/or PPV for nonrespiratory disease (e.g., central
apnea or diaphragmatic paralysis) do not have BPD unless parenchymal lung disease also
develops and they have clinical features of respiratory distress. A day of treatment with >21%
oxygen means that the infant received >21% oxygen for >12 hr on that day. Treatment with >21%
oxygen and/or PPV at 36 wk PMA or at 56 days postnatal age or discharge should not reflect an
“acute” event, but should rather reflect the infant's usual daily therapy for several days preceding
and after 36 wk PMA, 56 days postnatal age, or discharge.
† A physiologic test confirming that the oxygen requirement at the assessment time point remains

to be defined. This assessment may include a pulse oximetry saturation range.

NCPAP, Nasal continuous positive airway pressure; PMA, postmenstrual age; PPV, positive
pressure ventilation.
From Jobe AH, Bancalari E: Bronchopulmonary dysplasia, Am J Respir Crit Care Med 163:1723–
1729, 2001.

Despite its simplicity, the current severity-based definition of BPD has

limitations. Because of incomplete or inaccurate data related to hospital transfer
or early discharge, in a significant number of infants the diagnosis of BPD is
NEC rarely occurs before the initiation of enteral feeding and is much less
common in infants fed human milk. Aggressive enteral feeding may predispose
to the development of NEC.
Although nearly 90% of all cases of NEC occur in preterm infants, the disease
can occur in full-term neonates. NEC in term infants is often a secondary
disease, seen more frequently in infants with history of birth asphyxia, Down
syndrome, congenital heart disease, rotavirus infections, gastroschisis, and
Hirschsprung disease.

Clinical Manifestations
Infants with NEC have a variety of signs and symptoms and may have an
insidious or sudden catastrophic onset (Table 123.1 ). The onset of NEC is
usually in the 2nd or 3rd week of life but can be as late as 3 mo in VLBW
infants. Age of onset is inversely related to gestational age. The first signs of
impending disease may be nonspecific, including lethargy and temperature
instability, or related to GI pathology, such as abdominal distention, feeding
intolerance, and bloody stools. Because of nonspecific signs, sepsis may be
suspected before NEC. The spectrum of illness is broad, ranging from mild
disease with only guaiac-positive stools to severe illness with bowel perforation,
peritonitis, systemic inflammatory response syndrome, shock, and death.
Laboratory derangements may include neutropenia, anemia, thrombocytopenia,
coagulopathy, and metabolic acidosis. Hypotension and respiratory failure are
common. Progression may be rapid, but it is unusual for the disease to progress
from mild to severe after 72 hr.

Table 123.1
Signs and Symptoms Associated With Necrotizing
Enterocolitis
GASTROINTESTINAL
Abdominal distention
Abdominal tenderness
Feeding intolerance
Delayed gastric emptying
Vomiting
Occult/gross blood in stool
Change in stool pattern/diarrhea
Abdominal mass
 Erythema of abdominal wall
SYSTEMIC
Lethargy
Apnea/respiratory distress
Temperature instability
“Not right”
Acidosis (metabolic and/or respiratory)
Glucose instability
Poor perfusion/shock
Disseminated intravascular coagulopathy
Positive results of blood cultures
From Kanto WP Jr, Hunter JE, Stoll BJ: Recognition and medical management of necrotizing
enterocolitis, Clin Perinatol 21:335–346, 1994.

Diagnosis
A very high index of suspicion in treating preterm at-risk infants is crucial. Plain
abdominal radiographs are essential to make a diagnosis of NEC. The finding of
pneumatosis intestinalis (air in the bowel wall) confirms the clinical suspicion
of NEC and is diagnostic; 50–75% of patients have pneumatosis when treatment
is started (Fig. 123.5 ). Portal venous gas is a sign of severe disease, and
pneumoperitoneum indicates a perforation (Figs. 123.6 and 123.7 ). Ultrasound
with Doppler flow assessment may be useful to evaluate for free fluid, abscess,
and bowel wall thickness, peristalsis, and perfusion.

specific transcutaneous bilirubin measurement, progressing jaundice, or risk for
hemolysis or sepsis. Infants with severe hyperbilirubinemia may present with
lethargy and poor feeding and, without treatment, can progress to acute bilirubin
encephalopathy (kernicterus) (see Chapter 123.4 ).

Differential Diagnosis
The distinction between physiologic and pathologic jaundice relates to the
timing, rate of rise, and extent of hyperbilirubinemia, because some of the same
causes of physiologic jaundice (e.g., large RBC mass, decreased capacity for
bilirubin conjugation, increased enterohepatic circulation) can also result in
pathologic jaundice. Evaluation should be determined on the basis of risk
factors, clinical appearance, and severity of the hyperbilirubinemia (Tables 123.2
to 123.4 ). Jaundice that is present at birth or appears within the 1st 24 hr after
birth should be considered pathologic and requires immediate attention.
Potential diagnoses would include erythroblastosis fetalis, concealed
hemorrhage, sepsis, or congenital infections, including syphilis, cytomegalovirus
(CMV), rubella, and toxoplasmosis. Hemolysis is suggested by a rapid rise in
serum bilirubin concentration (>0.5 mg/dL/hr), anemia, pallor, reticulocytosis,
hepatosplenomegaly, and a positive family history. An unusually high proportion
of direct-reacting bilirubin may characterize jaundice in infants who have
received intrauterine transfusions for erythroblastosis fetalis. Jaundice that first
appears on the 2nd or 3rd day is usually physiologic but may represent a more
severe form. Familial nonhemolytic icterus (Crigler-Najjar syndrome ) and
early-onset breastfeeding jaundice are seen initially on the 2nd or 3rd day.
Jaundice appearing after the 3rd day and within the 1st week suggests bacterial
sepsis or urinary tract infection; it may also be caused by other infections,
notably syphilis, toxoplasmosis, CMV, and enterovirus. Jaundice secondary to
extensive ecchymosis or blood extravasation may occur during the 1st day or
later, especially in premature infants. Polycythemia may also lead to early
jaundice.

Table 123.2
Risk Factors for Development of Severe
Hyperbilirubinemia*
 MAJOR RISK FACTORS
Predischarge TSB or TcB level in the high-risk zone (see Fig. 123.10 )
Jaundice observed in the 1st 24 hr
Blood group incompatibility with positive direct antiglobulin test, other known hemolytic disease (G6PD
deficiency), elevated end-tidal CO concentration
Gestational age 35-36 wk
Previous sibling received phototherapy
Cephalohematoma or significant bruising
Exclusive breastfeeding, particularly if nursing is not going well and weight loss is excessive
East Asian race †
MINOR RISK FACTORS
Predischarge TSB or TcB level in the high intermediate-risk zone
Gestational age 37-38 wk
Jaundice observed before discharge
Previous sibling with jaundice
Macrosomic infant of a diabetic mother
Maternal age ≥25 yr
Male gender
DECREASED RISK ‡
TSB or TcB level in the low-risk zone (see Fig. 123.10 )
Gestational age ≥41 wk
Exclusive bottle feeding
Black race
Discharge from hospital after 72 hr
* In infants ≥35 wk of gestation; factors in approximate order of importance.

† Race as defined by mother's description.

‡ These factors are associated with decreased risk of significant jaundice, listed in order of
decreasing importance.
G6PD, Glucose-6-phosphate dehydrogenase; TcB, transcutaneous bilirubin; TSB, total serum
bilirubin.
Adapted from American Academy of Pediatrics Subcommittee on Hyperbilirubinemia:
Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation,
Pediatrics 114:297–316, 2004.

Table 123.3

Evaluation of the Neonate With Significant Jaundice

CONCERN POSSIBLE INITIAL LABORATORY TESTS

DIAGNOSIS
Jaundice on day 1 Hemolysis ++ CBC, smear
TORCH/sepsis Total and direct bilirubin
Hepatic failure Blood type and Coombs test
syndromes*
Internal
hemorrhage
Jaundice requiring Hemolysis ++ As above
phototherapy TORCH/sepsis
 Direct/conjugated TORCH/sepsis Hepatic enzymes, INR, check newborn screen for metabolic disease,
hyperbilirubinemia Biliary atresia blood glucose, blood ammonia and lactate, urine and blood cultures,
Other causes CMV and HSV PCR
of cholestasis
+
Hepatic failure
syndromes*
+ See Chapter 383 .

++ Hemolysis may be immune or nonimmune (RBC membrane or enzyme defects).

CMV, Cytomegalovirus; CBC, complete blood count; HSV, herpes simplex virus; PCR,
polymerase chain reaction; INR, international normalized ratio; TORCH, toxoplasmosis, other,
rubella, CMV, herpes; * Hepatic failure syndromes: HSV, CMV, gestational alloimmune liver
disease, mitochondrial liver disease, familial hemophagocytic syndrome; RBC, red blood cell.

Table 123.4
Diagnostic Features of the Various Types of Neonatal
Jaundice

NATURE PEAK BILIRUBIN

JAUNDICE BILIRUBIN RATE
OF VAN CONCENTRATION
OF
DIAGNOSIS DEN COMMENTS
Age in ACCUMULATION
BERGH Appears Disappears mg/dL
Days (mg/dL/day)
REACTION
“Physiologic Usually relates to
jaundice”: degree of maturity
Full-term Indirect 2-3 days 4-5 days 10-12 2-3 <5
Premature Indirect 3-4 days 7-9 days 15 6-8 <5
Hyperbilirubinemia Metabolic factors:
caused by hypoxia, respiratory
metabolic factors: distress, lack of
carbohydrate
Full-term Indirect 2-3 days Variable >12 1st wk <5 Hormonal
influences: cretinism,
hormones, Gilbert
syndrome
Premature Indirect 3-4 days Variable >15 1st wk <5 Genetic factors:
Crigler-Najjar
syndrome,
Gilbert
syndrome
Drugs: vitamin
K, novobiocin
Hemolytic states Indirect May Variable Unlimited Variable Usually >5 Erythroblastosis:
and hematoma appear Rh, ABO, Kell
in 1st 24 congenital
hr hemolytic states:
spherocytic,
nonspherocytic
 Infantile
pyknocytosis
Drug: vitamin K
Enclosed
hemorrhage—
hematoma
Mixed hemolytic Indirect and May Variable Unlimited Variable Usually >5 Infection:
and hepatotoxic direct appear bacterial sepsis,
factors in 1st 24 pyelonephritis,
hr hepatitis,
toxoplasmosis,
cytomegalic
inclusion
disease, rubella,
syphilis
Drug: vitamin K
Hepatocellular Indirect and Usually Variable Unlimited Variable Variable, can be >5 Biliary atresia;
damage direct 2-3 paucity of bile ducts,
days; familial cholestasis,
may galactosemia;
appear hepatitis, infection
by 2nd
wk
From Brown AK: Neonatal jaundice, Pediatr Clin North Am 9:575–603, 1962.

There is a long differential diagnosis for jaundice first recognized after the 1st
week of life, including breast milk jaundice, septicemia, congenital atresia or
paucity of the bile ducts, hepatitis, galactosemia, hypothyroidism, CF, and
congenital hemolytic anemia crises related to RBC morphology and enzyme
deficiencies (Fig. 123.9 ). The differential diagnosis for persistent jaundice
during the 1st mo of life includes hyperalimentation-associated cholestasis,
hepatitis, cytomegalic inclusion disease, syphilis, toxoplasmosis, familial
nonhemolytic icterus, congenital atresia of the bile ducts, galactosemia, and
inspissated bile syndrome following hemolytic disease of the newborn. Rarely,
physiologic jaundice may be prolonged for several weeks, as in infants with
hypothyroidism or pyloric stenosis.
 metalloporphyrins
opisthions
phototherapy

Kernicterus, or bilirubin encephalopathy , is a neurologic syndrome resulting

from the deposition of unconjugated (indirect) bilirubin in the basal ganglia and
brainstem nuclei. The pathogenesis of kernicterus is multifactorial and involves
an interaction between unconjugated bilirubin levels, albumin binding and
unbound bilirubin levels, passage across the blood-brain barrier (BBB), and
neuronal susceptibility to injury. Disruption of the BBB by disease, asphyxia,
and other factors and maturational changes in BBB permeability affect risk.
The precise blood level above which indirect-reacting bilirubin or free
bilirubin will be toxic for an individual infant is unpredictable. In a large series,
however, kernicterus occurred only in infants with a bilirubin >20 mg/dL, 90%
of whom were previously healthy, predominantly breastfed, term and near-term
infants. The duration of exposure to high bilirubin levels needed to produce toxic
effects are unknown; the more immature the infant, the greater the susceptibility
to kernicterus. Chapter 123.3 discusses the factors that potentiate the movement
of bilirubin across the BBB and into brain cells.

Clinical Manifestations
Signs and symptoms of kernicterus usually appear 2-5 days after birth in term
infants and as late as the 7th day in preterm infants, but hyperbilirubinemia may
lead to encephalopathy at any time during the neonatal period. The early signs
may be subtle and indistinguishable from those of sepsis, asphyxia,
hypoglycemia, intracranial hemorrhage, and other acute systemic illnesses in a
neonate. Lethargy, poor feeding, and loss of the Moro reflex are common initial
signs. Subsequently, the infant may appear gravely ill and prostrate, with
diminished tendon reflexes and respiratory distress. Opisthotonos with a bulging
fontanel, twitching of the face or limbs, and a shrill, high-pitched cry may
follow. In advanced cases, convulsions and spasm occur, with affected infants
stiffly extending their arms in an inward rotation with the fists clenched (Table
123.5 ). Rigidity is rare at this late stage.

Table 123.5
Clinical Features of Kernicterus
ACUTE FORM
Phase 1 (1st 1-2 days): poor suck, stupor, hypotonia, seizures
Phase 2 (middle of 1st wk): hypertonia of extensor muscles, opisthotonos, retrocollis, fever
Phase 3 (after the 1st wk): hypertonia
CHRONIC FORM
1st yr: hypotonia, active deep tendon reflexes, obligatory tonic neck reflexes, delayed motor skills
After 1st yr: movement disorders (choreoathetosis, ballismus, tremor), upward gaze, sensorineural hearing loss
From Dennery PA, Seidman DS, Stevenson DK: Neonatal hyperbilirubinemia, N Engl J Med
344:581–590, 2001.

Many infants who progress to these severe neurologic signs die; the survivors
are usually seriously damaged but may appear to recover and for 2-3 mo show
few abnormalities. Later in the 1st yr, opisthotonos, muscle rigidity, irregular
movements, and convulsions tend to recur. In the 2nd yr the opisthotonos and
seizures abate, but irregular, involuntary movements, muscle rigidity, or, in some
infants, hypotonia increase steadily. By 3 yr of age, the complete neurologic
syndrome is often apparent: bilateral choreoathetosis with involuntary muscle
spasms, extrapyramidal signs, seizures, mental deficiency, dysarthric speech,
high-frequency hearing loss, squinting, and defective upward eye movements.
Pyramidal signs, hypotonia, and ataxia occur in a few infants. In mildly affected
infants, the syndrome may be characterized only by mild to moderate
neuromuscular incoordination, partial deafness, or “minimal brain dysfunction,”
occurring singly or in combination; these problems may be unapparent until the
child enters school (see Table 123.5 ).

Incidence and Prognosis

By pathologic criteria, kernicterus develops in 30% of infants (all gestational
ages) with untreated hemolytic disease and bilirubin levels >25-30 mg/dL. The
incidence at autopsy in hyperbilirubinemic preterm infants is 2–16% and is
related to the risk factors discussed in Chapter 123.3 . Reliable estimates of the
frequency of the clinical syndrome are not available because of the wide
spectrum of manifestations. Overt neurologic signs carry a grave prognosis;
>75% of infants die, and 80% of affected survivors have bilateral
choreoathetosis with involuntary muscle spasms. Developmental delay, deafness,
and spastic quadriplegia are common.
Treatment of Hyperbilirubinemia
Regardless of the cause, the goal of therapy is to prevent neurotoxicity related to
indirect-reacting bilirubin while not causing undue harm. Phototherapy and, if it
is unsuccessful, exchange transfusion remain the primary treatment modalities
used to keep the maximal total serum bilirubin below pathologic levels (Table
123.6 and Figs. 123.13 and 123.14 ). The risk of injury to the central nervous
system from bilirubin must be balanced against the potential risk of treatment.
There is lack of consensus regarding the exact bilirubin level at which to initiate
phototherapy. Because phototherapy may require 6-12 hr to have a measurable
effect, it must be started at bilirubin levels below those indicated for exchange
transfusion. When identified, underlying medical causes of elevated bilirubin
and physiologic factors that contribute to neuronal susceptibility should be
treated, with antibiotics for septicemia and correction of acidosis (Table 123.7 ).

Table 123.6

Suggested Maximal Indirect Serum Bilirubin Concentrations (mg/dL) in Preterm

Infants
BIRTHWEIGHT (g) UNCOMPLICATED* COMPLICATED*
<1,000 12-13 10-12
1,000-1,250 12-14 10-12
1,251-1,499 14-16 12-14
1,500-1,999 16-20 15-17
2,000-2,500 20-22 18-20
* Complications include perinatal asphyxia, acidosis, hypoxia, hypothermia, hypoalbuminemia,
meningitis, intraventricular hemorrhage, hemolysis, hypoglycemia, or signs of kernicterus.
Phototherapy is usually started at 50–70% of the maximal indirect level. If values greatly exceed
this level, if phototherapy is unsuccessful in reducing the maximal bilirubin level, or if signs of
kernicterus are evident, exchange transfusion is indicated.

FIG. 123.14 Guidelines for exchange transfusion in hospitalized infants of ≥35 wk of
gestation. Note: These suggested levels represent a consensus of most of the
committee but are based on limited evidence, and the levels shown are
approximations. During birth hospitalization, exchange transfusion is recommended if
the total serum bilirubin (TSB) rises to these levels despite intensive phototherapy. In a
readmitted infant, if the TSB level is above the exchange level, TSB measurement
should be repeated every 2-3 hr; exchange transfusion should be considered if the TSB
remains above the levels indicated after intensive phototherapy for 6 hr. The following
B:A (bilirubin:albumin) ratios can be used together with, but not instead of, the TSB
level as an additional factor in determining the need for exchange transfusion. G6PD,
Glucose-6-phosphate dehydrogenase. (From American Academy of Pediatrics
Subcommittee on Hyperbilirubinemia: Management of hyperbilirubinemia in the
newborn infant 35 or more weeks of gestation, Pediatrics 114:297–316, 2004.)

Table 123.7
Example of a Clinical Pathway for Management of the
Newborn Infant Readmitted for Phototherapy or Exchange
Transfusion
TREATMENT
Use intensive phototherapy and/or exchange transfusion as indicated in Figs. 123.13 and 123.14 .
LABORATORY TESTS
TSB and direct bilirubin levels
Blood type (ABO, Rh)
Direct antibody test (Coombs)
Serum albumin
Complete blood cell count with differential and smear for red cell morphology
Reticulocyte count
 End-tidal CO concentration (if available)
Glucose-6-phosphate dehydrogenase if suggested by ethnic or geographic origin or if poor response to
phototherapy
Urine for reducing substances
If history and/or presentation suggest sepsis, perform blood culture, urine culture, and cerebrospinal fluid for
protein, glucose, cell count, and culture.
INTERVENTIONS
If TSB ≥25 mg/dL (428 µmol/L) or ≥20 mg/dL (342 µmol/L) in a sick infant or infant <38 wk gestation, obtain a
type and crossmatch, and request blood in case an exchange transfusion is necessary.
In infants with isoimmune hemolytic disease and TSB level rising in spite of intensive phototherapy or within 2-3
mg/dL (34-51 µmol/L) of exchange level (see Fig. 123.14 ), administer intravenous immune globulin 0.5-1 g/kg
over 2 hr and repeat in 12 hr if necessary.
If infant's weight loss from birth is >12% or there is clinical or biochemical evidence of dehydration, recommend
formula or expressed breast milk. If oral intake is in question, give intravenous fluids.
FOR INFANTS RECEIVING INTENSIVE PHOTOTHERAPY:
Breastfeed or bottle-feed (formula or expressed breast milk) every 2-3 hr.
If TSB ≥25 mg/dL (428 µmol/L), repeat TSB within 2-3 hr.
If TSB 20-25 mg/dL (342-428 µmol/L), repeat within 3-4 hr. If TSB <20 mg/dL (342 µmol/L), repeat in 4-6 hr. If
TSB continues to fall, repeat in 8-12 hr.
If TSB is not decreasing or is moving closer to level for exchange transfusion, or if the TSB/albumin ratio exceeds
levels shown in Fig. 123.14 , consider exchange transfusion (see Fig. 123.14 for exchange transfusion
recommendations).
When TSB is <13-14 mg/dL (239 µmol/L), discontinue phototherapy.
Depending on the cause of the hyperbilirubinemia, it is an option to measure TSB 24 hr after discharge to check
for rebound.
TSB, Total serum bilirubin.
From American Academy of Pediatrics Subcommittee on Hyperbilirubinemia: Management of
hyperbilirubinemia in the newborn infant 35 or more weeks of gestation, Pediatrics 114:297–316,
2004.

Phototherapy
Clinical jaundice and indirect hyperbilirubinemia are reduced by exposure to
high-intensity light in the visible spectrum. Bilirubin absorbs light maximally in
the blue range (420-470 nm). Broad-spectrum white, blue, and special narrow-
spectrum (super) blue lights have been effective in reducing bilirubin levels.
Bilirubin in the skin absorbs light energy, causing several photochemical
reactions. One major product from phototherapy is a result of a reversible
photoisomerization reaction converting the toxic native unconjugated 4Z,15Z-
bilirubin into an unconjugated configurational isomer, 4Z,15E-bilirubin, which
can then be excreted in bile without conjugation. The other major product from
phototherapy is lumirubin, which is an irreversible structural isomer converted
from native bilirubin that can be excreted by the kidneys in the unconjugated
state.
The therapeutic effect of phototherapy depends on the light energy emitted in
 FIG. 124.2 Reference range for hematocrit and hemoglobin concentration during 1st
28 days of life. A and B, Late preterm and term infants (35-42 wk gestation). C and D,
Preterm infants (29-34 wk gestation). The reference ranges are shown for hematocrit (A
and C ) (41,957 patients) and blood hemoglobin (B and D ) (39,559 patients) during the
28 days after birth. Values were divided into 2 groups (A/B and C/D ) on the basis of
gestational age at delivery. Patients were excluded when their diagnosis included
abruption, placenta previa, or fetal anemia, or when a blood transfusion was given.
Analysis was not possible for patients <29 wk gestation because virtually all these had
repeated phlebotomy and erythrocyte transfusions. (From Jopling J, Henry E,
Wiedmeier SE, Christensin RD: Reference ranges for hematocrit and blood hemoglobin
concentration during the neonatal period: data from a multihospital health care system,
Pediatrics 123(2):e333–e337, 2009.)

Classification of Anemia and Diagnostic

Evaluation
As with any diagnostic approach to anemia, low hemoglobin concentration in the
newborn period can be classified into 3 broad categories: blood loss; erythrocyte
destruction; or underproduction of erythrocytes. Table 124.1 summarizes the
most common causes of neonatal anemia according to these categories.

Table 124.1
Differential Diagnosis of Neonatal Anemia
BLOOD LOSS ↑ RBC ↓ RBC PRODUCTION
Iatrogenic blood loss (phlebotomy) DESTRUCTION Physiologic anemia and anemia of prematurity
Placental hemorrhage Immune- Infection (rubella, CMV, parvovirus B19)
Placental previa Mediated Bone marrow suppression (acute stress in
Injury of umbilical or placental vessels Hemolysis perinatal period)
Fetomaternal transfusion Rh incompatibility Hemoglobinopathy (γ-globin mutation, unstable
Fetoplacental transfusion ABO incompatibility β-hemoglobinopathy, α-thalassemia major)
Twin-twin transfusion Minor antigen Bone marrow suppression (CMV, EBV)
Acute perinatal hemorrhage (e.g., incompatibility Diamond Blackfan anemia
cesarean birth, other obstetric trauma) RBC Membrane Schwachman-Diamond syndrome
Chronic in utero blood loss Disorders Congenital dyserythropoietic anemia
Hereditary Fanconi anemia
spherocytosis Pearson syndrome
Hereditary Congenital leukemia
elliptocytosis
Hereditary
pyropoikilocytosis
Hereditary
stomatocytosis
RBC Enzyme
Disorders
G6PD deficiency
Pyruvate kinase
 deficiency
CMV, Cytomegalovirus, EBV, Epstein-Barr virus; G6PD, glucose-6-phosphate dehydrogenase;
RBC, red blood cell.

Prior to laboratory testing, a complete medical history, including careful

review of the pregnancy and perinatal course, and a careful physical examination
are important because they often suggest a specific diagnosis more effectively
than extensive laboratory testing. A simple and efficient laboratory workup is
critical to the timely diagnosis and associated treatment of neonatal anemia. In
addition to a complete blood count (CBC), additional laboratory tests on the
infant include the reticulocyte count, direct antiglobulin test, serum bilirubin,
infant and maternal blood ABO group, and Rh type. The mother should also be
screened with an indirect (serum) antiglobulin test for erythrocyte alloantibodies,
and the Kleihauer-Betke test can identify fetal erythrocytes in the maternal
circulation (Fig. 124.3 ). Fig. 124.4 shows a proposed diagnostic approach to
anemia in newborn infants. Hemolytic anemia is usually associated with
difficult-to-treat hyperbilirubinemia (Fig. 124.5 ), whereas congenital
aregenerative anemias (e.g., Diamond-Blackfan anemia) usually do not
manifest jaundice but have other features (Table 124.2 ).

FIG. 124.3 Acid elution technique of Kleithauer (Kleihauer-Betke test). Fetal red blood
cells stain with eosin and appear dark . Adult RBCs do not stain and appear as
“ghosts.” (From Liley HG, Gardener G, Lopriore E, Smits-Wintjens V: Immune hemolytic
disease. In Orkin SH, Nathan DG, Ginsburg D, et al, editors: Nathan and Oski's
hematology and oncology of infancy and childhood, ed 8, Philadelphia, 2015, Elsevier,
Fig 3-2.)

FIG. 124.5 Evaluation of neonate with problematic jaundice of unclear cause. Not all
neonates who receive phototherapy for 2 days or more have hemolytic jaundice.
However, if hemolytic jaundice is suspected, this algorithm for stepwise evaluation of
the cause might be useful. CBC, Complete blood count; DAT, direct antiglobulin test;
EMA, eosin 5-maleimide; G6PD, glucose 6-phosphate dehydrogenase; HS, hereditary
spherocytosis; MCHC, mean corpuscular hemoglobin concentration; MCV, mean
corpuscular volume; RBC, red blood cell. (From Christensen RD: Neonatal erythrocyte
disorders. In Gleason CA, Juul SE, editors: Avery's diseases of the newborn, ed 10,
Philadelphia, 2018, Elsevier, Fig 81-15.)

Table 124.2

Syndromes Associated With Congenital Hyporegenerative Anemia

SYNDROME PHENOTYPIC FEATURES GENOTYPIC FEATURES
Adenosine Autoimmune hemolytic anemia, reduced AR, 20q13.11
deaminase erythrocyte adenosine deaminase activity
deficiency
Congenital Type I (rare): megaloblastoid erythroid Type I: 15q15.1-q15.3
dyserythropoietic hyperplasia and nuclear chromatin Type II: 20q11.2
anemias bridges between nuclei Type III: 15q21
Type II (most common): hereditary
erythroblastic multinuclearity with
positive acidified serum test result,
 increased lysis to anti-i antibodies
Type III: erythroblastic multinuclearity
(“gigantoblasts”), macrocytosis
Diamond- Steroid-responsive hypoplastic anemia, AR; sporadic mutations and AD inheritance
Blackfan often macrocytic after 5 mo of age described; 19q13.2, 8p23.3-p22
syndrome
Dyskeratosis Hypoproliferative anemia usually presenting X-linked recessive, locus on Xq28; some cases
congenita between 5 and 15 yr of age with AD inheritance
Fanconi Steroid-responsive hypoplastic anemia, AR, multiple genes: complementation; group A
syndrome reticulocytopenia, some macrocytic 16q24.3; group B Xp22.3; group C 9q22.3;
RBCs, shortened RBC life span group D2 3p25.3; group E 6p22-p21; group F
Cells are hypersensitive to DNA cross- 11p15; group G 9p13
linking agents.
Osler Hemorrhagic anemia AD, 9q34.1
hemorrhagic
telangiectasia
syndrome
Osteopetrosis Hypoplastic anemia from marrow AR, 16p13, 11q13.4-q13.5; AD, 1p21; lethal,
compression; extramedullary erythropoiesis reduced levels of osteoclasts
Pearson Hypoplastic sideroblastic anemia, marrow Pleioplasmatic rearrangement of mitochondrial
syndrome cell vacuolization DNA; X-linked or AR
Peutz-Jeghers Iron-deficiency anemia from chronic blood AD, 19p13.3
syndrome loss
ATR-X and ATR-X: hypochromic, microcytic ATR-16, 16p13.3, deletions of α-globin locus
ATR-16 anemia; mild form of hemoglobin H
syndromes disease
ATR-16: more significant hemoglobin
H disease and anemia are present.
AD, Autosomal dominant; AR, autosomal recessive; ATR-16, chromosome 16–related α-
thalassemia/mental retardation; ATR-X, X-linked α-thalassemia/mental retardation; RBC, red
blood cell.
From Christensen RD: Neonatal erythrocyte disorders. In Gleason CA, Juul SE, editors: Avery's
diseases of the newborn, ed 10, Philadelphia, 2018, Elsevier (Table 81-2).

Review of the peripheral blood smear is an essential component of the

evaluation of neonatal anemia. The presence of reticulocytes and nucleated red
blood cells (RBCs) indicate chronic anemia with compensatory active
erythropoiesis, while distinct erythrocyte morphologies (e.g., elliptocytes,
acanthocytes) suggest a congenital intrinsic hemolytic anemia. The presence of
spherocytes (often microspherocytes ) is consistent with immune-mediated
hemolysis but can also indicate hereditary spherocytosis ; the direct
antiglobulin test (DAT, formerly the direct Coombs test) is needed to distinguish
these 2 important diagnoses (Fig. 124.6 ). Neonatal blood smears often include
atypical erythrocyte morphology with macrocytosis, poikilocytosis, and
anisocytosis that reflect normal fetal erythropoiesis, and an experienced
hematologist or pathologist may be required to identify a pathologic feature
(Table 124.3 ) (see Chapter 474 ).

FIG. 124.6 Microspherocytes. Left, Neonate with ABO hemolytic disease. Right,
Neonate with hereditary spherocytosis (right ). (From Christensen RD: Neonatal
erythrocyte disorders. In Gleason CA, Juul SE, editors: Avery's diseases of the
newborn, ed 10, Philadelphia, 2018, Elsevier, Fig 81-8.)

Table 124.3
Morphologic Abnormalities of Erythrocytes From Neonates
With Jaundice

ABNORMAL MOST SUGGESTED

ERYTHROCYTE LIKELY LABORATORY OTHER FEATURES
MORPHOLOGY CAUSES TESTING/FINDINGS
Microspherocytes Hereditary DAT (−) MCHC/MCV elevated (>36, likely >40)
spherocytosis EMA flow (+)
Persistent
spherocytosis
Reticulocytosis
ABO DAT (+) MCHC/MCV normal (<36, likely <34)
hemolytic Transient
disease spherocytosis
Reticulocytosis
Elliptocytes Hereditary DAT (−) MCHC normal
elliptocytosis MCV normal
Bite and blister G6PD G6PD enzyme activity Typically affects males, but rarely females are
cells deficiency also affected
Unstable Heinz body preparation Ethnicity of equatorial origin
hemoglobin
Echinocytes PK PK enzyme activity Autosomal recessive, likely to have no family
deficiency history
Other Quantify activity of
 glycolytic other glycolytic
enzyme enzymes
deficiency
Schistocytes DIC Low levels of FV Low or falling platelet count
and/or and FVIII, elevated Normal to high IPF
perinatal levels of D-dimers Normal to high MPV DIC, perinatal asphyxia
asphyxia Positive result of ADAMTS-13 deficiency, early neonatal HUS,
Heinz Heinz body and giant hemangiomas all involve platelet
body preparation consumption from endothelial injury and all
HA have a similar neonatal presentation
ADAMTS- Severely decreased
13 deficiency ADAMTS-13 activity
(TTP) (<0.1 U/mL) high
levels of LDH
Neonatal Acute renal failure
hemolytic-
uremic
syndrome
Homozygous Severely decreased
protein C functional protein C
deficiency activity (<1%)
Giant May be internal or
hemangioma external
DAT, Direct antiglobulin test; DIC, disseminated intravascular coagulation; EMA, eosin 5-
maleimide; FV, factor V; FVIII, factor VIII; G6PD, glucose-6-phosphate dehydrogenase; HA,
hemolytic anemia; HUS, hemolytic uremic syndrome; IPF, immature platelet fraction; LDH, lactic
dehydrogenase; MCHC, mean corpuscular hemoglobin concentration; MCV, mean corpuscular
volume; MPV, mean platelet volume; PK, pyruvate kinase; TTP, thrombotic thrombocytopenic
purpura.
From Christensen RD, Yaish HM: Hemolytic disorders causing severe neonatal
hyperbilirubinemia, Clin Perinatol 42:515–527, 2015 (Table 3).

Red Blood Cell Loss

Blood loss is the most common cause of neonatal anemia. Repeated or frequent
phlebotomy for routine laboratory tests, especially from premature or acutely ill
neonates, is one of the most common causes of anemia. Several reports have
documented large volumes of blood removed for laboratory testing among
children in neonatal intensive care units (NICUs), with weekly phlebotomy
volumes ranging from 15–30% of the infant's total blood volume (11-22
mL/kg/wk). Most other causes of blood loss occur just before or during delivery,
such as placental abruption, and fetal hemorrhage is more common in emergent
or traumatic deliveries (see Table 124.1 ).
Fetomaternal hemorrhage (FMH) is caused by bleeding from the fetal into
the maternal circulation, either before or during delivery. Such bleeding occurs
to some extent in most pregnancies, although the volume lost is typically small.
Treatment Options for Neonatal Anemia
Packed Red Blood Cell Transfusions
Treatment of neonatal anemia by blood transfusion depends on the severity of
symptoms, the hemoglobin concentration, and the presence of comorbidities
(e.g., bronchopulmonary dysplasia, cyanotic congenital heart disease, respiratory
distress syndrome) that interfere with oxygen delivery. The benefits of blood
transfusion should be balanced against its risks, which include hemolytic and
nonhemolytic reactions; exposure to blood product preservatives and toxins;
volume overload; possible increased risk of retinopathy of prematurity and
necrotizing enterocolitis; graft-versus-host reaction; and transfusion-acquired
infections such as cytomegalovirus (CMV), HIV, parvovirus, and hepatitis B and
C (see Chapter 501 ). The frequency of transfusion for neonates in the NICU is
high, particularly among premature and very-low-birthweight (VLBW) infants.
Few studies have evaluated the efficacy or safety of specific
hemoglobin/hematocrit thresholds, but a Cochrane review summarized the
available evidence and proposed guidelines for transfusion of VLBW infants.
The review identified 4 trials comparing restrictive (lower) to liberal (higher)
hemoglobin thresholds. There were no statistically significant differences in
death or serious morbidity, and the restrictive thresholds modestly reduced
exposure to blood products. Evidence was inconclusive, however, regarding the
effectiveness of either threshold in optimizing long-term neurocognitive
outcomes. The proposed guideline for the transfusion of neonates was based
primarily on postnatal age and the presence or absence of respiratory support
(Table 124.4 ). In addition to these factors, transfusion should be considered for
infants with acute blood loss (>20%) or significant hemolysis, as well as before
surgery. With no similar evidence-based guidelines for term infants, transfusion
should be based on hemodynamic stability, respiratory status, overall clinical
condition, and laboratory values.

Table 124.4
Suggested Transfusion Thresholds

PRESENCE OF RESPIRATORY ABSENCE OF RESPIRATORY

POSTNATAL
SUPPORT SUPPORT
AGE
Hemoglobin Concentration, g/dL (Hematocrit %)
Week 1 11.5 (35%) 10.0 (30%)
 Week 2 10.0 (30%) 8.5 (25%)
Week 3 8.5 (25%) 7.5 (23%)

When the decision to transfuse has been made, the appropriate blood product
should be selected and a safe volume of blood should be transfused at a safe rate.
It is important to transfuse packed erythrocytes (PRBCs) to all neonates in the
form of leukocyte-reduced or CMV-seronegative PRBCs, to reduce the risk of
CMV transmission. Irradiation of PRBCs removes the risk of transfusion-
associated graft-versus-host disease (GVHD) but does not eliminate the risk of
CMV transmission. The volume of transfusion should achieve the intended
therapeutic goal while limiting blood product exposure. Typical transfusion
protocols choose a transfusion volume ranging from 10-20 mL/kg. There are no
clear data to favor a specific amount, but lower volumes exposure infants to risks
unnecessarily while higher volumes may cause fluid overload. One logical goal
is to target a specific goal hemoglobin (Hb) concentration. The following
commonly used shorthand equation can provide a good estimate of required
blood volume, which usually results in a transfusion volume within the 10-20
mL/kg range:

Transfusion of PRBCs is typically delivered at a rate of 3-5 mL/kg/hr, with a

slower rate preferred for very small, acutely ill infants with a tenuous fluid
status. Each transfusion should be completed within 4 hours.

Erythropoietin
Because of the low physiologic levels of erythropoietin in neonates, the role of
recombinant human erythropoietin (rhEPO ) has been investigated for the
treatment of anemia in neonates, particularly VLBW infants. A Cochrane review
documented that rhEPO is associated with a significant reduction in the number
of blood transfusions per infant, but also a significantly increased risk of
retinopathy of prematurity. There were no differences in mortality or other
neonatal morbidities among infants who did or did not receive rhEPO. Because
of these limited benefits and potential serious risks of early rhEPO therapy, there
is currently no strong indication for the routine use of rhEPO in infants with
anemia, although it should be considered in individual settings.
anemia is difficult to predict based on previous obstetric history, amniotic fluid
bilirubin determinants, or maternal antibody titer. Kell-alloimmunized infants
often have inappropriately low numbers of circulating reticulocytes caused by
erythroid suppression, and even low maternal titers of anti-Kell antibodies may
cause significant hypoproliferative anemia. Table 124.5 summarizes the clinical
characteristics of hemolytic disease caused by Rh, ABO, and Kell antigen
systems. There are no specific pharmacologic therapies available to prevent
sensitization caused by any blood group other than RhD. As with cases of Rh
and ABO incompatibility, exchange transfusion may be indicated for severe
hyperbilirubinemia or severe anemia in infants with HDFN caused by minor
antigen incompatibility.

Table 124.5
Hemolytic Disease of the Fetus and Newborn

Rh ABO KELL
BLOOD GROUPS
Mother Rh-negative O (occasionally B) K1-negative
Infant Rh-positive (D is most A (sometimes B) K1-positive
common)
CLINICAL FEATURES
Occurrence in 5% 40–50% Rare
firstborn
Severity in Predictable Difficult to predict Somewhat predictable
subsequent
pregnancies:
Stillbirth/hydrops Frequent (less with Rare 10%
Rh-immunoglobulin
use)
Severe anemia Frequent Rare Frequent
Jaundice Prominent, severe Mild-moderate Mild
LABORATORY TESTS
Direct Positive Positive or negative Positive or negative
antiglobulin test
(infant)
Reticulocyte Elevated Elevated Variable
count
Red blood cell Usually detectable May not be Usually detectable
(RBC) antibodies Antibody titers detectable Antibody titers may not correlate with fetal
(mother) may help predict Antibody titers disease; fetus can be affected at titers lower
severity of fetal may not than for Rh-mediated hemolysis.
disease. correlate with
fetal disease.
necessary for its full coagulation effects. In the absence of carboxylation, such
factors form PIVKA (proteins induced in vitamin K absence), which have
greatly reduced function; these can be measured and represent a sensitive marker
for vitamin K status. In contrast, factors V and VIII, fibrinogen, bleeding time,
clot retraction, and platelet count and function are normal for maturity.
Classically, vitamin K deficiency bleeding occurs early in the newborn period,
typically between day 2 and 7 of life, and most often in exclusively
breastfeeding infants who did not receive vitamin K prophylaxis at birth. Severe
vitamin K deficiency is also more common in premature infants. This
pathogenesis occurs from a lack of free vitamin K from the mother, coupled with
absence of bacterial intestinal flora normally responsible for the synthesis of
vitamin K. Breast milk is a poor source of vitamin K, which explains why
hemorrhagic complications are more frequent in exclusively breastfed than in
mixed-fed or formula-fed infants. This classic form of hemorrhagic disease of
the newborn, which is responsive to (and entirely prevented by) exogenous
vitamin K therapy, should be distinguished from rare congenital deficiencies of
clotting factors that are unresponsive to vitamin K, which can occur in otherwise
well-appearing infants (see Chapter 503 ).
Early-onset vitamin K deficiency bleeding (after birth but in 1st 24 hr) occurs
if the mother has been treated chronically with certain drugs (e.g., anticoagulant
warfarin, anticonvulsant phenytoin or phenobarbital, cholesterol-lowering
medication) that interfere with vitamin K absorption or function. These infants
can have severe bleeding, which is usually corrected promptly by vitamin K
administration, although some have a poor or delayed response. If a mother is
known to be receiving such drugs late in gestation, an infant PT should be
measured using cord blood, and the infant immediately given 1-2 mg of vitamin
K intravenously. If PT is greatly prolonged and fails to improve, or in the
presence of significant hemorrhage, 10-15 mL/kg of fresh-frozen plasma should
be administered. In contrast, late-onset vitamin K deficiency bleeding (after 2
wk of life) is usually associated with conditions that feature malabsorption of the
fat-soluble vitamin K, such as cystic fibrosis, neonatal hepatitis, or biliary
atresia, and bleeding can be severe (Table 124.6 ).

Table 124.6
Vitamin K Deficiency Bleeding (Hemorrhagic Disease of the
Newborn)
 CLASSIC
EARLY-ONSET DISEASE LATE-ONSET DISEASE
DISEASE
Age 0-24 hr 2-7 days 1-6 mo
Potential sites Cephalohematoma Gastrointestinal Intracranial
of Subgaleal Ear-nose-throat- Gastrointestinal
hemorrhage mucosal
Intracranial Intracranial Cutaneous
Gastrointestinal Post-circumcision Ear-nose-throat-mucosal
Umbilicus Cutaneous Injection sites
Intraabdominal Injection sites Thoracic
Etiology/risks Maternal drugs (phenobarbital, phenytoin, Vitamin K Cholestasis: malabsorption of
warfarin, rifampin, isoniazid) that interfere deficiency vitamin K (biliary atresia, cystic
with vitamin K levels or absorption Exclusive fibrosis, hepatitis)
breastfeeding
Inherited coagulopathy Abetalipoprotein deficiency
Idiopathic in Asian breastfed
infants
Warfarin ingestion
Prevention Avoidance of high-risk medications Prevented by Prevented by parenteral and
Possibly antenatal vitamin K to parenteral high-dose oral vitamin K during
treatment of mother (20 mg) before vitamin K at periods of malabsorption or
birth and postnatal administration to birth cholestasis
infant soon after birth Oral vitamin
K regimens
require
repeated
dosing.
Incidence Very rare ~2% if infant not Dependent on primary disease
given vitamin K
soon after birth

Intramuscular (IM) administration of 1 mg of vitamin K (typically

phytonadione , or vitamin K1 , the only form of vitamin K available in the
United States) soon after birth prevents the pathologic decrease in vitamin K–
dependent factors in full-term infants. However, such vitamin K prophylaxis is
not uniformly effective to prevent all hemorrhagic disease of the newborn,
particularly in exclusively breastfed and premature infants. When an infant
presents with hemorrhage, a slow IV infusion of 1-5 mg of vitamin K1 is
effective treatment and leads to improvement in coagulation defects and
cessation of bleeding within a few hours. Serious bleeding, particularly in
premature infants or those with liver disease, may require transfusion of fresh-
frozen plasma or even whole blood. With prompt recognition and treatment, the
mortality rate is low.
Decades of experience have demonstrated that the routine use of IM vitamin
K for prophylaxis in the United States is safe, and specifically is not associated
with an increased risk of childhood cancer or leukemia. Although multiple doses
of oral vitamin K (1-2 mg at birth, again at discharge, and again at 3-4 wk of

FIG. 124.8 Hydrops fetalis. Longitudinal sonographic image of the fetus, with ascitic
fluid outlining the liver (large arrow). The small arrow shows pleural effusion above the
diaphragm. (From Wilkins I: Nonimmune hydrops. In Creasy RK, Resnick R, Iams JD, et
al, editors: Creasy & Resnik's maternal-fetal medicine, ed 7, Philadelphia, 2014,
Elsevier, Fig 37-2.)

The incidence of nonimmune hydrops is approximately 1 in 3,000 births,

many of whom are premature. The etiologies are broad; cardiac (structural and
SVT) and chromosome disorders are the most common identifiable etiologies
(Table 124.7 ). The etiology is unknown in 10–20%. The mechanisms for the
development of nonimmune hydrops are not well established (Fig. 124.9 ).

Table 124.7
Conditions Associated With Nonimmune Hydrops
CARDIOVASCULAR HEMATOLOGIC
Malformation α-Thalassemia
Left heart hypoplasia Fetomaternal transfusion
Atrioventricular canal defect Parvovirus B19 infection
Right heart hypoplasia In utero hemorrhage
Closure of foramen ovale G6PD deficiency
Single ventricle Red cell enzyme deficiencies
Transposition of the great vessels THORACIC
Ventral septal defect Congenital cystic adenomatoid malformation of lung
Atrial septal defect Diaphragmatic hernia
Tetralogy of Fallot Intrathoracic mass
Ebstein anomaly Pulmonary sequestration
Premature closure of ductus Chylothorax
Truncus arteriosus Airway obstruction
Tachyarrhythmia Pulmonary lymphangiectasia
Atrial flutter Pulmonary neoplasia
Paroxysmal atrial tachycardia Bronchogenic cyst
Wolff-Parkinson-White syndrome INFECTIONS
Supraventricular tachycardia
 Bradyarrhythmia Cytomegalovirus
Other arrhythmias Toxoplasmosis
High-output failure Parvovirus B19 (fifth disease)
Neuroblastoma Syphilis
Sacrococcygeal teratoma Herpes
Large fetal angioma Rubella
Placental chorioangioma MALFORMATION SEQUENCES
Umbilical cord hemangioma Noonan syndrome
Cardiac rhabdomyoma Arthrogryposis
Other cardiac neoplasia Multiple pterygia
Cardiomyopathy Neu-Laxova syndrome
CHROMOSOMAL Pena-Shokeir syndrome
45,X Myotonic dystrophy
Trisomy 21 Saldino-Noonan syndrome
Trisomy 18 METABOLIC
Trisomy 13 Gaucher disease
18q+ GM1 gangliosidosis
13q− Sialidosis
45,X/46,XX Mucopolysaccharide disorders
Triploidy
URINARY
Other
Urethral stenosis or atresia
CHONDRODYSPLASIAS
Posterior urethral valves
Thanatophoric dwarfism
Congenital nephrosis (Finnish)
Short rib polydactyly
Prune-belly syndrome
Hypophosphatasia
GASTROINTESTINAL
Osteogenesis imperfecta
Achondrogenesis Midgut volvulus
TWIN PREGNANCY Malrotation of the intestines
Twin-twin transfusion syndrome Duplication of the intestinal tract
Acardiac twin Meconium peritonitis
OTHER Hepatic fibrosis
Familial hemophagocytic lymphohistiocytosis Cholestasis
Fetal akinesia syndromes Biliary atresia
Congenital leukemia Hepatic vascular malformations
Infantile arterial calcification syndrome
Maternal diabetes
Lymphatic disorders
IPEX
Idiopathic
IPEX, Immune dysregulation polyendocrinopathy enteropathy, X-linked.
Adapted from Wilkins I: Nonimmune hydrops. In Creasy RK, Resnick R, Iams JD, et al, editors:
Creasy & Resnik's maternal-fetal medicine, ed 7, Philadelphia, 2014, Elsevier (Box 37-1).
 FIG. 126.1 Neonatal abstinence score used for the assessment of infants displaying
neonatal abstinence syndrome. Evaluator should check sign or symptom observed at
various time intervals. Add scores for total at each evaluation. (Adapted from Finnegan
LP, Kaltenbach K. The assessment and management of neonatal abstinence syndrome.
In Hoekelman RA et al, editors: Primary pediatric care, ed 3, St Louis, 1992, Mosby, p
1367.)

Identifying which infants are at risk for NAS before discharge is important
because of the late onset of signs. Universal maternal screening for drug use is
recommended by the American College of Obstetricians and Gynecologists
(ACOG), and maternal consent should be obtained if drug testing is indicated.
Universal maternal drug testing has been shown to improve identification of
infants at risk for NAS but is more expensive and may not be helpful in states
with punitive legislation. Maternal testing is preferred over infant testing
because results are available promptly, typically by the time the infant is
delivered. Testing mothers on admission to the hospital can also exclude
iatrogenic exposure. Infant urine, meconium and umbilical cord testing are also
used to help identify infants at risk for withdrawal and identify more distant use
that can be given twice a day after loading doses, and a pharmacokinetic weight-
based weaning protocol is available. Sublingual buprenorphine has been
proposed as an alternate treatment. Buprenorphine and some methadone
formulations contain high ethanol levels, which may be deleterious to the infant.
Following a stringent NAS protocol with guidelines on initiation and weaning
has been shown to decrease both length of stay and number of opioid treatment
days and may be as important as which primary opioid is used for first-line
treatment.

Table 126.1
Medications Used in Pharmacologic Treatment of Neonatal
Abstinence Syndrome (NAS)
ADD
INITIAL DOSING
DRUG WEANING SCHEDULE ADJUVANT
DOSING INCREASES
THERAPY
Morphine 0.05 mg/kg/dose Increase dose 10– 10% of stabilizing dose q24h >1
q3h 20% mg/kg/day of
morphine
Unable to
wean for 2
days
Methadone 0.1 mg/kg/dose Increase to q4h if 0.7 mg/kg/dose q12h × 2 doses, Unable to wean
q6h for 4 doses unable to capture then 0.05 mg/kg/dose q12h × 2; for 2 days
0.04 mg/kg/dose q12h × 2;
0.03 mg/kg/dose q12h × 2;
0.02 mg/kg/dose q12h × 2;
0.01 mg/kg/dose q12h × 2;
0.01 mg/kg/dose q24h × 1
Buprenorphine 4 µg/kg q8h 2 µg/kg until 3 µg/kg/dose q8h × 3 doses; Unable to wean
maximum of 15 2 µg/kg/dose q8h × 3; for 2 days
µg/kg 2 µg/kg/dose q8h × 2;
2 µg/kg/dose q24h × 1
Phenobarbital 20 mg/kg — 5 mg/kg daily N/A
Clonidine 1.5 µg/kg/dose 25% dose 10% every day N/A
q3h escalation q24hr
N/A, Not available; q24h, every 24 hours.

Adjuvant therapy is initiated when the primary opioid is not effective in

controlling the signs of NAS. The 2 most common medications used as adjuvant
therapy are phenobarbital and clonidine . Infants with NAS may also expend
additional energy. Therefore, the infant should be weighted regularly and
strategies to increase caloric intake implemented if weight loss beyond that
expected in the 1st week of life occurs.
absence of a confirmed maternal history of PAE. The key facial dysmorphologic
features include short palpebral fissures, a thin vermilion border of the upper lip,
and a smooth philtrum (Fig. 126.2 ). The differential diagnosis for FAS includes
Williams syndrome, Dubowitz syndrome, fetal valproate syndrome, maternal
phenylketonuria (PKU) effects, and other prenatal toxin exposures, and when
there is unconfirmed PAE, a genetics evaluation may be warranted. ND-PAE is
included in the DSM-5 as a “condition for further study” and is also provided as
an example under “Other Specified Neurodevelopmental Disorder.” Although
the diagnosis of ND-PAE overlaps with ARND , ND-PAE aims to describe the
behavioral and mental health effects on an individual with PAE. Unlike ARND,
a diagnosis of ND-PAE can be given in addition to FAS or pFAS. ND-PAE has
organized the deficits seen into 3 areas: neurocognitive impairment, impaired
self-regulation, and impairment in adaptive functioning. In the updated Canadian
guidelines, “fetal alcohol spectrum disorder” is considered a diagnostic term
with 2 categories: FASD with sentinel facial features and FASD without sentinel
facial features. These guidelines have also eliminated growth restriction as a
diagnostic criterion and have included an at-risk category for children with
confirmed PAE who were too young to meet the criteria for neurodevelopmental
deficits, or in whom assessment was incomplete, and for children with cardinal
facial features without documentation or evidence of severe impairment in
neurodevelopmental domains.

Table 126.2
Diagnostic Features of Fetal Alcohol Spectrum Disorders
(FASDs)

DEFICIENT BRAIN
GROWTH,
FACIAL ABNORMAL NEUROBEHAVIORAL
TYPE OF FASD GROWTH
DYSMORPHOLOGY MORPHOGENESIS, FEATURES
OR ABNORMAL
NEUROPHYSIOLOGY
Fetal alcohol ≥2 of the Height OR Head circumference With cognitive
syndrome (FAS) following: and/or ≤10th centile impairment:
Short palpebral weight Structural brain Evidence of global
fissures (≤10th ≤10th anomalies impairment (general
centile) centile Recurrent nonfebrile conceptual ability
Thin vermilion seizures ≥1.5 SD below the
border of upper lip mean
Smooth philtrum or
Cognitive deficit in
at least 2
 neurobehavioral
domains ≥1.5 SD
below the mean
With behavioral
impairment without
cognitive
impairment:
Evidence of
behavioral deficit in
at least 2 domains
≥1.5 SD below the
mean
Partial FAS (pFAS) ≥2 of the Height OR Head circumference With cognitive
following: and/or ≤10th centile impairment:
Short palpebral weight Structural brain Evidence of global
fissures (≤10th ≤10th anomalies impairment (general
centile) centile Recurrent nonfebrile conceptual ability
Thin vermilion seizures ≥1.5 SD below the
border of upper lip mean
Smooth philtrum or
Cognitive deficit in
at least 2
neurobehavioral
domains ≥1.5 SD
below the mean
With behavioral
impairment without
cognitive
impairment:
Evidence of
behavioral deficit in
at least 2 domains
≥1.5 SD below the
mean
Alcohol-related — — — With cognitive
neurodevelopmental impairment:
disorder (ARND) Evidence of global
impairment (general
conceptual ability
≥1.5 SD below the
mean
or
Cognitive deficit in
at least 2
neurobehavioral
domains ≥1.5 SD
below the mean
With behavioral
impairment without
cognitive
impairment:
Evidence of
behavioral deficit in
at least 2 domains
≥1.5 SD below the
mean
Alcohol-related — — One or more specific —
birth defect major malformations
(ARBD) demonstrated in animal
models and human
studies to be the result of
prenatal alcohol exposure
Neurobehavioral — — — Neurocognitive
disorder associated impairment (1)
with prenatal Global intellect
alcohol exposure Executive
(ND-PAE) functioning
Learning
Memory
Visual-spatial
reasoning
Impaired self-
regulation (1)
Mood or behavior
Attention
Impulse control
Impairments in
adaptive
functioning (2)
Language
Social
communication and
interaction
Daily living skills
Motor skills

* Documented prenatal alcohol exposure:

≥6 drinks/wk for ≥2 wk during pregnancy.
≥3 drinks per occasion on ≥2 occasions during
pregnancy.
Documentation of alcohol-related social or legal
problems in proximity to (before or during) the
index pregnancy (e.g., driving while intoxicated or
history of treatment of an alcohol-related condition).
Documentation of intoxication during pregnancy by
blood, breath, or urine alcohol content testing.
Increased prenatal risk associated with drinking during
pregnancy as assessed by a validated screening tool.
 FIG. 127.2 Large, plump, plethoric infant of a mother with gestational diabetes. The
baby was born at 38 wk of gestation but weighed 9 lb, 11 oz (4,408 g). Mild respiratory
distress was the only symptom other than appearance.

Table 127.1
Morbidity in Infants of Diabetic Mothers
• Congenital anomalies
• Heart failure and septal hypertrophy of heart
• Surfactant deficiency, respiratory distress syndrome, transient tachypnea of the newborn, persistent pulmonary
hypertension
• Hyperbilirubinemia
• Hypoglycemia, hypocalcemia, hypomagnesemia
• Macrosomia, nerve injury related to birth trauma
• Renal vein thrombosis
• Small left colon
• Unexplained intrauterine demise
• Polycythemia
• Visceromegaly
• Predisposition to later-life obesity, insulin resistance, and diabetes
From Devaskar SU, Garg M: Disorders of carbohydrate metabolism in the neonate. In Martin RJ,
Fanaroff AA, Walsh MC, editors: Fanaroff & Martin's neonatal-perinatal medicine, ed 10,
Philadelphia, 2015, Elsevier (Box 95-3).

Hypoglycemia develops in approximately 25–50% of infants of mothers with

pregestational diabetes and 15–25% of infants of mothers with gestational
diabetes, but only a small percentage of these infants become symptomatic. The
probability that hypoglycemia will develop in such infants increases with higher
cord or maternal fasting blood glucose levels. The nadir in an infant's blood
glucose concentration is usually reached between 1 and 3 hr of age.
Hypoglycemia can persist for 72 hr and in rare cases last up to 7 days. Frequent
feedings can be used to treat the hypoglycemia, but some infants require
intravenous (IV) dextrose.
The infants tend to be jittery, tremulous, and hyperexcitable during the 1st 3
days after birth, although hypotonia, lethargy, and poor sucking may also occur.
Early appearance of these signs is more likely to be related to hypoglycemia but
can also be caused by hypocalcemia and hypomagnesemia, which also occur in
the 1st 24-72 hr of life due to delayed response of the parathormone system.
Perinatal asphyxia is associated with increased irritability and also increases the
risk of hypoglycemia, hypomagnesemia, and hypocalcemia.
Tachypnea develops in many IDMs during the 1st 2 days after birth and may
be a manifestation of hypoglycemia, hypothermia, polycythemia, cardiac failure,
formed normally before the insult.

Table 128.1

Mechanisms, Terminology, and Definitions of Dysmorphology

TERMINOLOGY DEFINITION EXAMPLE
Sequence Single error in Pierre-Robin sequence, in which a small jaw results in
morphogenesis that results glossoptosis and cleft palate
in a series of subsequent DiGeorge sequence of primary 4th brachial arch and 3rd
defects and 4th pharyngeal pouch defects, leading to aplasia or
hypoplasia of the thymus and parathyroid glands, aortic
arch anomalies, and micrognathia
Deformation Mechanical (uterine) force Oligohydramnios produces deformations by in utero
sequence that alters structure of compression of limbs (e.g., dislocated hips, equinovarus foot
intrinsically normal tissue deformity), crumpled ears, or small thorax
Disruption In utero tissue destruction Amnionic membrane rupture sequence, leading to amputation
sequence after a period of normal of fingers/toes, tissue fibrosis, and tissue bands
morphogenesis
Dysplasia sequence Atypical organization of Neurocutaneous melanosis sequence, with atypical migration
cells into tissues or organsof melanocyte precursor cells from the neural crest to the
periphery, manifesting as melanocytic hamartomas of skin and
meninges
Malformation Appearance of multiple Trisomy 21
syndrome malformations in unrelated Teratogens
tissues that have a known, Numerous multiple congenital anomaly syndromes as
unifying cause described above
From Kliegman RM, Greenbaum LA, Lye PS: Practical strategies in pediatric diagnosis and
therapy , ed 2, Philadelphia, 2004, Elsevier Saunders.

FIG. 128.1 Four major types of problems in morphogenesis: malformation,

deformation, disruption, and dysplasia. A, Infant with camptomelic dysplasia syndrome,
which results in a multiple malformation syndrome caused by a mutation in SOX9 . B,
Infant with oligohydramnios deformation sequence caused by premature rupture of
membranes from 17 wk gestation until birth at 36 wk; the infant was delivered from
 persistent transverse lie. C, Fetus with early amnion rupture sequence with attachment
of the placenta to the head and resultant disruption of craniofacial structures with
distal limb contractures. D, Infant with diastrophic dysplasia caused by inherited
autosomal recessive mutations in a sulfate transporter protein. (From Graham Jr JM:
Smith's recognizable patterns of human deformation, ed 3, Philadelphia, 2007,
Saunders, Fig 1-1, p 4.)

Most inherited human disorders with altered morphogenesis display multiple

malformations rather than isolated birth defects. When several malformations
coexist in a single individual, they can be classified as a syndrome, sequence, or
an association. A syndrome is defined as a pattern of multiple abnormalities that
are related by pathophysiology, resulting from a single, defined etiology.
Sequences consist of multiple malformations that are caused by a single event,
although the sequence itself can have different etiologies. An association refers
to a nonrandom grouping of malformations in which there is an unclear, or
unknown, relationship among the malformations, such that they do not fit the
criteria for a syndrome or sequence.

Malformations and Dysplasias

Human malformations and dysplasias can be caused by gene mutations,
chromosome aberrations and copy number variants, environmental factors, or
interactions between genetic and environmental factors (Table 128.2 ). Some
malformations are caused by deleterious sequence variants in single genes,
whereas other malformations arise because of deleterious sequence variants in
multiple genes acting in combination (digenic or oligogenic inheritance). In
1996 it was thought that malformations were caused by monogenic defects in
7.5% of patients; chromosomal anomalies in 6%; multigenic defects in 20%; and
known environmental factors, such as maternal diseases, infections, and
teratogens, in 6–7% (Table 128.3 ). In the remaining 60–70% of patients,
malformations were classified as caused by unknown etiologies. Currently, the
percentages have increased for all categories of known causes of malformations,
the result of improved cytogenetic and molecular genetic methods for detecting
small chromosomal abnormalities and next-generation sequencing studies that
can screen multiple genes simultaneously and identify novel genes and
deleterious sequence variants.

Table 128.2
Examples of Malformations with Distinct Causes, Clinical
Features, and Pathogenesis
SELECTED
DISORDER CAUSE/INHERITANCE CLINICAL PATHOGENESIS
FEATURES
Spondylocostal Mendelian; autosomal Abnormal vertebral Deleterious sequence variants in DLL3
dysostosis recessive and rib and other genes
syndrome segmentation
Rubinstein-Taybi Autosomal dominant Intellectual Deleterious sequence variants in CBP and
syndrome disability EP300
Broad thumbs
and halluces;
valgus
deviation of
these digits
Hypoplastic
maxillae
Prominent nose
and columella
Congenital
heart disease
X-linked X-linked Male: severe Deleterious sequence variants in DCX
lissencephaly intellectual
disability,
seizures
Female:
variable
Aniridia Autosomal dominant Absent iris or Deleterious sequence variants in PAX6
iris/foveal
hypoplasia
Waardenburg Autosomal dominant Deafness Deleterious sequence variants in PAX3
syndrome, type I White forelock
Wide-spaced
eyes
Iris
heterochromia
and/or pale skin
pigmentation
Holoprosencephaly Loss of function or Microcephaly SHH, multiple other genes
heterozygosity for Cyclopia
multiple genes Single central
incisor
Velocardiofacial Microdeletion Congenital heart TBX1 haploinsufficiency/mutations;
syndrome 22q11.2 disease, including haploinsufficiency for other genes in the
conotruncal defects deleted interval also contributes to the
Cleft palate phenotype.
T-cell defects
Facial anomalies
Down syndrome Additional copy of Intellectual Increase in dosage of an estimated 250
chromosome 21 (trisomy disability genes on chromosome 21
21) Characteristic
dysmorphic features
Congenital heart
 disease
Increased risk of
leukemia
Alzheimer disease
Neural tube defects Multifactorial Meningomyelocele Defects in folate sensitive enzymes or
folic acid uptake
Fetal alcohol Teratogenic Microcephaly Ethanol toxicity to developing brain
syndrome Developmental
delay
Facial abnormalities
Behavioral
abnormalities
Retinoic acid Teratogenic Microtia Isotretinoin effects on neural crest and
embryopathy Congenital heart branchial arch development
disease

Table 128.3
Causes of Congenital Malformations
MONOGENIC
X-linked hydrocephalus
Achondroplasia
Ectodermal dysplasia
Apert syndrome
Treacher Collins syndrome
CHROMOSOMAL ABERRATIONS and COPY NUMBER VARIANTS
Trisomy 21, 18, 13
XO, XXY
Deletions 4p−, 5p−, 7q−, 13q−, 18p−, 18q−, 22q−
Prader-Willi syndrome (70% of affected patients have deletion of chromosome 15 q11.2-q13)
MATERNAL INFECTION
Intrauterine infections (e.g., herpes simplex virus, cytomegalovirus, varicella-zoster virus, rubella virus, Zika
virus, toxoplasmosis)
MATERNAL ILLNESS
Diabetes mellitus
Phenylketonuria
Hyperthermia
UTERINE ENVIRONMENT
Deformation
Uterine pressure, oligohydramnios: clubfoot, torticollis, congenital hip dislocation, pulmonary hypoplasia, 7th
nerve palsy
Disruption
Amniotic bands, congenital amputations, gastroschisis, porencephaly, intestinal atresia
Twinning
ENVIRONMENTAL AGENTS
Polychlorinated biphenyls
Herbicides
Mercury
Alcohol
MEDICATIONS
Thalidomide
 Diethylstilbestrol
Phenytoin
Warfarin
Cytotoxic drugs
Paroxetine
Angiotensin-converting enzyme inhibitors
Isotretinoin (vitamin A)
D -Penicillamine
Valproic acid
Mycophenolate mofetil
UNKNOWN ETIOLOGIES
Neural tube defects, such as anencephaly and spina bifida
Cleft lip/palate
Pyloric stenosis
SPORADIC SEQUENCE COMPLEXES
VATER/VACTERL sequence (vertebral defects, anal atresia, cardiac defects, tracheoesophageal fistula with
esophageal atresia, radial and renal anomalies)
Pierre Robin sequence
NUTRITIONAL
Neural tube defects due to low folic acid
From Behrman RE, Kliegman RM, editors: Nelson's essentials of pediatrics, ed 4, Philadelphia,
2002, Saunders.

Many developmental abnormalities that are caused by deleterious sequence

variants (mutations)in a single gene display characteristic, mendelian patterns of
inheritance (autosomal dominant, autosomal recessive, and X-linked
inheritance). Genes that cause birth defects or multiple congenital anomaly
syndromes are often transcription factors, part of evolutionarily conserved signal
transduction pathways, or regulatory proteins required for key developmental
events (Figs. 128.2 and 128.3 ). Examples include spondylocostal dysostosis
syndromes, Smith-Lemli-Opitz syndrome, Rubinstein-Taybi syndrome, and X-
linked lissencephaly (“smooth brain”) syndrome (see Table 128.2 ).
(Table 128.6 and Fig. 128.10 ). By cataloging physical parameters, the clinician
may be able to recognize the diagnosis.

Table 128.5

Definitions of Common Clinical Signs of Dysmorphic Syndromes

SIGN DEFINITION
Brachycephaly A condition in which head shape is shortened from front to back along the sagittal plane;
typically the back of the skull (occiput) and face are flatter than normal.

Brachydactyly Short digits.

Brushfield Speckled white spots or rings about two thirds of the distance to the periphery of the iris of the
spots eye.
Camptodactyly Permanent flexion of 1 or more fingers that can be associated with missing interphalangeal
crease.
Clinodactyly A medial or lateral curving of the fingers or toes; usually refers to incurving of the 5th finger.
Hypoplastic or A small nail on a digit.
small nail
Low-set ears This designation is made when the helix meets the cranium at a level below a horizontal plane
that is an extension of a line through both inner canthi.
Melia A suffix meaning “limb” (e.g., amelia—missing limb; brachymelia—short limb).
Ocular Increased distance between the center of the pupils of the 2 eyes; also known as increased
hypertelorism interpupillary distance (IPD).
or wide-set
eyes
Plagiocephaly A condition in which head shape is asymmetric in the sagittal or coronal plane; can result from
asymmetry in cranial suture closure, asymmetry of brain growth, or deformation of the skull.
Posterior hair A single hair whorl occurs to the right or left of midline and is within 2 cm anterior to the
whorl posterior fontanel in 95% of cases.
Postaxial Extra finger or toe present on the lateral side of the hand or foot.
polydactyly
Preaxial Extra finger or toe present on the medial side of the hand or foot.
polydactyly
Prominent Relative overgrowth of the lateral palatine ridges that can be caused by a deficit of tongue thrust
lateral palatine into the hard palate.
ridges
Scaphocephaly A condition in which the head is elongated from front to back in the sagittal plane; most normal
skulls are scaphocephalic; also termed dolichocephaly .
Shawl scrotum The scrotal skin joins around the superior aspect of the penis and represents a mild deficit in full
migration of the labial-scrotal folds.
Short palpebral Decreased horizontal distance of the eyelid folds based on measurements from the inner canthus
fissures to the outer canthus,
Syndactyly Incomplete separation of the fingers or toes. It most commonly occurs between the 3rd and 4th
fingers and between the 2nd and 3rd toes.
Synophrys Eyebrows that meet in the midline.
Telecanthus Lateral displacement of the inner canthi. The inner canthal distance (ICD) is increased, but the
interpupillary distance (IPD) is normal.
Widow's peak V -shaped midline, downward projection of the scalp hair in the frontal region. It represents an
upper forehead intersection of the bilateral fields of periocular hair growth suppression. It usually
occurs because the fields are widely spaced, as in ocular hypertelorism.
Table 128.6
Minor Anomalies and Phenotype Variants*
CRANIOFACIAL
Large anterior fontanel
Flat or low nasal bridge
Anteverted (upturned) nose
Mild micrognathia
Cutis aplasia of scalp
EYE
Epicanthus
Telecanthus
Slanting of the palpebral fissures
Hypertelorism (widely spaced eyes)
Brushfield spots
EAR
Lack of helical folds
Posteriorly rotated pinna
Small pinnae
Auricular or preauricular pit
Atypical folding of helices
Crushed (crumpled) ear
Asymmetric ear sizes
Low-set ears
SKIN
Skin dimpling over bones
Capillary hemangioma (face, posterior neck)
Dermal melanosis (African Americans, Asians)
Sacral dimple
Pigmented nevi
Redundant skin
Cutis marmorata
HAND
Single palmar creases
Bridged palmar creases
Clinodactyly of 5th digits
Hyperextensibility of thumbs
Mild partial cutaneous syndactyly
Polydactyly
Short, broad thumb
Narrow, hyperconvex nails
Small nails
Camptodactyly
Shortened 4th digit
FOOT
Partial syndactyly of 2nd and 3rd toes
Asymmetric toe length
Clinodactyly of 2nd toe
Overlapping toes
Small nails
Wide gap between hallux and 2nd toe (wide sandal gap)
Deep plantar crease between hallux and 2nd toe
 OTHER
Hydrocele
Shawl scrotum
Hypospadias
Hypoplasia of labia majora
* Approximately 15% of newborns have 1 minor anomaly, 0.8% have 2 minor anomalies, and

0.5% have 3. If 2 minor anomalies are present, the probability of an underlying syndrome or a
major anomaly (congenital heart disease, renal, central nervous system, limbic) is 5-fold that in
the general population. If 3 minor anomalies are present, there is a 20–30% probability of a major
anomaly.
From Kliegman RM, Greenbaum LA, Lye PS: Practical strategies in pediatric diagnosis and
therapy , ed 2, Philadelphia, 2004, Elsevier Saunders.

FIG. 128.10 Frequency of major malformations in relation to the number of
minor anomalies detected in a given newborn baby. (From Jones KJ:
Smith's recognizable patterns of human malformation, ed 6, Philadelphia,
2006, Saunders.)

Imaging Studies
Imaging studies can be critical in diagnosing an underlying genetic etiology. If
short stature or disproportionate stature (e.g., long trunk and short limbs) is
noted, a full skeletal survey with radiographs should be performed. The skeletal
survey can detect anomalies in bone number or structure that can be used to
narrow the differential diagnosis. When there are abnormal neurologic signs or
symptoms, such as microcephaly or hypotonia, brain imaging can be indicated.
Other studies, such as echocardiography and renal ultrasonography, can also be
useful to identify additional major or minor malformations that may serve as
diagnostic clues.
associated with birth defects and multiple congenital anomalies.

Table 128.7

Chromosomal Deletion Syndromes

CONDITION BRIEF DESCRIPTION PROBE
Williams syndrome Proportionate short stature, mild-moderate to severe intellectual disability, 7q11
“cocktail patter” for conversation, stellate pattern of iris pigmentation,
supravalvular aortic stenosis, recessed nasal bridge, and wide mouth with full
lips
WAGR syndrome Wilms tumor, aniridia, growth delay, intellectual disability, and genitourinary 11p13
anomalies
Prader-Willi Distinct syndromes with common or overlapping areas of deletion; 15q11
syndrome phenotype depends on gender of the parent of origin of the deletion.
Angelman Prader-Willi syndrome: hypotonia in infancy, short stature, obesity, mild-
syndrome moderate and occasionally severe intellectual disability, small hands and
feet (caused by paternal deletion of 15q11-13 or maternal uniparental
disomy for chromosome 15)
Angelman syndrome: severe intellectual disability, absence of speech,
ataxia, tremulous movements, large mouth, frequent drooling (caused by
maternal deletion of chromosome 15q11-13 or paternal uniparental
disomy)
Smith-Magenis Brachycephaly, prognathism, self-destructive behavior, wrist biting, pulling out 17p11.2
syndrome nails, head banging, indifference to pain, severe intellectual disability,
hyperactivity, social behavior problems
Miller-Dieker Microcephaly, narrow temples, hypotonia/hypertonia, abnormal posturing, 17p13
syndrome seizures, severe to profound intellectual disability, poor growth, lissencephaly
and other brain abnormalities on CT or MRI
Velocardiofacial VCF: cleft palate, congenital heart disease, learning/behavior problems, 22q11
(VCF) syndrome long face, prominent nose, limb hypotonia, slender hands with tapering
(overlaps with fingers
DiGeorge syndrome) DiGeorge syndrome: T-cell deficiency, immunoglobulin deficiency
CT, Computed tomography; MRI, magnetic resonance imaging; WAGR, Wilms tumor, aniridia,
genitourinary anomalies, and mental retardation.
From Kliegman RM, Lye PS, et al, editors: Nelson pediatric symptom-based diagnosis,
Philadelphia, 2018, Elsevier (Table 25-10).

Molecular testing for deleterious sequence variants that cause pleiotropic

malformation syndromes is also available for many disorders as clinical or
research testing. In most cases, however, such testing should not be performed
indiscriminately, but instead should be ordered thoughtfully after the differential
diagnosis has been considered. The introduction of next-generation sequencing
has led to the identification of innumerable novel genes and revolutionized the
testing that is now available for patients and families with intellectual disability,
birth defects, or other suspected genetic diseases. A strong suspicion of a genetic
diagnosis warrants consideration of testing to confirm the diagnosis, facilitate
Incidence and Epidemiology
Despite advances in maternal and neonatal care, infections remain a frequent and
important cause of neonatal and infant morbidity and mortality. Up to 10% of
infants have infections in the 1st mo of life. Newborn infection is more common
in areas with limited access to healthcare than in areas with well-established
healthcare infrastructure. The overall incidence of neonatal sepsis ranges from 1
to 5 cases per 1,000 live births. Estimated incidence rates vary based on the case
definition and the population studied. Globally, neonatal sepsis and other severe
infections were responsible for an estimated 430,000 neonatal deaths in 2013,
accounting for approximately 15% of all neonatal deaths.
A number of bacterial and nonbacterial agents may infect newborns in the
intrapartum or postpartum period (Table 129.1 ). Although herpes simplex virus
(HSV), human immunodeficiency virus (HIV), hepatitis B virus (HBV),
hepatitis C virus (HCV), and tuberculosis (TB) can each result in transplacental
infection, the most common mode of transmission for these agents is
intrapartum , during labor and delivery with passage through an infected birth
canal (HIV, HSV, HBV), or postpartum , from contact with an infected mother
or caretaker (TB) or with infected breast milk (HIV) (Fig. 129.2 and Table 129.2
). Any microorganism inhabiting the genitourinary or lower gastrointestinal tract
may cause intrapartum and postpartum infection. The most common bacteria are
group B streptococcus (GBS), Escherichia coli, and Klebsiella spp. Salmonella
spp. are common causes of gram-negative sepsis in developing countries; less
common causes of bacterial infection in the United States include Citrobacter ,
enterococci, gonococci, Listeria monocytogenes , Streptococcus pneumoniae,
and Haemophilus influenzae . The more common viruses are cytomegalovirus
(CMV), HSV, enteroviruses, and HIV (Table 129.2 ).

Table 129.1
Nonbacterial Causes of Systemic Neonatal Infections
VIRUSES
Adenovirus
Cytomegalovirus (CMV)
Enteroviruses
Parechoviruses
Hepatitis B and C viruses
Herpes simplex virus (HSV)
Human immunodeficiency virus (HIV)
Parvovirus
Rubella virus
Varicella-zoster virus (VZV)
MYCOPLASMA
Mycoplasma hominis
Ureaplasma urealyticum
FUNGI
Candida spp.
Malassezia spp.
PROTOZOA
Plasmodia
Toxoplasma gondii
Trypanosoma cruzi

FIG. 129.2 Relative importance of neonatal viral infections related to the timing of
acquisition of infection. Viruses are listed in declining order of importance relative to
prenatal, perinatal (intrapartum), and postnatal timing of typical infection. Some
neonatal virus infections (e.g., cytomegalovirus) can be substantial causes of disease
whether acquired during gestation or acquired postpartum, whereas others (e.g.,
respiratory syncytial virus) are typically acquired in the postnatal period. EBV, Epstein-
Barr virus; HHV, human herpesvirus; HIV, human immunodeficiency virus; HSV, herpes
simplex virus; LCMV, lymphocytic choriomeningitis virus. (From Schleiss MR, Marsh
KJ: Viral infections of the fetus and newborn. In Gleason CA, Juul SE, editors: Avery's
diseases of the newborn, ed 10, Philadelphia, 2018, Elsevier, Fig 37-1.)

Table 129.2
Period of Transmission of Selected Viruses to the Fetus or
Newborn Infant

VIRUSES CONGENITAL NATAL POSTNATAL

Adenovirus + + +
Chikungunya ++ + −
 Cytomegalovirus ++ ++ ++
Dengue ++ − −
Ebola virus ++ + +
Echoviruses + + +
Epstein-Barr + − +
Hepatitis A − ++ +
Hepatitis B + ++ +
Hepatitis C + ++ −
Herpes simplex + ++ +
Herpesvirus-6 + − +
Human immunodeficiency virus + ++ +
Human parvovirus B19 + − −
Influenza (+) − +
Lymphocytic choriomeningitis virus ++ − −
Measles + − +
Mumps + − −
Parechovirus − + +
Polioviruses + + +
Rubella ++ − −
Smallpox + + +
St. Louis encephalitis (+) − (+)
Type B coxsackieviruses + + +
Vaccinia + + +
Varicella-zoster virus ++ + +
West Nile virus + − +
Western equine encephalitis + − +
Zika virus ++ ? (+)
++ , Major demonstrated route; +, minor demonstrated route; (+), suggested route, few supporting
data; −, route not demonstrated.
From Harrison GJ: Approach to infections in the fetus and newborn. In Cherry JD, Demmler-
Harrison GJ, Kaplan SL, et al, editors: Feigin and Cherry's textbook of pediatric infectious
diseases, ed 7, Philadelphia, 2014, Elsevier (Table 66.1, p 878).

Microorganisms causing pneumonia acquired during labor and delivery

include GBS, gram-negative enteric aerobes, L. monocytogenes, genital
Mycoplasma, Chlamydia trachomatis, CMV, HSV, and Candida spp. (Table
129.3 ).

Table 129.3
Etiologic Agents of Neonatal Pneumonia According to
Timing of Acquisition
TRANSPLACENTAL
Cytomegalovirus (CMV)
Herpes simplex virus (HSV)
Mycobacterium tuberculosis
Rubella virus
 Treponema pallidum
Varicella-zoster virus (VZV)
Listeria monocytogenes
PERINATAL
Anaerobic bacteria
Chlamydia
CMV
Enteric bacteria
Group B streptococci
Haemophilus influenzae
HSV
Listeria monocytogenes
Mycoplasma
POSTNATAL
Adenovirus
Candida spp.*
Coagulase-negative staphylococci
CMV
Enteric bacteria*
Enteroviruses
Influenza viruses A, B
Parainfluenza
Pseudomonas *
Respiratory syncytial virus (RSV)
Staphylococcus aureus
Mycobacterium tuberculosis
Legionella
* More likely with mechanical ventilation or indwelling catheters, or after abdominal surgery.

The most common bacterial causes of neonatal meningitis are GBS, E. coli,
and L. monocytogenes. S. pneumoniae, other streptococci, nontypable H.
influenzae, both coagulase-positive and coagulase-negative staphylococci,
Klebsiella, Enterobacter, Pseudomonas, Treponema pallidum, and
Mycobacterium tuberculosis infection involving the central nervous system
(CNS) may also result in meningitis.

Early- and Late-Onset Neonatal Infections

The terms early-onset infection and late-onset infection refer to the different ages
at onset of infection in the neonatal period. Early-onset sepsis is defined as the
onset of symptoms before 7 days of age, although some experts limit the
definition to infections occurring within the 1st 72 hr of life. Late-onset sepsis is
generally defined as the onset of symptoms at ≥7 days of age. Similar to early-
onset sepsis, there is variability in the definition, ranging from an onset at >72 hr
of life to ≥7 days of age. Early-onset infections are acquired before or during
delivery (vertical mother-to-child transmission). Late-onset infections develop
after delivery from organisms acquired in the hospital or the community. The age
at onset depends on the timing of exposure and virulence of the infecting
organism. Very-late-onset infections (onset after age 1 mo) may also occur,
particularly in very-low-birthweight (VLBW) preterm infants or term infants
requiring prolonged neonatal intensive care.
The incidence of neonatal bacterial sepsis varies from 1-4 per 1,000 live
births, with geographic variation and changes over time. Studies suggest that
term male infants have a higher incidence of sepsis than term females. This sex
difference is less clear in preterm low-birthweight (LBW) infants. Attack rates of
neonatal sepsis increase significantly in LBW infants in the presence of maternal
chorioamnionitis, congenital immune defects, mutations of genes involved in the
innate immune system, asplenia, galactosemia (E. coli), and malformations
leading to high inocula of bacteria (e.g., obstructive uropathy).
Data from the Eunice Kennedy Shriver National Institute of Child Health and
Human Development (NICHD) Neonatal Research Network documented rates
of early-onset sepsis among almost 400,000 live births at Network centers. The
overall rate of early-onset sepsis was 0.98 cases per 1,000 live births, with rates
inversely related to birthweight: 401-1,500 g, 10.96 per 1,000 births; 1,501-
2,500 g, 1.38/1,000; and >2,500 g, 0.57/1,000 (Table 129.4 ).

Table 129.4
Rates of Early-Onset Sepsis Per 1,000 Live Births*

BIRTHWEIGHT (g)
401-1,500 1,501-2,500 >2,500 All
All 10.96 1.38 0.57 0.98
Group B streptococci 2.08 0.38 0.35 0.41
Escherichia coli 5.09 0.54 0.07 0.28
* NICHD Neonatal Research Network/CDC Surveillance Study of Early-Onset Sepsis.

Adapted from Stoll BJ, Hansen NI, Sanchez PJ, et al: Early onset neonatal sepsis: the burden of
group B streptococcal and E. coli disease continues, Pediatrics 127(5):817–826, 2011.

The incidence of meningitis is 0.2-0.4 per 1,000 live births in newborn infants
and is higher in preterm infants. Bacterial meningitis may be associated with
sepsis or may occur as a local meningeal infection. Up to one third of VLBW
infants with late-onset meningitis have negative blood culture results . The
discordance between results of blood and cerebrospinal fluid (CSF) cultures
suggests that meningitis may be underdiagnosed among VLBW infants and
emphasizes the need for culture of CSF in VLBW infants when late-onset sepsis
and obstetric risk factors (prematurity, prolonged ruptured membranes, maternal
chorioamnionitis). Signs and symptoms in the neonate are often subtle and
nonspecific. Temperature instability, tachypnea, lethargy, and poor feeding are
common initial signs and should raise suspicion for systemic or focal infection
(Table 129.5 ).

Table 129.5
Initial Signs and Symptoms of Infection in Newborn Infants
GENERAL
Fever, temperature instability
“Not doing well”
Poor feeding
Edema
GASTROINTESTINAL SYSTEM
Abdominal distention
Vomiting
Diarrhea
Hepatomegaly
RESPIRATORY SYSTEM
Apnea, dyspnea
Tachypnea, retractions
Flaring, grunting
Cyanosis
RENAL SYSTEM
Oliguria
CARDIOVASCULAR SYSTEM
Pallor; mottling; cold, clammy skin
Tachycardia
Hypotension
Bradycardia
CENTRAL NERVOUS SYSTEM
Irritability, lethargy
Tremors, seizures
Hyporeflexia, hypotonia
Abnormal Moro reflex
Irregular respirations
Full fontanel
High-pitched cry
HEMATOLOGIC SYSTEM
Jaundice
Splenomegaly
Pallor
Petechiae, purpura
Bleeding

Bacterial Sepsis
Neonates with bacterial sepsis may have either nonspecific manifestations or
focal signs of infection (Table 129.5 ), including temperature instability,
hypotension, poor perfusion with pallor and mottled skin, metabolic acidosis,
tachycardia or bradycardia, apnea, respiratory distress, grunting, cyanosis,
irritability, lethargy, seizures, feeding intolerance, abdominal distention,
jaundice, petechiae, purpura, and bleeding. Table 129.6 lists World Health
Organization international criteria for bacterial sepsis. The initial manifestation
may involve only limited symptomatology and only one system, such as apnea
alone or tachypnea with retractions, or tachycardia, or the infant may present
with an acute catastrophic manifestation with multiorgan dysfunction and shock.
Infants should be reevaluated over time to determine whether the symptoms
have progressed from mild to severe. Later complications of sepsis include
respiratory failure, pulmonary hypertension, cardiac failure, shock, renal failure,
liver dysfunction, cerebral edema or thrombosis, adrenal hemorrhage and/or
insufficiency, bone marrow dysfunction (neutropenia, thrombocytopenia,
anemia), and disseminated intravascular coagulopathy (DIC).

Table 129.6
Clinical Criteria for the Diagnosis of Sepsis in the
International Setting
IMCI AND WHO CRITERIA FOR SEVERE INFECTIONS IN CHILDREN
Neurologic: convulsions, drowsy or unconscious, decreased activity, bulging fontanel
Respiratory: respiratory rate >60 breaths/min, grunting, severe chest indrawing, central cyanosis
Cardiac: poor perfusion, rapid and weak pulse
Gastrointestinal: jaundice, poor feeding, abdominal distention
Dermatologic: skin pustules, periumbilical erythema or purulence
Musculoskeletal: edema or erythema overlying bones or joints
Other: temperature >37.7°C (99.9°F; or feels hot) or <35.5°C (95.9°F; or feels cold)
IMCI, Integrated Management of Childhood Illness; WHO, World Health Organization.
Adapted from WHO: Pocket book of hospital care for children: guidelines for the management of
common childhood illnesses, ed 2, Geneva, 2013, WHO, pp 45–69.
http://www.who.int/maternal_child_adolescent/documents/child_hospital_care/en/ .

A variety of noninfectious conditions can occur together with neonatal

infection or can make the diagnosis of infection more difficult. Respiratory
distress syndrome (RDS) secondary to surfactant deficiency can coexist with
bacterial pneumonia. Because bacterial sepsis can be rapidly progressive, the
physician must be alert to the signs and symptoms of possible infection and must
initiate diagnostic evaluation and empirical therapy in a timely manner. The
differential diagnosis of many of the signs and symptoms that suggest infection
is extensive; noninfectious disorders must also be considered (Table 129.7 ).

Table 129.7
Serious Systemic Illness in Newborns: Differential
Diagnosis of Neonatal Sepsis
CARDIAC
Congenital: hypoplastic left heart syndrome, other structural disease, persistent pulmonary hypertension of the
newborn (PPHN)
Acquired: myocarditis, hypovolemic or cardiogenic shock, PPHN
GASTROINTESTINAL
Necrotizing enterocolitis
Spontaneous gastrointestinal perforation
Midgut volvulus
Hepatic failure (inborn errors of metabolism, neonatal iron storage disease)
HEMATOLOGIC
Neonatal purpura fulminans
Immune-mediated thrombocytopenia
Immune-mediated neutropenia
Severe anemia
Malignancies (congenital leukemia)
Langerhans cell histiocytosis
Hereditary clotting disorders
Familial hemophagocytosis syndrome
METABOLIC
Hypoglycemia
Adrenal disorders: adrenal hemorrhage, adrenal insufficiency, congenital adrenal hyperplasia
Inborn errors of metabolism: organic acidurias, lactic acidoses, urea cycle disorders, galactosemia
NEUROLOGIC
Intracranial hemorrhage: spontaneous, caused by child abuse
Hypoxic-ischemic encephalopathy
Neonatal seizures
Infant botulism
RESPIRATORY
Respiratory distress syndrome
Aspiration pneumonia: amniotic fluid, meconium, or gastric contents
Lung hypoplasia
Tracheoesophageal fistula
Transient tachypnea of the newborn

Systemic Inflammatory Response Syndrome

The clinical manifestations of infection depend on the virulence of the infecting
organism and the body's inflammatory response. The term systemic
inflammatory response syndrome (SIRS) is most frequently used to describe this
unique process of infection and the subsequent systemic response (see Chapters
88 ). In addition to infection, SIRS may result from trauma, hemorrhagic shock,
other causes of ischemia, necrotizing enterocolitis, and pancreatitis.
Patients with SIRS have a spectrum of clinical symptoms that represent
progressive stages of the pathologic process. In adults, SIRS is defined by the
presence of 2 or more of the following: (1) fever or hypothermia, (2)
tachycardia, (3) tachypnea, and (4) abnormal white blood cell (WBC) count or
an increase in immature forms. In neonates and pediatric patients, SIRS
manifests as temperature instability, respiratory dysfunction (altered gas
exchange, hypoxemia, acute respiratory distress syndrome), cardiac dysfunction
(tachycardia, delayed capillary refill, hypotension), and perfusion abnormalities
(oliguria, metabolic acidosis) (Table 129.8 ). Increased vascular permeability
results in capillary leak into peripheral tissues and the lungs, with resultant
peripheral and pulmonary edema. DIC results in the more severely affected
cases. The cascade of escalating tissue injury may lead to multisystem organ
failure and death.

Table 129.8
Definitions of Systemic Inflammatory Respiratory
Response Syndrome (SIRS) and Sepsis in Pediatric
Patients
SIRS: the systemic inflammatory response to a variety of clinical insults, manifested by 2 or more of the
following conditions:
Temperature instability <35°C (95°F) or >38.5°C (101.3°F)
Respiratory dysfunction:
Tachypnea >2 SD above the mean for age
Hypoxemia (PaO 2 <70 mm Hg on room air)
Cardiac dysfunction:
Tachycardia >2 SD above the mean for age
Delayed capillary refill >3 sec
Hypotension >2 SD below the mean for age
Perfusion abnormalities:
Oliguria (urine output <0.5 mL/kg/hr)
Lactic acidosis (elevated plasma lactate and/or arterial pH <7.25)
Altered mental status
Sepsis: the systemic inflammatory response to an infectious process
From Adams-Chapman I, Stoll BJ: Systemic inflammatory response syndrome, Semin Pediatr
Infect Dis 12:5–16, 2001.

Temperature Instability
Laboratory Findings
Maternal history and infant signs should guide diagnostic evaluation (Table
129.9 ). Additionally, signs of systemic infection in newborn infants may be
unrevealing, so laboratory investigation plays a particularly important role in
diagnosis. Cultures and cell counts are obtained from blood and urine. CSF
should be sent for Gram stain, routine culture, cell count with differential, and
protein/glucose concentrations. Surface swabs, blood, and CSF are often
obtained for HSV testing. Except for culture and directed pathogen testing, no
single laboratory test is completely reliable for diagnosis of invasive infection in
the newborn. Complete blood count may demonstrate elevated or decreased
WBC count, often with a shift toward more immature forms. Thrombocytopenia
can be seen in systemic bacterial or viral infection. Hyponatremia, acidosis, and
other electrolyte abnormalities can be seen. Hyperbilirubinemia is nonspecific
but may be an indication of systemic infection. Elevated serum transaminases
may be a clue to systemic HSV or enterovirus infection.

Table 129.9
Evaluation of a Newborn for Infection or Sepsis
HISTORY (SPECIFIC RISK FACTORS)
Maternal infection during gestation or at parturition (type and duration of antimicrobial therapy):
Urinary tract infection
Chorioamnionitis
Maternal colonization with group B streptococci, Neisseria gonorrhoeae , herpes simplex
Low gestational age/birthweight
Multiple birth
Duration of membrane rupture
Complicated delivery
Fetal tachycardia (distress)
Age at onset (in utero, birth, early postnatal, late)
Location at onset (hospital, community)
Medical intervention:
Vascular access
Endotracheal intubation
Parenteral nutrition
Surgery
EVIDENCE OF OTHER DISEASES *
Congenital malformations (heart disease, neural tube defect)
Respiratory tract disease (respiratory distress syndrome, aspiration)
Necrotizing enterocolitis
Metabolic disease (e.g., galactosemia)
EVIDENCE OF FOCAL OR SYSTEMIC DISEASE
General appearance, neurologic status
Abnormal vital signs
 Organ system disease
Feeding, stools, urine output, extremity movement
LABORATORY STUDIES
Evidence of Infection
Culture from a normally sterile site (blood, CSF, other)
Demonstration of a microorganism in tissue or fluid
Molecular detection (blood, urine, CSF) by specific PCR and/or 16S ribosomal DNA
Maternal or neonatal serology (syphilis, toxoplasmosis)
Evidence of Inflammation
Leukocytosis, increased immature/total neutrophil count ratio
Acute-phase reactants: C-reactive protein, erythrocyte sedimentation rate, procalcitonin
Cytokines: interleukin-6, interleukin-B, tumor necrosis factor
Pleocytosis in CSF or synovial or pleural fluid
Disseminated intravascular coagulation: fibrin degradation products, D-dimer
Evidence of Multiorgan System Disease
Metabolic acidosis: pH, PCO 2
Pulmonary function: PO 2 , PCO 2
Renal function: blood urea nitrogen, creatinine
Hepatic injury/function: bilirubin, alanine transaminase, aspartate transaminase, ammonia, prothrombin time,
partial thromboplastin time
Bone marrow function: neutropenia, anemia, thrombocytopenia
* Diseases that increase the risk of infection or may overlap with signs of sepsis.

CSF, Cerebrospinal fluid; PCR, polymerase chain reaction.

Various serum biomarkers have been investigated for their ability to identify
infants with serious bacterial infection (SBI). An immature-to-total phagocyte
count (I/T ratio) (≥0.2) has the best sensitivity of the neutrophil indices for
predicting neonatal sepsis. After the newborn period, serum C-reactive protein
(CRP) and procalcitonin have demonstrated reasonable sensitivity and
specificity for SBI. CRP may be monitored in newborn infants to assess response
to therapy. Their value in the initial diagnosis of sepsis in the newborn period has
yet to be clarified, as does the value of these biomarkers in determining optimal
length of empirical therapy in infants with negative cultures. Cytokines (both
proinflammatory cytokines such as interleukin (IL)-6 and tumor necrosis factor-
α and antiinflammatory cytokines such as IL-4 and IL-10), chemokines, and
other biomarkers are increased in infected infants. Elevations of serum amyloid
A and the cell surface antigen CD64 also have high sensitivity for identifying
infants with sepsis. Chest radiography is generally not indicated in infants
without signs of respiratory infection.
Table 129.9 and 129.10 list clinical features and laboratory parameters that are
useful in the diagnosis of neonatal infection or sepsis.

Table 129.10
Culture-Based and Non–Culture-Based Diagnostics for
Neonatal Sepsis

OPTIMAL TIMING, VOLUME OF

APPLICABILITY FOR
CATEGORY PARAMETER SPECIMEN,
NEONATAL SEPSIS
ROUTINE/INVESTIGATIONAL*
CULTURE BASED
Blood Culture >1 mL of whole blood, from 2 sites Gold standard for bacteremia
CSF Culture When clinically feasible Optimize antimicrobial therapy
Urine Culture >72 hr of life Not useful for EOS; potential
benefits for LOS
Tracheal Culture Neonates with endotracheal tube in Usually reflects colonization
aspirate place and signs of progressive
respiratory distress
NON–CULTURE BASED
Immune MHC II Investigational Both decreased in chorioamnionitis
function TNF-α Investigational and sepsis
Neutrophil Neutropenia After 12 hr of life Neutropenia better predictor for
indices Absolute Consider GA, delivery mode, sepsis than leukocytosis
neutrophil altitude, arterial versus venous
count sampling, time since birth
Absolute
immature
neutrophil
count
Neutrophil CD64 Elevated for 24 hr after infection Cut points between 2.38 and 3.62
markers Requires 50 µL blood optimal sensitivity, specificity, and
Results within hours NPV for EOS
Investigational
Platelet count Thrombocytopenia Late findings; slow to respond Thrombocytopenia associated with
and fungal infection
thrombocytosis
CSF cell CSF WBC Uninfected neonates: mean 10 Does not predict culture-proven
count cells/mm3 ; range up to 20 cells/mm3 meningitis
CSF CSF protein Term <100 mg/dL Elevated in fungal meningitis
chemistries CSF glucose Preterm higher; 70–80% of serum Low glucose specific for
glucose bacterial meningitis
Acute phase CRP 8–24 hr after infection Good NPV
reactants Procalcitonin 2–12 hr after infection Better sensitivity but less
specificity than CRP
Sepsis After 24 hr of life Most useful for NPV and
panels/scores Investigational discontinuation of antimicrobial
therapy
* Investigational refers to an assay or parameter that is undergoing evaluation for clinical use and
applicability.
CRP, C-reactive protein; CSF, cerebrospinal fluid; EOS, early-onset sepsis; GA, gestational age;
LOS, late-onset sepsis; MHC II, major histocompatibility complex class II; NPV, negative
predictive value; TNF, tumor necrosis factor; WBC, white blood cell count.
From Shane AL, Stoll BJ. Recent developments and current issues in the epidemiology,
diagnosis, and management of bacterial and fungal neonatal sepsis, Am J Perinatol 30(2):131–
141, 2013.
General Approach to Management
In the absence of specific signs of focal infection, therapy for presumed infection
in the neonate is often empirical and initiated on the basis of fever or
hypothermia, listlessness, irritability, or apneic episodes. Antibiotics are chosen
to cover the organisms typically causing neonatal sepsis, including GBS, gram-
negative organisms, Listeria , and Enterococcus . Since the latter 2 organisms are
intrinsically resistant to cephalosporins, ampicillin is generally included in the
empirical treatment of infants with presumed neonatal infection (Table 129.11 ).

Table 129.11
Management and Prevention of Neonatal Sepsis

CONDITION THERAPY ADDITIONAL CONSIDERATIONS

EMPIRICAL MANAGEMENT
Early-onset sepsis Ampicillin + aminoglycoside Consider a third-generation
10 days for bacteremia; 14 days for GBS cephalosporin (cefotaxime preferred)
and uncomplicated meningitis; extend to or carbapenem for meningitis.
21-28 days for complicated infections Tailor therapy to pathogen.
Consider discontinuation of therapy if
pathogen not isolated.
Late-onset sepsis Vancomycin + aminoglycoside Alternatives to vancomycin may be
Duration dependent on pathogen and site considered based on local
epidemiology and clinical
presentation.
Aminoglycoside-based regimen
preferred to cephalosporin given
reduced risk of resistance.
Consider cephalosporin if meningitis
suspected.
Consider a carbapenem if third-
generation cephalosporin recently
received.
Consider amphotericin for fungal
etiologies.
Tailor therapy to pathogen. Consider
discontinuation of therapy if pathogen
not isolated.
NONANTIMICROBIAL TREATMENT STRATEGIES
Recombinant Enhance neutrophil number and function, but Insufficient evidence to support the clinical
G-CSF no reduction in infection when administered as use of G-CSF or GM-CSF either as
Recombinant prophylaxis or improvement in survival when treatment or prophylaxis to prevent
GM-CSF administered as therapy. systemic infections.
IVIG Augments antibody-dependent cytotoxicity and Insufficient evidence from 10 RCTs or
improves neutrophilic function, but no evidence quasi-RCTs to support use in neonates with
that IVIG in suspected or proven sepsis reduces confirmed or suspected sepsis.
death.
PREVENTION STRATEGIES
 IAP Administration of penicillin or ampicillin 4 hr Successfully reduces rates of EOS
before parturition caused by GBS
No effect on LOS GBS
Fluconazole Administration of weight-based dosing to Most beneficial in NICUs with high
prophylaxis neonates <1,500 g baseline rates of invasive candidiasis
BLF BLF is a human milk glycoprotein with a role BLF supplementation with and
supplementation in innate immune response. LGG enhances the without LGG reduced the incidence of
with a probiotic, activity of lactoferrin. 1st LOS in 472 VLBW neonates in
Lactobacillus large randomized, double-blind RCT.
rhamnosus (GG) Additional confirmatory studies
warranted.
BLF, Bovine lactoferrin supplementation; EOS, early-onset sepsis; GBS, group B streptococcus;
G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte-macrophage colony-
stimulating factor; IAP, intrapartum antimicrobial prophylaxis; IVIG, intravenous immune globulin,
LGG, Lactobacillus rhamnosus GG; LOS, late-onset sepsis; NICUs, neonatal intensive care units;
RCTs, randomized controlled trials; VLBW, very-low-birthweight.
Created with data from Carr R, Modi N, Doré C: G-CSF and GM-CSF for treating or preventing
neonatal infections, Cochrane Database Syst Rev (3):CD003066, 2003; Brocklehurst P, Farrell B,
King A, et al; INIS Collaborative Group: Treatment of neonatal sepsis with intravenous immune
globulin, N Engl J Med 365:1201–1211, 2011; and Manzoni P, Decembrino L, Stolfi I, et al; Italian
Task Force for the Study and Prevention of Neonatal Fungal Infections; Italian Society of
Neonatology: Lactoferrin and prevention of late-onset sepsis in the pre-term neonates, Early Hum
Dev 86(Suppl 1):59–61, 2010.
Used with permission from Shane AL, Stoll BJ. Recent developments and current issues in the
epidemiology, diagnosis, and management of bacterial and fungal neonatal sepsis. Am J Perinatol
30(2):131–141, 2013.

An empirical regimen for suspected early-onset sepsis in a term or late

preterm infant is ampicillin , 150 mg/kg/dose intravenously (IV) every 12 hr,
and gentamicin , 4 mg/kg/dose IV every 24 hr. This has long been a standard
regimen for early-onset sepsis and provides coverage for the most prevalent
organisms, predominantly GBS and gram-negative ones. Ampicillin plus
cefotaxime (if available) or cefepime may be substituted if the patient presents
with infection after discharge from the nursery, or when infection with
ampicillin-resistant E. coli is suspected. Ceftriaxone may be substituted if
premature infants are ≥41 wk postconception age; it may be used in term infants
if they are not receiving intravenous calcium or do not have hyperbilirubinemia.
There is concern this regimen may be associated with higher rates of mortality in
NICU patients compared to ampicillin and gentamicin. Alterations to the
standard regimen may be appropriate in some circumstances, such as suspected
infection with S. aureus , in which case vancomycin may be substituted for
ampicillin, and in environments where infections from antibiotic-resistant
bacteria are prevalent.
Herpes simplex virus infection may present without cutaneous signs, in the
Table 129.12
Indications for Intrapartum Antibiotic Prophylaxis to
Prevent Early-Onset GBS Disease

INTRAPARTUM GBS PROPHYLAXIS NOT

INTRAPARTUM GBS PROPHYLAXIS INDICATED
INDICATED
Previous infant with invasive GBS disease Colonization with GBS during a previous pregnancy
(unless an indication for GBS prophylaxis is present
for current pregnancy)
GBS bacteriuria during any trimester of the current GBS bacteriuria during previous pregnancy (unless
pregnancy another indication for GBS prophylaxis is present for
current pregnancy)
Positive GBS screening culture during current pregnancy Cesarean delivery before onset of labor or amniotic
(unless a cesarean delivery is performed before onset of membrane rupture, regardless of GBS colonization
labor or amniotic membrane rupture) status or gestational age
Unknown GBS status at the onset of labor (culture not Negative vaginal and rectal GBS screening culture in
done, incomplete, or results unknown) and any of the late gestation during the current pregnancy,
following: regardless of intrapartum risk factors
Delivery at <37 weeks' gestation*
Amniotic membrane rupture ≥18 hr
Intrapartum temperature ≥38.0°C (100.4°F) †
Intrapartum NAAT ‡ positive for GBS
* Recommendations for the use of intrapartum antibiotics for prevention of early-onset GBS
disease in the setting of threatened preterm delivery are presented in Chapter 211 .
† If amnionitis is suspected, broad-spectrum antibiotic therapy that includes an agent known to be

active against GBS should replace GBS prophylaxis.

‡ If intrapartum NAAT is negative for GBS but any other intrapartum risk factor (delivery at <37 wk

gestation, amniotic membrane rupture ≥18 hr, or temperature ≥38.0°C/100.4°F) is present,

intrapartum antibiotic prophylaxis is indicated.
GBS, Group B streptococcus; NAAT, nucleic acid amplification test.
From Verani J, McGee L, Schrag S: Prevention of perinatal group B streptococcal disease—
revised guidelines from CDC, 2010, MMWR Recomm Rep 59(RR-10):1–36, 2010.

Aggressive management of suspected maternal chorioamnionitis with

antibiotic therapy during labor, along with rapid delivery of the infant, reduces
the risk of early-onset neonatal sepsis. Vertical transmission of GBS and early-
onset GBS disease is significantly reduced by selective intrapartum
chemoprophylaxis (see Fig. 211.4 ). A number of candidate GBS vaccines are
currently being studied. Neonatal infection with Chlamydia can be prevented by
identification and treatment of infected pregnant women (see Chapter 253 ).
Mother-to-child transmission of HIV is significantly reduced by maternal
antiretroviral therapy during pregnancy, labor, and delivery, by cesarean delivery
before rupture of membranes, and by antiretroviral treatment of the infant after
CHAPTER 130

Healthcare-Acquired Infections
David B. Haslam

Premature and very-low-birthweight (VLBW) infants often have prolonged

hospitalizations and are particularly prone to healthcare-acquired infection (HAI
) because of their inefficient innate immunity, deficient skin barriers, presence of
indwelling catheters and other devices, and prolonged endotracheal intubation
(Table 130.1 ). HAIs are associated with increased length of hospitalization,
increased cost of care, and significant morbidity and mortality.

Table 130.1
Definitions of Healthcare-Acquired Infections for Patients
<12 Mo Old*
NOSOCOMIAL BLOODSTREAM INFECTIONS
Laboratory-Confirmed Bloodstream Infection (LCBI)
Must meet 1 of the following definitions:
• Recognized pathogen in 1 or more blood specimens (culture-based or non–culture-based microbiologic
methods), performed for clinical diagnostic or therapeutic purposes and not related to infection at another site.
• Commensal organism (e.g., coagulase-negative staphylococci, diphtheroids, bacillus, viridans streptococci,
aerococcus, micrococcus, propionibacterium), identified from 2 or more blood specimens obtained on separate
instances (culture- or non–culture-based microbiologic methods), performed for clinical diagnostic or
therapeutic purposes and not related to infection at another site and at least 1 of the following signs: (1) fever
(temperature >38.0°C), (2) hypothermia (temperature <36.0°C), or (3) apnea or bradycardia.
Central Line–Associated Bloodstream Infection (CLABSI)
• LCBI (as defined above) and
• Central line or umbilical catheter in place for >2 days and
• Central line in place on day of or day before CLABSI diagnosis.
Pneumonia
• Two or more serial chest radiographs with new/progressive and persistent infiltrate, cavitation, consolidation, or
pneumatoceles for patients with underlying pulmonary or cardiac disease (respiratory distress syndrome,
bronchopulmonary dysplasia, pulmonary edema) or 1 chest radiograph with the aforementioned abnormalities
for patients without underlying pulmonary or cardiac disease and
• Worsening gas exchange and
• At least 3 of the following; (1) temperature instability; (2) white blood cell count <4,000/µL or >15,000/µL with
 10% or more bands, (3) new-onset purulent sputum, change in character of sputum, increased respiratory
secretions, or increased suctioning requirements; (4) physical examination findings consistent with increased
work of breathing or apnea, wheezing, rales, or rhonchi; (5) cough; (6) bradycardia (<100 beats/min), and (7)
tachycardia (>170 beats/min).
Ventilator-Associated Pneumonia (VAP)
• Pneumonia (as defined above) and
• Patient on ventilator for >2 days and
• Ventilator in place on day of or day before VAP diagnosis
URINARY TRACT INFECTION
Symptomatic Urinary Tract Infection (SUTI)
• At least 1 of the following symptoms: (1) fever (temperature >38.0°C), (2) hypothermia (temperature <36.0°C),
(3) apnea, (4) bradycardia, (5) lethargy, (6) vomiting, or (7) suprapubic tenderness and
• Urine culture with no more than 2 species identified, at least 1 of which is present at >105 CFU/mL.
Asymptomatic Bacteremic Urinary Tract Infection (ABUTI)
• Urine culture with no more than 2 species identified, at least 1 of which is present at >105 CFU/mL and
• Bacteria identified in blood (culture-based or nonculture-based microbiologic method) that matches at least one
of the bacteria present at more than 105 CFU/mL in urine.
Catheter–Associated Urinary Tract Infection:
• Urinary tract infection (as defined above, either SUTI or ABUTI) and
• Indwelling urinary catheter for >2 days and
• Urinary catheter in place on day of or day before urinary tract infection diagnosis.
* Centers for Disease Control and Prevention/National Healthcare Safety Network.

CFU, Colony-forming units.

Adapted from Horan TC, Andrus M, Dudeck MA. CDC/NHSN surveillance definition of health
care–associated infection and criteria for specific types of infections in the acute care setting, Am
J Infect Control 36:309–332, 2008.

Incidence
The most common HAIs in the neonatal intensive care unit (NICU) are
bloodstream infections, predominantly central line–associated bloodstream
infections. Ventilator-associated pneumonia (VAP) is the next most common,
followed by surgical site infection and catheter-associated urinary tract infection.
Approximately 11% of NICU patients develop nosocomial infection during
their hospitalization; up to 25% of VLBW infants will have blood culture–
proven sepsis during their hospitalization. Infection rates are highest among the
most premature infants. Ventilator-associated pneumonia accounts for
approximately 25% of HAIs.

Epidemiology
HAIs in the NICU are predominantly caused by gram-positive organisms. The
largest fraction of bloodstream infections (BSIs) in the NICU are caused by
coagulase-negative staphylococci (Table 130.2 ). Other agents that often cause
HAIs in the newborn include Staphylococcus aureus, enterococci, gram-negative
bacilli (Escherichia coli, Klebsiella pneumoniae, Enterobacter spp.,
Pseudomonas aeruginosa ), and Candida. Viruses contributing to HAIs in the
neonate include rotavirus, enteroviruses, hepatitis A virus (HAV), adenoviruses,
influenza, respiratory syncytial virus (RSV), rhinovirus, parainfluenza, and
herpes simplex virus (HSV).

Table 130.2
Distribution of Organisms Responsible for Late-Onset
Sepsis
VLBW INFANTS: NICHD NRN (%)
ORGANISM
1991–1993 1998–2000 2002–2008
Incidence of late-onset sepsis 25 21 25
GRAM POSITIVE
Staphylococcus, coagulase-negative 55 48 53
Staphylococcus aureus 9 8 11
Enterococcus /group D streptococcus 5 3 4
Group B streptococcus 2 2 2
Other 2 9 7
GRAM NEGATIVE
Enterobacter 4 3 3
Escherichia coli 4 5 5
Klebsiella 4 4 4
Pseudomonas 2 3 2
Other 4 1 2
Fungi
Candida albicans 5 6 5
Candida parapsilosis
Other 2 2 1
VLBW, Very-low-birthweight (≤1,500 g); NICHD NRN, National Institutes of Child Health and
Human Development Neonatal Research Network.
Data from (1) 1991–1993: Stoll BJ, Gordon T, Korones SB, et al: Late-onset sepsis in very low
birth weight neonates: a report from the NICHD NRN, J Pediatr 129:63–71, 1996; (2) 1998–2000:
Stoll BJ, Hansen N, Fanaroff AA, et al: Late-onset sepsis in very low birth weight neonates: the
experience of the NICHD NRN, Pediatrics 110:285–291, 2002; (3) 2002–2008: Boghossian NS,
Page GP, Bell EF, et al: Late-onset sepsis in very low birth weight infants from singleton and
multiple gestation births, J Pediatr 162:1120–1120, 2015.
Adapted from Ramasethu J. Prevention and treatment of neonatal nosocomial infections, Matern
Health Neonatol Perinatol 3(5), 2017.

Bacteria responsible for most cases of nosocomial pneumonia typically

Clostridium difficile , HAV, rotavirus, enterovirus, and adenovirus. Time
constraints and workload are considered important barriers to adequate hand
care, and recent evidence suggests that shortening the application time of
alcohol-based sanitizers to 15 sec may improve frequency of use without
impacting antimicrobial efficacy. Observational studies suggest that monitoring
with personal or group-level feedback is among the most effective means to
improve hand hygiene compliance.

Table 130.3
U.S. Centers for Disease Control and Prevention (CDC)
Guidelines for Hand Hygiene
• When hands are visibly dirty or contaminated with proteinaceous material or are visibly soiled with blood or
other body fluids, wash hands with either a nonantimicrobial soap and water or an antimicrobial soap and water
(categorization of recommendation: IA)
• If hands are not visibly soiled, use an alcohol-based hand rub for routinely decontaminating hands in all other
clinical situations described below (categorization of recommendation: IA). Alternatively, wash hands with an
antimicrobial soap and water in all clinical situations described below (categorization of recommendation: IB).
• Decontaminate hands before having direct contact with patients (categorization of recommendation: IB).
• Decontaminate hands before donning sterile gloves when inserting an intravascular catheter (categorization of
recommendation: IB).
• Decontaminate hands before inserting indwelling urinary catheters, peripheral vascular catheters, or other
invasive devices that do not require a surgical procedure (categorization of recommendation: IB).
• Decontaminate hands after contact with a patient's intact skin (categorization of recommendation: IB).
• Decontaminate hands after contact with body fluids or excretions, mucous membranes, nonintact skin, and
wound dressings if hands are not visibly soiled (categorization of recommendation: IB).
• Decontaminate hands if moving from a contaminated body site to a clean body site during patient care
(categorization of recommendation: II).
• Decontaminate hands after contact with inanimate objects (including medical equipment) in the immediate
vicinity of the patient (categorization of recommendation: II).
• Decontaminate hands after removing gloves (categorization of recommendation: IB).
• Before eating and after using a restroom, wash hands with a nonantimicrobial soap and water or with
antimicrobial soap and water (categorization of recommendation: IB).
• Antimicrobial-impregnated wipes may be considered as an alternative to washing hands with nonantimicrobial
soap and water. Because they are not as effective as alcohol-based hand rubs or washing hands with an
antimicrobial soap and water for reducing bacterial counts on the hands of healthcare workers, they are not a
substitute for hand antisepsis (categorization of recommendation: IB).
• Wash hands with nonantimicrobial soap and water or with antimicrobial soap and water if exposure to Bacillus
anthracis is suspected or proven (categorization of recommendation: II).
• No recommendation can be made regarding the routine use of non–alcohol-based hand rubs for hand hygiene in
healthcare settings. Unresolved issue.
CDC/Healthcare Infection Control Practices Advisory Committee System for Categorizing Recommendations
Category IA: Strongly recommended for implementation and strongly supported by well-designed experimental,
clinical, or epidemiologic studies.
Category IB: Strongly recommended for implementation and supported by certain experimental, clinical, or
epidemiologic studies and using theoretical rationale.
Category IC: Required for implementation, as mandated by federal or state regulation or standard.
 Category II: Suggested for implementation and supported by suggestive clinical or epidemiologic studies or a
theoretic rationale.
No recommendation; Unresolved issue: Practices for which insufficient evidence or no consensus regarding
efficacy exists.
Adapted from Boyce JM, Pittet D; Healthcare Infection Control Practices Advisory Committee:
Guideline for hand hygiene in health-care settings: recommendations of the Healthcare Infection
Control Practices Advisory Committee and the HIPAC/SHEA/APIC/IDSA Hand Hygiene Task
Force, Am J Infect Control 30(8):S1–S46, 2002.

Central Line–Associated Bloodstream Infection

Hand hygiene is the most important intervention to prevent CLABSI in the
NICU. “Care bundles” have been studied in numerous neonatal populations and
found to reduce catheter-related infection. Insertion bundles include a
combination of barrier precaution, hand hygiene standards, skin disinfection,
dedicated teams and equipment, catheter site evaluation, checklists, and
empowerment to stop the procedure. Maintenance bundles include
recommendations for aseptic technique when accessing the line, dressing change
protocols, and prompt removal when the line is no longer required (Table 130.4
).

Table 130.4
Interventions to Prevent Catheter-Related Infections
• Perform effective hand hygiene before and after any interaction with the catheter.
• Use sterile gowns, gloves, drapes, cap, and mask during catheter insertion.
• Disinfect skin with appropriate agent (chlorhexidine is most often used in United States; other disinfectants may
be as effective).
• Use a transparent, semipermeable dressing to cover catheter site.
• Change the dressing when soiled or loose.
• Scrub access point with alcoholic chlorhexidine for at least 15 sec.
• Use aseptic nontouch technique to access the catheter.
• Change administration sets no more frequently than 96 hr unless required by the infused product.
• Avoid use of systemic prophylactic antibiotics for catheter insertion.
• Evaluate daily, and remove central venous catheter when no longer required.
• Ensure all healthcare professionals who interact with the patient are educated on central line management.
Adapted from Taylor JE, McDonald SJ, Tan K: Prevention of central venous catheter–related
infection in the neonatal unit: a literature review, J Matern Fetal Neonatal Med 28(10):1224–1230,
2015.

Ventilator-Associated Pneumonia

FIG. 131.1 Pathogenesis of hematogenous transplacental infections. (Adapted from
Klein JO, Remington JS: Current concepts of infections of the fetus and newborn
infant. In Remington JS, Klein JO, editors: Infectious diseases of the fetus and newborn
infant, ed 5, Philadelphia, 2002, Saunders.)

Table 131.1
Specific Agents in Effects of Transplacental Fetal Infection
on the Fetus and Newborn Infant

DISEASE
Intrauterine
ORGANISM Persistent
Growth Developmental Congenital
Prematurity Postnatal
Restriction/Low Anomalies Disease
Infection
Birthweight
Viruses CMV CMV CMV CMV CMV
HSV Rubella Rubella Rubella Rubella
Rubeola VZV* VZV VZV VZV
Smallpox HIV* Coxsackievirus HSV HSV
HBV B* Mumps* HBV
HIV* HIV* Rubeola HIV
Zika Vaccinia Zika
Smallpox
Coxsackievirus
 B
Poliovirus
HBV
HIV
LCV
Parvovirus
Bacteria Treponema T. pallidum T. pallidum
pallidum M. tuberculosis M.
Mycobacterium L. tuberculosis
tuberculosis monocytogenes
Listeria C. fetus
monocytogenes S. typhi
Campylobacter Borrelia
fetus burgdorferi
Salmonella
typhi
Protozoa Toxoplasma T. gondii T. gondii T. gondii
gondii Plasmodium Plasmodium Plasmodium
Plasmodium * T. cruzi T. cruzi
Trypanosoma
cruzi
* Association of effect with infection has been suggested and is under consideration.

CMV , Cytomegalovirus; HBV , hepatitis B virus; HIV , human immunodeficiency virus; HSV ,
herpes simplex virus; LCV , lymphocytic choriomeningitis virus; VZV , varicella-zoster virus.
From Maldonado YA, Nizet V, Klein JO, et al: Current concepts of infections of the fetus and
newborn infant. In Wilson CB, Nizet V, Maldonado Y, et al, editors: Remington and Klein's
infectious diseases of the fetus and newborn, ed 8, Philadelphia, 2016, Elsevier (Table 1-5).

Intrauterine infection from cytomegalovirus (CMV), Treponema pallidum ,

Toxoplasma gondii , rubella virus, varicella-zoster virus (VZV), and human
parvovirus B19 may cause minimal or no symptoms in the mother but still may
be transmitted across the placenta to the fetus. The presence of maternal
antibodies to rubella prevents infection, but transmission of CMV can occur
despite preexisting antibodies. Regardless of the mother's immune status, the
placenta may act as a barrier, and the fetus may or may not be infected. If
infection occurs, signs may or may not be noted in the fetus during pregnancy.
Infection can result in spontaneous abortion, congenital malformation,
intrauterine growth restriction (IUGR), premature birth, stillbirth, acute or
delayed disease in the neonate, or asymptomatic persistent infection with
sequelae later in life.

Clinical Manifestations
The clinical manifestations of intrauterine infections can range from
asymptomatic to severe multiorgan system complications. For some agents (e.g.,
CMV, T. pallidum ), ongoing injury after birth leads to late sequelae. The
specific clinical signs in the newborn period are usually not sufficient to make a
definitive diagnosis but are useful to guide more specific laboratory testing.
Symptomatic congenital infections often affect the central nervous system (CNS;
brain and eyes) and the reticuloendothelial system (RES; bone marrow, liver, and
spleen). Table 131.2 presents the clinical manifestations of some specific
congenital infections. Congenital Zika virus infection has features that are rarely
seen with other congenital infections (Table 131.3 ). No hematologic or hepatic
laboratory abnormalities have been documented in infants with congenital Zika
virus infection. Table 131.4 provides late sequelae of some congenital infections.

Table 131.2
Clinical Manifestations of Specific Neonatal Infections
Acquired in Utero or at Delivery

Rubella Virus Cytomegalovirus Toxoplasma gondii Herpes Simplex Virus Treponema pallidum
Hepatosplenomegaly Hepatosplenomegaly Hepatosplenomegaly Hepatosplenomegaly Hepatosplenomegaly
Jaundice Jaundice Jaundice Jaundice Jaundice
Pneumonitis Pneumonitis Pneumonitis Pneumonitis Pneumonitis
Petechiae or purpura Petechiae or purpura Petechiae or purpura Petechiae or purpura Petechiae
Meningoencephalitis Meningoencephalitis Meningoencephalitis Meningoencephalitis Meningoencephalitis
Hydrocephalus Hydrocephalus Hydrocephalus* Hydrocephalus Adenopathy
Adenopathy Microcephaly* Microcephaly Microcephaly Maculopapular
Hearing deficits Intracranial Maculopapular Maculopapular exanthems
Myocarditis calcifications* exanthems exanthems Bone lesions
Congenital defects* Hearing deficits Intracranial Vesicles* Glaucoma
Bone lesions* Chorioretinitis or calcifications* Myocarditis Chorioretinitis
Glaucoma* retinopathy Myocarditis Chorioretinitis or retinopathy
Chorioretinitis or Optic atrophy Bone lesions retinopathy Uveitis
retinopathy* Chorioretinitis or Cataracts
Cataracts* retinopathy* Conjunctivitis or
Microphthalmia Cataracts keratoconjunctivitis*
Optic atrophy
Microphthalmia
Uveitis
* Has special diagnostic significance for this infection

From Maldonado YA, Nizet V, Klein JO, et al: Current concepts of infections of the fetus and
newborn infant. In Wilson CB, Nizet V, Maldonado Y, et al, editors: Remington and Klein's
infectious diseases of the fetus and newborn, ed 8, Philadelphia, 2016, Elsevier (Table 1-6).

Table 131.3

Syndromes in the Neonate Caused by Other Congenital Infections

 ORGANISM SIGNS
VZV Limb hypoplasia, cicatricial skin lesions, ocular abnormalities, cortical atrophy
Parvovirus Nonimmune hydrops fetalis
B19
HIV Severe thrush, failure to thrive, recurrent bacterial infections, calcification of basal ganglia
Zika virus Microcephaly, lissencephaly, cerebellar hypoplasia, akinesia syndrome, macular scarring, retinal
mottling, subcortical calcifications, hypertonia
HIV , Human immunodeficiency virus; VZV , varicella-zoster virus.
From Maldonado YA, Nizet V, Klein JO, et al: Current concepts of infections of the fetus and
newborn infant. In Wilson CB, Nizet V, Maldonado Y, et al, editors: Remington and Klein's
infectious diseases of the fetus and newborn, ed 8, Philadelphia, 2016, Elsevier (Table 1-7).

Table 131.4
Late Sequelae of Intrauterine Infections.

INFECTION
CLINICAL SIGN
Cytomegalovirus Rubella Virus Toxoplasma gondii Treponema pallidum
Deafness + + + +
Dental/skeletal problems + + (−) +
Mental retardation + + + +
Seizures + + + +
+, Present; (−), rare or absent.

Diagnosis
During Pregnancy
The presence of IUGR or a physical abnormality on a prenatal fetal ultrasound
raises concern for a congenital infection. The well-known acronym TORCH —
T oxoplasma gondii , O ther (Treponema pallidum , human parvovirus B19, HIV,
Zika virus, others), R ubella, C ytomegalovirus, and H erpes simplex virus
(HSV)—is a useful mnemonic. However, the routine ordering of TORCH
serology panels is not recommended because the presence of a TORCH agent
IgG antibody in the mother indicates past infection but does not establish if the
infection occurred during pregnancy. Maternal IgM titers to specific pathogens
are only moderately sensitive, and a negative result cannot be used to exclude
infection.
In certain cases, a fetal blood sample with cordocentesis can be obtained and
tested for total and pathogen-specific IgM assays, polymerase chain reaction
The human birth canal is colonized with aerobic and anaerobic bacteria.
Ascending amniotic infection may occur with either apparently intact
membranes or relatively brief duration of membrane rupture. Infectious agents
can also be acquired as the newborn infant passes through the vaginal canal. This
acquisition may result in either colonization or disease. Factors influencing
which colonized infants will experience disease are not well understood but
include prematurity, underlying illness, invasive procedures, inoculum size,
virulence of the infecting organism, genetic predisposition, the innate immune
system, host response, and transplacental maternal antibodies.
Chorioamnionitis has been historically used to refer to microbial invasion of
the amniotic fluid, often as a result of prolonged rupture of the chorioamniotic
membrane for >18 hr. The term chorioamnionitis is confusing because it does
not convey the spectrum of inflammatory or infectious diseases, it leaves out
other intrauterine components that can be involved (e.g., decidua), and it results
in significant variability in clinical practice, with the potential for a significant
number of well newborns being exposed to antimicrobial agents. The term
intrauterine inflammation or infection at birth , abbreviated as Triple I , has
become more accepted because of the heterogeneous nature of conditions that
can affect the mother and neonate (Table 131.5 ). Regardless of the definition
used, prematurity (<37 wk) is associated with a greater risk of early-onset sepsis,
especially with group B streptococcus.

Table 131.5
Classification of Triple I and Isolated Maternal Fever

TERMINOLOGY FEATURES
Isolated maternal Maternal oral temperature ≥39°C is considered a “documented fever.”
fever If the oral temperature is ≥38°C but ≤39°C, repeat the measurement in 30 min. If the
repeat value is ≥38°C, it is considered a “documented fever.”
Suspected Triple I Fever without a clear source with any of the following:
1. Baseline fetal tachycardia (>160 beats/min for 10 min)
2. Maternal WBC >15,000/mm3
3. Purulent fluid from the cervical os
Confirmed Triple I All the above (from suspected Triple I) with any of the following:
1. Amniocentesis-proven infection through positive Gram stain
2. Low glucose of amniotic fluid or positive amniotic fluid culture
3. Placental pathology consistent with infection
Triple I, Intrauterine inflammation or infection at birth; WBC, white blood cell count.
Adapted from Higgins RD, Saade G; Chorioamnionitis Workshop participants: Evaluation and
management of women and newborns with a maternal diagnosis of chorioamnionitis: summary of
Fungi
Candida spp. (Chapter 261 )

Diagnosis
The maternal history provides important information about maternal exposures
to infectious diseases, bacterial colonization, immunity (natural and acquired),
and obstetric risk factors (prematurity, prolonged ruptured membranes,
chorioamnionitis). STIs acquired by a pregnant woman, including syphilis, N.
gonorrhoeae , and C. trachomatis, have the potential for perinatal transmission.
Neonates with perinatal infections often present with nonspecific symptoms
and signs; therefore the general diagnostic evaluation for the ill neonate as
discussed in Chapter 202 should be followed. Table 131.6 provides a summary
of laboratory tests that are useful to diagnose specific perinatal infections.

Table 131.6
Laboratory Tests in the Diagnosis of Specific Perinatal
Infections

ACCEPTABLE SPECIMEN(S)
INFECTIOUS AGENT FROM INFANT UNLESS LABORATORY TEST
OTHERWISE INDICATED
Chlamydia trachomatis Conjunctiva, nasopharyngeal swab, Culture using special transport
tracheal aspirate media
Nucleic acid amplification tests
(NAATs) are not FDA-approved
for specimens from neonates.*
Genital mycoplasmas Tracheal aspirate, blood, or cerebrospinal Culture using special transport
(Mycoplasma hominis , M. fluid (CSF) media
genitalium , Ureaplasma Real-time polymerase chain
urealyticum ) reactions (PCRs)
Neisseria gonorrhoeae Conjunctiva, blood, CSF, or synovial Finding gram-negative
fluid intracellular diplococci on Gram
stain is suggestive.
Culture on special media
establishes the diagnosis.
Syphilis (Treponema pallidum ) Serum (mother) Rapid plasma reagin (RPR) and if
reactive, a specific treponemal test †
Serum RPR
CSF Venereal Disease Research
Laboratories (VDRL)
Cytomegalovirus Urine, saliva, blood, or CSF PCR for detection of CMV DNA
 Obtain within 2-4 wk of birth.
Enteroviruses Blood, nasopharyngeal swab, throat PCR
swab, conjunctival swab, tracheal Cell culture (sensitivity depends
aspirate, urine, stool, rectal swab, or CSF on serotype and cell lines used)
Hepatitis B Serum (mother) Hepatitis B surface antigen (HBsAg)
Serum If mother's HBsAg is positive, at age
9 mo, test the infant for HBsAg and
hepatitis B surface antibody.
Herpes simplex viruses 1 and 2 Conjunctiva, skin vesicle scraping, PCR or cell culture
whole blood, or mouth vesicles
CSF PCR
“Surface cultures” (mouth, nasopharynx, PCR or cell culture
conjunctiva, and anus)
Human immunodeficiency virus Serum (mother) Fourth-generation HIV
(HIV) antigen/antibody test
Whole blood HIV DNA PCR
Candida species Blood, skin biopsy, or CSF Culture
Zika virus Blood, urine, CSF NAT and serum IgM
NAT may be falsely negative
IgG antibodies may reflect
maternal exposure
Antibodies may cross react with
other flaviviruses
* Published evaluations of NAATs for these indications are limited, but sensitivity and specificity is

expected to be at least as high as those for culture. FDA, U.S. Food and Drug Administration.
† Treponemal tests include the T. pallidum particle agglutination (TP-PA) test, T. pallidum enzyme
immunoassay (TP-EIA), T. pallidum chemiluminescent assay (TP-CIA), and fluorescent
treponemal antibody absorption (FTA-ABS) test.

Bibliography
American Academy of Pediatrics. Syphilis. Kimberlin DW,
Brady MT, Jackson MA, Long SS. Red book: 2018-2021
report of the committee on infectious diseases . ed 31.
American Academy of Pediatrics: Itasca, IL; 2018:773–788.
Bilavsky E, Pardo J, Attias J, et al. Clinical implications for
children born with congenital cytomegalovirus infection
following a negative amniocentesis. Clin Infect Dis .
2016;63:33–38.
Boppana SB, Ross SA, Fowler KB. Congenital cytomegalovirus
infection: clinical outcome. Clin Infect Dis . 2013;57(Suppl
4):S178–S181.
CHAPTER 132

Adolescent Physical and Social

Development
Cynthia M. Holland-Hall

See also Part XV and Chapters 577 and 578 .

During the preteen, teenage, and young adult years, young people undergo not
only dramatic changes in physical appearance, but also rapid changes in
physiologic, psychological, and social functioning. Hormonally driven
physiologic changes and ongoing neurologic development occur in the setting of
social structures that foster the transition from childhood to adulthood. This
period of development comprises adolescence , which is divided into 3 phases—
early, middle, and late adolescence—each marked by a characteristic set of
biologic, cognitive, and psychosocial milestones (Table 132.1 ). Although
individual variations in the timing and pace of development undoubtedly exist,
these changes follow a fairly predictable pattern of occurrence. Gender and
culture profoundly affect the developmental course, as do physical, social, and
environmental influences. Given the interaction of these domains, a
biopsychosocial perspective is best suited to approach the healthcare of the
adolescent.

Table 132.1
Milestones in Early, Middle, and Late Adolescent
Development

LATE
VARIABLE EARLY ADOLESCENCE MIDDLE ADOLESCENCE
ADOLESCENCE
Approximate 10-13 yr 14-17 yr 18-21 yr
age range
Sexual maturity 1-2 3-5 5
rating*
 Physical Females: secondary sex Females: peak growth velocity, Physical
characteristics (breast, menarche (if not already attained) maturation
pubic, axillary hair), start of Males: growth spurt, secondary sex slows
growth spurt characteristics, nocturnal Increased lean
Males: testicular emissions, facial and body hair, muscle mass in
enlargement, start of genital voice changes males
growth Change in body composition
Acne
Cognitive and Concrete operations Emergence of abstract thought Future-oriented
moral Egocentricity (formal operations) with sense of
Unable to perceive long- May perceive future implications, perspective
term outcome of current but may not apply in decision- Idealism
decisions making Able to think
Follow rules to avoid Strong emotions may drive things through
punishment decision-making independently
Sense of invulnerability Improved
Growing ability to see others' impulse control
perspectives Improved
assessment of
risk vs reward
Able to
distinguish law
from morality
Self- Preoccupied with changing Concern with attractiveness More stable
concept/identity body Increasing introspection body image
formation Self-consciousness about Attractiveness
appearance and may still be of
attractiveness concern
Consolidation
of identity
Family Increased need for privacy Conflicts over control and Emotional and
Exploration of boundaries independence physical
of dependence vs Struggle for greater autonomy separation from
independence Increased separation from parents family
Increased
autonomy
Reestablishment
of “adult”
relationship
with parents
Peers Same-sex peer affiliations Intense peer group involvement Peer group and
Preoccupation with peer culture values recede in
Conformity importance
Sexual Increased interest in sexual Testing ability to attract partner Consolidation
anatomy Initiation of relationships and of sexual
Anxieties and questions sexual activity identity
about pubertal changes Exploration of sexual identity Focus on
Limited capacity for intimacy and
intimacy formation of
stable
relationships
Planning for
future and
commitment
* See text and Figs. 132.1 and 132.2 .

FIG. 132.2 Sexual maturity ratings (1-5) of breast changes in adolescent
females. (Courtesy of J.M. Tanner, MD, Institute of Child Health,
Department for Growth and Development, University of London.)

Table 132.2

Sexual Maturity Rating (SMR) Stages in Females

SMR
PUBIC HAIR BREASTS
STAGE
1 Preadolescent Preadolescent
2 Sparse, lightly pigmented, straight, medial Breast and papilla elevated as small mound; diameter
border of labia of areola increased
3 Darker, beginning to curl, increased amount Breast and areola enlarged, no contour separation
4 Coarse, curly, abundant, but less than in Areola and papilla form secondary mound
adult
 5 Adult feminine triangle, spread to medial Mature, nipple projects, areola part of general breast
surface of thighs contour
From Tanner JM: Growth at adolescence, ed 2, Oxford, England, 1962, Blackwell Scientific.

Table 132.3
Sexual Maturity Rating (SMR) Stages in Males

SMR
PUBIC HAIR PENIS TESTES
STAGE
1 None Preadolescent Preadolescent
2 Scant, long, slightly pigmented Minimal change/enlargement Enlarged scrotum, pink,
texture altered
3 Darker, starting to curl, small amount Lengthens Larger
4 Resembles adult type, but less Larger; glans and breadth Larger, scrotum dark
quantity; coarse, curly increase in size
5 Adult distribution, spread to medial Adult size Adult size
surface of thighs
From Tanner JM: Growth at adolescence, ed 2, Oxford, England, 1962, Blackwell Scientific.

FIG. 132.3 Sequence of pubertal events in males. Although the age of
activities, demanding privacy, and increasing argumentativeness, are normal;
extreme withdrawal or antagonism may be dysfunctional, signaling a mental
health or substance use concern. Bewilderment and dysphoria at the start of
middle school are normal; continued failure to adapt several months later
suggests a more serious problem. Although some degree of risk taking is normal,
progressive escalation of risk-taking behaviors is problematic. In general, when
the adolescent's behaviors cause significant dysfunction in the domains of home
life, academics, or peer relationships, they should be addressed by the parents
and healthcare provider, and referral to a mental health provider may be
considered. In most cases, parents can be reassured that although adolescence
can pose unique challenges, their adolescent, like most adolescents, will come
through it to become a successful and happy adult.
At national and international levels, adolescents are at risk for environmental,
health, behavioral, and societal challenges. Table 132.4 provides suggestions to
address these issues.

Table 132.4
Recommended Action Bundles* for Adolescent and Young
Adult Health Problems and Risks

COMMUNITY ELECTRONIC
PROBLEM/RISK SOCIAL INTERVENTIONS HEALTH,
STRUCTURAL SCHOOLS
AREA MARKETING INCLUDING MOBILE
FAMILY HEALTH
Sexual and Legislation Promote Cash transfer Target Quality
reproductive 18 years as the community programs, with knowledge, secondary
health, including minimum age of support for payments linked attitudes, and education
HIV marriage sexual and to staying in risk behaviors Comprehensive
Allow provision reproductive school sexuality
of contraception health, and HIV Positive youth education
to legal minors health access for development Safe schools
Legalize abortion adolescents Peer education with clean
toilets and
facilities for
menstrual care
School-based
health services
with condoms
and modern
contraceptives

Undernutrition Fortification of Micronutrient Micronutrient

 foods (e.g., iron, supplements supplements
folate) (particularly in Healthy school
pregnancy) meals
Protein-energy
supplementation
Deworming
Cash transfer
program
Nutrition
education
Infectious diseases Deworming HPV
Bednet vaccination
distribution Deworming

Violence Gun control Promote Promote parent Multicomponent

Legalize knowledge of the skills and interventions that
homosexuality effects of parent–child target violent
and protect violence and communication behavior and
women from available Positive youth substance use
violence and services development
sexual coercion Promote gender
Youth justice equality
reforms to Economic
promote second empowerment
chances and Group training
diversion from for awareness,
custody knowledge, and
16 years as the skills
minimum age for
criminal
responsibility
Unintentional Graduated Promote Police enforcement of
injury licensing knowledge of traffic injury control
Mandatory risks
helmet wearing
Multicomponent
traffic injury
control
Alcohol and illicit Limit alcohol Advertising Promote parent– Target Alcohol-free policies
drugs sales to restrictions child knowledge,
underage Campaigns communication attitudes, and
adolescents to build and parenting risk behaviors
Taxation on community skills
alcohol awareness Needle-syringe
Drink-driving exchange access
legislation Mentoring
 Restrict illicit
alcohol
Interventions in
licensed
premises
Diversion from
youth justice
and custody
Graduated
drinking
Tobacco Tobacco control Anti-tobacco Interventions to Text messaging Smoke-free
including campaigns promote parent skills adjunct to policies
taxation, and parent–child quitting Multicomponent
pricing, and communication
advertising
control
Youth access
restrictions
Legislation for
smoke-free air
Mental disorders Restriction of access Promote Gatekeeper training Electronic Educational
and suicide to means adolescent mental health interventions
mental health interventions Gatekeeper
literacy training
School-based
mental health
services

Chronic physical Peer support School-based health

disorders initiatives services

Overweight and Taxation of Promote Create opportunities Interactive or Multicomponent

obesity high-sugar, physical activity for maintenance of personalized interventions,
high-salt, and physical activity in feedback involving education
high-fat foods daily life interventions about healthy diet
Front-of-pack and increasing
nutrition labels opportunities for
Restriction of fast physical education
food advertising
* Actions in bold have an evidence base, and actions in italics are promising but without yet a
strong evidence base, in adolescents and young adults.
HIV, Human immunodeficiency virus; HPV, human papillomavirus; STI, sexually transmitted
infection.
From Patton GC, Sawyer SM, Santelli JS, et al: Our future: a Lancet commission on adolescent
health and wellbeing, Lancet 387:2458, 2016.
choices about certain preferences (e.g., a boy who likes to wear feminine attire)
to limit these to times and environments that are more accepting. Most health
professionals agree that too much focus on curtailing gender-nonconforming
behavior leads to increased shame and undermines the child's self-esteem.
The health professional and family can also assist the child or adolescent to
find others with similar interests (within and beyond the gender-related interests)
to strengthen positive peer support. Equally important are interventions in school
and society to raise awareness and promote accepting and positive attitudes, take
a stand against bullying and abuse, and implement antibullying policies and
initiatives. Gay, lesbian, bisexual, transgender, and straight alliance groups are
helpful in providing a haven for gender-nonconforming youth, as well as
recognizing them as part of diversity to be respected and embraced within the
school system. Healthcare system level approaches are outlined in Table 133.1 .

Table 133.1

Systems-Level Principles Underlying Lesbian, Gay, Bisexual, Transgender,

Questioning (LGBTQ) Youth-Friendly Services
PRINCIPLE DEFINITION EXAMPLES
Availability The presence of healthcare providers with Providers from various disciplines
knowledge, competence, and experience working (e.g., physicians, nonphysician
with young people and with people with current or healthcare professionals) provide care
possibly developing LGBTQ identities, feelings, sensitive to the needs of LGBTQ youth.
and/or behavior Quality of care is high, with LGBTQ
youth (and when appropriate, their
caregivers) universally receiving
recommended screening and
anticipatory guidance.
Accessibility The relative ease with which LGBTQ youth can Clinical services are located near where
obtain care from an available provider LGBTQ youth live, study, work, or
otherwise spend time.
Clinical services are easily obtained,
with expanded hours during evenings
and weekends, same-day urgent
bookings, drop-in visits, and
allowances for late appointments.
Technology (e.g., online patient portals,
email, telemedicine) is increasingly
used to improve access for youth.
Acceptability The extent to which clinical services are culturally The clinic has a policy affirming its
competent and developmentally appropriate for inclusive services for LGBTQ, and the
LGBTQ youth, and to which confidentiality is clinical environment has signs, stickers,
ensured and protected and other statements showing it is
LGBT-friendly.
Health brochures and other reading
materials are tailored to the needs of
Critics have also expressed concern about children with normal variation in
gender role being labeled with a mental disorder perpetuating social stigma, yet
there is a tendency of clinicians to underdiagnose rather than overdiagnose
children whose gender nonconformity goes beyond behavior and who report
gender dysphoria. These children may benefit from the diagnosis to receive early
treatment in the form of support, education, advocacy, and, in case of clinically
significant distress, changes in gender role, puberty suppression, and/or
feminizing or masculinizing hormone therapy in adolescence .
Table 133.2
Summary of DSM-5 Diagnostic Criteria for
Gender Dysphoria
GENDER DYSPHORIA IN CHILDREN (302.6) (F64.2)

A. A marked incongruence between one's experienced/expressed gender and

assigned gender, of at least 6 mo duration, as manifested by at least 6 of the
following (1 of which must be criterion A1):
1. A strong desire to be of the other gender or an insistence that one
is the other gender (or some alternative gender different from
one's assigned gender).
2. In boys (assigned gender), a strong preference for cross-dressing
or simulating female attire; or in girls (assigned gender), a strong
preference for wearing only typical masculine clothing and a
strong resistance to the wearing of typical feminine clothing.
3. A strong preferences for cross-gender roles in make-believe play
or fantasy play.
4. A strong preference for the toys, games, or activities
stereotypically used or engaged in by the other gender.
5. A strong preference for playmates of the other gender.
6. In boys (assigned gender), a strong rejection of typically
masculine toys, games, and activities and a strong avoidance of
rough-and-tumble play; or in girls (assigned gender), a strong
rejection of typically feminine toys, games, and activities.
7. A strong dislike of one's sexual anatomy.
8. A strong desire for the primary and/or secondary sex
characteristics that match one's experienced gender.
 B. The condition is associated with clinically significant distress or
impairment in social, school, or other important areas of functioning.

SPECIFY IF WITH A DISORDER OF SEX DEVELOPMENT (E.G.,

CONGENITAL ADRENAL HYPERPLASIA OR ANDROGEN
INSENSITIVITY SYNDROME)
GENDER DYSPHORIA IN ADOLESCENTS OR ADULTS

A. A marked incongruence between one's experienced/expressed gender and

assigned gender, of at least 6 mo duration, as manifested by at least 2 of the
following:
1. A marked incongruence between one's experienced/expressed
gender and primary and/or secondary sex characteristics (or in
young adolescents, the anticipated secondary sex characteristics).
2. A strong desire to be rid of one's primary and/or secondary sex
characteristics because of a marked incongruence with one's
experienced/expressed gender (or in young adolescents, a desire
to prevent the development of the anticipated secondary sex
characteristics).
3. A strong desire for the primary and/or secondary sex
characteristics of the other gender.
4. A strong desire to be of the other gender (or some alternative
gender different from one's assigned gender).
5. A strong desire to be treated as the other gender (or some
alternative gender different from one's assigned gender).
6. A strong conviction that one has the typical feelings and reactions
of the other gender (or some alternative gender different from
one's assigned gender).
B. The condition is associated with clinically significant distress or
impairment in social, occupational, or other important areas of functioning.

SPECIFY IF WITH A DISORDER OF SEX DEVELOPMENT (E.G.,

CONGENITAL ADRENAL HYPERPLASIA OR ANDROGEN
INSENSITIVITY SYNDROME)

SPECIFY IF POSTTRANSITION: The individual has transitioned to full-

 time living in the desired gender (with or without legalization of gender
change) and has undergone (or is preparing to have) at least one cross-sex
medical procedure or treatment regimen, namely, regular cross-sex
hormone treatment or gender reassignment surgery confirming the
desired gender (e.g., penectomy, vaginoplasty in a natal male;
mastectomy or phalloplasty in a natal female).

Adapted from the American Psychiatric Association: Diagnostic and Statistical

Manual of Mental Disorders , ed 5, Washington, DC, 2013, American
Psychiatric Publishing.

Transgender Identity Development

A stages model of coming out might be helpful to understand the experience and
potential challenges transgender youth might face. In the pre–coming out stage,
the child or adolescent is aware that their gender identity is different from that of
most boys and girls. In addition to a gender identity that varies from sex
assigned at birth, some of these children are also nonconforming in gender
expression while others are not. Those who are also nonconforming in gender
expression cannot hide their transgender identity, are noticed for who they are,
and may face teasing, ridicule, abuse, and rejection. They must learn to cope
with these challenges at an early age and usually proceed quickly to the next
stage of coming out . Children who are not visibly nonconforming in gender
expression are able to avoid stigma and rejection by hiding their transgender
feelings. They often experience a split between their gender identity cherished in
private and expressed in fantasy and a false self presented outwardly to fit in and
meet gendered expectations. These children and adolescents often proceed to
coming out later in adolescence or adulthood.
Coming out involves acknowledging one's transgender identity to self and
others (parents, other caregivers, trusted health providers, peers). An open and
accepting attitude is essential; rejection can perpetuate stigma and its negative
emotional consequences. By accessing transgender community resources,
including peer support (either online or offline), transgender youth can then
proceed to the exploration stage. This is a time of learning as much as possible
about being transgender, getting to know similar others, and experimenting with
various options for gender expression. Changes in gender role are carefully
considered, as are medical interventions to delay puberty and/or feminize or
 Cognitive and affective development in adolescence, Trends Cogn Sci
9:69–74, 2005.)

Table 136.1

Identified Risk and Protective Factors for Adolescent Health Behaviors

PROTECTIVE
BEHAVIOR RISK FACTORS
FACTORS
Smoking Depression and other mental health problems, alcohol use, Family connectedness,
disconnectedness from school or family, difficulty talking with perceived healthiness,
parents, minority ethnicity, low school achievement, peer smoking higher parental
expectations, low
prevalence of smoking in
school
Alcohol and Depression and other mental health problems, low self-esteem, easy Connectedness with
drug misuse family access to alcohol, working outside school, difficulty talking school and family,
with parents, risk factors for transition from occasional to regular religious affiliation
substance misuse (smoking, availability of substances, peer use, other
risk behaviors)
Teenage Deprivation, city residence, low educational expectations, lack of Connectedness with
pregnancy access to sexual health services, drug and alcohol use school and family,
religious affiliation
Sexually Mental health problems, substance misuse Connectedness with
transmitted school and family,
infections religious affiliation
Adapted from McIntiosh N, Helms P, Smyth R, editors. Fofar and Arneil's textbook of pediatrics,
ed 6, Edinburgh, 2003, Churchill Livingstone, pp 1757–1768; and Viner R, Macfarlane A: Health
promotion, BMJ 330:527–529, 2005.

Many adolescents continually confront the task of making healthy choices

while struggling with impulsivity that can lead to unintentional consequences,
such as injuries, sexually transmitted infections (STIs), or drug overdoses.
Adolescents are also challenged with adopting behaviors that will affect their
future adult health, such as eating nutritiously, engaging in physical activity, and
choosing not to use tobacco. Environmental factors, such as family, peers,
school, community, and religiosity, also contribute to adolescents' health and risk
behaviors. The U.S. Centers for Disease Control and Prevention (CDC) Youth
Risk Behavior Surveillance Survey , a school-based survey of a nationally
representative sample of U.S. high school students, demonstrates that youth
begin engaging in behaviors that place their health at risk during adolescence
(Fig. 136.2 ).

FIG. 136.2 Selected health behaviors among 9th and 12th grade high
school students. ENDs, Electronic nicotine delivery system. (Data from
Centers for Disease Control and Prevention: 1991–2015 High school youth
risk behavior survey data. http://nccd.cdc.gov/youthonline .)

Although according to the 2015 CDC National Health Interview Survey

(https://www.cdc.gov/nchs/nhis/shs/tables.htm ), a probability sample survey
conducted annually, an estimated 82% of 12-17 yr olds report excellent or very
good health, 11% reported limitation in usual activities due to one or more
chronic conditions, 10% missed 6-10 school days in the past year, 6% are
uninsured, 6% have no usual place of healthcare, 10% have asthma, 12% have
respiratory allergies, 10% have a learning disability, 14% have attention-
deficit/hyperactivity disorder, and 18% take prescription medications routinely.
In 2014 the mortality rate among adolescents 15-19 yr of age was 45 deaths per
100,000 population. While varying by gender, the leading causes of death
overall among adolescents 15-19 yr of age are (1) unintentional injuries; (2)
suicide; and (3) homicide (Table 136.2 ).

Table 136.2
Leading Causes of Death Among 15-19 Yr Olds by Gender,
United States, 2014*

MALE FEMALE
LEADING
 CAUSES OF Cause of Death Mortality Rate per Cause of Death Mortality Rate per
DEATH 100,000 Population 100,000 Population
#1 Accidents 24.9 Accidents 10.1
(unintentional (unintentional
injuries) injuries)
#2 Intentional self- 13.0 Intentional self- 4.2
harm (suicide) harm (suicide)
#3 Assault (homicide) 11.2 Malignant 2.5
neoplasms
* Based on data from Heron M: Deaths: leading causes for 2014, Natl Vital Stat Rep 65(5), 2016.

Within the adolescent population, disparities in health occur. Adolescent

health outcomes and behaviors vary among populations that can be defined by
race or ethnicity, gender, education or income, disability, geographic location
(e.g., rural or urban), or sexual orientation. Health disparities result from
multiple factors, including poverty, environmental threats, inadequate access to
healthcare, individual and behavioral factors, and educational inequalities (Table
136.3 ).

Table 136.3
Adolescent Health Outcomes by Race/Ethnicity, United
States, 2010–2012

OUTCOME WHITE BLACK AI/AN API HISPANIC

Deaths* 43.5 62.3 49.7 23.1 38.1
Births † 17.3 34.9 27.3 7.7 38.0
Obese ‡ 12.4 16.8 15.9 5.5 § 16.4
Asthma ‡ 22.1 27.8 17.7 17.7 § 22.5
Depressed ‡ 28.6 25.2 34.9 22.9 § 35.3
Chlamydia* 775.2 4,200.8 2,229.6 267.9 § 1,067.0
Gonorrhea* 94.4 1,218.5 393.8 37.6 § 150.6
HIV* 1.8 36.2 4.9 2.8 § 7.0
* 2015 Rates per 100,000 15-19 yr old population by race/ethnicity.

† 2014 Rates of births in per 1,000 15-19 yr old females by race/ethnicity.

‡ Percent high school students reporting health outcome in 2015.

§ Rates of Asian-only race.

AI/AN, American Indian or Alaska Native; API, Asian or Pacific Islander; HIV, human
immunodeficiency virus.
Access to Healthcare
Adolescents in the United States make fewer visits to physicians for ambulatory
office visits than any other age group; school-age children and adolescents are
more likely than younger children to have unmet health needs and delayed
medical care. Adolescents who actually receive preventive care may still not
have access to time alone with their provider to discuss confidential health
issues such as STIs, HIV, or pregnancy prevention. Less than half (40%) of
adolescents have time alone with their healthcare provider during a preventive
healthcare visit; sexually experienced teens report sexual health discussions
more often than nonsexually experienced teens, but the frequency is still low at
64% and 33.5% for sexually experienced females and males, respectively.
Young adults 18-24 yr are more likely to be insured with the 2010 Patient
Protection and Affordable Care Act (ACA ). Currently, the ACA permits
children to receive benefits from their parents' health plans through age 26 yr.
Healthy People provides science-based, 10-yr national objectives for measuring
and improving the health of all Americans by establishing benchmarks and
monitoring progress over time. The Healthy People 2020 agenda includes 11
adolescent-specific objectives with a goal of improving the healthy development,
health, safety, and well-being of adolescents and young adults over the next 10
yr (Table 136.4 ). This science-based initiative is centered around a framework
for public health prevention priorities and actions to improve the health status of
U.S. youth.
Table 136.4
Healthy People 2020 Adolescent Health (AH)
Objectives

• AH-1 : Increase the proportion of adolescents who have had a wellness

checkup in the past 12 months
• AH-2 : Increase the proportion of adolescents who participate in
extracurricular and out-of-school activities
• AH-3 : Increase the proportion of adolescents who are connected to a parent
or other positive adult caregiver
AH-3.1 : Increase the proportion of adolescents who have an adult
in their lives with whom they can talk about serious problems
 AH-3.2 : Increase the proportion of parents who attend events and
activities in which their adolescents participate
• AH-4 : (Developmental) Increase the proportion of adolescents and young
adults who transition to self-sufficiency from foster care
• AH-5 : Increase educational achievement of adolescents and young adults
AH-5.1 (Leading Health Indicator) : Increase the proportion of
students who graduate with a regular diploma 4 years after
starting 9th grade
AH-5.2 : Increase the proportion of students who are served under
the Individuals with Disabilities Education Act who graduate high
school with a diploma
AH-5.3 : Increase the proportion of students whose reading skills
are at or above the proficient achievement level for their grade
AH-5.4 : Increase the proportion of students whose mathematics
skills are at or above the proficient achievement level for their
grade
AH-5.5 : Increase the proportion of adolescents who consider their
school work to be meaningful and important
AH-5.6 : Decrease school absenteeism among adolescents due to
illness or injury
• AH-6 : Increase the proportion of schools with a school breakfast program
• AH-7 : Reduce the proportion of adolescents who have been offered, sold,
or given an illegal drug on school property
• AH-8 : Increase the proportion of adolescents whose parents consider them
to be safe at school
• AH-9 : (Developmental) Increase the proportion of middle and high schools
that prohibit harassment based on a student's sexual orientation or gender
identity
• AH-10 : Decrease the proportion of public schools with a serious violent
incident
• AH-11 : Reduce adolescent and young adult perpetration of, as well as
victimization by, crimes
AH-11.1 : Decrease the rate of minor and young adult perpetration
of violent crimes
AH-11.2 : Decrease the rate of minor and young adult perpetration
of serious property crimes
 AH-11.3 : (Developmental) Decrease the percentage of counties and
cities reporting youth gang activity
AH-11.4 : (Developmental) Reduce the rate of adolescent and
young adult victimization from crimes of violence

From US Department of Health and Human Services: Healthy People 2020,

available at: https://www.healthypeople.gov/2020/topics-
objectives/topic/Adolescent-Health/objectives .

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the 21st century. Lancet . 2012;379:1567–1568.
Catalano RF, Fagan AA, Gavin LE, et al. Worldwide application
of prevention science in adolescent health. Lancet .
2012;379:1653–1662.
Centers for Disease Control and Prevention. Tables of summary
health statistics, National Health Interview Survey .
https://www.cdc.gov/nchs/nhis/shs/tables.htm ; 2015.
Centers for Disease Control and Prevention. HIV surveillance
report . [Vol 27, 2016]
http://www.cdc.gov/hiv/library/reports/hiv-surveillance.html ;
2015.
Centers for Disease Control and Prevention. Sexually
transmitted disease surveillance 2015 . [Atlanta; US
Department of Health and Human Services]
https://www.cdc.gov/std/stats15/default.htm ; 2016.
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school youth risk behavior survey data .
http://nccd.cdc.gov/youthonline .
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dissemination of provider education about adolescent preventive health
guidelines have been demonstrated to improve the content of recommended care
(Table 137.1 ). The ease of recognition or expectation that an adolescent's needs
can be addressed in a setting relates to the visibility and flexibility of sites and
services. Staff at sites should be approachable, linguistically capable, and
culturally competent. Health services should be coordinated to respond to goals
for adolescent health at the local, state, and national levels. The coordination
should address service financing and delivery in a manner that reduces
disparities in care.

Table 137.1
Bright Futures/American Academy of Pediatrics
Recommendations for Preventive Healthcare for 11-21 Yr
Olds

PERIODICITY AND INDICATIONS

HISTORY Annual
MEASUREMENTS
Body mass index Annual
Blood pressure Annual
SENSORY SCREENING
Vision At 12 yr and 15 yr visits or if risk assessment positive
Hearing Screen with audiometry, including 6,000 and 8,000 Hz high frequencies once at 11-
14 yr, once at 15-17 yr, and once at 18-21 yr.
DEVELOPMENTAL/BEHAVIORAL ASSESSMENT
Developmental surveillance Annual
Psychosocial/behavioral Annual
assessment
Depression screening Annual for 12 yr and older
Tobacco, alcohol, and drug If risk assessment positive
use assessment
PHYSICAL Annual
EXAMINATION
PROCEDURES
Immunization* Annual
Hematocrit or hemoglobin If risk assessment positive
Tuberculin test If risk assessment positive
Dyslipidemia screening Once at 9-11 yr, and once at 17-21 yr
STI screening If sexually active
HIV screening † Once between ages 15 and 18 yr
Discuss and offer at earlier age and annually if risk assessment positive.
Cervical dysplasia Beginning at age 21 yr
screening ‡
ORAL HEALTH Annual; refer to dental home
ANTICIPATORY Annual §
 GUIDANCE
* Schedules per the Advisory Committee on Immunization Practices, published annually at

http://www.cdc.gov/vaccines/schedules/hcp/index.html and
http://redbook.solutions.aap.org/SS/Immunization_Schedules.aspx .
† CDC recommends universal, voluntary HIV screening of all sexually active people, beginning at

age 13 yr. The American Academy of Pediatrics recommends offering routine HIV screening to all
adolescents at least once by 16-18 yr of age and to those younger if at risk. US Preventive
Services Task Force recommends offering routine HIV screening to all adolescents age 15 yr and
older at least once and to those younger if at risk. Patients who test positive for HIV should
receive prevention counseling and referral to care before leaving the testing site.
‡ Screening for cervical cancer, April 2012, US Preventive Services Task Force.

http://www.uspreventiveservicestaskforce.org/uspstf/uspscerv.htm .
§ Refer to specific guidance by age as listed in Bright Futures guidelines.

HIV, Human immunodeficiency virus; STI, sexually transmitted infection.

Adapted from Hagan JF, Shaw JS, Duncan PM, editors: Bright Futures: guidelines for health
supervision of infants, children, and adolescents, ed 4, Elk Grove Village, IL, 2017, American
Academy of Pediatrics.

Although most adolescents in the United States have seen a healthcare

provider in the past year and report a usual source of healthcare, adolescents are
less likely to receive preventive care services. According to the 2011 National
Health Interview Survey, an estimated 90% of 12-17 yr old U.S. adolescents had
1 or more contacts with a healthcare professional in the past year, 98% identify a
usual source of care at a physician's office or clinic, and 17% made at least 1
emergency department visit in the past year. Uninsured adolescents are the least
likely to receive care. In 2015, 63% of people under age 19 yr were covered at
some point during the year by private insurance, and 43% of children had public
health insurance at some point during 2015. However, even among adolescents
who are fully insured with a usual source of care, most do not receive preventive
healthcare. An analysis of claims data from a large Minnesota health plan with
approximately 700,000 members found that among patients age 11-18 yr who
were enrolled for at least 4 yr between 1998 and 2007, few received preventive
care visits. One third of adolescents had no preventive care visits from age 13
through 17 yr, and another 40% had only a single such visit. Nonpreventive care
visits were more frequent in all age-groups, averaging about 1 per yr at age 11
yr, climbing to about 1.5 per yr at age 17 yr. Among older adolescents, females
had both more preventive care and more nonpreventive care visits than did
males.
The Patient Protection and Affordable Care Act (ACA) , enacted in March
2010, has expanded access to both commercial health plans and Medicaid for
Department of Health and Human Services, Health Resources and Services
Administration, Maternal and Child Health Bureau, published the 4th edition of
Bright Futures: Guidelines for Health Supervision of Infants, Children, and
Adolescents , which offers providers a strategy for delivery of adolescent
preventive health services with screening and counseling recommendations for
early, middle, and late adolescence (Table 137.2 ). Bright Futures is rooted in the
philosophy of preventive care and reflects the concept of caring for children in a
“medical home.” These guidelines emphasize effective partnerships with parents
and the community to support the adolescent's health and development.

Table 137.2
Adolescent Screening Recommendations

18-21 YR OLD
11-14 YR OLD VISIT 15-17 YR OLD VISIT
VISIT
Universal
Action Action Action
Screening
Cervical N/A N/A Pap smear all
dysplasia* young women at
21 yr visit
Depression Adolescent depression screen Adolescent depression screen Adolescent
beginning at 12 yr visit depression screen
Dyslipidemia Lipid screen once at 9-11 yr Lipid screen once at 17-21 yr Lipid screen once
at 17-21 yr
Hearing Once at 11-14 yr Once at 15-17 yr Once at 18-
Audiometry, including 6,000 and Audiometry, including 6,000 and 21 yr
8,000 Hz high frequencies 8,000 Hz high frequencies Audiometry,
including
6,000 and
8,000 Hz
high
frequencies
HIV † Selective screening (see below) HIV test once at 15-18 yr HIV test once at
15-18 yr
Tobacco, Tobacco, alcohol, or drug use screen Tobacco, alcohol, or drug use screen Tobacco, alcohol,
alcohol, or or drug use screen
drug use
Vision At 12 yr visit At 15 yr visit N/A
Objective measure with age- Objective measure with age-
appropriate visual-acuity appropriate visual-acuity
measurement using HOTV or Lea measurement using HOTV or Lea
symbols, Sloan letters, or Snellen symbols, Sloan letters, or Snellen
letters letters

11-14 YR OLD VISIT 15-17 YR OLD VISIT 18-21 YR OLD VISIT

Risk
Selective Assessment Action If RA+ Action If RA+ Action If RA+
 Screening (RA)

Anemia + on risk Hemoglobin or Hemoglobin or hematocrit Hemoglobin or hematocrit

screening hematocrit
questions
Dyslipidemia + on risk Lipid profile Lipid profile Lipid profile
(if not screening
universally questions and
screened at not previously
this visit screened with
normal results
HIV † + on risk HIV test HIV test (if not HIV test (if not
screening universally screened at universally screened at
questions this visit) this visit)
Oral health Primary water Oral fluoridation Oral fluoridation N/A
(through 16 source fluoride supplementation supplementation
yr visit) deficient
STIs
• Chlamydia Sexually Chlamydia and gonorrhea Chlamydia and gonorrhea Chlamydia and gonorrhea
• Gonorrhea active NAAT (use tests NAAT (use tests NAAT (use tests
females appropriate for population appropriate for population appropriate for population
Sexually and clinical setting) and clinical setting) and clinical setting)
active
males and
+ on risk
screening
questions
• Syphilis Sexually active Syphilis test Syphilis test Syphilis test
and + on risk
screening
questions
Tuberculosis + on risk Tuberculin skin test Tuberculin skin test Tuberculin skin test
screening
questions
Vision at + on risk Objective measure with Objective measure with Objective measure with
other ages screening age-appropriate visual- age-appropriate visual- age-appropriate visual-
questions at 11, acuity measurement using acuity measurement using acuity measurement using
13, and 14 yr HOTV or Lea symbols, HOTV or Lea symbols, HOTV or Lea symbols,
visits Sloan letters, or Snellen Sloan letters, or Snellen Sloan letters, or Snellen
letters letters letters
* Screening for Cervical Cancer. April 2012. U.S. Preventive Services Task Force.
http://www.uspreventiveservicestaskforce.org/uspstf/uspscerv.htm .
† Centers for Disease Control and Prevention recommends universal, voluntary HIV screening of
all sexually active people, beginning at age 13 yr. American Academy of Pediatrics recommends
routine HIV screening offered to all adolescents at least once by 16-18 yr of age and to those
younger if at risk. U.S. Preventive Services Task Force recommends routine HIV screening
offered to all adolescents age 15 yr and older at least once and to those younger if at risk.
Patients who test positive for HIV should receive prevention counseling and referral to care before
leaving the testing site.
NA, Not applicable; NAAT, nucleic acid amplification test; STIs, sexually transmitted infections.
Adapted from Hagan JF, Shaw JS, Duncan PM, editors: Bright Futures: guidelines for health
supervision of infants, children, and adolescents, ed 4, Elk Grove Village, IL, 2017, American
minor consent laws . Some consent laws are based on a minor's status, such as
minors who are emancipated, parents, married, pregnant, in the armed services,
or mature. In some states, minors can be considered emancipated if they are or
have served in the armed services or are living apart from parents and are
economically independent through gainful employment. A mature minor is a
minor who is emotionally and intellectually mature enough to give informed
consent and who lives under the supervision of a parent or guardian. Courts have
held that if a minor is mature, a physician is not liable for providing beneficial
treatment. There is no formal process for recognition of a mature minor. The
determination is made by the healthcare provider.
Some minor consent laws are based on services a minor is seeking, such as
emergency care, sexual healthcare, substance abuse, or mental healthcare (Table
137.3 ). All 50 states and the District of Columbia explicitly allow minors to
consent for their own health services for STIs . Approximately 25% of states
require that minors be a certain age (generally 12-14 yr) before they can consent
for their own care for STIs. No state requires parental consent for STI care or
requires that providers notify parents that an adolescent minor child has received
STI services, except in limited or unusual circumstances.

Table 137.3
Types of Minor Consent Statutes or Rules of Common Law
That Allow for Medical Treatment of a Minor Patient
Without Parental Consent

LEGAL
EXCEPTIONS
TO INFORMED MEDICAL CARE SETTING
CONSENT
REQUIREMENT
The “emergency” • The child is suffering from an emergent condition that places his or her life or health in
exception danger.
• The child's legal guardian is unavailable or unable to provide consent for treatment or
transport.
• Treatment or transport cannot be safely delayed until consent can be obtained.
• The professional administers only treatment for emergent conditions that pose an
immediate threat to the child.
The “emancipated • Married
minor” exception • Economically self-supporting and not living at home
• Active-duty status in the military
• In some states, a minor who is a parent or pregnant
• Some states might require a court to declare the emancipation of a minor.
The “mature Most states recognize a mature minor, in which a minor, usually ≥14 yr, displays sufficient
 minor” exception maturity and intelligence to understand and appreciate the benefits, risks, and alternatives of
the proposed treatment and to make a voluntary and reasonable choice on the basis of that
information. States vary or whether a judicial determination is required.
Exceptions based Minor seeks:
on specific medical • Mental health services
condition (state • Pregnancy and contraceptive services
laws vary) • Testing or treatment for HIV infection or AIDS
• Sexually transmitted infection testing and treatment
• Drug and alcohol addiction treatment
Data from American Academy of Pediatrics: Consent for emergency medical services for children
and adolescents, Pediatrics 128:427–433, 2011.

Minors' right to consent for contraceptive services varies from state to state.
Almost 50% of states and the District of Columbia explicitly authorize all
minors to consent for their own contraceptive services; and 50% of states permit
minors to consent for their own contraceptive services under specific
circumstances, such as being married, a parent, currently or previously pregnant,
over a certain age, or a high school graduate, or per physician's discretion.
A minor's right to consent for mental healthcare and substance abuse
treatment services vary by state and age of minor, whether care is medical vs
nonmedical (e.g., counseling), and whether care is delivered as an inpatient vs
outpatient basis. Minor consent laws often contain provisions regarding
confidentiality and disclosure, even when general state consent laws do not have
such provisions.
The confidentiality of medical information and records of a minor who has
consented for his or her own reproductive healthcare is governed by numerous
federal and state laws. Laws in some states explicitly protect the confidentiality
of STI or contraceptive services for which minors have given their own consent
and do not allow disclosure of the information without the minor's consent. In
other states, laws grant physicians discretion to disclose information to parents.
The confidentiality of medical information and records of a minor who has
consented for his or her own healthcare is also governed by numerous federal
and state laws. Laws in some states explicitly protect the confidentiality of STI,
contraceptive, or mental health services for which minors have given their own
consent, and do not allow disclosure of the information without the minor's
consent. In other states, laws grant physicians discretion to disclose information
to parents. Title X and Medicaid both provide confidentiality protection for
family planning services provided to minors with funding from these programs.
Federal regulations issued under the Federal Health Insurance Portability and
Accountability Act of 1996, known as the HIPAA Privacy Rule , defer to state
and “other applicable laws” with respect to the question of whether parents have
can share even the most personal secret?), self-image (Is there anything you
would like to change about yourself?), depression (What do you see yourself
doing 5 yr from now?), school (How are your grades this year compared with
last year?), personal decisions (Are you feeling pressured to engage in any
behavior for which you do not feel you are ready?), and an eating disorder (Do
you ever feel that food controls you, rather than vice versa?). Bright Futures
materials provide questions and patient encounter forms to structure the
assessments. The HEADS/SF/FIRST mnemonic, basic or expanded, can be
useful in guiding the interview if encounter forms are not available (Table 137.4
). Based on the assessments, appropriate counseling or referrals are
recommended for more thorough probing or for in-depth interviewing.
Table 137.4
Adolescent Psychosocial Assessment:
HEADS/SF/FIRST Mnemonic
H ome. Space, privacy, frequent geographic moves, neighborhood
E ducation/School. Frequent school changes, repetition of a grade/in each
subject, teachers' reports, vocational goals, after-school educational clubs
(e.g., language, speech, math), learning disabilities
A buse. Physical, sexual, emotional, verbal abuse; parental discipline
D rugs. Tobacco, electronic cigarettes or vaping devices, alcohol,
marijuana, inhalants, “club drugs,” “rave” parties, others; drug of choice,
age at initiation, frequency, mode of intake, rituals, alone or with peers,
quit methods, number of attempts
S afety. Seat belts, helmets, sports safety measures, hazardous activities,
driving while intoxicated
S exuality/S exual Identity. Reproductive health (use of contraceptives,
presence of sexually transmitted infections, feelings, pregnancy)
F amily and F riends
Family: Family constellation; genogram;
single/married/separated/divorced/blended family; family
occupations and shifts; history of addiction in first- and second-
degree relatives; parental attitude toward alcohol and drugs;
parental rules; chronically ill, physically or mentally challenged
parent
Friends: Peer cliques and configuration (“preppies,” “jocks,”
 “nerds,” “computer geeks,” cheerleaders), gang or cult
affiliation
I mage. Height and weight perceptions, body musculature and physique,
appearance (including dress, jewelry, tattoos, body piercing as fashion
trends or other statement)
R ecreation. Sleep, exercise, organized or unstructured sports, recreational
activities (television, video games, computer games, internet and chat
rooms, church or community youth group activities [e.g., Boy (BSA)/Girl
Scouts; Big Brother/Sister groups, campus groups]). How many hours per
day, days per week involved?
S pirituality and Connectedness. Use HOPE* or FICA † acronym;
adherence, rituals, occult practices, community service or involvement
T hreats and Violence. Self-harm or harm to others, running away, cruelty
to animals, guns, fights, arrests, stealing, fire setting, fights in school

* HOPE, H ope or security for the future; o rganized religion; p ersonal

spirituality and p ractices; e ffects on medical care and end-of-life issues.

† FICA, Faith beliefs; importance and influence of faith; community support.

From Dias PJ: Adolescent substance abuse: assessment in the office, Pediatr
Clin North Am 49:269–300, 2002.

Physical Examination
Vision Testing
The pubertal growth spurt may involve the optic globe, resulting in its
elongation and myopia in genetically predisposed individuals (see Chapter 636 ).
Vision testing should therefore be performed to detect this problem before it
affects school performance.

Audiometry
Highly amplified music of the kind enjoyed by many adolescents may result in
hearing loss or tinnitus (see Chapter 654 ). A hearing screening is recommended
CHAPTER 138

Transitioning to Adult Care

Cynthia M. Holland-Hall, Gale R. Burstein, Lisa K. Tuchman

The importance of successfully transitioning the care of adolescents with special

healthcare needs (SHCN) from pediatric to adult services has been recognized
for more than 2 decades. Successful transition is associated with improved health
outcomes and quality of life; poorly managed transition may lead to loss of a
medical home and worsening of chronic disease control and previous care.
The American Academy of Pediatrics, in conjunction with other key
professional societies, published detailed, comprehensive guidelines for
incorporating transition services into the medical home for all adolescents,
regardless of the presence or absence of SHCN. These guidelines are based on
expert opinion because the evidence on transition outcomes is limited. This
clinical report emphasizes that transition encompasses much more than simply
the transfer of care to another provider. The guidelines go beyond
recommendations for the pediatric medical home by providing guidance and
practice-based resources for implementing elements of transition support in
family medicine and internal medicine practices. This includes providing
assistance for the patient in adapting to an adult model of healthcare delivery.
Table 138.1 represents the key elements of healthcare transition. Tools to assist
providers with these steps are available online from the National Center for
Health Care Transition Improvement (www.gottransition.org ).
Table 138.1
Key Elements of the Transition of Healthcare
Process
• Written transition policy to be shared with youth, families, providers, and
staff, explaining the process and the responsibilities of all team members
 • Transitioning youth registry to track the progress of each patient through
the transition process
• Longitudinal readiness checklists assessing the youth's ability for
independence, self-management, and communicating with the adult
healthcare system, as well as the family's readiness to assist the patient in
achieving these goals
• Written transition plan documenting the steps to be conducted to meet the
needs identified in the readiness assessment, as well as identifying
appropriate adult care resources
• For youth with SHCN, expanded transition services, including attention to
insurance, entitlements, guardianship, and vocational needs, in addition to
adult subspecialty care
• Appropriate communication between the pediatric and adult medical home
and subspecialists, including a portable medical summary and care plan
delivered to the patient and caregivers
• Transfer of care, within the 18-21 yr old range, to adult providers, to whom
pediatric providers continue to serve as a resource until transition is
complete

The process begins with the development of a transition policy and its
dissemination to all families of young adolescents, ensuring that families
understand that transition planning will be an element of health maintenance and
chronic care management visits throughout the adolescent years. By middle
adolescence, a transition plan should be developed with the youth and family
caregivers and updated at subsequent visits until the patient is ready for
implementation of the adult care model in early adulthood. Periodic readiness
assessments are key to plan and anticipate challenges. Critical to the transition
process is skills training for the adolescent in communication, self-advocacy,
and self-care. Some youth with SHCN depend on caregivers for navigating the
healthcare system on their behalf, and it is not realistic to expect increased
independence. For these youth, addressing guardianship, long-term care
planning, and advanced directives are important. Care coordination has been
found to facilitate navigation and engagement in an adult-oriented health system,
especially for adolescents with SHCN. The goal is to help all youth maximize
their potential as they become young adults.
specific psychiatric diagnoses whose definitions are associated with violent
behavior (Table 139.1 ). They occur with other disorders such as ADHD (see
Chapter 49 ) and increase an adolescent's vulnerability for juvenile delinquency,
substance use or abuse, sexual promiscuity, adult criminal behavior,
incarceration, and antisocial personality disorder. Other co-occurring risk factors
for youth violence include use of anabolic steroids, gang tattoos, belief in one's
premature death, preteen alcohol use, and placement in a juvenile detention
center.

Table 139.1
Oppositional Defiant Disorder, Conduct Disorder, and
Juvenile Delinquency
PSYCHIATRIC DISORDER LABELS
Oppositional Defiant Legal Label Juvenile Delinquency
Conduct Disorder
Disorder
Recurrent pattern of Repetitive and persistent pattern of Offenses that are illegal because of age;
negativistic, defiant, behavior that violates the basic rights illegal acts
disobedient, and hostile of others or major age-appropriate
behavior toward authority societal norms or rules
figures that has a significant
adverse effect on functioning
(e.g., social, academic,
occupational)
Examples: losing temper; Examples: physical fighting, Examples: single or multiple instances
arguing with adults; defying or deceitfulness, stealing, destruction of of being arrested or adjudicated for any
refusing to comply with request property, threatening or causing of the following: stealing, destruction of
or rules of adults; annoying physical harm to people or animals, property, threatening or causing
behavior; blaming others; being driving without a license, prostitution, physical harm to people or animals,
irritable, spiteful, resentful rape (even if not adjudicated in the driving without a license, prostitution,
legal system) rape
Diagnosed by a mental health Diagnosed by a mental health Adjudicated in the legal system
clinician practitioner
From Greydanus DE, Pratt HD, Patel DR, et al: The rebellious adolescent, Pediatr Clin North Am
44:1460, 1997.

Diagnosis
The assessment of an adolescent at risk or with a history of violent behavior or
victimization should be a part of the health maintenance visit of all adolescents.
The answers to questions about recent history of involvement in a physical fight,
carrying a weapon, or firearms in the household, as well as concerns that the
adolescent may have about personal safety, may suggest a problem requiring a
more in-depth evaluation. The FISTS mnemonic provides guidance for
structuring the assessment (Table 139.2 ). The additional factors of physical or
sexual abuse, serious problems at school, poor school performance and
attendance, multiple incidents of trauma, substance use, and symptoms
associated with mental disorders are indications for evaluation by a mental
health professional. In a situation of acute trauma, assault victims are not always
forthcoming about the circumstances of their injuries for fear of retaliation or
police involvement. Stabilization of the injury or the gathering of forensic
evidence in sexual assault is the treatment priority; however, once this is
achieved, addressing a more comprehensive set of issues surrounding the assault
is appropriate.
Table 139.2
FISTS Mnemonic to Assess an Adolescent's
Risk of Violence

F: Fighting (How many fights were you in last year? What was the last?)
I: Injuries (Have you ever been injured? Have you ever injured someone
else?)
S: Sex (Has your partner hit you? Have you hit your partner? Have you
ever been forced to have sex?)
T: Threats (Has someone with a weapon threatened you? What happened?
Has anything changed to make you feel safer?)
S: Self-defense (What do you do if someone tries to pick a fight? Have you
carried a weapon in self-defense?)

The FISTS mnemonic is adapted with permission from the Association of

American Medical Colleges. Alpert EJ, Sege RD, Bradshaw YS: Interpersonal
violence and the education of physicians, Acad Med 72:S41–S50, 1997.

Treatment
In the patient with acute injury secondary to violent assault, the treatment plan
should follow standards established by the American Academy of Pediatrics
model protocol, which includes the stabilization of the injury, evaluation and
violent behaviors.

Table 139.3
WHO Youth Violence Prevention Strategies: Effectiveness
by Context

STRATEGIES CONTEXT/PROGRAMS EFFECTIVENESS

Parenting and early childhood development Home visiting programs ?
strategies Parenting programs +
Early childhood development +
programs
School-based academic and social skills Life and social skills development +
development strategies Bullying prevention +
Academic enrichment programs
Dating violence prevention programs +
Financial incentives for adolescents to ?
attend school
Peer mediation +/−
After-school and other structured ?
leisure-time activities
Strategies for young people at higher risk of, or Therapeutic approaches +
already involved in, violence Vocational training ?
Mentoring ?
Gang and street violence prevention ?
programs
Community- and society-level strategies “Hot spots” policing +
Community- and problem-oriented +
policing
Reducing access to and the harmful +
use of alcohol
Drug control programs +
Reducing access to and misuse of +
firearms
Spatial modification and urban +
upgrading
Poverty deconcentration +
+, Promising (strategies that include 1 or more programs supported by at least 1 well-designed
study showing prevention of perpetration and/or experiencing of youth violence, or at least 2
studies showing positive changes in key risk or protective factors for youth violence).
?, Unclear because of insufficient evidence (strategies that include 1 or more programs of unclear
effectiveness).
+/−, Unclear because of mixed results (strategies for which the evidence is mixed; some
programs have a significant positive effect and others a significant negative effect on youth
violence).
From World Health Organization (WHO) Library Cataloguing-in Publication Data, Preventing youth
violence: an overview of the evidence, 2015.
 Risk factors for adolescent drug use may differ from those associated with
adolescent drug abuse . Adolescent use is more commonly related to social and
peer factors, whereas abuse is more often a function of psychological and
biologic factors. The likelihood that an otherwise normal adolescent would
experiment with drugs may depend on the availability of the drug to the
adolescent, the perceived positive or otherwise functional value to the
adolescent, the perceived risk associated with use, and the presence or absence
of restraints, as determined by the adolescent's cultural or other important value
systems. An adolescent who abuses drugs may have genetic or biologic factors
coexisting with dependence on a particular drug for coping with day-to-day
activities.
Specific historical questions can assist in determining the severity of the drug
problem through a rating system (Table 140.1 ). The type of drug used
(marijuana vs heroin), the circumstances of use (alone or in a group setting), the
frequency and timing of use (daily before school vs occasionally on a weekend),
current mental health status, and general functional status, including sleep habits
and screen use, should all be considered in evaluating any child or adolescent
found to be using a drug. The stage of drug use/abuse should also be considered
(Table 140.2 ). A teen may spend months or years in the experimentation phase
trying a variety of illicit substances, including the most common drugs:
cigarettes, alcohol, and marijuana. Often it is not until regular use of drugs
resulting in negative consequences (problem use) that the teen is identified as
having a problem, either by parents, friends, teachers, or a healthcare provider.
Certain protective factors play a part in buffering the risk factors as well as
assisting in anticipating the long-term outcome of experimentation. Having
emotionally supportive parents with open communication styles, involvement in
organized school activities, having mentors or role models outside the home, and
recognition of the importance of academic achievement are examples of the
important protective factors.

Table 140.1
Assessing the Seriousness of Adolescent Drug Abuse

VARIABLE 0 +1 +2
Age (yr) >15 <15
Sex Male Female
Family history of drug Yes
abuse
 Setting of drug use In group Alone
Affect before drug use Happy Always poor Sad
School performance Good, improving Recently poor
Use before driving None Yes
History of accidents None Yes
Time of week Weekend Weekdays
Time of day After school Before or during school
Type of drug Marijuana, beer, Hallucinogens, Whiskey, opiates, cocaine,
wine amphetamines barbiturates
Total score: 0-3, less worrisome; 3-8, serious; 8-18, very serious.

Table 140.2
Stages of Adolescent Substance Abuse

STAGE DESCRIPTION
1 Potential for abuse
• Decreased impulse control
• Need for immediate gratification
• Available drugs, alcohol, inhalants
• Need for peer acceptance
2 Experimentation: learning the euphoria
• Use of inhalants, tobacco, marijuana, and alcohol with friends
• Few, if any, consequences
• Use may increase to weekends regularly
• Little change in behavior
3 Regular use: seeking the euphoria
• Use of other drugs, e.g., stimulants, LSD, sedatives
• Behavioral changes and some consequences
• Increased frequency of use; use alone
• Buying or stealing drugs
4 Regular use: preoccupation with the “high”
• Daily use of drugs
• Loss of control
• Multiple consequences and risk taking
• Estrangement from family and “straight” friends
5 Burnout: use of drugs to feel normal
• Polysubstance use/cross-addiction
• Guilt, withdrawal, shame, remorse, depression
• Physical and mental deterioration
• Increased risk taking, self-destructive, suicidal

Epidemiology
Alcohol, cigarettes, and marijuana are the most commonly reported substances
used among U.S. teens (Table 140.3 ). The prevalence of substance use and
associated risky behaviors vary by age, gender, race/ethnicity, and other
sociodemographic factors. Younger teenagers tend to report less use of drugs
than do older teenagers, except for inhalants (in 2016, 4.4% in 8th grade, 2.8%
in 10th grade, 1.0% in 12th grade). Males have higher rates of both licit and
illicit drug use than females, with greatest differences seen in their higher rates
of frequent use of smokeless tobacco, cigars, and anabolic steroids. For a
number of years, black 12th graders have reported lifetime, annual, 30-day, and
daily prevalence levels for nearly all drugs that were lower than those for white
or Hispanic 12th graders. That is less true today, with levels of drug use among
blacks more similar to the other groups.

Table 140.3
Trends in Annual Prevalence (%) of Use of Various Drugs
for Grades 8, 10, and 12 Combined

1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005
Any illicit drug c 20.2 19.7 23.2 27.6 31.0 33.6 34.1 32.2 31.9 31.4 31.8 30.2 28.4 27.6 27.1
Any illicit drug 12.0 12.0 13.6 14.6 16.4 17.0 16.8 15.8 15.6 15.3 16.3 14.6 13.7 13.5 13.1
other than ‡
marijuana c
Any illicit drug 23.5 23.2 26.7 31.1 34.1 36.6 36.7 35.0 34.6 34.1 34.3 32.3 30.8 30.1 30.1
including
inhalants c
Marijuana/hashish 15.0 14.3 17.7 22.5 26.1 29.0 30.1 28.2 27.9 27.2 27.5 26.1 24.6 23.8 23.4
Synthetic ― ― ― ― ― ― ― ― ― ― ― ― ― ― ―
marijuana
Inhalants 7.6 7.8 8.9 9.6 10.2 9.9 9.1 8.5 7.9 7.7 6.9 6.1 6.2 6.7 7.0
Hallucinogens 3.8 4.1 4.8 5.2 6.6 7.2 6.9 6.3 6.1 5.4 ‡ 6.0 4.5 4.1 4.0 3.9
LSD 3.4 3.8 4.3 4.7 5.9 6.3 6.0 5.3 5.3 4.5 4.1 2.4 1.6 1.6 1.5
Hallucinogens 1.3 1.4 1.7 2.2 2.7 3.2 3.2 3.1 2.9 2.8 ‡ 4.0 3.7 3.6 3.6 3.4
other than LSD
Ecstasy (MDMA), ― ― ― ― ― 3.1 3.4 2.9 3.7 5.3 6.0 4.9 3.1 2.6 2.4
d original

MDMA, revised ― ― ― ― ― ― ― ― ― ― ― ― ― ― ―
Salvia ― ― ― ― ― ― ― ― ― ― ― ― ― ― ―
Cocaine 2.2 2.1 2.3 2.8 3.3 4.0 4.3 4.5 4.5 3.9 3.5 3.7 3.3 3.5 3.5
Crack 1.0 1.1 1.2 1.5 1.8 2.0 2.1 2.4 2.2 2.1 1.8 2.0 1.8 1.7 1.6
Other cocaine 2.0 1.8 2.0 2.3 2.8 3.4 3.7 3.7 4.0 3.3 3.0 3.1 2.8 3.1 3.0
Heroin 0.5 0.6 0.6 0.9 1.2 1.3 1.3 1.2 1.3 1.3 0.9 1.0 0.8 0.9 0.8
With a needle ― ― ― ― 0.7 0.7 0.7 0.7 0.7 0.5 0.5 0.5 0.5 0.5 0.5
Without a needle ― ― ― ― 0.9 0.9 1.0 0.9 1.0 1.1 0.7 0.7 0.6 0.7 0.7
OxyContin ― ― ― ― ― ― ― ― ― ― ― 2.7 3.2 3.3 3.4
Vicodin ― ― ― ― ― ― ― ― ― ― ― 6.0 6.6 5.8 5.7
Amphetamines c 7.5 7.3 8.4 9.1 10.0 10.4 10.1 9.3 9.0 9.2 9.6 8.9 8.0 7.6 7.0
Ritalin ― ― ― ― ― ― ― ― ― ― 4.2 3.8 3.5 3.6 3.3
Adderall ― ― ― ― ― ― ― ― ― ― ― ― ― ― ―
Methamphetamine ― ― ― ― ― ― ― ― 4.1 3.5 3.4 3.2 3.0 2.6 2.4
Bath salts ― ― ― ― ― ― ― ― ― ― ― ― ― ― ―
(synthetic
stimulants)
Tranquilizers 2.8 2.8 2.9 3.1 3.7 4.1 4.1 4.4 4.4 4.5 ‡ 5.5 5.3 4.8 4.8 4.7
OTC cough/cold ― ― ― ― ― ― ― ― ― ― ― ― ― ― ―
medicines
Rohypnol ― ― ― ― ― 1.1 1.1 1.1 0.8 0.7 0.9 ‡ 0.8 0.8 0.9 0.8
GHB b ― ― ― ― ― ― ― ― ― 1.4 1.2 1.2 1.2 1.1 0.8
Ketamine b ― ― ― ― ― ― ― ― ― 2.0 1.9 2.0 1.7 1.3 1.0
Alcohol 67.4 66.3 59.7 60.5 60.4 60.9 61.4 59.7 59.0 59.3 58.2 55.3 54.4 54.0 51.9
‡
Been drunk 35.8 34.3 34.3 35.0 35.9 36.7 36.9 35.5 36.0 35.9 35.0 32.1 31.2 32.5 30.8
Flavored alcoholic ― ― ― ― ― ― ― ― ― ― ― ― ― 44.5 43.9
beverages
Alcoholic ― ― ― ― ― ― ― ― ― ― ― ― ― ― ―
beverages
containing
caffeine
Any vaping ― ― ― ― ― ― ― ― ― ― ― ― ― ― ―
Vaping nicotine ― ― ― ― ― ― ― ― ― ― ― ― ― ― ―
Vaping marijuana ― ― ― ― ― ― ― ― ― ― ― ― ― ― ―
Vaping just ― ― ― ― ― ― ― ― ― ― ― ― ― ― ―
flavoring
Dissolvable ― ― ― ― ― ― ― ― ― ― ― ― ― ― ―
tobacco products
Snus ― ― ― ― ― ― ― ― ― ― ― ― ― ― ―
Steroids 1.2 1.1 1.0 1.2 1.3 1.1 1.2 1.3 1.7 1.9 2.0 2.0 1.7 1.6 1.3

PEAK YEAR–2017
2016– CHANGE
2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2017
CHANGE Absolute
Change
Any illicit drug c 25.8 24.8 24.9 25.9 27.3 27.6 27.1 28.6 27.2 26.8 25.3 26.5 +1.2 -0.7
‡
Any illicit drug 12.7 12.4 11.9 11.6 11.8 11.3 10.8 11.4‡ 10.9 10.5 9.7 9.4 -0.3 -1.5 ss
other than
marijuana c
Any illicit drug 28.7 27.6 27.6 28.5 29.7 29.8 29.0 30.5 28.5 28.4 26.3 28.3 +2.0 ss -0.2
including ‡
inhalants c
Marijuana/hashish 22.0 21.4 21.5 22.9 24.5 25.0 24.7 25.8 24.2 23.7 22.6 23.9 +1.3 s -6.2 sss
Synthetic ― ― ― ― ― ― 8.0 6.4 4.8 4.2 3.1 2.8 -0.4 s -5.2 sss
marijuana
Inhalants 6.9 6.4 6.4 6.1 6.0 5.0 4.5 3.8 3.6 3.2 2.6 2.9 +0.2 -7.3 sss
Hallucinogens 3.6 3.8 3.8 3.5 3.8 3.7 3.2 3.1 2.8 2.8 2.8 2.7 0.0 -3.2 sss
LSD 1.4 1.7 1.9 1.6 1.8 1.8 1.6 1.6 1.7 1.9 2.0 2.1 +0.1 -4.3 sss
Ecstasy (MDMA), 2.7 3.0 2.9 3.0 3.8 3.7 2.5 2.8 2.2 ― ― ― ― ―
d original
MDMA, revised ― ― ― ― ― ― ― ― 3.4 2.4 1.8 1.7 -0.1 -1.6 sss
Salvia ― ― ― ― 3.5 3.6 2.7 2.3 1.4 1.2 1.2 0.9 -0.3 ss -2.7 sss
Cocaine 3.5 3.4 2.9 2.5 2.2 2.0 1.9 1.8 1.6 1.7 1.4 1.6 +0.2 -2.9 sss
 Crack 1.5 1.5 1.3 1.2 1.1 1.0 0.9 0.8 0.7 0.8 0.6 0.7 +0.1 -1.7 sss
Other cocaine 3.1 2.9 2.6 2.1 1.9 1.7 1.7 1.5 1.5 1.5 1.2 1.3 +0.1 -2.7 sss
Heroin 0.8 0.8 0.8 0.8 0.8 0.7 0.6 0.6 0.5 0.4 0.3 0.3 0.0 -1.0 sss
With a needle 0.5 0.5 0.5 0.5 0.6 0.5 0.4 0.4 0.4 0.3 0.3 0.2 0.0 -0.5 sss
Without a needle 0.6 0.7 0.6 0.5 0.6 0.5 0.4 0.4 0.3 0.3 0.2 0.2 0.0 -0.9 sss
OxyContin 3.5 3.5 3.4 3.9 3.8 3.4 2.9 2.9 2.4 2.3 2.1 1.9 -0.2 -2.0 sss
Vicodin 6.3 6.2 6.1 6.5 5.9 5.1 4.3 3.7 3.0 2.5 1.8 1.3 -0.5 -5.2 sss
Amphetamines c 6.8 6.5 5.8 5.9 6.2 5.9 5.6 7.0 ‡ 6.6 6.2 5.4 5.0 -0.4 -1.6 sss
Ritalin 3.5 2.8 2.6 2.5 2.2 2.1 1.7 1.7 1.5 1.4 1.1 0.8 -0.2 -3.4 sss
Adderall ― ― ― 4.3 4.5 4.1 4.4 4.4 4.1 4.5 3.9 3.5 -0.3 -0.5 s
Methamphetamine 2.0 1.4 1.3 1.3 1.3 1.2 1.0 1.0 0.8 0.6 0.5 0.5 0.0 -3.6 sss
Bath salts ― ― ― ― ― ― 0.9 0.9 0.8 0.7 0.8 0.5 -0.3 s -0.4 s
(synthetic
stimulants)
Tranquilizers 4.6 4.5 4.3 4.5 4.4 3.9 3.7 3.3 3.4 3.4 3.5 3.6 +0.1 -1.9 sss
OTC cough/cold 5.4 5.0 4.7 5.2 4.8 4.4 4.4 4.0 3.2 3.1 3.2 3.0 -0.2 -2.4 sss
medicines
Rohypnol 0.7 0.8 0.7 0.6 0.8 0.9 0.7 0.6 0.5 0.5 0.7 0.5 -0.2 s -0.5 sss
GHB b 0.9 0.7 0.9 0.9 0.8 0.8 ― ― ― ― ― ― ― ―
Ketamine b 1.1 1.0 1.2 1.3 1.2 1.2 ― ― ― ― ― ― ― ―
Alcohol 50.7 50.2 48.7 48.4 47.4 45.3 44.3 42.8 40.7 39.9 36.7 36.7 0.0 -24.7 sss
Been drunk 30.7 29.7 28.1 28.7 27.1 25.9 26.4 25.4 23.6 22.5 20.7 20.4 -0.3 -16.5 sss
Flavored alcoholic 42.4 40.8 39.0 37.8 35.9 33.7 32.5 31.3 29.4 28.8 25.3 25.9 +0.5 -18.6 sss
beverages
Alcoholic ― ― ― ― ― 19.7 18.6 16.6 14.3 13.0 11.2 10.6 -0.6 -9.1 sss
beverages
containing
caffeine
Any vaping ― ― ― ― ― ― ― ― ― ― ― 21.5 ― ―
Vaping nicotine ― ― ― ― ― ― ― ― ― ― ― 13.9 ― ―
Vaping marijuana ― ― ― ― ― ― ― ― ― ― ― 6.8 ― ―
Vaping just ― ― ― ― ― ― ― ― ― ― ― 17.2 ― ―
flavoring
Dissolvable ― ― ― ― ― ― 1.4 1.4 1.2 1.1 0.9 0.9 0.0 -0.5
tobacco products
Snus ― ― ― ― ― ― 5.6 4.8 4.1 3.8 3.6 2.6 -1.0 sss -3.0 sss
Steroids 1.3 1.1 1.1 1.0 0.9 0.9 0.9 0.9 0.9 1.0 0.8 0.8 0.0 -1.2 sss
a The proportional change is the percent by which the most recent year deviates from the peak

year (or the low year) for the drug in question. Thus, if a drug was at 20% prevalence in the peak
year and declined to 10% prevalence in the most recent year, this would reflect a proportional
decline of 50%.
b Question was discontinued among 8th and 10th graders in 2012.

c In 2013, for the questions on the use of amphetamines, the text was changed on 2 of the
questionnaire forms for 8th and 10th graders and 4 of the questionnaire forms for 12th graders.
This change also impacted the any illicit drug indices. Data presented here include only the
changed forms beginning in 2013.
d In 2014, the text was changed on 1 of the questionnaire forms for 8th, 10th, and 12th graders to
include “Molly” in the description. The remaining forms were changed in 2015. Data for both
versions of the question are presented here.
considered in the differential diagnosis of a teen with an altered sensorium
(Table 140.5 ). An adolescent presenting to an emergency setting with an
impaired sensorium should be evaluated for substance use as a part of the
differential diagnosis (Table 140.6 ). Screening for substance use is
recommended for patients with psychiatric and behavioral diagnoses. Other
clinical manifestations of substance use are associated with the route of use;
intravenous drug use is associated with venous “tracks” and needle marks, and
nasal mucosal injuries are associated with nasal insufflation of drugs. Seizures
can be a direct effect of drugs such as cocaine, synthetic marijuana, and
amphetamines or an effect of drug withdrawal in the case of barbiturates or
tranquilizers.

Table 140.5
Common Names and Salient Features of Club Drugs Used
Recreationally

γ- γ- 1,4-
MDMA EPHEDRINE KETAMINE
HYDROXYBUTYRATE BUTYROLACTONE BUTANEDIOL
Common Ecstasy, Herbal Liquid Ecstasy, goop Blue nitro, longevity, Thunder nectar, K, special K,
name XTC, Ecstasy, herbal soap, Georgia homeboy, revivarant, GH serenity, pine vitamin K,
E, X, fuel, zest grievous bodily harm revitalizer, gamma G, needle extract, ket, kat
Adam, nitro, insom-X, zen, enliven,
hug remforce, firewater, revitalize plus,
drug, invigorate lemon drops
Molly
Duration of 4-6 hr 4-6 hr 1.5-3.5 hr 1.5-3.5 hr 1.5-3.5 hr 1-3 hr
action
Elimination 8-9 hr 5-7 hr 27 min ND ND 2 hr
half-life
Peak plasma 1-3 hr 2-3 hr 20-60 min* 15-45 min 15-45 min 20 min
concentration
Physical No No Yes Yes Yes No
dependence
Antidote No No No No No No

DEA I None III None None III

schedule
Detection Yes † Yes † No No No No
with routine
drug screen
Best GC/MS GC/MS (4 hr– GC/MS (1-12 hr) GC/MS (1-12 hr) GC/MS (1-12 GC/MS (1
detection (4 hr–2 2 days) hr) day)
method (time days)
frame)
* Depends on dose.
† Concentrations that are sufficiently high can give positive results for amphetamine because of

cross-reactions.
‡ Flunitrazepam can give positive results for benzodiazepines; ketamine can give positive results

for phencyclidine.
DEA, U.S. Drug Enforcement Agency, currently reviewing possibility of flunitrazepam being placed
into schedule of the U.S. Controlled Substance Act; GC/MS, gas chromatography–mass
spectroscopy. Duration, half-life, and peak plasma are probably different after high or sequential
doses because of nonlinear kinetics; ND, not determined in humans.
Modified from Ricaurte GA, McCann UD: Recognition and management of complications of new
recreational drug use. Lancet 365:2137–2145, 2005.

Table 140.6
Most Common Toxic Syndromes
ANTICHOLINERGIC SYNDROMES
Common Delirium with mumbling speech, tachycardia, dry, flushed skin, dilated pupils, myoclonus, slightly
signs elevated temperature, urinary retention, and decreased bowel sounds. Seizures and dysrhythmias may
occur in severe cases.
Common Antihistamines, antiparkinsonian medication, atropine, scopolamine, amantadine, antipsychotic agents,
causes antidepressant agents, antispasmodic agents, mydriatic agents, skeletal muscle relaxants, and many
plants (notably jimsonweed and Amanita muscaria ).
SYMPATHOMIMETIC SYNDROMES
Common Delusions, paranoia, tachycardia (or bradycardia if the drug is a pure α-adrenergic agonist),
signs hypertension, hyperpyrexia, diaphoresis, piloerection, mydriasis, and hyperreflexia. Seizures,
hypotension, and dysrhythmias may occur in severe cases.
Common Cocaine, amphetamine, methamphetamine (and its derivatives 3,4-methylenedioxyamphetamine, 3,4-
causes methylenedioxymethamphetamine, 3,4-methylenedioxyethamphetamine, and 2,5-dimethoxy-4-
bromoamphetamine), some synthetic marijuana, and OTC decongestants (phenylpropanolamine,
ephedrine, and pseudoephedrine). In caffeine and theophylline overdoses, similar findings, except for
the organic psychiatric signs, result from catecholamine release.
OPIATE, SEDATIVE, OR ETHANOL INTOXICATION
Common Coma, respiratory depression, miosis, hypotension, bradycardia, hypothermia, pulmonary edema,
signs decreased bowel sounds, hyporeflexia, and needle marks. Seizures may occur after overdoses of some
narcotics, notably propoxyphene.
Common Narcotics, barbiturates, benzodiazepines, ethchlorvynol, glutethimide, methyprylon, methaqualone,
causes meprobamate, ethanol, clonidine, and guanabenz.
CHOLINERGIC SYNDROMES
Common Confusion, central nervous system depression, weakness, salivation, lacrimation, urinary and fecal
signs incontinence, gastrointestinal cramping, emesis, diaphoresis, muscle fasciculations, pulmonary edema,
miosis, bradycardia or tachycardia, and seizures.
Common Organophosphate and carbamate insecticides, physostigmine, edrophonium, and some mushrooms.
causes
From Kulig K: Initial management of ingestions of toxic substances, N Engl J Med 326:1678,
1992. ©1992 Massachusetts Medical Society. All rights reserved.
Screening for Substance Abuse
Disorders
In a primary care setting the annual health maintenance examination provides an
opportunity for identifying adolescents with substance use or abuse issues. The
direct questions as well as the assessment of school performance, family
relationships, and peer activities may necessitate a more in-depth interview if
there are suggestions of difficulties in those areas. Several self-report screening
questionnaires also are available, with varying degrees of standardization,
length, and reliability. The CRAFFT mnemonic is specifically designed to
screen for adolescents' substance use in the primary setting (Table 140.7 ).
Privacy and confidentiality must be established when asking the teen about
specifics of their substance experimentation or use. Interviewing the parents can
provide additional perspective on early warning signs that go unnoticed or
disregarded by the teen. Examples of early warning signs of teen substance use
are change in mood, appetite, or sleep pattern; decreased interest in school or
school performance; loss of weight; secretive behavior about social plans; or
valuables such as money or jewelry missing from the home. The use of urine
drug screening is recommended when select circumstances are present: (1)
psychiatric symptoms to rule out comorbidity or dual diagnoses, (2) significant
changes in school performance or other daily behaviors, (3) frequently occurring
accidents, (4) frequently occurring episodes of respiratory problems, (5)
evaluation of serious motor vehicular or other injuries, and (6) as a monitoring
procedure for a recovery program. Table 140.8 shows common tests used for
detection by substance, along with the approximate retention time between use
and identification in the urine. Most initial screening uses an immunoassay
method, such as the enzyme-multiplied immunoassay technique, followed by a
confirmatory test using highly sensitive, highly specific gas chromatography–
mass spectrometry. The substances that can cause false-positive results should be
considered, especially when there is a discrepancy between the physical findings
and the urine drug screen result. In 2007 the American of Academy of Pediatrics
(AAP) released guidelines that strongly discourage routine home-based or
school-based testing.
Table 140.7
CRAFFT Mnemonic Tool
 • Have you ever ridden in a C ar driven by someone (including yourself) who
was high or had been using alcohol or drugs?
• Do you ever use alcohol or drugs to R elax, feel better about yourself or fit
in?
• Do you ever use alcohol or drugs while you are by yourself (A lone)?
• Do you ever F orget things you did while using alcohol or drugs?
• Do your Family or F riends ever tell you that you should cut down on your
drinking or drug use?
• Have you ever gotten into T rouble while you were using alcohol or drugs?

From the Center for Adolescent Substance Abuse Research (CeASAR): The
CRAFFT screening interview. (Copyright John R. Knight, MD, Boston
Children's Hospital, 2015.)

Table 140.8
Urine Screening for Drugs Commonly Abused by
Adolescents

APPROXIMATE
MAJOR FIRST SECOND
DRUG INITIAL RETENTION
METABOLITE CONFIRMATION CONFIRMATION
TIME
Alcohol (blood) Acetaldehyde GC IA 7-10 hr
Alcohol (urine) Acetaldehyde GC IA 10-13 hr
Amphetamines TLC IA GC, GC/MS 48 hr
Barbiturates IA TLC GC, GC/MS Short-acting (24
hr); long-acting (2-
3 wk)
Benzodiazepines IA TLC GC, GC/MS 3 days
Cannabinoids Carboxy- and IA TLC GC/MS 3-10 days
hydroxymetabolites (occasional user);
1-2 mo (chronic
user)
Cocaine Benzoylecgonine IA TLC GC/MS 2-4 days
Methaqualone Hydroxylated TLC IA GC/MS 2 wk
metabolites
Opiates
Heroin Morphine IA TLC GC, GC/MS 2 days
Glucuronide
Morphine Morphine IA TLC GC, GC/MS 2 days
Glucuronide
Codeine Morphine IA TLC GC, GC/MS 2 days
Glucuronide
 Phencyclidine TLC IA GC, GC/MS 8 days
GC, Gas chromatography; IA, immunoassay; MS, mass spectrometry; TLC, thin-layer
chromatography.
Modified from Drugs of abuse—urine screening [physician information sheet], Los Angeles,
Pacific Toxicology. From MacKenzie RG, Kipke MD: Substance use and abuse. In Friedman SB,
Fisher M, Schonberg SK, editors: Comprehensive adolescent health care, St Louis, 1998, Mosby.

Diagnosis
The Diagnostic and Statistical Manual of Mental Disorders (DSM-5) no longer
identifies substance use disorders as those of abuse or of dependence . A
substance use disorder is defined by a cluster of cognitive, behavioral, and
physiologic symptoms that indicate that an adolescent is using a substance even
though there is evidence that the substance is harming the adolescent. Even after
detoxification, a substance use disorder may leave persisting changes in brain
circuits with resulting behavioral changes. There are 11 criteria that describe a
pathologic pattern of behaviors related to use of the substance, falling into 4
categories: impaired control, social impairment, increased risk, and
pharmacologic criteria. The 1st category, impaired control , describes an
individual taking increasing amounts of the substance who expresses a persistent
desire to decrease use, with unsuccessful efforts. The individual may spend a
great deal of time obtaining the substance, using the substance, or recovering
from its effects and expresses an intense desire for the drug, usually in settings
where the drug had been available, such as a specific type of social situation.
The 2nd cluster of criteria (5-7) reflects social impairment, including the
inability to perform as expected in school, at home, or at a job; increasing social
problems; and withdrawing from the family. The 3rd cluster of 2 criteria
addresses increased risk associated with use of the substance, and the 4th
cluster includes 2 criteria addressing pharmacologic responses (tolerance
and/or withdrawal). The total number of criteria present is associated with a
determination of a mild, moderate, or severe disorder.
These criteria may have limitations with adolescents because of differing
patterns of use, developmental implications, and other age-related consequences.
Adolescents who meet diagnostic criteria should be referred to a program for
substance use disorder treatment unless the primary care physician has additional
training in addiction medicine.
assistance from a health professional qualified in substance abuse management
should be obtained.

Prevention
Preventing drug use among children and teens requires prevention efforts aimed
at the individual, family, school, and community levels. The National Institute on
Drug Abuse (NIDA) of the U.S. National Institutes of Health has identified
essential principles of successful prevention programs. Programs should enhance
protective factors (parent support) and reduce risk factors (poor self-control);
should address all forms of drug abuse (legal and illegal); should address the
specific type(s) of drug abuse within an identified community; and should be
culturally competent to improve effectiveness (Table 140.9 ). The highest-risk
periods for substance use in children and adolescents are during life transitions,
such as the move from elementary school to middle school, or from middle
school to high school. Prevention programs need to target these emotionally and
socially intense times for teens to adequately anticipate potential substance use
or abuse. Examples of effective research-based drug abuse prevention programs
featuring a variety of strategies are listed on the NIDA website
(www.drugabuse.gov ), and on the Center for Substance Abuse Prevention
website (www.prevention.samhsa.gov ).

Table 140.9

Domains of Risk and Protective Factors for Substance Abuse Prevention

RISK FACTORS DOMAIN PROTECTIVE FACTORS
Early aggressive behavior Individual Self-control
Lack of parental supervision Family Parental monitoring
Substance abuse Peer Academic competence
Drug availability School Anti–drug use policies
Poverty Community Strong neighborhood attachment
From National Institute on Drug Abuse: Preventing drug use among children and adolescents: a
research-based guide for parents, educators, and community leaders, NIH Pub No 04-4212(B),
ed 2, Bethesda, MD, 2003, NIDA.

140.1
(50.8%); higher among 11th-grade female (72.1%) and 12th-grade female
(75.2%) than 9th-grade female (53.0%) and higher among 10th-grade male
(58.8%), 11th-grade male (68.7%), and 12th-grade male (71.5%) than 9th-grade
male (48.9%) students.
Multiple factors can affect a young teen's risk of developing a drinking
problem at an early age (Table 140.10 ). One third of high school seniors admit
to combining drinking behaviors with other risky behaviors, such as driving or
taking additional substances. Binge drinking remains especially problematic
among the older teens and young adults; 31% of high school seniors report
having 5 or more drinks in a row in the last 30 days. Higher use is seen in males
(23.8%) than in females (19.8%), and whites (24.0%) and Hispanics (24.2%)
than in blacks (12.4%). Teens with binge-drinking patterns are more likely to be
assaulted, engage in high-risk sexual behaviors, have academic problems, and be
injured than those teens without binge drinking patterns.
Table 140.10
Risk Factors for a Teen Developing a
Drinking Problem
Family Risk Factors

• Low parental supervision

• Poor parent to teen communication
• Family conflicts
• Severe or inconsistent family discipline
• Having a parent with an alcohol or drug problem

Individual Risk Factors

• Poor impulse control

• Emotional instability
• Thrill-seeking behaviors
• Behavioral problems
• Perceived risk of drinking is low
• Begins drinking before age 14 yr
depression occurs. Its inhibitory effect on pituitary antidiuretic hormone release
is responsible for its diuretic effect. The gastrointestinal (GI) complications of
alcohol use can occur from a single large ingestion. The most common is acute
erosive gastritis , manifesting as epigastric pain, anorexia, vomiting, and heme-
positive stools. Less frequently, vomiting and mid-abdominal pain may be
caused by acute alcoholic pancreatitis ; diagnosis is confirmed by the finding of
elevated serum amylase and lipase levels.

Diagnosis
Primary care settings provide the opportunity to screen teens for alcohol use or
problem behaviors. Brief alcohol screening instruments such as CRAFFT (see
Table 140.7 ) or AUDIT (Alcohol Use Disorders Identification Test, Table
140.11 ) perform well in a clinical setting as techniques to identify alcohol use
disorders. A score of ≥8 on the AUDIT questionnaire identifies people who drink
excessively and who would benefit from reducing or ceasing drinking. Teenagers
in the early phases of alcohol use exhibit few physical findings. Recent use of
alcohol may be reflected in elevated GGT and aspartate transaminase levels.

Table 140.11
Alcohol Use Disorders Identification Test (AUDIT)

SCORE (0-4)*
1. How often do you have a drink containing alcohol? Never (0) to more than
4 per wk (4)
2. How many drinks containing alcohol do you have on a typical day? One or 2 (0) to more
than 10 (4)
3. How often do you have 6 or more drinks on 1 occasion? Never (0) to daily or
almost daily (4)
4. How often during the last year have you found that you were not able to stop drinking Never (0) to daily or
once you had started? almost daily (4)
5. How often during the last year have you failed to do what was normally expected Never (0) to daily or
from you because of drinking? almost daily (4)
6. How often during the last year have you needed a first drink in the morning to get Never (0) to daily or
yourself going after a heavy drinking session? almost daily (4)
7. How often during the last year have you had a feeling of guilt or remorse after Never (0) to daily or
drinking? almost daily (4)
8. How often during the last year have you been unable to remember what happened the Never (0) to daily or
night before because you had been drinking? almost daily (4)
9. Have you or someone else been injured as a result of your drinking? No (0) to yes, during
the last year (4)
10. Has a relative, friend, doctor or other health worker been concerned about your No (0) to yes, during
drinking or suggested that you should cut down? the last year (4)
responsive to messages that emphasize the effects of tobacco use on appearance,
breath, and sports performance; lack of benefit for weight loss; monetary cost of
tobacco addiction; and deceptive marketing by the tobacco industry.
The approach to smoking cessation in adolescents includes the 5 A s (ask,
advise, assess, assist, and arrange) and use of nicotine replacement therapy
(NRT) in addicted teens who are motivated to quit. Consensus panels
recommend the 5 As, although evidence of efficacy in adolescents is limited.
Studies of the NRT patch in adolescents suggest a positive effect on reducing
withdrawal symptoms; pharmacotherapy should be combined with behavioral
therapy to increase cessation and lower relapse rates. In a limited number of
studies, cessation rates of 15% were reported at 3 and 6 mo. NRT is also
available as a gum, inhaler, nasal spray, lozenge, or microtab (Table 140.12 ).
Medications such as bupropion and varenicline improve smoking cessation rates
in adults but are not FDA approved for use in adolescents <18 yr old.
Preliminary studies in adolescents report cessation efficacy with 150 mg of
bupropion twice daily. In postmarketing surveillance, suicidal ideation and
suicide have been reported among patients taking bupropion and varenicline.

Table 140.12
Smoking Cessation Pharmacotherapy Available in the
United States

FDA-
THERAPY APPROVED STUDIED IN QUIT
NAME STRENGTHS ADULT AVAILABILITY*
BRAND ADOLESCENTS DATE
DOSING
NICOTINE REPLACEMENT THERAPY
Gum ‡ Nicorette 2 mg, 4 mg The 4-mg OTC* Yes
strength
should be
used by
patients
who smoke
≥25
cigarettes a
day;
otherwise,
2-mg
strength
should be
used.
Wk 1-6: 1
piece every
 1-2 hr
Wk 7-9: 1
piece every
2-4 hr
Wk 10-12:
1 piece
every 4-8 hr
Inhaler Nicotrol 4 mg 6-16 cartridges a Rx No
Inhaler day for up to 12
wk
Lozenge Commit, 2 mg, 4 mg The 4-mg OTC No Prior to
Nicorette strength beginning
mini should be nicotine
used by replacement
patients therapy
who smoke
1st cigarette
within 30
min of
waking;
otherwise,
2-mg
strength
should be
used.
Wk 1-6: 1
lozenge
every 1-2 hr
Wk 7-9: 1
lozenge
every 2-4 hr
Wk 10-12:
1 lozenge
every 4-8 hr
Nasal Spray Nicotrol 0.5 mg/spray 1-2 sprays/hr up Rx Yes
NS to a maximum
of 80 sprays per
day

Transdermal NicoDerm 7, 14, 21 For patients OTC Yes

Patch ‡ CQ mg/24 hr who smoke
>10
cigarettes
daily:
Step 1: one
21-mg
patch daily
for wk 1-6
Step 2: one
14-mg
patch daily
for wk 7-8
Step 3: one
7-mg patch
daily for wk
 9-10
For patients
who smoke
<10
cigarettes
daily:
Begin with
14-mg
patch daily
for 6 wk,
followed by
7-mg patch
for 2 wk.
NONNICOTINE THERAPY
Bupropion Zyban 150-mg 150 mg PO in Rx Yes 1 wk after
SR ‡ sustained- morning for 3 starting
release tablets days, then therapy
increase to 150
mg PO bid
Varenicline Chantix 0.5-, 1-mg 0.5 mg PO in Rx No
tablets morning for 3
days; increase to
0.5 mg PO bid
for 4 days, then
increase to 1 mg
PO bid
* OTC, Over the counter; Rx, prescription product; PO, by mouth (orally); bid, twice daily.

‡ Generics available.

†
None is FDA approved for use in patients younger than 18 yr.
From JP Karpinski et al: Smoking cessation treatment for adolescents, J Pediatr Pharmacol Ther
15(4):249–260, 2010.

Pediatric clinicians can connect patients to effective behavioral interventions,

including telephone, text message, smartphone app, internet, and community-
based resources. Free telephone-based treatment (1-800-QUIT-NOW) has been
shown to improve smoking cessation rates. Smoke-free TXT, offered by the
National Cancer Institute, engages teens to quit smoking using free, daily text
messaging. Teens can sign up online (teen.smokefree.gov ) or text QUIT to
iQUIT (47848). A smartphone-based app, QuitSTART, helps teens track
cravings, monitor moods, use cessation tips, and follow quitting attempts. The
American Lung Association's Not-On-Tobacco Program (NOT) is a nationally
recognized best-practice model for teen smoking cessation (see www.lung.org ).

Bibliography
report a higher use of cannabis “edibles.” It is important to recognize that as
perceived harm drops, marijuana use increases (Fig. 140.4 ).

FIG. 140.4 As the perceived harm of marijuana drops, use goes up. The
36.4% using in 2013 equates to about 11 students in the average class.
(From NIH National Institute on Drug Abuse.)

Clinical Manifestations
In addition to the “desired” effects of elation and euphoria, marijuana may cause
impairment of short-term memory, poor performance of tasks requiring divided
attention (e.g., those involved in driving), loss of critical judgment, decreased
coordination, and distortion of time perception (Table 140.13 ). Visual
hallucinations and perceived body distortions occur rarely, but “flashbacks” or
recall of frightening hallucinations experienced under marijuana's influence may
occur, usually during stress or with fever.
Table 140.13
Acute and Chronic Adverse Effects of
Cannabis Use
Acute Adverse Effects

• Anxiety and panic, especially in naïve users

 • Psychotic symptoms (at high doses)
• Road crashes if a person drives while intoxicated

Chronic Adverse Effects

• Cannabis dependence syndrome (in about 1 in 10 users)

• Chronic bronchitis and impaired respiratory function in regular smokers
• Psychotic symptoms and disorders in heavy users, especially those with a
history of psychotic symptoms or a family history of these disorders
• Impaired educational attainment in adolescents who are regular users
• Subtle cognitive impairment in those who are daily users for 10 yr or more

From Hall W, Degenhardt L: Adverse health effects of non-medical cannabis

use, Lancet 374:1383–1390, 2009.

Smoking marijuana for a minimum of 4 days/wk for 6 mo appears to result in

dose-related suppression of plasma testosterone levels and spermatogenesis,
prompting concern about the potential deleterious effect of smoking marijuana
before completion of pubertal growth and development. There is an antiemetic
effect of oral THC or smoked marijuana, often followed by appetite stimulation,
which is the basis of the drug's use in patients receiving cancer chemotherapy.
Although the possibility of teratogenicity has been raised because of findings in
animals, there is no evidence of such effects in humans.
An amotivational syndrome has been described in long-term marijuana users
who lose interest in age-appropriate behavior; proof of the causative relationship
remains equivocal. Chronic use is associated with increased anxiety and
depression, learning problems, poor job performance, hyperemesis, and
respiratory problems such as pharyngitis, sinusitis, bronchitis, and asthma (see
Table 140.13 ).
The cannabinoid hyperemesis syndrome is characterized by recurrent
episodes of vomiting associated with abdominal pain and nausea; patients often
find relief by taking a hot shower or bath. Cannabis use has been chronic (>1-2
yr) and frequent (multiple times per week). Treatment includes stopping
marijuana use, antiemetics, and topical capsaicin.
The increased THC content of marijuana of 5-15–fold compared to that of the
Inhalants
Cora Collette Breuner

Keywords
huffing

Inhalants, found in many common household products, comprise a diverse group

of volatile substances whose vapors can be inhaled to produce psychoactive
effects. The practice of inhalation is popular among younger adolescents and
decreases with age. Young adolescents are attracted to these substances because
of their rapid action, easy availability, and low cost. Products that are abused as
inhalants include volatile solvents (paint thinners, glue, e-cigarette solvents
known as “dripping,” toluene, acetone, refrigerants, gasoline, cleaning fluids,
correction fluids), aerosols (spray paint, nitrous oxide, hair spray), gases
(propane tanks, lighter fluid), nitrites (“poppers” or “video head cleaner”), and
propellants used in whipped cream dispensers. The most popular inhalants
among young adolescents are glue, shoe polish, and spray paint. The various
products contain a wide range of chemicals with serious adverse health effects
(Table 140.14 ). Huffing , the practice of inhaling fumes, can be accomplished
using a paper bag containing a chemical-soaked cloth, spraying aerosols directly
into the nose/mouth, or using a balloon, plastic bag, or soda can filled with
fumes. The percentage of adolescents using inhalants has remained stable, with
5.8% of high school students reporting having ever used inhalants. Eighth and
9th graders report highest use, suggesting targeted prevention strategies for this
age-group.
Table 140.14
Hazards of Chemicals Found in Commonly
Abused Inhalants
 Amyl nitrite, butyl nitrite (“poppers,” “video head cleaner”): sudden
sniffing death syndrome, suppressed immunologic function, injury to red
blood cells (interfering with oxygen supply to vital tissues)
Benzene (found in gasoline): bone marrow injury, impaired immunologic
function, increased risk of leukemia, reproductive system toxicity
Butane, propane (found in lighter fluid, hair and paint sprays): sudden
sniffing death syndrome via cardiac effects, serious burn injuries
(because of flammability)
Freon (used as a refrigerant and aerosol propellant): sudden sniffing death
syndrome, respiratory obstruction and death (from sudden cooling/cold
injury to airways), liver damage
Methylene chloride (found in paint thinners and removers, degreasers):
reduction of oxygen-carrying of blood, changes to the heart muscle and
heartbeat
Nitrous oxide (“laughing gas”), hexane : death from lack of oxygen to the
brain, altered perception and motor coordination, loss of sensation, limb
spasms, blackouts caused by blood pressure changes, depression of heart
muscle functioning
Toluene (found in gasoline, paint thinners and removers, correction fluid):
brain damage (loss of brain tissue mass, impaired cognition, gait
disturbance, loss of coordination, loss of equilibrium, limb spasms,
hearing and vision loss), liver and kidney damage
Trichloroethylene (found in spot removers, degreasers): sudden sniffing
death syndrome, cirrhosis of the liver, reproductive complications,
hearing and vision damage

Clinical Manifestations
The major effects of inhalants are psychoactive (Table 140.15 ). The intoxication
lasts only a few minutes, so a typical user will huff repeatedly over an extended
period (hours) to maintain the high. The immediate effects of inhalants are
similar to alcohol: euphoria, slurred speech, decreased coordination, and
dizziness. Toluene , the main ingredient in model airplane glue and some rubber
cements, causes relaxation and pleasant hallucinations for up to 2 hr. Euphoria is
followed by violent excitement; coma may result from prolonged or rapid
inhalation. Volatile nitrites , such as amyl nitrite, butyl nitrite, and related
compounds marketed as room deodorizers, are used as euphoriants, enhancers of
musical appreciation, and sexual enhancements among older adolescents and
young adults. They may result in headaches, syncope, and lightheadedness;
profound hypotension and cutaneous flushing followed by vasoconstriction and
tachycardia; transiently inverted T waves and depressed ST segments on
electrocardiography; methemoglobinemia; increased bronchial irritation; and
increased intraocular pressure. There may be dermatologic findings, including
perianal/perioral dermatitis (“huffer rash”), frostbite, and contact dermatitis, as
well as epistaxis, nasal ulcers, and conjunctivitis.

Table 140.15
Stages in Symptom Development After Use of Inhalants

STAGE SYMPTOMS
1: Excitatory Euphoria, excitation, exhilaration, dizziness, hallucinations, sneezing, coughing, excess
salivation, intolerance to light, nausea and vomiting, flushed skin and bizarre behavior
2: Early CNS Confusion, disorientation, dullness, loss of self-control, ringing or buzzing in the head, blurred or
depression double vision, cramps, headache, insensitivity to pain, and pallor or paleness
3: Medium Drowsiness, muscular uncoordination, slurred speech, depressed reflexes, and nystagmus or rapid
CNS involuntary oscillation of the eyeballs
depression
4: Late CNS Unconsciousness that may be accompanied by bizarre dreams, epileptiform seizures, and EEG
depression changes
CNS, Central nervous system; EEG, electroencephalogram.
From Harris D: Volatile substance abuse, Arch Dis Child Educ Pract Ed 91:ep93-ep100, 2006.

Complications
Model airplane glue is responsible for a wide range of complications, related to
chemical toxicity, to the method of administration (in plastic bags, with resultant
suffocation), and to the dangerous setting in which the inhalation occurs (inner-
city roof tops). Common neuromuscular changes reported in chronic inhalant
abusers include difficulty coordinating movement, gait disorders, muscle
tremors, and spasticity, particularly in the legs (Table 140.16 ). Chronic use may
cause pulmonary hypertension, restrictive lung defects or reduced diffusion
capacity, peripheral neuropathy, hematuria, tubular acidosis, and possibly
cerebral and cerebellar atrophy. Chronic inhalant abuse has long been linked to
widespread brain damage and cognitive abnormalities that can range from mild
impairment (poor memory, decreased learning ability) to severe dementia. High-
frequency inhalant users were significantly more likely than moderate- and low-
frequency users to experience adverse consequences of inhalant intoxication,
such as behavioral, language, and memory problems. Certain risky behaviors
and consequences, such as engaging in unprotected sex or fighting while high on
inhalants, were dramatically more common among high-frequency than low-
frequency inhalant users. Death in the acute phase may result from cerebral or
pulmonary edema or myocardial involvement (Table 140.16 ).

Table 140.16

Documented Clinical Presentations of Acute and Chronic Volatile Substance Abuse

Ventricular fibrillation Muscle weakness
Asystolic cardiac arrest Abdominal pain
Myocardial infarction Cough
Ataxia Aspiration pneumonia
Agitation Chemical pneumonitis
Limb and trunk uncoordination Coma
Tremor Visual and auditory hallucinations
Visual loss Acute delusions
Tinnitus Nausea and vomiting
Dysarthria Pulmonary edema
Vertigo Photophobia
Hyperreflexia Rash
Acute confusional state Jaundice
Conjunctivitis Anorexia
Acute paranoia Slurred speech
Depression Diarrhea
Oral and nasal mucosal ulceration Weight loss
Halitosis Epistaxis
Convulsions/fits Rhinitis
Headache Cerebral edema
Peripheral neuropathy Visual loss
Methemoglobinemia Burns
Acute trauma Renal tubular acidosis

Diagnosis
Diagnosis of inhalant abuse is difficult because of the ubiquitous nature of the
products and decreased parental awareness of the dangers. In the primary care
setting, providers need to ask parents if they have witnessed any unusual
behaviors in their teen; noticed high-risk products in the teen's bedroom; seen
paint on the teen's hands, nose, or mouth; or found paint- or chemical-coated
rags. Complete blood count, coagulation studies, and hepatic and renal function
methamphetamine at least once, reflecting a steady decline in use.

Clinical Manifestations
Methamphetamine rapidly increases the release and blocks the reuptake of
dopamine, a powerful “feel good” neurotransmitter (Table 140.17 ). The effects
of amphetamines can be dose related. In small amounts, amphetamine effects
resemble other stimulants: increased physical activity, rapid and/or irregular
heart rate, increased blood pressure, and decreased appetite. High doses produce
slowing of cardiac conduction in the face of ventricular irritability. Hypertensive
and hyperpyrexic episodes can occur as seizures (see Table 140.6 ). Binge
effects result in the development of psychotic ideation with the potential for
sudden violence. Cerebrovascular damage, psychosis, severe receding of the
gums with tooth decay, and infection with HIV and hepatitides B and C can
result from long-term use. A withdrawal syndrome is associated with
amphetamine use, with early, intermediate, and late phases (Table 140.17 ). The
early phase is characterized as a “crash” phase with depression, agitation,
fatigue, and desire for more of the drug. Loss of physical and mental energy,
limited interest in the environment, and anhedonia mark the intermediate phase.
In the final phase, drug craving returns, often triggered by particular situations or
objects.

Table 140.17
Signs and Symptoms of Intoxication and Withdrawal

OPIATES AMPHETAMINES/COCAINE BENZODIAZEPINES

INTOXICATION
Behavior Apathy and sedation; Euphoria and sensation of Euphoria; apathy and sedation;
disinhibition; psychomotor increased energy; abusiveness or aggression; labile
retardation; impaired hypervigilance; grandiosity, mood; impaired attention;
attention and judgment aggression, argumentative; labile anterograde amnesia; impaired
mood; repetitive stereotyped psychomotor performance;
behaviors; hallucinations, interference with personal
usually with intact orientation; functioning
paranoid ideation; interference
with personal functioning
Signs Drowsiness; slurred speech; Dilated pupils; tachycardia Unsteady gait; difficulty in
pupillary constriction (except (occasionally bradycardia, standing; slurred speech;
anoxia from severe overdose cardiac arrhythmias); nystagmus; decreased level
—dilation); decreased level hypertension; nausea/vomiting; consciousness; erythematous skin
of consciousness sweating and chills; evidence of lesions or blisters
 weight loss; dilated pupils; chest
pain; convulsions
Overdose Respiratory depression; Sympathomimetic symptoms Hypotension; hyperthermia;
hypothermia depression of gag reflex; coma
Withdrawal Craving to use; lacrimation; Dysphoric mood Tremor of tongue, eyelids, or
yawning; (sadness/anhedonia); lethargy outstretched hands; nausea or
rhinorrhea/sneezing; muscle and fatigue; psychomotor vomiting; tachycardia; postural
aches or cramps; abdominal retardation or agitation; craving; hypotension; psychomotor
cramps; increased appetite; insomnia or agitation; headache; insomnia;
nausea/vomiting/diarrhea; hypersomnia; bizarre or malaise or weakness; transient
sweating; dilated pupils; unpleasant dreams visual, tactile, or auditory
anorexia; irritability; tremor; hallucinations or illusions;
piloerection/chills; paranoid ideation; grand mal
restlessness; disturbed sleep convulsions
From Haber PS, Demirkol A, Lange K, et al: Management of injecting drug users admitted to
hospital, Lancet 374:1284–1292, 2009.

Treatment
Acute agitation and delusional behaviors can be treated with haloperidol or
droperidol. Phenothiazines are contraindicated and may cause a rapid drop in
blood pressure or seizure activity. Other supportive treatment consists of a
cooling blanket for hyperthermia and treatment of the hypertension and
arrhythmias, which may respond to sedation with lorazepam or diazepam. For
the chronic user, comprehensive CBT interventions have been demonstrated as
effective treatment options.

Bibliography
Setlik J, Bond R, Ho M. Adolescent prescription ADHA
medication abuse is rising along with prescriptions for these
medications. Pediatrics . 2009;124:875–880.
Spoth RL, Clair S, Shin C, et al. Long-term effects of universal
preventive interventions on methamphetamine use among
adolescents. Arch Pediatr Adolesc Med . 2006;160:876–882.

140.8
CHAPTER 142

Menstrual Problems
Krishna K. Upadhya, Gina S. Sucato

See also Chapter 565 .

Menstrual disturbances, including delayed onset, irregularity, heavy flow, and
pain, occur in 75% of females during adolescence. Menstrual problems vary in
presentation. For adolescents with minor variations from normal (Table 142.1 ),
an explanation of symptoms and reassurance may be all that is needed. Severe
dysmenorrhea or prolonged menstrual bleeding can be not only frightening, but a
cause of persistent morbidity requiring more aggressive management, potentially
including referral to a specialist in adolescent gynecology.

Table 142.1

Characteristics of Normal Menses*

Cycle length 21-35 days from the 1st day of one period to the 1st day of the next (during 1st 3 yr after
menarche can be 21-45 days)
Duration of 7 or fewer days
menses
Blood flow 6 or fewer (soaked) pads or tampons per day
* Adolescents with 2 or more cycles outside this range or who skip their period for 3 consecutive
mo warrant evaluation.

Normal Menstruation
Data from many countries, including the United States, suggest that the average
age of menarche, or first menses, varies according to ethnic origin and
socioeconomic status. There is often a close concordance of the age at menarche
between mother and daughter, suggesting that genetic factors are determinants in
addition to individual factors such as weight, exercise level, and chronic medical
 amenorrhea
polycystic ovary syndrome
PCOS
female athlete triad

Amenorrhea, the absence of menstruation, generally requires evaluation at age

15 yr, or if there has been no menstruation within 3 yr of the onset of puberty
(primary amenorrhea ), or if there has been no menstruation for the length of 3
previous cycles in a postmenarchal patient (secondary amenorrhea ). However,
the following caveats exist: lack of any pubertal signs by age 13 yr in a girl
should prompt evaluation for pubertal delay; in sexually active patients, or those
with other symptoms suggesting pathology, evaluation should be initiated
without waiting for 3 missed cycles; in patients whose breast development
started between age 8 and 9 yr, observation for >3 yr may be warranted in some
cases, given data suggesting that the age of thelarche has decreased but the age
of menarche has not. Conversely, expectant management with close follow-up
can be considered in a patient whose history, physical examination (showing
some signs of pubertal development), and family history suggest constitutional
delay of puberty.
The differential diagnosis of amenorrhea is broad (Table 142.2 ) and requires a
careful history and physical exam to guide any necessary diagnostic studies. Key
to the evaluation is understanding the timing and tempo of the patient's pubertal
milestones. The evaluation of a patient presenting with amenorrhea should begin
by ascertaining whether she has ever had any prior menstrual bleeding. Some
aspects of the evaluation of both primary and secondary amenorrhea are
identical; conditions that can interrupt the menstrual cycle can also prevent
menarche. In females with primary amenorrhea, however, genetic and anatomic
conditions must also be considered (Table 142.3 ).
Table 142.2
Causes of Amenorrhea (Primary or
Secondary)

Pregnancy (regardless of history can cause primary or secondary

amenorrhea)
Functional hypothalamic causes (stress, weight loss, undernutrition, high
 levels of exercise, energy deficit even at normal weight)
Female athlete triad (inadequate energy intake, amenorrhea, and low bone
density)
Eating disorders
Premature ovarian insufficiency (autoimmune, idiopathic, galactosemia, or
secondary to radiation or chemotherapy)
Hypothalamic and/or pituitary damage (e.g., irradiation, tumor, traumatic
brain injury, surgery, hemochromatosis, midline central nervous system
defects such as septooptic dysplasia, autoimmune pituitary hypophysitis)
Thyroid disease (hyper- or hypo-; hypothyroidism more likely to be
associated with increased bleeding)
Prolactinoma
Systemic disease (e.g., inflammatory bowel disease, cyanotic congenital
heart disease, sickle cell disease, cystic fibrosis, celiac disease)
Hyperandrogenism (polycystic ovary syndrome, nonclassic congenital
adrenal hyperplasia, adrenal tumor or dysfunction)
Drugs and medications (e.g., illicit drugs, atypical antipsychotics,
hormones)
Turner syndrome (including mosaicism)
Table 142.3
Additional Causes of Primary Amenorrhea
Physiologic/constitutional delay
Anatomic abnormalities
Müllerian agenesis
Imperforate hymen
Transverse vaginal septum
Genetic disorders
46,XY disorders of sexual development (e.g., androgen
insensitivity syndrome, 5α-reductase deficiency, 17α-
hydroxylase deficiency)
Mixed gonadal dysgenesis (associated with a number of different
chromosome patterns)
Turner syndrome (resulting from 45,X or a variety of mosaic or
other abnormal karyotypes)
Genetic hypogonadotropic hypogonadism (e.g., X-linked
Laboratory Studies
A urine pregnancy test, serum levels of prolactin, thyroid-stimulating hormone,
and follicle-stimulating hormone (FSH) are reasonable to measure in all patients
presenting with amenorrhea (Fig. 142.1 ). Elevation of FSH (>30 mIU/mL) in an
amenorrheic female suggests ovarian insufficiency, and if confirmed with repeat
testing, should be followed with a pelvic ultrasound, karyotype, and specialist
referral. Diagnostic tests in the patient presenting with amenorrhea should be
tailored to her history and physical exam (Table 142.4 ).

FIG. 142.1 Initial diagnostic testing to evaluate amenorrhea. FSH, Follicle-stimulating
hormone; HCG, human chorionic gonadotropin; LH, luteinizing hormone; MRI,
magnetic resonance imaging; US, ultrasound.

Table 142.4
Laboratory Tests to Evaluate Patients With
Abnormal Uterine Bleeding

Total and free testosterone*

Liver, kidney, and thyroid function studies
Complete blood count with platelets
Urine pregnancy test (regardless of history)
Nucleic acid amplification test (NAAT) or other equivalent testing for
Chlamydia, gonorrhea, and Trichomonas
Prothrombin time and partial thromboplastin time
Ferritin level
Von Willebrand factor antigen, ristocetin cofactor, and factor VIII †
activities
Pelvic ultrasound (if bleeding persists despite treatment)

* In patients with signs or symptoms suggestive of polycystic ovary syndrome,

such as acne, hirsutism, obesity, acanthosis nigricans, and a history of infrequent

menses.
† Any abnormalities should be followed with a ristocetin-induced platelet

aggregation and von Willebrand factor multimers. Testing in the 1st 3 days of
menses and before any estrogen treatment is started minimizes the chances of
false-negative tests. Repeat testing can be warranted in patients for whom there
is a high pretest suspicion.

In patients with signs of androgen excess (e.g., severe acne or hirsutism) or

other physical stigmata associated with PCOS (rapid pubertal weight gain,
acanthosis nigricans) consider measuring levels of 17-hydroxyprogesterone (17-
OHP) (collected in the morning, approximately 8 AM ), free and total
testosterone, dehydroepiandrosterone sulfate (DHEAS), and androstenedione.
PCOS affects up to 15% of females; diagnostic criteria for adolescents are
controversial but include variations of menstrual irregularity (ranging from
amenorrhea to AUB) and physical or biochemical evidence of androgen excess.
The interpretation of polycystic ovarian morphology identified on ultrasound in
adolescents can be challenging, and an ultrasound is not necessary for diagnosis
in adolescents.
typically occur every 21-35 days, lasting 3-7 days. An adolescent's personal
cycle duration is usually established by age 19 or 20 yr.
Adolescents rarely present with complaints of unusually short or light menses.
However, short, light, or infrequent menses should be evaluated similarly to
secondary amenorrhea. Females whose menses are excessive are much more
likely to come to attention for AUB.
In the early postmenarcheal years, the most common cause of AUB in
adolescents is anovulation caused by immaturity of the hypothalamic-pituitary-
ovarian axis. In the absence of a mid-cycle surge of LH to stimulate ovulation,
there is no corpus luteum production of progesterone. Without the stabilizing
effects of progesterone on the endometrial lining, there is increased risk of
irregular bleeding. Irregular bleeding because of anovulation, in the absence of
anatomic, systemic, or endocrinologic disease, is categorized as AUB caused by
ovulatory dysfunction (AUB-O ; previously referred to as dysfunctional uterine
bleeding). Although it is the most common cause of abnormal menstrual
bleeding in adolescents, AUB-O is a diagnosis of exclusion. In generating a
differential diagnosis, it is important to remember that most conditions that lead
to amenorrhea can cause anovulation first, and anovulation is a key risk for
heavy irregular bleeding. Table 142.5 lists the causes of AUB.

Table 142.5

Causes of Irregular Menstrual Bleeding/Abnormal Uterine Bleeding (AUB)

CAUSES OF
EXAMPLES FEATURES
AUB
Immature Patient within 2 yr of menarche Painless; patient responds to hormonal
hypothalamic- treatment.
pituitary-
ovarian axis
(AUB-O)
Weight Anorexia nervosa, bulimia, weight gain or loss of Weight loss more frequently results in
changes, more than 10 pounds from any etiology lighter, less frequent menses.
disordered
eating, or
excessive
exercise
Endocrinologic Thyroid disease, polycystic ovary syndrome Bleeding typically increases with
causes (PCOS) hypothyroidism and decreases with PCOS
and hyperthyroidism.
Complication Threatened abortion, postpartum or postabortal History of sexual activity and/or pregnancy
of pregnancy endometritis
Infection Cervicitis, condyloma, pelvic inflammatory Bleeding is usually not heavy and may
disease occur with sexual intercourse.
 Trauma Sexual assault, straddle injuries History will be evident in patients of
menstruating age unless there is cognitive
disability.
Vaginal foreign Toilet paper, broken condoms, tampons Associated with odor and vaginal discharge,
body but usually not heavy bleeding.
Hematologic Von Willebrand disease, platelet function disorder, Bleeding is heavy and/or long and
causes thrombocytopenia (idiopathic thrombocytopenic frequently regular, may present at menarche,
purpura, drug induced), hemophilia carriage, and may be accompanied by a suggestive
clotting factor deficiency, leukemia family history (hysterectomy, uterine
ablation, cautery for epistaxis) or physical
exam (ecchymoses, petechiae).
Medications Estrogens, progestins, (in pills, patches, rings, Affect the hypothalamic-pituitary-ovarian
injections, implants, and intrauterine devices), axis, endometrial lining, platelets, or
androgens, drugs that cause prolactin release coagulation pathway.
(estrogens, phenothiazines, tricyclic
antidepressants, metoclopramide), anticoagulants
(heparin, warfarin, aspirin, NSAIDs), SSRIs
Anatomic Partial obstruction of vagina or uterus causing Most of these entities are extremely rare,
asynchronous bleeding; cervical or endometrial especially reproductive tract cancers.
polyps or myomas; hemangioma; uterine vascular
malformation; genital/reproductive tract cancer
Systemic Celiac disease, rheumatoid arthritis, Ehlers-Danlos Accompanied by other signs of the
disease syndrome condition.

Unscheduled bleeding during the use of hormonal contraception frequently

occurs, particularly with progestin-only methods. Common causes include
medication nonadherence, interacting medications (prescribed or over-the-
counter), and smoking. Patients should be reassured such bleeding is benign and
not an indication to stop an otherwise satisfactory contraceptive method.

Heavy and Prolonged Menstrual

Bleeding
Irregular bleeding, particularly that resulting from anovulation, can be long and
heavy (Table 142.5 ). However, in patients who have regular, cyclic menses that
are long and/or heavy, particularly if menses are heavy from the onset of
menarche, a hematologic cause should be strongly considered. Von Willebrand
disease and coagulation disorders are found in up to 13% and 20%, respectively,
of women with heavy menstrual bleeding; prevalence goes up significantly
among women with bleeding severe enough to warrant hospitalization. Other
symptoms suggestive of bleeding disorders include flooding (changing a pad or
tampon more than hourly), passing clots larger than 1 inch in diameter, menses
longer than 7 days, a history of hemorrhagic ovarian cysts, excessive bleeding
from wounds or postoperatively, and first-degree relatives with heavy menses or
cases. After ovulation, withdrawal of progesterone results in synthesis of
prostaglandins by the endometrium, which stimulates local vasoconstriction,
uterine ischemia and pain, and smooth muscle contraction, explaining both
uterine and GI symptoms. Because of the association with ovulation, primary
dysmenorrhea typically presents at least 12 mo after menarche.
Secondary dysmenorrhea results from underlying pathology, such as
anatomic abnormality, or infection, such as pelvic inflammatory disease.
However, the most common cause of secondary dysmenorrhea in adolescents is
endometriosis , a condition in which implants of endometrial tissue are found
outside the uterus, usually near the fallopian tubes and ovaries. Often, other
family members have endometriosis. Although characteristically there is severe
pain at menses, adolescents can present with noncyclic pain as well.
Although primary dysmenorrhea is almost always the cause, a careful history
and physical examination are required for adolescents who present with pelvic
pain. An internal pelvic exam is not required in females who are not sexually
experienced and whose presentation is consistent with primary dysmenorrhea.
Constipation can vary cyclically in many females, especially those with irritable
bowel syndrome, and often significantly contributes to the pain. Mittelschmerz ,
brief severe pain with ovulation, occurs at mid-cycle and can explain what
initially appeared to be noncyclic pelvic pain. Table 142.6 lists the differential
diagnosis and “red flags” for secondary dysmenorrhea. Ovarian cysts, a frequent
concern of families, are usually transient and painless.

Table 142.6

Differential Diagnosis of Dysmenorrhea in Adolescents*

PRESENTATION DIAGNOSIS
Primary Crampy pelvic pain may be accompanied Normal physical exam; internal exam only for
by aching/heaviness in lower back and sexually active adolescents. Ultrasound can be
upper thighs, nausea, emesis, diarrhea, reserved for those patients with atypical presentations
headache, mastalgia, fatigue, and (e.g., onset at menarche) or those whose pain does not
dizziness; symptoms begin at or shortly respond to NSAIDs and hormonal therapy.
before onset of menstrual flow and last 1-
3 days.
Endometriosis Increasingly severe dysmenorrhea Increased risk in patients with obstructive anomalies
and despite adequate therapy; pain and possibly bleeding disorders; however, most
adenomyosis exacerbated during menses can occur teenagers with endometriosis have normal anatomy
† acyclically as well. and bleeding indices; diagnosis is made visually
during surgery. Found in up to 69% of adolescents
who underwent laparoscopy for persistent pelvic pain.
Müllerian Pain begins at or shortly after Pelvic ultrasound will demonstrate uterine anomalies
anomalies menarche and occurs with bleeding; (e.g., rudimentary uterine horn); MRI may be required
 with partial presence of known renal tract anomaly to identify some lesions (e.g., obstructed hemivagina).
outflow (often coexists with müllerian anomaly). Found in 8% of adolescents who underwent
obstruction laparoscopy for persistent pelvic pain.
Pelvic Abrupt onset of dysmenorrhea more Clinical diagnosis made by findings of uterine or
inflammatory severe than baseline in a sexually active adnexal tenderness on bimanual pelvic examination
disease adolescent; presentation can range from (see Chapter 146 ); supporting features include
mild discomfort to acute abdomen. dysuria, dyspareunia, vaginal discharge, fever, and
increased white blood cell count.
Pregnancy Coincident pain and bleeding may be Urine test positive for human chorionic gonadotropin.
complication misdiagnosed as dysmenorrhea.
* Bold entries indicate ”red flags” for diagnosis.

†
Adenomyosis is the presence of endometrial tissue within the uterine myometrium.

Treatment for primary dysmenorrhea is aimed at preventing or decreasing

prostaglandin production. The mainstay of treatment is prostaglandin synthetase
inhibition with NSAIDs (Table 142.7 ) beginning at, or preferably the day
before, menstruation. High doses of around-the-clock treatment are rarely
needed for more than the 1st 2 days. More data are needed to make specific
treatment recommendations regarding exercise, but females should be reassured
that participation in usual sports and extracurricular activities is not only
permissible but a benchmark of adequate treatment.

Table 142.7
Treatment for Dysmenorrhea

MEDICATION REGIMEN COMMENTS

NSAIDs for Ibuprofen, 200 2 tablets PO q 4-6 hr Over-the-counter
up to 5 days) mg
Naproxen 550 mg loading dose, then 275 mg PO Patients may prefer the equivalent 550
sodium, 275 mg q 6 hr mg PO q 12 hr dosing regimen.
Celecoxib 400 mg, then 200 mg PO q 12 hr prn Can be used for patients with von
(cyclooxygenase pain Willebrand disease.
[COX]-2
inhibitor)*
Hormonal Combined oral Continuous hormone regimens (vs The data favoring rings and pills over
contraception contraceptive standard 21 hormone days followed the combined hormone patch for this
pills or vaginal by 7 placebo days) may offer better indication are sparse; treatment can be
ring relief but may increase the risk of based on patient preference.
unscheduled intermenstrual bleeding.
Progestin-only DMPA 150 mg IM or 104 mg SC q 3 DMPA has potential side effects of
methods mo; levonorgestrel intrauterine device weight gain and interference with
for up to 5 yr; etonogestrel implant for expected bone density increase during
up to 3 yr adolescence, as well as a higher
discontinuation rate than LARC
methods.
Gonadotropin- Depot 11.25 mg IM q 3 mo Consider for patients with presumed
releasing leuprolide endometriosis not responsive to
 hormone hormonal methods; add-back hormones
agonist are recommended to prevent bone loss.
* This medication may cause serious cardiovascular and gastrointestinal events. Use with caution

in patients with impaired renal or liver dysfunction, heart failure, or a history of GI bleeding or
ulcer. Full prescribing information can be found at:
http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020998s033 ,021156s003lbl.pdf.
DMPA, Depot medroxyprogesterone acetate; LARC, long-acting reversible contraceptive;
NSAIDs, nonsteroidal antiinflammatory drugs.

For those adolescents whose pain does not respond to optimally dosed
NSAIDs, or who also require contraception, the currently available forms of
hormonal contraception will improve dysmenorrhea. A number of trials have
investigated adjuvant treatments including heat, aromatherapy, acupressure,
acupuncture, transcutaneous nerve stimulation, herbal remedies, yoga, and
dietary supplements; however, the mainstay second-line treatment is hormones.
The mechanisms are not fully delineated but are presumed to include elimination
of progesterone production from the corpus luteum for those methods that
prevent ovulation, and decreased prostaglandin production from the diminished
endometrial lining. Up to 3 cycles may be required to appreciate the full benefit.
Methods and regimens that eliminate a placebo interval may provide better
relief. Females whose pain persists despite more than 3 mo of adequate
hormonal therapy require further evaluation and treatment.

Bibliography
Ryan SA. The treatment of dysmenorrhea. Pediatr Clin North
Am . 2017;64(2):331–342.
Youngster M, Laufer MR, Divasta AD. Endometriosis for the
primary care physician. Curr Opin Pediatr . 2013;25(4):454–
462.

142.4
Premenstrual Syndrome and
Premenstrual Dysphoric Disorder
Krishna K. Upadhya, Gina S. Sucato

Keywords
premenstrual syndrome
PMS
premenstrual dysphoric disorder
PMDD

Premenstrual dysphoric disorder (PMDD) is a depressive disorder that is

distinguished from other depressive disorders by its timing. Symptoms of
anxiety and depressed mood begin in the luteal phase of the menstrual cycle (i.e.,
in the 2nd half, after ovulation) and improve within a few days after the onset of
menses. PMDD causes significant distress and functional impairment and may
be accompanied by physical and behavioral symptoms. PMDD occurs in 2–6%
of menstruating females worldwide. Based on a large body of scientific
evidence, it has been included in the Diagnostic and Statistical Manual of
Mental Disorders, Fifth Edition (DSM-5) as a distinct, treatment-responsive,
depressive disorder (Table 142.8 ). PMDD is distinguished from premenstrual
syndrome (PMS) , which has similar timing and occurs in up to 30% of
adolescents, by the severity and consequences of the affective symptoms.
Premenstrual symptoms are precipitated by ovulation; symptoms recur in the
luteal phase and should disappear at the end of menstruation. Up to half of
women who report PMS do not meet diagnostic criteria for PMDD when
symptoms are rated prospectively. Consequently, use of a menstrual calendar to
document symptoms prospectively is necessary, because it is important to
distinguish PMDD from anxiety, depression, or another mental health disorder,
the symptoms of which are exacerbated cyclically but occur throughout the
cycle.
Table 142.8
Criteria for Premenstrual Dysphoric Disorder
A. In the majority of menstrual cycles, at least 5 symptoms must be present in
the final week before the onset of menses, start to improve with a few days
after the onset of menses, and become minimal or absent in the week post
menses.
B. One (or more) of the following symptoms must be present:
1. Marked affective lability (e.g., mood swings; feeling suddenly sad
or tearful, or increased sensitivity to rejection).
2. Marked irritability or anger or increased interpersonal conflicts.
3. Marked depressed mood, feelings of hopelessness, or self-
deprecating thoughts.
4. Marked anxiety, tension, and/or feelings of being keyed up or on
edge.
C. One (or more) of the following symptoms must additionally be present, to
reach a total of 5 symptoms when combined with symptoms from criterion
B above.
1. Decreased interest in usual activities (e.g., work, school, friends,
and hobbies).
2. Subjective difficulty in concentration.
3. Lethargy, easy fatigability, or marked lack of energy.
4. Marked change in appetite; overeating; or specific food cravings.
5. Hypersomnia or insomnia.
6. A sense of being overwhelmed or out of control.
7. Physical symptoms such as breast tenderness or swelling, joint or
muscle pain, a sensation of “bloating,” or weight gain.

Note: The symptoms in criteria A-C must have been met for most
menstrual cycles that occurred in the preceding year.
D. The symptoms are associated with clinically significant distress or
interference with work, school, usual social activities, or relationships with
others (e.g., avoidance of social activities; decreased productivity and
efficiency at work, school, or home).
E. The disturbance is not merely an exacerbation of the symptoms of another
disorder, such as major depressive disorder, panic disorder, persistent
depressive disorder (dysthymia), or a personality disorder (although it may
co-occur with any of these disorders).
F. Criterion A should be confirmed by prospective daily ratings during at least
 2 symptomatic cycles. (Note: The diagnosis may be made provisionally
prior to this confirmation).
G. The symptoms are not attributable to the physiological effects of a
substance (e.g., a drug of abuse, a medication, other treatment) or another
medical condition (e.g., hyperthyroidism).

From Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition

(Copyright 2013), American Psychiatric Association, pp 171–172.

Treatment success is gauged by improvement in patient symptoms. In mild

cases of PMS, adolescents may have adequate relief following education about
the relationship of symptoms to the menstrual cycle and instruction on stress
management techniques, including exercise. There is not strong evidence
supporting the effectiveness of most combined hormonal contraceptive methods
for PMS, particularly in adolescents. However, some experts suggest this
treatment option for those patients who also have dysmenorrhea or contraceptive
needs.
The treatment option for severe PMS and PMDD with the most supportive
evidence is use of selective serotonin reuptake inhibitors (SSRIs), which are
first-line therapy for adult women. In contrast to the treatment of depression,
SSRIs can be rapidly effective for PMDD and thus can be prescribed either
continuously or intermittently, beginning at ovulation (or whenever in the luteal
phase symptoms begin) and ending when symptoms resolve. Adolescents can be
prescribed the standard doses used for adults, such as fluoxetine, 20 mg PO
daily.

Bibliography
American Psychiatric Association. Diagnostic and statistical
manual of mental health disorders, ed 5 (DSM-5) . American
Psychiatric Publishing: Washington, DC; 2013.
Hofmeister S, Bodden S. Premenstrual syndrome and
premenstrual dysphoric disorder. Am Fam Physician .
2016;94(3):236–240.
Marjoribanks J, Brown J, O'Brien PM, et al. Selective serotonin
intrauterine devices (IUDs) and implants. Tier 2 methods have failure rates of 4-
7 pregnancies per 100 women in a year of typical use and include injectable
contraception, oral contraceptive pills, contraceptive patch, and vaginal ring.
Tier 3 methods have failure rates of >13 pregnancies per 100 women per year of
typical use and include the male and female condom, the diaphragm, withdrawal,
the sponge, fertility awareness–based methods, and spermicides.

FIG. 143.1 Effectiveness of contraceptive methods. (From Trussell J, Aiken ARA, Micks
E, Guthrie K. Contraceptive efficacy, safety, and personal considerations. In Hatcher
RA, Nelson AL, Trussell J, et al, eds. Contraceptive technology, ed 21, New York, 2018,
Ayer Company Publishers p. 102.)

Table 143.1
Efficacy of Contraceptives

FAILURE
RATE* SOME ADVERSE EFFECTS AND
METHOD SOME ADVANTAGES
Typical Perfect DISADVANTAGES
Use Use
Implant Convenience; long-term Irregular bleeding; removal complications
contraception; no patient
Nexplanon 0.1% 0.1% compliance required; rapid
 return of fertility after
removal
Intrauterine Convenience; long-term Rare uterine perforation; risk of infection with
devices (lUDs) contraception; no patient insertion; anemia
compliance required; rapid
return of fertility after
removal
ParaGard 0.8% 0.6% Effective for 10 yr; Irregular/heavy bleeding and dysmenorrhea
T380A nonhormonal
Mirena 0.1% 0.1% Decreased menstrual Irregular bleeding in 1st 3-6 mo, followed by
bleeding and dysmenorrheal amenorrhea; ovarian cysts
Liletta 0.1% 0.1% Decreased menstrual Irregular bleeding in 1st 3-6 mo; ovarian cysts
bleeding and dysmenorrheal
Kyleena 0.2% 0.2% Smaller T-frame and Irregular bleeding in 1st 3-6 mo; ovarian cysts;
narrower insertion tube amenorrhea in 13% of users after 1 yr
Skyla 0.4% 0.3% Smaller T -frame and Irregular bleeding in 1st 3-6 mo; ovarian cysts;
narrower insertion tube amenorrhea in only 6% of users after 1 yr
Sterilization
Female 0.5% 0.5% Long-term contraception; no Potential for surgical complications; regret
patient compliance required among young women; reversal often not
possible and expensive
Male 0.15% 0.1% Long-term contraception; no Pain at surgical site, regret among young men;
patient compliance required reversal often not possible and expensive
Injectable Convenience; same as Delayed return to fertility, irregular bleeding
Depo-Provera 4% 0.2% progestin-only oral and amenorrhea; weight gain; may decrease
contraceptives bone mineral density
Combination 7% 0.3% Protection against ovarian Increased rate of thromboembolism, stroke, and
oral and endometrial cancer, PID, myocardial infarction in older smokers; nausea;
contraceptives and dysmenorrhea headache; contraindicated with breastfeeding
Progestin-only 7% 0.3% Protection against PID. iron- Irregular, unpredictable bleeding; must take at
oral deficiency anemia, and same time every day
contraceptives dysmenorrhea; safe in
breastfeeding women and
those with cardiovascular
risk
Transdermal Convenience of once-weekly Dysmenorrhea and breast discomfort may be
Evra 7% 0.3% application; same benefits as more frequent than with oral contraceptives;
combination oral application site reactions; detachment;
contraceptives increased estrogen exposure compared to oral
contraceptives
Vaginal Excellent cycle control; rapid Discomfort; vaginal discharge
NuvaRing 7% 0.3% return to fertility after
removal; convenience of
once-monthly insertion
Diaphragm 17% 16% Low cost; may reduce risk of High failure rate; cervical irritation; increased
with cervical cancer risk of urinary tract infection and toxic shock
spermicide syndrome; some require fitting by healthcare
professional; may be difficult to obtain;
available only by prescription
Condom
without
spermicide
Female 21% 5% Protection against STIs; High failure rate; difficult to insert; poor
covers external genitalia; acceptability
 OTC
Male 13% 2% Protection against STIs, OTC High failure rate; allergic reactions; poor
acceptability; breakage possible
Withdrawal 20% 4% No drugs or devices High failure rate
Sponge 14-27% 9-20% OTC; low cost; no fitting High failure rate; contraindicated during
required; provides 24 hr of menses; increased risk of toxic shock syndrome
protection
Fertility 15% - Low cost; no drugs or High failure rate; may be difficult to learn;
awareness– devices requires relatively long periods of abstinence
based methods
Standard Days 12% 5%
method
TwoDay 14% 4%
method
Ovulation 23% 3%
method
Symptothermal 2% 0.4%
method
Spermicide 21% 16% OTC High failure rate; local irritation; must be
alone reapplied with repeat intercourse; increased
risk of HIV transmission
No method 85% 85% - –
* Risk of unintended pregnancy during first year of use; data from Trussel J, et al: In Hatcher RA
et al: Contraceptive technology. ed 21, New York, 2018, Ayer Company Publishers.
STIs, Sexually transmitted infections; PID, pelvic inflammatory disease; OTC, over the counter.
Adapted from The Medical Letter : Choice of contraceptives. Med Lett 57(1477):128, 2015.

143.1
Contraceptive Use
Tara C. Jatlaoui, Yokabed Ermias, Lauren B. Zapata

Keywords
sexual activity
sexual debut
Tara C. Jatlaoui, Yokabed Ermias, Lauren B. Zapata

Keywords
LARC
intrauterine devices
implants

Long-acting reversible contraception (LARC ) includes 4 levonorgestrel (LNG)

IUDs, the copper (Cu) IUD, and the etonogestrel subdermal implant. LARC
methods are the only Tier 1 methods that are reversible (see Fig. 143.1 ).
Considered “forgettable” contraception, LARC does not require frequent office
or pharmacy visits and does not depend on user compliance for effectiveness. In
the Contraceptive CHOICE Project in St. Louis, MO, >9,000 women were given
the contraceptive method of their choice at no cost and were followed for 2-3 yr.
The failure rates among women who used oral contraceptive pills, transdermal
patch, or vaginal ring were >20 times higher than the failure rates for women
using a LARC method. Acceptance, continuation, and satisfaction in this project
were also higher among adolescents using LARC compared with adolescents
using non-LARC methods. ACOG and AAP support the use of LARC methods
for adolescents. The U.S. Medical Eligibility Criteria supports safe use of both
IUDs and implants for adolescents and nulliparous women. Implants are
considered category 1 for all ages, and IUDs are considered category 2 for
women <20 yr old and for nulliparous women (Table 143.2 ).
Table 143.2
Categories of Medical Eligibility Criteria for
Contraceptive Use
Category 1 : A condition for which there is no restriction for the use of the
contraceptive method.
Category 2 : A condition for which the advantages of using the method
generally outweigh the theoretical or proven risks.
 Category 3 : A condition for which the theoretical or proven risks usually
outweigh the advantages of using the method.
Category 4 : A condition that represents an unacceptable health risk if the
contraceptive method is used.

Intrauterine Devices
IUDs are small, flexible, plastic objects introduced into the uterine cavity
through the cervix. They differ in size, shape, and the presence or absence of
pharmacologically active substances. In the United States, 5 IUDs are currently
approved by the Food and Drug Administration (FDA): the CuT380A (Paragard)
and 4 LNG IUDs (Liletta, Kyleena, Mirena, and Skyla). The effectiveness of the
Cu IUD is enhanced by the copper ions released into the uterine cavity, with
possible mechanisms including inhibition of sperm transport and prevention of
implantation; this IUD is effective for at least 10 yr.
The LNG IUDs also have various actions, from thickening of cervical mucus
and inhibiting sperm survival to suppressing the endometrium. LNG IUDs are
effective for at least 3 and 5 years. All IUDs have typical-use failure rates of
<1% (see Fig. 143.1 ).
Common misconceptions of IUDs among healthcare providers are that IUDs
cause infections, infertility, and generally are not safe for teens or nulliparous
women to use; these misconceptions are a barrier to teens accessing these highly
effective and acceptable methods. IUDs do not increase risk of infertility and
may be inserted safely in teens as well as nulliparous women (category 2; see
Table 143.2 ).
Although early studies suggested an increased risk for upper genital tract
infection, theoretically as a result of passing a foreign body through the cervix,
newer work has refuted these earlier concerns. Therefore, clinicians are
encouraged to consider use of IUDs in adolescents despite relatively high
prevalence rates of STIs in this population. Teens should be screened for
gonorrhea and chlamydia at or before IUD placement, although placement
should not be delayed if results have not returned and there are no signs of
current infection (e.g., purulent discharge, erythematous cervix). If STI testing is
positive with an IUD in place, the patient may be treated without removing the
IUD if she wants to continue the method. Evidence from 2 systematic reviews
did not find benefit in routinely administering misoprostol to women undergoing
routine IUD placement to decrease pain or improve provider ease of insertion. A
 2007.

143.4
Other Progestin-Only Methods
Tara C. Jatlaoui, Yokabed Ermias, Lauren B. Zapata

Keywords
Depo-Provera
depot medroxyprogesterone acetate
DMPA
progestin-only pills
mini pills

Several progestin-only contraceptive methods are available and include the LNG
IUDs and implant (see Chapter 143.3 ), as well as an injectable and progestin-
only pills. These methods do not contain estrogen and may be useful for teens
with contraindications to estrogen (Table 143.3 ) and are considered generally
safe for use in teens (category 1 or 2; see Table 143.2 ). Progestins thicken
cervical mucus to block sperm entry into the uterine cavity as well as induce an
atrophic endometrium leading to either amenorrhea or less menstrual blood loss;
the implant and injectable additionally suppress ovulation. Teens should be
provided anticipatory counseling regarding bleeding irregularities that may
normally occur in the 1st 3-6 mo of hormonal contraception use.
Table 143.3
Conditions Classified as Category 3 and 4 for
Combined Hormonal Contraceptive Use
Category 4
 Complicated valvular heart disease
Current breast cancer
Severe decompensated cirrhosis
Deep venous thrombosis/pulmonary embolism (acute; history, not on
anticoagulation or on established therapy for at least 3 mo with higher
risk recurrence; major surgery with prolonged immobilization)
Complicated diabetes with nephropathy, retinopathy, neuropathy, or other
vascular disease or duration of diabetes >20 yr
Migraine with aura
Hypertension (blood pressure >160/100 mm Hg) or hypertension with
vascular disease
Ischemic heart disease (history of or current)
Hepatocellular adenoma
Malignant liver tumor
Peripartum cardiomyopathy (diagnosed <6 mo prior or with moderately or
severely impaired cardiac function)
Postpartum <21 days
History of cerebrovascular accident
Systemic lupus erythematosus with positive antiphospholipid antibodies
Thrombogenic mutations
Viral hepatitis (acute or flare)

Category 3

Past breast cancer with no evidence of disease for 5 yr

Breastfeeding and <1 mo postpartum
Deep venous thrombosis/pulmonary embolism (history of DVT/PE with
lower risk recurrence)
Gallbladder disease (current, medically treated)
History of malabsorptive bariatric surgery
History of cholestasis and past combined oral contraceptive–related
Hypertension (adequately controlled or blood pressure <160/100 mm Hg)
Peripartum cardiomyopathy with mild impairment or >6 mo
Postpartum 21-42 days with other risk factors for venous
thromboembolism
Drug interactions (Ritonavir-boosted protease inhibitors; certain
anticonvulsants; rifampin or rifabutin)
From Curtis KM, Tepper NK, Jatlaoui TC, et al: U.S. medical eligibility criteria
for contraceptive use, 2016, MMWR Recomm Rep 65(RR-3):1–104, 2016.

Depo-Provera
An injectable progestin, depot medroxyprogesterone acetate (DMPA , Depo-
Provera) is a Tier 2 contraceptive method available as a deep intramuscular (IM)
injection (150 mg), or as a subcutaneous (SC) injection (104 mg) with typical-
use failure rates of 4% (see Table 143.1 ). Both preparations must be
readministered every 3 mo (13 wk) and act to inhibit ovulation. DMPA is
particularly attractive for adolescents who have difficulty with compliance, are
intellectually or physically impaired, and are chronically ill or have a condition
for which estrogen use is not recommended. Common concerns with DMPA
include bleeding changes, bone effects, and weight gain. After 1 yr of use, 50%
of DMPA users develop amenorrhea, which may be an added advantage for teens
with heavy menstrual bleeding, dysmenorrhea, anemias, or blood dyscrasias, or
for those with impairments that make hygiene difficult. Although studies have
demonstrated bone mineral density (BMD) loss in adolescents, potentially
increasing their risk for osteoporosis later in life, other studies have found that
BMD is recovered after discontinuation of this method, and it is thus considered
safe for use in this population. Healthcare providers may want to consider a
contraceptive containing estrogen in teens who are already at high risk for low
BMD, such as those receiving chronic corticosteroid therapy or those with eating
disorders (see Chapter 726 ). Although the FDA issued a black box warning in
2004, AAP and ACOG do not recommend limiting DMPA use to 2 yr for all
women and do not recommend routine BMD screening for females using
DMPA. Early weight gain may be predictive of progressive gain over time; thus
those teens gaining weight in the 1st 3-6 mo should consider another method.

Progestin-Only Pills
Progestin-only oral contraceptive pills (POPs ) are available for the adolescent
in whom the use of estrogen is potentially harmful, such those with active liver
disease, replaced cardiac valves, or hypercoagulable states (see Table 143.3 ).
POPs (mini pills ) are quickly effective after 2 days of initiation in thickening
cervical mucus, but are less reliable in inhibiting ovulation. Effects are short-
eliminated by interventions known collectively as emergency contraception (EC
) up to 120 hr after unprotected intercourse or contraceptive failure. Table 143.4
lists the indications for use of EC. EC methods include the Cu IUD and
emergency contraceptive pills, which include ulipristal acetate, levonorgestrel
(LNG), and COCs following the Yuzpe method. Although the mechanism of
action of the Cu IUD as EC is unclear, all emergency contraceptive pills work to
delay ovulation and are effective only for intercourse that occurs before
administration. Initiation of a regular contraceptive method is necessary to
prevent pregnancy for any intercourse that occurs for the remainder of the cycle
and for future cycles. If pregnancy has already occurred, emergency
contraceptive pills will not cause an abortion or have teratogenic effects on the
fetus.

Table 143.4

Possible Indications for Emergency Contraception

HIGH RISK SEXUAL ACTIVITY

No contraception during intercourse
Rape
Coitus interruptus
Intoxication (alcohol, drugs)
CONTRACEPTION FAILURES
Condom breaking, spillage, leaks, removal by male (purposeful)
Dislodgement, breaking of diaphragm, female condom, cervical cap
Expulsion of IUD
Spermicide failure to melt before coitus
DELAYED OR MISSED CONTRACEPTION
2 consecutive missed days of combined oral contraceptive
1 missed day of progestin only oral contraceptives
> 2-week late injection of depot medroxyprogesterone
≥ 2 day late start of vaginal ring or patch cycle
OTHER
Exposure to teratogens in absence of contraception

Teens can access EC information through a hotline at 1-888-NOT-2-LATE to

obtain EC pills over the counter (OTC). AAP recommends advance provision of
EC pills for teens who are or may become sexually active. A follow-up
Diagnosis
Table 144.1 provides classic symptoms, laboratory tests, and physical changes in
the diagnosis of pregnancy.
Table 144.1
Diagnosis of Pregnancy Dated from First Day
of Last Menstrual Cycle
Classic Symptoms

Missed menses, breast tenderness, nipple sensitivity, nausea, vomiting,

fatigue, abdominal and back pain, weight gain, urinary frequency.
Teens may present with unrelated symptoms that enable them to visit the
doctor and maintain confidentiality.

Laboratory Diagnosis

Tests for human chorionic gonadotropin in urine or blood may be positive

7-10 days after fertilization, depending on sensitivity.
Irregular menses make ovulation/fertilization difficult to predict.
Home pregnancy tests have a high error rate.

Physical Changes

2-3 wk after implantation: cervical softening and cyanosis.

8 wk: uterus size of orange.
12 wk: uterus size of grapefruit and palpable suprapubically.
20 wk: uterus at umbilicus.
If physical findings are not consistent with dates, ultrasound will confirm.

On physical examination, the findings of an enlarged uterus, cervical cyanosis

(Chadwick sign ), a soft uterus (Hegar sign ), or a soft cervix (Goodell sign )
are highly suggestive of an intrauterine pregnancy. A confirmatory pregnancy
test is always recommended, either qualitative or quantitative . Modern
qualitative urinary detection methods are efficient at detecting pregnancy,
attainment at least through their 3rd decade. Maternal lack of education limits
the income of many of these young families (see Chapter 1 ).
The children of teenage mothers are more likely to have lower school
achievement and to drop out of high school, have more health problems, and
face unemployment as a young adult.

Substance Use
See also Chapter 140 .
Teenagers who abuse drugs, alcohol, and tobacco have higher pregnancy rates
than their peers. Most substance-abusing mothers appear to decrease or stop their
substance use while pregnant. Use begins to increase again about 6 mo
postpartum, complicating the parenting process and the mother's return to
school.

Repeat Pregnancy
In the United States, approximately 20% of all births to adolescent mothers (age
15-19) are second order or higher. Prenatal care is begun even later with a 2nd
pregnancy, and the 2nd infant is at higher risk of poor outcome than the 1st birth.
Mothers at risk of early repeat pregnancy (<2 yr) include those who do not
initiate long-acting contraceptives after the index birth, those who do not return
to school within 6 mo of the index birth, those with mood disorders, those
receiving major childcare assistance from the adolescent's mother, those who are
married or living with the infant's father, those having peers who were
adolescent parents, and those who are no longer involved with the baby's father
and who meet a new boyfriend who wants to have a child. To reduce repeat
pregnancy rates in these teens, programs must be tailored for this population,
preferably offering comprehensive healthcare for both the young mother and her
child (Table 144.2 ). Healthcare providers should remember to provide positive
reinforcement for teen parenting successes (i.e., compliment teen parents when
they are doing a good job).

Table 144.2

2012 American Academy of Pediatrics Clinical Guidelines: Care of Adolescent

Parents and Their Children
 GUIDELINE INTERVENTIONS
Create a medical home for adolescent Involve both adolescent mothers and coparenting father.
parents and their children. Emphasize anticipatory guidance, parenting, and basic childcare
skills, especially for teen dads.
Provide comprehensive, Access community resources such as special Supplemental Nutrition
multidisciplinary care. Program for Women, Infants, and Children.
Provide medical and developmental services to low-income parents
and children.
Facilitate coordination of services.
Contraceptive counseling. Emphasize condom use.
Encourage long-acting contraceptive methods.
Encourage breastfeeding. Support breastfeeding in home, work, and school settings.
Encourage high school completion.
Assess risk of domestic violence.
Encourage adolescent parenting. Work with other involved adults such as grandparents to encourage
developmental growth of adolescent as parent as well as optimize infant
developmental outcomes.
Adapt counseling to developmental Utilize school-, home-, and office-based interventions.
level of adolescent. Consider use of support groups.
Awareness and monitoring of Advocate for high-quality community resources for adolescents,
developmental progression of infant including developmental resources, childcare, and parenting classes.
and adolescent parent. Facilitate access to Head Start and education resources for
individuals with disability.
Data from Pinzon JL, Jones VF; Committee on Adolescence and Committee on Early Childhood:
Care of adolescent parents and their children, Pediatrics 130(6):e1743–e1755, 2012.

Children Born to Teen Mothers

Many children born to teen mothers have behavioral problems that may be seen
as early as the preschool period. Many drop out of school early (33%), become
adolescent parents (25%), or, if male, are incarcerated (16%). Explanations for
these poor outcomes include poverty, parental learning difficulties, negative
parenting styles of teen parents, maternal depression, parental immaturity, poor
parental modeling, social stress, exposure to surrounding violence, and conflicts
with grandparents, especially grandmothers. Continued positive paternal
involvement throughout the child's life may be somewhat protective against
negative outcomes. Many of these poor outcomes appear to be attributable to the
socioeconomic/demographic situation in which the teen pregnancy has occurred,
not solely to maternal age. Even when socioeconomic status and demographics
are controlled, infants of teen mothers have lower achievement scores, lower
high school graduation rates, increased risk of teen births themselves, and, at
least in Illinois (where records include age of birth mother), a higher probability
of abuse and neglect.
Comprehensive programs focused on supporting adolescent mothers and
infants utilizing life skills training, medical care, and psychosocial support
demonstrate higher employment rates, higher income, and less welfare
dependency in participating adolescents.

Prevention of Teen Pregnancies

Adolescent pregnancy is a multifaceted problem that requires multifactorial
solutions. The provision of contraception and education about fertility risk from
the primary care physician is important, but insufficient to address the problem
fully. Family and community involvement are essential elements for teen
pregnancy prevention. Strategies for primary prevention (preventing 1st birth)
are different from the strategies needed for secondary prevention (preventing
2nd or more births). Over the last 30 yr, many models of teen pregnancy
prevention programs have been implemented and evaluated. Table 144.3 lists the
common components of many successful evidence-based programs.
Table 144.3
Common Components of Most Successful
Evidence-Based Programs to Prevent Teen
Pregnancy
• Information is provided about the benefits of abstinence.
• Information is provided about contraception for those who are already
sexually active.
• Information is provided about the signs and symptoms of STIs and how to
prevent STIs.
• Interactive sessions on peer pressure are presented.
• Teenagers are taught communication skills.
• Programs are tailored to meet the needs of specific groups of young people
(e.g., young men or young women, cultural groups, younger or older teens).

Adapted from Suellentrop K: What works 2011–2012: curriculum-based

programs that help prevent teen pregnancy, Washington, DC, National
Campaign to Prevent Teen and Unplanned Pregnancy. http://www.c-
hubonline.org/sites/default/files/resources/main/What_Works_0.pdf .
victimization if they had any witness to violence. Among older adolescents age
18-24 yr, the rate of rape and sexual assault was 1.2 times higher for those not
enrolled in college than those in college. Further, several studies of youth in the
juvenile justice system demonstrate a particularly high prevalence of prior sexual
victimization of girls in the juvenile justice system.
Rape occurs worldwide and is especially prevalent in war and armed conflicts.
The World Health Organization estimates that rape and domestic violence are
responsible for 5–16% of healthy years of life lost by females of reproductive
age.
Female adolescents and young adults have the highest rates of rape compared
to any other age-group. The normal developmental growth tasks of adolescence
may contribute to this vulnerability in the following ways: (1) the emergence of
independence from parents and the establishment of relationships outside the
family may expose adolescents to environments with which they are unfamiliar
and situations that they are unprepared to handle; (2) dating and becoming
comfortable with one's sexuality may result in activities that are unwanted, but
the adolescent is too inexperienced to avoid the unwanted actions; and (3) young
adolescents may be naïve and more trusting than they should be (see Chapter
132 ). Many teens are technologically competent, which gives sexual
perpetrators access to unsuspecting vulnerable populations who were previously
beyond their reach. Social media, chat rooms, and online dating sites represent a
major risk for adolescents, resulting in correspondence with individuals
unknown to them or protective family members, while simultaneously providing
a false sense of security because of remote electronic communications. A
determined perpetrator can obtain specific information to identify the adolescent
and arrange for a meeting that is primed for sexual victimization.
Some adolescents are at higher risk of being victims of rape than others (Table
145.1 ).
Table 145.1
Adolescents at High Risk of Rape
Victimization
Male and Female Adolescents

Drug and alcohol users

Runaways
 Those with intellectual disability or developmental delay
Street youths
Transgender youth
Youths with a parental history of sexual abuse
Sex trafficking

Primarily Females

Survivors of prior sexual assault

Newcomers to a town or college

Primarily Males

Those in institutionalized settings (detention centers, prison)

Young male homosexuals

Types of Rape
Rape and sexual assault can occur in a variety of circumstances (Tables 145.2
and 145.3 ). A victim can be sexually assaulted or raped by someone they know
or a by stranger, though more often the assailant is someone known to the victim.
Understanding those circumstances allows for a more trauma-sensitive approach
and may impact the medical management and response to the patient. The
circumstances and relationship of the assailant to the victim may impact if,
when, and how a patient discloses. The gender of the victim may also affect
disclosure; transgendered people and males are uniformly less likely to disclose
rape/sexual assault than females. The gender of the assailant may be the same or
different than the victim's, and there may be one or more than one perpetrator. In
any scenario the sexual assault/rape can be facilitated by threats or coercion,
physical force, or drugs.
Table 145.2
Types of Nonstranger Rape
Acquaintance Rape
 Most common form of rape for adolescents age 16-24 yr.
Assailant may be a neighbor, classmate, or friend of the family.
Victims are more likely to delay seeking medical care, may never report the
crime (males > females), and are less likely to proceed with criminal
prosecution even after reporting the incident(s).

Date Rape

Assailant is in an intimate relationship with the victim.

May be associated with intimate partner violence.
Assailant may engage in more sexual activities than other men his age and
often has a history of aggressive behavior toward women.

Sexual Abuse

All sexual contact or exposure between an adult and a minor, or when there
is a significant age or developmental difference between the youth.
The assailant may be a relative, close family friend, or someone of
authority.

Statutory Rape

Sexual activity between an adult and an adolescent under the age of legal
consent, as defined by individual state law.
Based on the premise that below a certain age or beyond a specific age
difference with the assailant, an individual is not legally capable of giving
consent to engage in sexual intercourse.
The intent of such laws is to protect youth from being victimized, but they
may inadvertently lead a teenager to withhold pertinent sexual
information from a clinician for fear that her sexual partner will be
reported to the law.

Male Rape

Same-sex rape of males.

 More prevalent in institutional settings.
Males are less likely than females to report rape and less likely to seek
professional help.

Gang Rape

See Table 145.3 .

Table 145.3
Types of Stranger Rape
Sex Trafficking and Commercial Sexual Exploitation of Children
(CSEC)

The average age of recruitment into CSEC is between 12 and 13 yr.

The assailant(s) can be the pimp (acquaintance) or the john/“date”
(stranger).
Victims often have a history of child maltreatment.
Fear of the pimp results in reluctance to disclose.

Drug-Facilitated Rape

Alcohol is the most common drug associated with sexual victimization.

Gang Rape

When a group of males rapes a solitary female victim.

May be part of a ritualistic activity or rite of passage for some male groups
(e.g., gang, college fraternity), or may be displaced rage on the part of the
assailants.
Victims may fear retaliation or confrontation with assailants.
Victims may desire or require relocation.

Acquaintance rape , the most common form of rape, is committed by a

person known to the victim outside of the family. If the known assailant is a
family member, caregiver, or someone in a position of authority, it would be
Table 145.4
Laboratory Evaluation of Sexual Assault
Within 8-12 hr (if Indicated by History)

Urine and blood for date rape drugs (GHB, Rohypnol, ketamine)

Within 24 hr (if Indicated by History)

Blood for comprehensive toxicology screen (for other classes of drugs)

Within 72 hr (or Up to 96 hr Depending on the Protocol Used)

Forensic evidence kit

Pregnancy test
Hepatitis B screen (hepatitis B surface antigen, surface antibody, and core
antibody)
Syphilis (rapid plasma reagin [RPR], Venereal Disease Research
Laboratories [VDRL])
HIV infection
Bacterial vaginosis (BV) and candidiasis: point-of-care testing and/or wet
mouth with measurement of vaginal pH and KOH application for whiff
test
Trichomonas vaginalis : nucleic acid amplification tests (NAATs) by urine
or vaginal specimen or point-of-care testing (DNA probes) from vaginal
specimen
Chlamydia and Neisseria gonorrhoeae : nucleic acid amplification testing
(NAATs) at sites of penetration or possible penetration:
1. N. gonorrhoeae: oropharynx, rectum, urine*
2. Chlamydia : urine,* rectum

* Dirty urine sample may be used as alternate for genital swab.

From Centers for Disease Control and Prevention: Sexually transmitted diseases:
treatment guidelines 2015, MMWR Recomm Rep 64(RR-3):1–140, 2015, and
Updated guidelines for antiretroviral postexposure prophylaxis after sexual,
injection drug use, or other nonoccupational exposure to HIV—United States,
2016.

Treatment
Treatment includes prophylactic antimicrobials for STIs (see Chapter 146 )
and emergency contraception (see Chapter 143 ). The Centers for Disease
Control and Prevention (CDC) reports that trichomoniasis, bacterial vaginosis,
gonorrhea, and chlamydial infection are the most frequently diagnosed infections
among women who have been sexually assaulted. Antimicrobial prophylaxis is
recommended for adolescent rape victims because of the risk of acquiring an STI
and the risk of pelvic inflammatory disease (Table 145.5 ). A two- or three-drug
antiretroviral regimen for HIV postexposure prophylaxis (PEP) must be
considered and an infectious disease specialist consulted if higher transmission
risk factors are identified (e.g., knowing that the perpetrator is HIV-positive,
significant mucosal injury of the victim) to prescribe a triple-antiretroviral
regimen (Fig. 145.1 ). Similar considerations should be made for possible
exposure to the hepatitis B virus in vaccinated/unvaccinated individuals.
Clinicians should review the importance for patient's compliance with medical
and psychological treatment and follow-up care.
Table 145.5
Postexposure Prophylaxis (PEP) for Acute
Sexual Assault Victims
Routine
Recommended Regimen for STI Prophylaxis

Ceftriaxone 250 mg intramuscularly

plus
Azithromycin 1g orally in a single dose
plus
Metronidazole 2 g orally in a single dose or
Tinidazole 2 g orally in a single dose
Pregnancy Prophylaxis*

Levonorgestrel (Plan B) 1.5 mg orally in a single dose

OR
Ulipristal acetate (Ella) 30 mg is effective for up to 120 hr.

Human Papillomavirus (HPV)

Assess HPV vaccine history; to unimmunized, administer initial vaccine at

initial exam, with 2 follow-up doses at 1-2 mo and at 6 mo if >15 yr old
or a single follow-up dose at 6-12 mo if ≤15 yr old

As Indicated

All persons offered PEP should be prescribed a 28-day course of a two- or

three-drug antiretroviral regimen.

Human Immunodeficiency Virus (HIV) †

Preferred regimen:
Tenofovir 300 mg and fixed-dose combination emtricitabine, 200
mg (Truvada) once daily
plus
Raltegravir 400 mg twice daily or
Dolutegravir 50 mg daily ‡
Alternative regimens available (The National Clinicians Consultation
Center is a resource for providers prescribing PEP, reachable at 1-888-
448-4911.)

Hepatitis B virus (HBV)

Specific indications for vaccine, immunoglobulin and/or booster dependent

upon assailant's status
* Provided for patients with negative urine pregnancy screen. In addition,

antiemetic (Compazine, Zofran) can be prescribed for patients receiving

emergency contraception.
† HIV PEP is provided for patients with penetration and when the assailant is

known to be HIV-positive or at high risk because of a history of incarceration,

intravenous drug use, or multiple sexual partners. If provided, laboratory studies
must be drawn before administration of medication (HIV, CBC, LFTs, BUN/Cr,
amylase, lipase), and follow-up must be arranged.
‡ Dolutegravir has been associated with neural tube defects if the exposure

occurs within the first trimester of pregnancy. Therefore it should be avoided in

pregnant patients or those at risk for becoming pregnant. U.S. Department of
Health and Human Services, U.S. Food & Drug Administration. Julica, Tivicay,
Triumeq (dolutegravir): FDA to evaluate potential risk of neural tube birth
defects. May 18, 2018.
https://www.fda.gov/safety/medwatch/safetyinformation/safetyalertsforhumanmedicalproduct
.

Data from Centers for Disease Control and Prevention: Sexually transmitted
diseases: treatment guidelines 2015, MMWR Recomm Rep 64(RR-3):1–140,
2015, and Updated guidelines for antiretroviral postexposure prophylaxis after
sexual, injection drug use, or other nonoccupational exposure to HIV—United
States, 2016.

FIG. 146.3 Cervical ectopy. (From Seattle STD/HIV Prevention Training Center,
University of Washington, Claire E. Stevens.)

Screening
Early detection and treatment are primary STI control strategies. Some of the
most common STIs in adolescents, including HPV, HSV, chlamydia, and
gonorrhea, are usually asymptomatic and if undetected can be spread
inadvertently by the infected host. Screening initiatives for chlamydial
infections have demonstrated reductions in PID cases by up to 40%. Although
federal and professional medical organizations recommend annual chlamydia
screening for sexually active females <25 yr old, according to the National
Center for Quality Assurance, in 2015 among sexually active 16-20 yr old
females, approximately 42% of commercial health maintenance organization
(HMO) members and 52% Medicaid HMO members were tested for chlamydia
during the previous year. The lack of a dialog about STIs or the provision of STI
services at annual preventive service visits to sexually experienced adolescents
are missed opportunities for screening and education. Comprehensive,
confidential, reproductive health services, including STI screening, should be
offered to all sexually experienced adolescents (Table 146.2 ).
Table 146.2
Routine Laboratory Screening
Recommendations for Sexually Transmitted
Infections in Sexually Active Adolescents and
Young Adults
Chlamydia Trachomatis and Neisseria Gonorrhoeae

• Routine screening for C. trachomatis and N. gonorrhoeae of all sexually

active females aged <25 yr is recommended annually.
• Routinely screen sexually active adolescent and young adult MSM at sites
of contact for chlamydia (urethra, rectum) and gonorrhea (urethra, rectum,
pharynx) at least annually regardless of condom use. More frequent
screening (i.e., at 3-6 mo intervals) is indicated for MSM who have
multiple or anonymous partners or who have sex with illicit drug use.
• Consider screening for C. trachomatis of sexually active adolescent and
young adult males annually who have a history of multiple partners in
clinical settings with high prevalence rates, such as jails or juvenile
corrections facilities, national job training programs, STD clinics, high
school clinics, or adolescent clinics.

Human Immunodeficiency Virus (HIV)

• HIV screening should be discussed and offered to all adolescents at least

once by age 16-18 yr and throughout young adulthood in healthcare
settings. HIV risk should be assessed annually for >13 yr and offered if
HIV risk factors identified.
• Routinely screen sexually active adolescent and young adult MSM at least
annually regardless of condom use. More frequent screening (i.e., at 3-6 mo
intervals) is indicated for MSM who have multiple or anonymous partners
or who have sex with illicit drug use.

Syphilis

• Syphilis screening should be offered to sexually active adolescents reporting

risk factors, including MSM.
• Routinely screen sexually active adolescent and young adult MSM at least
annually regardless of condom use. More frequent screening (i.e., at 3-6 mo
intervals) is indicated for MSM who have multiple or anonymous partners
 or who have sex with illicit drug use.
• Providers should consult with their local health department regarding local
syphilis prevalence and associated risk factors that are associated with
syphilis acquisition.

Hepatitis C Virus (HCV)

• Screening adolescents for HCV who report risk factors, i.e., injection drug
use, receipt of an unregulated tattoo, received blood products or organ
donation before 1992, received clotting factor concentrates before 1987,
long-term hemodialysis.
• Given the high HCV prevalence among young injection drug users,
screening should be strongly considered.

MSM, Men who have sex with men; STD, sexually transmitted disease.

From Centers for Disease Control and Prevention.

https://www.cdc.gov/std/tg2015/screening-recommendations.htm .

Common Infections and Clinical

Manifestations
STI syndromes are generally characterized by the location of the manifestation
(vaginitis) or the type of lesion (genital ulcer). Certain constellations of
presenting symptoms suggest the inclusion of a possible STI in the differential
diagnosis.

Urethritis
Urethritis is an STI syndrome characterized by inflammation of the urethra,
usually caused by an infectious etiology. Urethritis may present with urethral
discharge, dysuria, urethral irritation, or meatal pruritus. Urgency, frequency of
urination, erythema of the urethral meatus, and urethral pain or burning are less
common clinical presentations. Approximately 30–50% of males are
asymptomatic but may have signs of discharge on diagnosis. On examination,
associated with fever and malaise. The diagnosis may require Epstein-Barr virus
titers, or polymerase chain reaction (PCR) testing. Treatment is supportive care
including pain management.

Table 146.3
Signs, Symptoms, and Presumptive and Definitive
Diagnoses of Genital Ulcers

HERPES
SIGNS/SYMPTOMS SIMPLEX SYPHILIS (PRIMARY) CHANCROID
VIRUS
Ulcers Vesicles rupture Ulcer with well-demarcated indurated Unindurated and
to form shallow borders and a clean base (chancre) undermined borders and a
ulcers purulent base
Painful Painful Painless* Painful
Number of lesions Usually multiple Usually single Multiple
Inguinal First-time Usually mild and minimally tender Unilateral or bilateral
lymphadenopathy infections may painful adenopathy in
cause >50%
constitutional Inguinal bubo
symptoms and formation and rupture
lymphadenopathy. may occur.
Clinical suspicion Typical lesions; Early syphilis: typical chancre plus Exclusion of other causes
positive HSV-2 reactive nontreponemal test (RPR, of ulcers in the presence of
type-specific VDRL) and no history of syphilis, or 4- (a) typical ulcers and
serology test fold increase in quantitative lymphadenopathy, (b)
nontreponemal test in person with typical Gram stain, and (c)
history of syphilis; positive treponemal history of contact with
EIA with reactive nontreponemal test high-risk individual
(RPR, VDRL) and no prior history of (prostitute) or living in an
syphilis treatment endemic area
Definitive diagnosis Detection of HSV Identification of Treponema pallidum Detection of Haemophilus
by culture or PCR from a chancre or lymph node aspirate ducreyi by culture
from ulcer on dark-field microscopy
scraping or
aspiration of
vesicle fluid
* Primary syphilitic ulcers may be painful if they become co-infected with bacteria or 1 of the other
organisms responsible for genital ulcers.
DFA, Direct fluorescent antibody; EIA, enzyme immunoassay; HSV, herpes simplex virus; PCR,
polymerase chain reaction; RPR, rapid plasma reagin; VDRL, Venereal Disease Research
Laboratories.
Data from Centers for Disease Control and Prevention: Sexually transmitted diseases: treatment
guidelines, MMWR 64(RR-3), 2015. https://www.cdc.gov/std/tg2015/default.htm .
 FIG. 146.8 Common normal and abnormal microscopic findings during
examination of vaginal fluid. KOH, Potassium hydroxide solution; PMN,
polymorphonuclear leukocyte; RBCs, red blood cells. (From Adolescent
medicine: state of the art reviews, vol 14, no 2, Philadelphia, 2003, Hanley
& Belfus, pp 350–351.)

Clinical laboratory–based vaginitis tests are also available. The Affirm VPIII
(Becton Dickenson, San Jose, CA) is a moderate-complexity nucleic acid probe
test that evaluates for T. vaginalis , G. vaginalis , and C. albicans and has a
sensitivity of 63% and specificity >99.9%, with results available in 45 min.
Some gonorrhea and chlamydia NAATs also offer an assay for T. vaginalis
testing of female specimens tested for N. gonorrhoeae and C. trachomatis ,
considered the gold standard for Trichomonas testing.
Objective signs of vulvar inflammation in the absence of vaginal pathogens,
along with a minimal amount of discharge, suggest the possibility of mechanical,
chemical, allergic, or other noninfectious irritation of the vulva (Table 146.4 ).

Table 146.4
Pathologic Vaginal Discharge

INFECTIVE DISCHARGE OTHER REASONS FOR DISCHARGE

 COMMON CAUSES COMMON CAUSES
Organisms Retained tampon or condom
Candida albicans Chemical irritation
Trichomonas vaginalis Allergic responses
Chlamydia trachomatis Ectropion
Neisseria gonorrhoeae Endocervical polyp
Mycoplasma genitalium Intrauterine device
Conditions Atrophic changes
Bacterial vaginosis LESS COMMON CAUSES
Acute pelvic inflammatory disease Physical trauma
Postoperative pelvic infection Vault granulation tissue
Postabortal sepsis Vesicovaginal fistula
Puerperal sepsis Rectovaginal fistula
LESS COMMON CAUSES Neoplasia
Ureaplasma urealyticum Cervicitis
Syphilis
Escherichia coli
From Mitchell H: Vaginal discharge—causes, diagnosis, and treatment, BMJ 328:1306–1308,
2004.

The definitive diagnosis of PID is difficult based on clinical findings alone.

Clinical diagnosis is imprecise, and no single historical, physical, or laboratory
finding is both sensitive and specific for the diagnosis of acute PID. Clinical
criteria have a positive predictive value of only 65–90% compared with
laparoscopy. Although healthcare providers should maintain a low threshold for
the diagnosis of PID, additional criteria to enhance specificity of diagnosis, such
as transvaginal ultrasonography, can be considered (Table 146.5 ).
Table 146.5
Evaluation for Pelvic Inflammatory Disease
(PID)
2015 CDC Diagnostic Criteria
Minimal Criteria

• Cervical motion tenderness

or
• Uterine tenderness
or
• Adnexal tenderness

Additional Criteria to Enhance Specificity of the Minimal Criteria

 • Oral temperature >38.3°C (101°F)
• Abnormal cervical or vaginal mucopurulent discharge*
• Presence of abundant numbers of WBCs on saline microscopy of vaginal
secretions*
• Elevated ESR or C-reactive protein
• Laboratory documentation of cervical Neisseria gonorrhoeae or Chlamydia
trachomatis infection

Most Specific Criteria to Enhance the Specificity of the Minimal Criteria

• Transvaginal sonography or MRI techniques showing thickened, fluid-filled

tubes, with or without free pelvic fluid or tuboovarian complex, or Doppler
studies suggesting pelvic infection (e.g., tubal hyperemia)
• Endometrial biopsy with histopathologic evidence of endometritis
• Laparoscopic abnormalities consistent with PID

Differential Diagnosis (Partial List)

• Gastrointestinal: appendicitis, constipation, diverticulitis, gastroenteritis,

inflammatory bowel disease, irritable bowel syndrome
• Gynecologic: ovarian cyst (intact, ruptured, or torsed), endometriosis,
dysmenorrhea, ectopic pregnancy, mittelschmerz, ruptured follicle, septic
or threatened abortion, tuboovarian abscess
• Urinary tract: cystitis, pyelonephritis, urethritis, nephrolithiasis

ESR, Erythrocyte sedimentation rate; WBCs, white blood cells.

* If the cervical discharge appears normal and no WBCs are observed on the wet

prep of vaginal fluid, the diagnosis of PID is unlikely, and alternative causes of
pain should be investigated.

Adapted from Centers for Disease Control and Prevention (CDC).

https://www.cdc.gov/std/tg2015/screening-recommendations.htm .
complications from untreated more serious infections must be considered before
using this approach. Minimizing noncompliance with treatment, notifying and
treating the sexual partners, addressing prevention and contraceptive issues,
offering available vaccines to prevent STIs, and making every effort to preserve
fertility are additional physician responsibilities.

Table 146.6

Management Guidelines for Uncomplicated Bacterial STIs in Adolescents and Adults

RECOMMENDED ALTERNATIVE REGIMENS AND SPECIAL
PATHOGEN
REGIMENS CONSIDERATIONS
Chlamydia Azithromycin 1 g For pregnancy:
trachomatis orally once Azithromycin 1 g orally once
or Alternative regimens:
Doxycycline 100 Erythromycin base 500 mg orally 4 times daily for 7 days
mg orally twice or
daily for 7 days Erythromycin ethylsuccinate 800 mg orally 4 times daily
for 7 days
or
Levofloxacin 500 mg orally once daily for 7 days
or
Ofloxacin 300 mg orally twice daily for 7 days
Neisseria Ceftriaxone 250 mg Single-dose injectable cephalosporin regimens (other than
gonorrhoeae (cervix, IM in a single dose ceftriaxone 250 mg IM) that are safe and effective against
urethra, and rectum) plus uncomplicated urogenital and anorectal gonococcal
Azithromycin 1 g infections include ceftizoxime 500 mg IM, cefoxitin 2 g IM
orally once with probenecid 1 g orally, and cefotaxime 500 mg IM
plus
Azithromycin 1 g orally once
Alternative if unable to offer IM:
Cefixime 400 mg orally in a single dose
plus
Azithromycin 1 g orally in a single dose
If patient is allergic to azithromycin:
Doxycycline 100 mg orally twice daily for 7 days may be
substituted for azithromycin as the 2nd antimicrobial.
Severe cephalosporin allergy:
Gemifloxacin 320 mg orally plus azithromycin 2 g orally in
a single dose
or
Gentamicin 240 mg IM plus oral azithromycin 2 g orally in
a single dose
N. gonorrhoeae Ceftriaxone 250 mg No recommended alternative therapy
(pharynx) IM in a single dose Possibly gemifloxacin plus azithromycin as above for
plus cervix, urethra, rectum
Azithromycin 1 g Patients treated with an alternative regimen should return
orally once 14 days after treatment for a test of cure using either culture
or NAAT.
Treponema pallidum Benzathine penicillin G Penicillin allergy: Doxycycline 100 mg orally twice daily
(primary and 2.4 million units IM in a for 14 days, or tetracycline 500 mg orally 4 times daily for
 secondary syphilis or single dose 14 days. Limited data suggest ceftriaxone 1-2 g daily either
early latent syphilis, IM or IV for 10-14 days.
i.e., infection <12 or
mo) Azithromycin 2 g orally in a single dose has been effective.
but treatment failures have been documented.
T. pallidum (late Benzathine penicillin G Penicillin allergy: Doxycycline 100 mg orally twice daily for
latent syphilis or 7.2 million units total, 28 days, or tetracycline 500 mg orally 4 times daily for 28 days,
syphilis of unknown administered as 3 doses with close serologic and clinical follow-up
duration) of 2.4 million units IM
each at 1 wk intervals
Haemophilus ducreyi Azithromycin 1 g
(chancroid: genital orally in a single
ulcers, dose
lymphadenopathy) or
Ceftriaxone 250 mg
IM in a single dose
or
Ciprofloxacin 500
mg orally twice
daily for 3 days
or
Erythromycin base
500 mg orally 3
times daily for 7
days
C. trachomatis Doxycycline 100 mg Alternative: Erythromycin base 500 mg orally 4 times
serovars L1, L2, or orally twice daily for 21 daily for 21 days
L3 days or
(lymphogranuloma Azithromycin 1 g orally once weekly for 3 wk
venereum)
IM, Intramuscularly; IV, intravenously; NAAT, nucleic acid amplification test.
Adapted for Centers for Disease Control and Prevention: Sexually transmitted diseases: treatment
guidelines, MMWR 64(RR-3), 2015. https://www.cdc.gov/std/tg2015/default.htm .

Table 146.7

Management Guidelines for Uncomplicated Miscellaneous Sexually Transmitted

Infections in Adolescents and Adults
ALTERNATIVE REGIMENS AND SPECIAL
PATHOGEN RECOMMENDED REGIMENS
CONSIDERATIONS
Trichomonas Metronidazole 2 g orally in a single Metronidazole 500 mg orally twice daily for 7 days
vaginalis dose
or
Tinidazole 2 g orally in a single dose
Phthirus Permethrin 1% cream rinse applied to Malathion 0.5% lotion applied for 8-12 hr and
pubis (pubic affected areas and washed off after 10 washed off
lice) min or
or Ivermectin 250 µg/kg orally, repeat in 2 wk
Pyrethrins with piperonyl butoxide
applied to affected areas and washed
off after 10 min
 Launder clothing and bedding
Sarcoptes Permethrin 5% cream applied to all Lindane (1%) 1 oz of lotion or 30 g of cream in thin
scabiei areas from the neck down, washed off layer to all areas of body from neck down; wash off
(scabies) after 8-14 hr in 8 hr
or
Ivermectin 200 µg/kg orally, repeated
in 2 wk
Launder clothing and bedding
Adapted from Centers for Disease Control and Prevention: Sexually transmitted diseases:
treatment guidelines, MMWR 64(RR-3), 2015. https://www.cdc.gov/std/tg2015/default.htm .

Table 146.8
Management Guidelines for Uncomplicated Genital Warts
and Genital Herpes in Adolescents and Adults

RECOMMENDED ALTERNATIVE REGIMENS AND SPECIAL

PATHOGEN
REGIMENS CONSIDERATIONS
HUMAN PAPILLOMAVIRUS (HPV)
External Patient applied: Provider administered:
anogenital warts Imiquimod 3.75% cream Podophyllin resin 10–25% in a compound tincture of
(penis, groin, self-applied to warts at benzoin applied to each wart and then allowed to air-
scrotum, vulva, bedtime nightly for up to 16 dry; thoroughly wash after off 1-4 hr; can be repeated
perineum, wk; wash off after 6-10 hr weekly. Systemic toxicity has been reported when
external anus, or podophyllin resin was applied to large areas of friable
and perianus) Imiquimod 3 5% cream self- tissue and was not washed off within 4 hr.
applied to warts at bedtime 3 Many persons with external anal warts also have
times weekly for up to 16 intraanal warts and might benefit from inspection of
wk; wash off after 6-10 hr anal canal by digital examination, standard anoscopy,
or or high-resolution anoscopy.
Podofilox 0.5% solution or
gel self-applied to warts
twice daily for 3 consecutive
days each wk followed by 4
days of no therapy. May be
repeated for up to 4 cycles.
or
Sinecatechins 15% ointment
self-applied 3 times daily for
up to 16 wk. Do not wash off
after use, and avoid genital,
anal, and oral sexual contact
while ointment is on skin.
Provider-administered:
Cryotherapy with liquid
nitrogen or cryoprobe.
Repeat applications every 1-2
wk.
or
Surgical removal either by
electrocautery, tangential
 excision with scissors or
scalpel, or by carbon dioxide
(CO2 ) laser
or
Trichloroacetic acid (TCA)
or bichloracetic acid (BCA)
80–90%; small amount
applied only to warts and
allowed to dry, when white
“frosting” develops; can be
repeated weekly.
Cervical warts Cryotherapy with liquid
nitrogen
or
Surgical removal
or
TCA or BCA 80–90%
solution
Management should include
consultation with a specialist.
Vaginal warts Cryotherapy with liquid
nitrogen; avoid cryoprobe
use.
or
Surgical removal
or
TCA or BCA 80–90%; small
amount applied only to warts
and allowed to dry, when
white “frosting” develops;
can be repeated weekly.
Urethral meatal Cryotherapy with liquid
warts nitrogen
or
Surgical removal

Intraanal WartsCryotherapy with liquid Management of intraanal warts should include consultation
nitrogen with a specialist.
or
Surgical removal
or
TCA or BCA 80-90% applied
to warts. A small amount
should be applied only to
warts and allowed to dry, at
which time a white “frosting”
develops. Can be repeated
weekly
HERPES SIMPLEX VIRUS (HSV; GENITAL HERPES)
First clinical Treat for 7-10 days with 1 Consider extending treatment if healing is incomplete after
episode of the following: 10 days of therapy
Acyclovir 400 mg orally 3
times daily
Acyclovir 200 mg orally 5
times daily
 Valacyclovir 1 g orally twice
daily
Famciclovir 250 mg orally 3
times daily
Episodic therapy Treat with 1 of the Effective episodic treatment of recurrences requires
for recurrences following: initiation of therapy within 1 day of lesion onset or during
Acyclovir 400 mg orally 3 the prodrome that precedes some outbreaks. The patient
times daily for 5 days should be provided with a supply or a prescription for the
Acyclovir 800 mg orally medication with instructions to initiate treatment
twice daily for 5 days immediately when symptoms begin.
Acyclovir 800 mg orally 3
times daily for 2 days
Valacyclovir 500 mg orally
twice daily for 3 days
Valacyclovir 1,000 mg orally
once daily for 5 days
Famciclovir 125 mg orally
twice daily for 5 days
Famciclovir 1,000 mg orally
twice daily for 1 day
Famciclovir 500 mg orally
once, then 250 mg twice
daily for 2 days
Suppressive Treat with 1 of the All patients should be counseled regarding suppressive
therapy to following: therapy availability, regardless of number of outbreaks per
reduce frequency Acyclovir 400 mg orally year. Since the frequency of recurrent outbreaks diminishes
of recurrences twice daily over time in many patients, providers should periodically
Valacyclovir 500 mg orally discuss the need to continue therapy.
once daily* or 1 g orally once
daily
Famciclovir 250 mg orally
twice daily
* Valacyclovir 500 mg once daily might be less effective than other valacyclovir or acyclovir dosing

regimens in patients who have very frequent recurrences (i.e., ≥10 episodes per year).
Adapted from Centers for Disease Control and Prevention: Sexually transmitted diseases:
treatment guidelines, MMWR 64(RR-3), 2015. https://www.cdc.gov/std/tg2015/default.htm .

Chlamydia- and gonorrhea-infected males and females should be retested

approximately 3 mo after treatment, regardless of whether they believe that their
sex partners were treated, or whenever persons next present for medical care in
the 12 mo following initial treatment. Once an infection is diagnosed, partner
evaluation, testing, and treatment are recommended for sexual contacts within 60
days of symptoms or diagnosis, or the most recent partner if sexual contact was
>60 days, even if the partner is asymptomatic. Abstinence is recommended for at
least 7 days after both patient and partner are treated. A test for pregnancy
should be performed for all females with suspected PID because the test
outcome will affect management. Repeat testing 3 mo after treatment is also
recommended for Trichomonas infection.
research (Table 147.1 ).

Table 147.1
Overview of Current Case Definitions for Systemic Exertion
Intolerance Disease (SEID) and Past Definitions of Chronic
Fatigue Syndrome or Myalgic Encephalomyelitis

SYMPTOM SEID CFS ME

Fatigue and impairment of daily function ≥ 6 mo ≥ 6 mo ≥ 6 mo
Sudden onset Yes Yes
Muscle weakness Yes
Muscle pain Yes
Postexertional symptoms Yes Yes Yes
Sleep disturbance Yes Yes
Memory or cognitive disturbances Yes Yes
Autonomic symptoms Yes
Sore throat Yes
Lymph node involvement Yes
Cardiovascular symptoms Yes
Headaches Yes
Arthralgias Yes Yes
CFS, Chronic fatigue syndrome; ME, myalgic encephalomyelitis.
Data from Institute of Medicine: Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Redefining an Illness. Washington, DC, National Academies Press 2015; Jason L, Evans M,
Porter N, et al: The development of a revised Canadian myalgic encephalomyelitis chronic fatigue
syndrome case definition. Am J Biochem Biotechnol 6:120 135, 2010; Reeves WC, Wagner D,
Nisenbaum R, et al: Chronic fatigue syndrome—a clinically empirical approach to its definition and
study. BMC Med 3:19, 2005.

The Institute of Medicine (IOM) 2015 recommendations apply to all ages and
include a special focus on pediatrics. The IOM suggested new diagnostic criteria
and a new name, systemic exertion intolerance disease (SEID) , to emphasize
the postexertion malaise criterion and better understand the illness (Table 147.2
). The most recent expert consensus report (June 2017) from the International
Writing Group for Pediatric ME/CFS provides a primer for diagnosis and
management.
Table 147.2
Criteria for Diagnosis of Myalgic
Encephalomyelitis/Chronic Fatigue Syndrome
(ME/CFS)
 Patient has each of the following 3 symptoms at least half the time, to
at least a moderately severe degree:
• A substantial reduction or impairment in the ability to engage in
preillness levels of occupational, educational, social, or
personal activities that persists for >6 mo and is accompanied
by fatigue, which is often profound, is of new or definite onset
(not lifelong), is not the result of ongoing excessive exertion,
and is not substantially alleviated by rest.
• Postexertional malaise*
• Unrefreshing sleep*
Plus at least 1 of the 2 following manifestations (chronic, severe):
• Cognitive impairment*
• Orthostatic intolerance

* Frequency and severity of symptoms should be assessed. The diagnosis of

ME/CFS should be questioned if patients do not have these symptoms at least

half of the time with moderate, substantial, or severe intensity.

From Institute of Medicine: Beyond myalgic encephalomyelitis/chronic fatigue

syndrome: redefining an illness, Washington, DC, 2015, National Academies
Press.

Epidemiology
Based on worldwide studies, 0.2–2.3% of adolescents or children have CFS.
Most epidemiology studies use the 1994 definition. CFS is more prevalent in
adolescents than in younger children. The variation in CFS prevalence estimates
may result from variations in case definition, study methodology and
application, study population composition (specialty vs general practice or
general population), and data collection (parent, self-reporting vs clinician
evaluation). Gender distribution in children differs from that in adults, with a
more equal distribution in children <15 yr old, while remaining 2-3–fold higher
in females 15-18 yr old. Few studies have reported the incidence of CFS among
children <10 yr old, leading to uncertainty in this group. In adolescents in The
Netherlands, the pediatrician-diagnosed incidence of CFS/ME was 0.01%, and in
CHAPTER 148

Evaluation of Suspected
Immunodeficiency
Kathleen E. Sullivan, Rebecca H. Buckley

Primary care physicians must have a high index of suspicion to diagnose

immune system defects early enough to institute appropriate treatment before
irreversible damage develops. Diagnosis can be difficult because most affected
patients do not have abnormal physical features. The most typical manifestation
of immunodeficiency in children is recurrent sinopulmonary infections.
Although infections are common in children in general, an infection exceeding
the expected frequency and usually involving multiple sites can suggest
immunodeficiency. A single, severe, opportunistic, or unusual infection can also
be the presentation of an immunodeficiency (Table 148.1 ). Increasingly
recognized is the co-occurrence of autoimmune disease or inflammatory
conditions and recurrent infections. Newborn screening for T-cell lymphopenia
has been instituted in most states; this has led to the identification of some
infants with immunodeficiency before any clear manifestations but is limited to
T-cell deficiencies. Additional clues to immunodeficiency include failure to
thrive with or without chronic diarrhea, persistent infections after receiving live
vaccines, and chronic oral or cutaneous candidiasis (Tables 148.2 and 148.3 ).

Table 148.1
Predisposition to Specific Infections in Humans

AFFECTED
PATHOGEN PRESENTATION GENE/CHROMOSOMAL COMMENTS
REGION
BACTERIA
Streptococcus Invasive disease IRAK4, MyD88, C1QA, Also susceptible to other encapsulated
pneumoniae C1QB, C1QC, C4A+ C4B, bacteria
 C2, C3
Neisseria Invasive disease C5, C6, C7, C8A, C8B, Recurrent disease common
C8G, C9, properdin
Burkholderia Invasive disease CYBB, CYBA, NCF1, NCF2 Also susceptible to staphylococcal and fungal
cepacia not pulmonary infections
colonization
Nocardia Invasive disease CYBB, CYBA, NCF1, NCF2 Also susceptible to staphylococcal and fungal
infections
Mycobacteria Usually IL12B, IL12RB1, IKBKG, Also susceptible to Salmonella typhi
nontuberculous IFNGR1, IFNGR2, STAT1 infections
mycobacteria (loss of function)
VIRUSES
Herpes Herpes simplex TRAF3, TRIF, TBK, Age of onset is typically outside the neonatal
simplex virus encephalitis UNC93B1, TLR3, STAT1 period.
Epstein-Barr Severe infectious SH2DIA, XIAP, ITK, CD27, Fulminant infectious mononucleosis,
virus mononucleosis, PRF1, STXBP2, UNC13D, malignant and nonmalignant
hemophagocytic LYST, RAB27A, STX11, lymphoproliferative disorders,
syndrome AP3B1 dysgammaglobulinemia, autoimmunity
Papillomavirus Warts RHOH, EVER1, EVER2, Warts are often progressive despite therapy.
CXCR4, DOCK8, GATA2,
STK4, SPINK5
Global Severe, progressive All types of severe Presentation depends on virus and infected
susceptibility viral infections combined immune organ
to viral deficiency, IFNAR2
infection
FUNGI
Candida Mucocutaneous AIRE, STAT1 (gain of AIRE deficiency is associated with
candida function), CARD9, STAT3, endocrinopathies, STAT1 (GOF) is associated
IL17F, IL17RC, IL17RA, with autoimmunity
ACT1
Dermatophytes Tissue invasion CARD9 Autosomal recessive
Aspergillus Deep infections CYBB, CYBA, NCF1, NCF2
Environmental Deep infections CYBB, CYBA, NCF1,
fungi NCF2, GATA2, STAT1 (gain
of function), CD40L

Table 148.2
Characteristic Clinical Patterns in Some Primary
Immunodeficiencies

FEATURES DIAGNOSIS
IN NEWBORNS AND YOUNG INFANTS (0-6 mo)
Hypocalcemia, unusual facies and ears, heart disease 22q11.2 deletion syndrome, DiGeorge
anomaly
Delayed umbilical cord detachment, leukocytosis, recurrent infections Leukocyte adhesion defect
Persistent thrush, failure to thrive, pneumonia, diarrhea Severe combined immunodeficiency
Bloody stools, draining ears, atopic eczema Wiskott-Aldrich syndrome
IN INFANTS AND YOUNG CHILDREN (6 mo to 5 yr)
Recurrent staphylococcal abscesses, staphylococcal pneumonia with Hyper-IgE syndrome, PGM3 deficiency
pneumatocele formation, coarse facial features, pruritic dermatitis
Persistent thrush, nail dystrophy, endocrinopathies Autoimmune polyendocrinopathy,
candidiasis, ectodermal dysplasia
Short stature, fine hair, severe varicella Cartilage hair hypoplasia with short-
limbed dwarfism
Oculocutaneous albinism, recurrent infection, hemophagocytic Chédiak-Higashi syndrome, Griscelli
syndrome syndrome, Hermansky-Pudlak syndrome

Table 148.3
Clinical Aids to the Diagnosis of
Immunodeficiency
Suggestive of B-Cell Defect (Humoral Immunodeficiency)

Recurrent bacterial infections of the upper and lower respiratory tracts

Recurrent skin infections, meningitis, osteomyelitis secondary to
encapsulated bacteria (Streptococcus pneumoniae. Haemophilus
influenzae. Staphylococcus aureus. Neisseria meningitidis)
Paralysis after vaccination with live-attenuated poliovirus
Reduced levels of immunoglobulins

Suggestive of T-Cell Defect (Combined Immunodeficiency)

Systemic illness after vaccination with any live virus or bacille Calmette-
Guérin (BCG)
Unusual life-threatening complication after infection with benign viruses
(giant cell pneumonia with measles; varicella pneumonia)
Chronic oral candidiasis after age 6 mo
Chronic mucocutaneous candidiasis
Graft-versus-host disease after blood transfusion
Reduced lymphocyte counts for age
Low levels of immunoglobulins
Absence of lymph nodes and tonsils
Small thymus
Chronic diarrhea
Failure to thrive
Recurrent infections with opportunistic organisms

Suggestive of Macrophage Dysfunction

 Disseminated atypical mycobacterial infection, recurrent Salmonella
infection
Fatal infection after BCG vaccination

Congenital Syndromes With Immunodeficiency

Ataxia-telangiectasia: ataxia, telangiectasia

Autoimmune polyglandular syndrome: hypofunction of 1 or more
endocrine organs, chronic mucocutaneous candidiasis
Cartilage-hair hypoplasia: short-limbed dwarfism, sparse hair, neutropenia
Wiskott-Aldrich syndrome: thrombocytopenia, male gender, eczema
Chédiak–Higashi syndrome: oculocutaneous albinism, nystagmus,
recurrent bacterial infections, peripheral neuropathies
DiGeorge syndrome (22q deletion syndrome): unusual facies, heart defect,
hypocalcemia

Suggestive of Asplenia

Heterotaxia. complex congenital heart disease, Howell-Jolly bodies on

blood smear, sickle cell anemia

From Kliegman RM, Lye PS, Bordini BJ, ET AL, editors: Nelson pediatric
symptom-based diagnosis, Philadelphia, 2018, Elsevier, p 750.

With >300 distinct primary immunodeficiencies, in order to focus the

diagnostic approach and appropriate testing. it is often useful to consider 5
categories: T-cell disorders, B-cell and antibody disorders, complement
disorders, phagocytic disorders, and natural killer cell disorders (Table 148.4 and
Fig. 148.1 ).

Table 148.4
Characteristic Features of Primary Immunodeficiency

PREDOMINANT PREDOMINANT GRANULOCYTE CYTOLYTIC COMPLEMENT

CHARACTERISTIC
T-CELL DEFECT B-CELL DEFECT DEFECT DEFECT DEFECT
Age at onset of Early onset, usually Onset after maternal Early onset most Childhood onset Onset at any age
 infection 2-6 mo antibodies diminish, frequently generally
usually after 5-7 mo,
later childhood to
adulthood
Specific pathogens Bacteria: common Bacteria: Bacteria: None usually Bacteria:
involved gram-positive and pneumococci, staphylococci, encapsulated
gram-negative streptococci, Serratia, organisms (C1, C4,
bacteria and staphylococci, Salmonella, C2, C3),
mycobacteria Haemophilus, mycobacteria (FP, FD, FH, FI,
Campylobacter, C3, C5, C6, C7,
Mycoplasma C8, C9)
Viruses: CMV, Viruses: enterovirus* None generally CMV, EBV None generally
EBV, adenovirus,
parainfluenza 3,
varicella,
enterovirus
Fungi: Candida and Fungi and parasites: Fungi and None generally None generally
Pneumocystis Giardia, parasites: Candida,
jiroveci Cryptosporidia Nocardia,
Aspergillus
Affected organs Extensive Recurrent Skin: Hemophagocytic Deep or systemic
mucocutaneous sinopulmonary abscesses, syndrome can infections
candidiasis, lungs, infections, chronic impetigo, affect any organ.
failure to thrive, gastrointestinal cellulitis
protracted diarrhea symptoms, Lymph nodes:
malabsorption, suppurative
arthritis, enteroviral adenitis
meningoencephalitis* Oral cavity:
gingivitis,
mouth ulcers
Internal
organs:
abscesses,
osteomyelitis
Special features Graft-vs-host Autoimmunity Prolonged SLE (C1, C4, C2),
disease caused Lymphoreticular attachment of Glomerulonephritis
by maternal malignancy: umbilical cord, (C3), atypical
engraftment or lymphoma, poor wound hemolytic-uremic
nonirradiated thymoma healing syndrome (FH, FI,
blood MCP, C3, FB)
transfusion
Postvaccination
disseminated
BCG or
varicella
Autoimmunity
common in
mild-moderate
T-cell defects
* X-linked (Bruton) agammaglobulinemia.

BCG, Bacille Calmette-Guérin; CMV, cytomegalovirus; EBV, Epstein-Barr virus; SLE, systemic
lupus erythematosus.
 FIG. 148.1 Diagnostic testing algorithm for primary immunodeficiency diseases.
Common clinical scenarios are listed at the top. The 1st tier of testing is listed below
each category between the dark lines. The 2nd tier of testing is located below the 2nd
dark line. CBC, Complete blood count; DHR, dihydrorhodamine; MAI, Mycobacterium
avium-intracellulare infection.

The initial evaluation of immunologic function includes a thorough history,

physical examination, and family history (Table 148.5 ). Over 10
immunodeficiencies are X-linked, and a growing number are autosomal
dominant with variable expressivity and/or incomplete penetrance. Close
attention to physical signs of autoimmune disease or end-organ effects from
recurrent infections should be noted. The history of infections should include the
age of onset, severity, involved locations, and assessment of the underlying
microbial cause. Viral, bacterial, fungal, and mycobacterial infections all require
distinct arms of the immune system for eradication; therefore identification of
microbiologic causes of infection can be extremely helpful in defining the
deficiency states in people with primary immunodeficiencies.

Table 148.5
Special Physical Features Associated With
Immunodeficiency Disorders
 CLINICAL FEATURES DISORDERS
DERMATOLOGIC
Eczema Wiskott-Aldrich syndrome, IPEX, hyper-IgE syndromes, hypereosinophilia
syndromes, IgA deficiency
Sparse and/or hypopigmented hair Cartilage-hair hypoplasia, Chédiak-Higashi syndrome, Griscelli syndrome
Ocular telangiectasia Ataxia-telangiectasia
Oculocutaneous albinism Chédiak-Higashi syndrome
Severe dermatitis Omenn syndrome
Erythroderma Omenn syndrome, SCID, graft-vs-host disease, Comel-Netherton syndrome
Recurrent abscesses with Hyper-IgE syndromes
pulmonary pneumatoceles
Recurrent organ granulomas or CGD
abscesses, lung, liver, and rectum
especially
Recurrent abscesses or cellulitis CGD, hyper-IgE syndrome, leukocyte adhesion defect
Cutaneous granulomas Ataxia telangiectasia, SCID, CVID, RAG deficiency
Oral ulcers CGD, SCID, congenital neutropenia
Periodontitis, gingivitis, stomatitis Neutrophil defects
Oral or nail candidiasis T-cell immune defects, combined defects (SCIDs); mucocutaneous
candidiasis; hyper-IgE syndromes; IL-12, -17, -23 deficiencies; CARD9
deficiency; STAT1 deficiency
Vitiligo B-cell defects, mucocutaneous candidiasis
Alopecia B-cell defects, mucocutaneous candidiasis
Chronic conjunctivitis B-cell defects
EXTREMITIES
Clubbing of nails Chronic lung disease caused by antibody defects
Arthritis Antibody defects, Wiskott-Aldrich syndrome, hyper-IgM syndrome
ENDOCRINOLOGIC
Hypoparathyroidism DiGeorge syndrome, mucocutaneous candidiasis
Endocrinopathies (autoimmune) Mucocutaneous candidiasis
Diabetes, hypothyroid IPEX and IPEX-like syndromes
Growth hormone deficiency X-linked agammaglobulinemia
Gonadal dysgenesis Mucocutaneous candidiasis
HEMATOLOGIC
Hemolytic anemia B- and T-cell immune defects, ALPS
Thrombocytopenia, small platelets Wiskott-Aldrich syndrome
Neutropenia Hyper-IgM syndrome, Wiskott-Aldrich variant, CGD
Immune thrombocytopenia B-cell immune defects, ALPS
SKELETAL
Short-limb dwarfism Short-limb dwarfism with T- and/or B-cell immune defects
Bony dysplasia ADA deficiency, cartilage-hair hypoplasia
ADA, Adenosine deaminase; ALPS, autoimmune lymphoproliferative syndrome; CGD, chronic
granulomatous disease; CVID, common variable immunodeficiency; IPEX, X-linked immune
dysfunction enteropathy polyendocrinopathy; SCID, severe combined immunodeficiency.
From Goldman L, Ausiello D: Cecil textbook of medicine, ed 22, Philadelphia, 2004, Saunders, p
1599.

Most immunologic defects can be excluded at minimal cost with the proper
choice of screening tests, which should be broadly informative, reliable, and
cost-effective (Table 148.6 and Figs. 148.2 and 148.3 ). A complete blood count
(CBC) with differential is the initial study if neutropenia is a consideration but is
less recognized as a screening test for T-cell defects. Lymphopenia is seen the
majority of T-cell defects. If an infant's neutrophil count is persistently elevated
in the absence of any signs of infection, a leukocyte adhesion deficiency should
be suspected. Normal lymphocyte counts are higher in infancy and early
childhood than later in life (Fig. 148.4 ). Knowledge of normal values for
absolute lymphocyte counts at various ages in infancy and childhood is crucial in
the detection of T-cell defects. Additional clues from the CBC include absence
of Howell-Jolly bodies, which argues against congenital asplenia. Normal
platelet size or count excludes Wiskott-Aldrich syndrome. When
immunodeficiency is suspected, obtaining IgG, IgA, IgM, and IgE levels can be
a useful strategy, since antibody defects are the most common type of
immunodeficiency. Immunoglobulin levels must be interpreted within the
context of age-specific normative data.
Table 148.6
Initial Screening Immunologic Testing of the
Child With Recurrent Infections
Complete Blood Count, Differential, and Erythrocyte
Sedimentation Rate

Absolute lymphocyte count (normal result rules against T-cell defect)

Absolute neutrophil count (normal result rules against congenital or
acquired neutropenia and [usually] both forms of leukocyte adhesion
deficiency, in which elevated counts are present even between infections)
Platelet count (normal result excludes Wiskott-Aldrich syndrome)
Howell-Jolly bodies (absence rules against asplenia)
Erythrocyte sedimentation rate (normal result indicates chronic bacterial or
fungal infection unlikely)

Screening Tests for B-Cell Defects

IgG, IgA, IgM (low in most antibody defects)

Isohemagglutinins (low in agammaglobulinemia)
Antibody titers tetanus, diphtheria, Haemophilus influenzae , and
 pneumococcus (low in most antibody defects)

Screening Tests for T-Cell Defects

Absolute lymphocyte count (normal result indicates T-cell defect unlikely)

Flow cytometry to examine for the presence of naïve T cells (CD3+
CD45RA+ cells)

Screening Tests for Phagocytic Cell Defects

Microscopy (abnormal in some neutropenias)

Respiratory burst assay (abnormal in chronic granulomatous disease)

Screening Test for Complement Deficiency

CH50 (nearly absent in classical pathway and terminal component

deficiencies)
AH50 (nearly absent in alternative pathway and terminal component
deficiencies)
Table 148.7
Laboratory Tests in Immunodeficiency
SCREENING TESTS ADVANCED TESTS RESEARCH/SPECIAL TESTS
B-CELL DEFICIENCY
IgG, IgM, IgA, and IgE levels B-cell enumeration (CD19 Advanced B-cell phenotyping
or CD20)
Isohemagglutinin titers Biopsies (e.g., lymph nodes)
Ab response to vaccine antigens (e.g., Ab responses to boosters or Ab responses to special antigens
tetanus, diphtheria, pneumococci, to new vaccines (e.g., bacteriophage φX174),
Haemophilus influenzae ) mutation analysis
T-CELL DEFICIENCY
Lymphocyte count T-cell subset enumeration Advanced flow cytometry
(CD3, CD4, CD8)
Chest x-ray examination for thymic size* Proliferative responses to Enzyme assays (e.g., ADA, PNP)
mitogens, antigens,
allogeneic cells
TRECs 22q11.2 deletion analysis Mutation analysis
T-cell activation studies
PHAGOCYTIC DEFICIENCY
WBC count, morphology Adhesion molecule assays Mutation analysis
(e.g., CD11b/CD18, selectin Macrophage functional testing
ligand)
Respiratory burst assay Mutation analysis
COMPLEMENT DEFICIENCY
CH50 activity AH50 , activity Specific component assays
* In infants only.

Ab, Antibody; ADA, adenosine deaminase; C, complement; CH, hemolytic complement; G6PD,
glucose-6-phosphate dehydrogenase; HLA, human leukocyte antigen; Ig, immunoglobulin; MPO,
myeloperoxidase; NADPH, nicotinamide adenine dinucleotide phosphate; PNP, purine nucleoside
phosphorylase; TRECs, T-cell receptor rearrangement excision circle; WBC, white blood cell; φX,
phage antigen.

One useful test for B-cell function is to determine the presence and titer of
isohemagglutinins , or natural antibodies to type A and B red blood cell
polysaccharide antigens. This test measures predominantly IgM antibodies.
Isohemagglutinins may be absent normally in the first 2 yr of life and are always
absent if the patient is blood type AB.
Because most infants and children are immunized with diphtheria-tetanus-
pertussis (dTP), conjugated Haemophilus influenzae type b, and pneumococcal
conjugate vaccine, it is often informative to test for specific antibodies to
diphtheria, tetanus, H. influenzae polyribose phosphate, and pneumococcal
antigens. If the titers are low, measurement of antibodies to diphtheria or tetanus
toxoids before and 2-8 wk after a pediatric dTP or dT booster is helpful in
assessing the capacity to form IgG antibodies to protein antigens. To evaluate a
CD Classification of Some Lymphocyte Surface Molecules
CD
TISSUE/LINEAGE FUNCTION
NUMBER
CD1 Cortical thymocytes; Lipid antigen presentation to TCRγδ cells
Langerhans cells
CD2 T and NK cells Binds LFA-3 (CD58); alternative pathway of T-cell activation
CD3 T cells TCR associated; transduces signals from TCR
CD4 T-helper cell subset Receptor for HLA class II antigens; associated with p56 Ick tyrosine
kinase
CD7 T and NK cells and their Mitogenic for T lymphocytes
precursors
CD8 Cytotoxic T-cell subset; Receptor for HLA class I antigens; associated with p56 Ick tyrosine
also on 30% of NK cells kinase
CD10 B-cell progenitors Peptide cleavage
CD11a T, B, and NK cells With CD18, ligand for ICAMs 1, 2, and 3
CD11b, c NK cells With CD18, receptors for C3bi
CD16 NK cells FcR for IgG
CD19 B cells Regulates B-cell activation
CD20 B cells Mediates B-cell activation
CD21 B cells C3d, also the receptor for EBV; CR2
CD25 T, B, and NK cells Mediates signaling by IL-2
CD34 Stem cells Binds to L -selectin
CD38 T, B, and NK cells and Associates with hyaluronic acid
monocytes
CD40 B cells and monocytes Initiates isotype switching in B cells when ligated
CD44 Bone marrow stromal and Matrix adhesion molecule
many other cells
CD45 All leukocytes Tyrosine phosphatase that regulates lymphocyte activation; CD45R0
isoform on memory T cells, CD45RA isoform on naïve T cells
CD56 NK cells Mediates NK homotypic adhesion
CD62L Marker for recent Cell adhesion molecule
thymic emigrants
Also found on other
leukocytes
CD69 T cells and NK cells Early activation marker
CD73 T and B cells Associates with AMP
CD80 B cells Co-stimulatory with CD28 on T cells to upregulate high-affinity IL-2
receptor
CD86 B cells Co-stimulatory with CD28 on T cells to upregulate high-affinity IL-2
receptor
CD117 Pro-B cells, double- Receptor for stem cell factor
negative thymocytes
CD127 T cells Mediates IL-7 signaling
CD132 T, B, and NK cells Mediates signaling by IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21
CD154 Activated CD4+ T cells Ligates CD40 on B cells and initiates isotype switching
CD278 T cells Interacts with B7-H2
AMP, Adenosine monophosphate; EBV, Epstein-Barr virus; ICAMs, intracellular adhesion
molecules; IL, interleukin; LFA, leukocyte function–activating antigen; NK, natural killer; TCR, T-
cell receptor.
Table 149.2
Common Cytokines

CATEGORY CYTOKINE FUNCTION

Interferons IFN-α Antiviral defense
IFN-β Antiviral defense
IFN-γ Antiviral defense
Innate responses TNF Regulates endothelial adhesion molecules for recruitment of neutrophils;
activates macrophages for killing
IL-1β Drives the inflammatory response, fever
IL-12 Polarizes T cells toward Th1; activates NK cells
Lymphocyte IL-2 Key growth factor for T cells
regulation IL-4 Polarizes T cells toward Th2
IL-6 Growth factor for B cells
IL-7 T-cell homeostatic factor
IL-10 Growth factor for B cells, immunosuppressive
IL-12 Polarizes T cells toward Th1, activates NK cells
IL-17 Polarizes T cells toward Th17, stimulates antimicrobial peptide expression
IL-21 Supports B-cell class switching
IL, Interleukin; NK, natural killer; Th, T-helper cell; TNF, tumor necrosis factor.

T-Cell Development and Differentiation

The primitive thymic rudiment is formed from the ectoderm of the 3rd branchial
cleft and endoderm of the 3rd branchial pouch at 4 wk gestation. Beginning at 7-
8 wk, the right and left rudiments fuse in the midline. Bloodborne T-cell
precursors from the fetal liver then begin to colonize the perithymic
mesenchyme at 8 wk gestation and move into the thymus at 8.0-8.5 wk. The
earliest cells to enter the thymus are found in the subcapsular region and do not
express CD3, CD4, CD8, or either type of T-cell receptor (TCR). These
lymphoid cell precursors are triggered to proliferate and become thymocytes
through interactions with the thymic stroma. The cells are arrested at this stage
until they productively rearrange the β-chain locus of the TCR. The β chain then
pairs with the surrogate pre-T α chain. This tests the function of the β chain, and
if signaling occurs, β-chain rearrangement ceases. CD4 and CD8 are then
expressed simultaneously (i.e., they are double-positive thymocytes). Fetal
cortical thymocytes are among the most rapidly dividing cells in the body and
increase in number by 100,000-fold within 2 wk after stem cells enter the
thymus. As these cells proliferate and mature, they migrate deeper into the
thymic cortex. The double-positive thymocytes begin efficient rearrangement of
the α-chain locus. TCR gene rearrangement occurs by a process in which large,
CHAPTER 150

Primary Defects of Antibody

Production
Kathleen E. Sullivan, Rebecca H. Buckley

Of the primary immunodeficiency diseases, those affecting antibody production

are the most prevalent. Selective absence of IgA is the most common defect,
with rates ranging from 1 in 333 to 1 in 18,000 persons among different races
and ethnicities. Patients with antibody deficiency are usually recognized because
they have recurrent infections with encapsulated bacteria, predominantly in the
upper and lower respiratory tracts. Some individuals with selective IgA
deficiency or infants with transient hypogammaglobulinemia may have few or
no infections. These conditions have a complex and likely polygenic inheritance,
as do the common variable immunodeficiency (CVID) syndromes. The gene
defects for many primary antibody deficiency disorders have been identified
(Table 150.1 ) and localized (Fig. 150.1 ). Sometimes the defect is not in the B
cell itself but in T cells, which are required for complete B-cell function. Some
disorders are caused by unknown factors or are secondary to an underlying
disease or its treatment (Table 150.2 ).

Table 150.1

Genetic Basis of the Most Common Primary Antibody Deficiency Disorders

GENE PHENOTYPE DISORDER
BAFFR CVID Hypogammaglobulinemia
CD19 CVID Hypogammaglobulinemia
CD20 CVID Hypogammaglobulinemia
CD21 CVID Hypogammaglobulinemia
CD81 CVID Hypogammaglobulinemia
CTLA4 CVID Hypogammaglobulinemia, pronounced lymphoproliferation and
autoimmunity
ICOS CVID Hypogammaglobulinemia, autoimmunity, neoplasia
 LRBA CVID Hypogammaglobulinemia, pronounced lymphoproliferation and
autoimmunity
NFKB2 CVID Hypogammaglobulinemia, autoimmunity
NFKB1 CVID Hypogammaglobulinemia, autoimmunity
PIK3CD CVID Hypogammaglobulinemia, adenopathy
PI3KR1 CVID Hypogammaglobulinemia
(AD)
TNFRSF13B CVID Hypogammaglobulinemia, low penetrance of disease
Unknown CVID Hypogammaglobulinemia, autoimmunity
Majority of patients with CVID have no known gene
defect.
Unknown IgG subclass deficiency Variable association with infection
Unknown Specific antibody deficiency Normal immunoglobulin levels with poor vaccine responses
Unknown Transient Vaccine responses are usually preserved, and most children
hypogammaglobulinemia of outgrow this by age 3 yr.
infancy
Unknown Selective IgA deficiency Low or absent IgA; low concentrations of all immunoglobulins
and of switched memory B cells in CVID
BLNK Agammaglobulinemia Absence of antibody production, lack of B cells
BTK Agammaglobulinemia Absence of antibody production, lack of B cells, X-linked
agammaglobulinemia
CD79A Agammaglobulinemia Loss of the Igα required for signal transduction, absence of
antibody production, lack of B cells
CD79B Agammaglobulinemia Loss of the Igβ required for signal transduction, absence of
antibody production, lack of B cells
IGHM Agammaglobulinemia Loss of the Ig heavy chain, absence of antibody production,
lack of B cells
IGLL1 Agammaglobulinemia Loss of the surrogate light chain, absence of antibody
production, lack of B cells
PI3KR1 Agammaglobulinemia Loss of signal transduction through the B-cell receptor, absence
(AR) of antibody production, lack of B cells
TCF3 Agammaglobulinemia Loss of a key transcription factor for B-cell development,
absence of antibody production, lack of B cells
AID Class switch defect Failure to produce IgG, IgA, and IgE antibodies
CD40 Class switch defect Failure to produce IgG, IgA, and IgE antibodies, Pneumocystis
and Cryptosporidium susceptibility
CD154 Class switch defect Failure to produce IgG, IgA, and IgE antibodies, Pneumocystis
and Cryptosporidium susceptibility
INO80 Class switch defect Failure to produce IgG, IgA, and IgE antibodies
MSH6 Class switch defect Failure to produce IgG, IgA, and IgE antibodies, malignancy
UNG Class switch defect Failure to produce IgG, IgA, and IgE antibodies
SH2D1A X-linked lymphoproliferative Various phenotypes including hypogammaglobulinemia
disease
XIAP X-linked lymphoproliferative Various phenotypes including hypogammaglobulinemia
disease
CD27 EBV lymphoproliferation Memory B-cell deficiency
Hypogammaglobulinemia
NEMO Anhidrotic ectodermal dysplasia Phenotype highly variable but includes specific antibody
with immunodeficiency deficiency and CVID
CVID, Common variable immunodeficiency; EBV, Epstein-Barr virus.
Other Conditions Associated With Humoral
Immunodeficiency
GENETIC DISORDERS
T-cell defects Most T-cell defects can have a secondary deficit in immunoglobulin.
Complex syndromes Transcobalamin II deficiency and hypogammaglobulinemia, Wiskott-Aldrich syndrome,
ataxia telangiectasia, etc.
Chromosomal Chromosome 18q− syndrome
anomalies 22q11.2 deletion
Trisomy 8, trisomy 21
SYSTEMIC DISORDERS
Malignancy Chronic lymphocytic leukemia
Immunodeficiency with thymoma
T-cell lymphoma
Metabolic or Immunodeficiency caused by hypercatabolism of immunoglobulin
physical loss Immunodeficiency caused by excessive loss of immunoglobulins and lymphocytes
ENVIRONMENTAL EXPOSURES
Drug induced Antimalarial agents
Captopril
Carbamazepine
Glucocorticoids
Fenclofenac
Gold salts
Imatinib
Penicillamine
Phenytoin
Sulfasalazine
Infectious diseases Congenital rubella
Congenital infection with cytomegalovirus
Congenital infection with Toxoplasma gondii
Epstein-Barr virus
Human immunodeficiency virus

X-Linked Agammaglobulinemia
Patients with X-linked agammaglobulinemia (XLA ), or Bruton
agammaglobulinemia , have a profound defect in B-lymphocyte development
resulting in severe hypogammaglobulinemia, an absence of circulating B cells,
small to absent tonsils, and no palpable lymph nodes.

Genetics and Pathogenesis

The abnormal gene in XLA maps to q22 on the long arm of the X chromosome
and encodes the B-cell protein tyrosine kinase Btk (Bruton tyrosine kinase). Btk
is a member of the Tec family of cytoplasmic protein tyrosine kinases and is
immunoglobulins are usually <100 mg/dL. Levels of natural antibodies to type A
and B red blood cell polysaccharide antigens (isohemagglutinins) and antibodies
to antigens given during routine immunizations are abnormally low in XLA,
whereas they are typically normal in transient hypogammaglobulinemia of
infancy. Flow cytometry is an important test to demonstrate the absence of
circulating B cells , which will distinguish XLA from most types of CVID, the
hyper-IgM syndrome, and transient hypogammaglobulinemia of infancy.

Common Variable Immunodeficiency

CVID is a syndrome characterized by hypogammaglobulinemia. Serum IgG
must be <2 standard deviations below the age-adjusted norms, with low IgA and
or IgM levels. CVID patients may appear similar clinically to those with XLA in
the types of infections experienced and bacterial etiologic agents involved,
except that enterovirus meningoencephalitis is rare in patients with CVID (Table
150.3 ). In contrast to XLA, the sex distribution in CVID is almost equal, the age
at onset is later, and infections may be less severe. CVID is the most common of
the antibody defects.

Table 150.3

Main Phenotypes of Primary Antibody Deficiencies

PHENOTYPE MAIN CLINICAL FEATURES MAIN B-CELL FEATURES
Agammaglobulinemia Bacterial infections (in respiratory tract) and Absence of CD19 B cells
enterovirus infections
Combined variable Bacterial infections (in respiratory tract and gut), Highly variable; may see
immunodeficiency autoimmunity, cancer, and increased risk of decreased memory B cells
(CVID) granuloma
Class switch defects Bacterial and opportunistic infections Decreased frequency of memory B
cells
Selective IgA Most often asymptomatic Normal
deficiency
IgG subclass Frequent bacterial infections; diagnosis after age 2 yr B-cell subsets normal
deficiency
Selective Bacterial infections (after age 2 yr) Normal IgG (including IgG2 and
polysaccharide IgG4) levels, normal B-cell
antibody deficiency subsets

Genetics and Pathogenesis

CVID is a phenotypic diagnosis with a polygenic inheritance in most cases.
IgM concentration in patients with AID deficiency is usually markedly elevated
and polyclonal. Patients with AID and UNG mutations have lymphoid
hyperplasia, are generally older at age at onset, do not have susceptibility to P.
jiroveci pneumonia, often do have isohemagglutinins, and are much less likely to
have neutropenia unless it occurs on an autoimmune basis. They have a
tendency, however, to develop autoimmune and inflammatory disorders,
including diabetes mellitus, polyarthritis, autoimmune hepatitis, hemolytic
anemia, immune thrombocytopenia, Crohn disease, and chronic uveitis.

Treatment and Prognosis

With early diagnosis and monthly infusions of IVIG, as well as good
management of infections with antibiotics, patients with AID and UNG
mutations generally have a more benign course than do boys with the CD40L or
CD40 defects. CD40 deficiency is rare but appears to mimic the manifestations
of CD40L quite closely.

X-Linked Lymphoproliferative Disease

There are two types of X-linked lymphoproliferative disease (Table 150.4 ).
They have distinct clinical features but share a susceptibility to Epstein-Barr
virus (EBV) and the development of hemophagocytic lymphohistiocytosis
(HLH) .

Table 150.4
Features of SAP (SH2D1A) and XIAP Deficiency

FEATURE SAP DEFICIENCY (XLP) XIAP DEFICIENCY

CLINICAL MANIFESTATIONS
HLH Yes Yes
Hypogammaglobulinemia Yes Yes
Lymphoma Yes No
Aplastic anemia Yes No
Vasculitis Yes No
GENETICS
Causative gene SH2D1A XIAP
Genetic locus Xq25 Xq25
Encoded protein SAP XIAP
Effect of mutation Reduced, absent protein expression Reduced, absent or truncated
protein
IMMUNE CELL FUNCTIONS
 Natural killer T (NKT) cell Reduced Normal
cytotoxicity/degranulation
NKT cell number (blood) Absent Variable
Restimulation-induced death Reduced Increased
Memory B-cell numbers Reduced Not reported
TREATMENT OPTIONS
HLH Immunosuppression and/or Immunosuppression and/or
chemotherapy (etoposide) chemotherapy (etoposide)
Consideration of rituximab
Humoral deficiency Intravenous IgG infusions Consider rituximab for EBV-
positive cases
Intravenous IgG infusions
Lymphoma Standard chemotherapy
Curative therapy Stem cell transplantation Stem cell transplantation
EBV, Epstein-Barr virus; HLH, hemophagocytic lymphohistiocytosis; SAP, SLAM-associated
protein; XIAP, X-linked inhibitor of apoptosis protein.
From Rezaei N, Mahmoudi E, Aghamohamadi A, et al: X-linked lymphoproliferative syndrome: a
genetic condition typified by the triad of infection, immunodeficiency and lymphoma, Br J
Haematol 152:14, 2010.

Genetics and Pathogenesis

The defective gene in XLP type I was localized to Xq25, cloned, and the gene
product was initially named SAP (SLAM-associated protein), but is now known
officially as SH2D1A. SLAM (signaling lymphocyte activation molecule) is an
adhesion molecule that is upregulated on both T and B cells with infection and
other stimulation. The absence of SH2D1A can lead to an uncontrolled cytotoxic
T-cell immune response to EBV. The SH2D1A protein associates permissively
with 2B4 on natural killer (NK) cells; thus selective impairment of 2B4-
mediated NK-cell activation also contributes to the immunopathology of XLP.
XLP type 2 is caused by a mutation in XIAP (X-linked inhibitor of apoptosis
protein). Disease manifestations are similar to XLP. The precise role of this
protein in the susceptibility to EBV has not been elucidated.

Clinical Manifestations
Affected males are usually healthy until they acquire EBV infection. The mean
age of presentation is <5 yr. There are 3 major clinical phenotypes: (1)
fulminant, often fatal, infectious mononucleosis (50% of cases); (2) lymphomas,
predominantly involving B-lineage cells (25%); and (3) acquired
hypogammaglobulinemia (25%). A less common manifestation is CNS
vasculitis. There is a marked impairment in production of antibodies to the EBV
transduction from the TCR to intracellular metabolic pathways (Fig. 151.1 ).
These patients have problems similar to those of other T-cell–deficient
individuals, and some with severe T-cell activation defects may clinically
resemble SCID patients (Table 151.1 ). In some cases, susceptibility to a single
pathogen or a limited number of pathogens dominates the clinical phenotype.
Susceptibility to Epstein-Barr virus, cytomegalovirus, and papillomavirus is
common in this set of T-cell defects. Most individuals with significant T-cell
activation defects will require a hematopoietic stem cell transplant. Although
each infection may be manageable early in life, the long-term prognosis is not
favorable in many of these conditions.

FIG. 151.1 Schematic representation of signaling through the T-cell receptor–CD3

complex. Molecules for which mutations have been associated with partial defect of T-
cell development and impaired T-cell function are indicated in red and highlighted in
boldface . AP1, Activator protein 1; DHR, DOCK-homology region; Grb2, growth factor
receptor-bound protein 2; IKK, IκB kinase; JNK, c-Jun N-terminal kinase; MAPK,
mitogen-activated protein kinase; NFAT, nuclear factor of activated T cells; NFκB,
nuclear factor κB; PI3K, phosphoinositide-3 kinase; PIP3, phosphatidylinositol (3,4,5)-
triphosphate. (From Notarangelo L: Partial defects of T-cell development associated
with poor T-cell function, J Allergy Clin Immunol 131:1299, 2013.)

Table 151.1

Genetic Basis of Primary Cellular Immunodeficiency Diseases

 GENE EFFECT ON T CELLS INFECTION
PRODUCT SUSCEPTIBILITY
Lck ↓↓ CD4 Viral infections predominantly
CD8
CD8α ↓↓ CD8 deficiency Viral infections predominantly
ZAP-70 CD8 deficiency Viral infections predominantly
RhoH ↓ Naïve CD4+ cells Warts
ITK ↓ Naïve CD4+ cells Epstein-Barr virus
Absence of NKT cells
22q11.2 Thymic hypoplasia (DiGeorge syndrome, velocardiofacial Highly variable
deletion syndrome)
CD3γ and ε CD3 deficiency Viral infections predominantly
TRAC TCR-αβ T-cell deficiency Similar to SCID
Coronin-1A ↓↓ CD4 Similar to SCID
↓↓ CD8
MST1/STK4 ↓ Naïve T cells Warts
Low number of recent thymic emigrants, restricted T-cell
repertoire
AIRE APECED, chronic mucocutaneous candidiasis, parathyroid and Candida
adrenal autoimmunity
TBX1 Thymic hypoplasia Similar phenotype with
22q11.2 deletion
AIRE, Autoimmune regulator; APECED, autoimmune polyendocrinopathy-candidiasis–ectodermal
dysplasia; Ig, immunoglobulin; ITK, IL-2–inducible tyrosine kinase deficiency; MST1, macrophage-
stimulating factor 1; NKT, natural killer T; RhoH, Ras homology family member H; SCID, severe
combined immunodeficiency; STK4, serine threonine kinase 4; TCR, T-cell receptor; TRAC, T-cell
receptor α chain constant region; ZAP-70, zeta-associated protein 70.

Chronic Mucocutaneous Candidiasis

Chronic mucocutaneous candidiasis (CMC ) is a syndrome characterized by
impaired immune responsiveness to Candida. Some of the known gene defects
with CMC have autoimmune polyendocrinopathy syndrome type 1 (APS1 ,
or autoimmune polyendocrinopathy-candidiasis–ectodermal dystrophy
[APECED ]). One of the other genetic types of CMC is associated with
autoimmunity and predisposition to other infections (STAT1 gain-of-function
mutations). However, most of the specific genetic types of CMC have isolated
susceptibility to Candida . These types of CMC relate to defects in the Th17 cell
pathway. Autosomal recessive deficiency in the interleukin-17 receptor A (IL-
17RA) chain, and an autosomal dominant deficiency of the cytokine IL-17F are
both associated with predisposition to Candida . Other immunodeficiencies in
which Candida occurs in the context of other infections also affect the Th17
cells. Another CMC genetic type, caused by mutations in CARD9 , has a strong
predisposition to Candida but also to other fungi.
 newborn screening
lymphoid development

Severe combined immunodeficiency (SCID ) is caused by diverse genetic

mutations that lead to absence of T- and B-cell function. Patients with this group
of disorders have the most severe immunodeficiency.

Pathogenesis
SCID is caused by mutations in genes crucial for lymphoid cell development
(Table 152.1 and Fig. 152.1 ). All patients with SCID have very small thymuses
that contain no thymocytes and lack corticomedullary distinction or Hassall
corpuscles. The thymic epithelium appears histologically normal. Both the
follicular and the paracortical areas of the spleen are depleted of lymphocytes.
Lymph nodes, tonsils, adenoids, and Peyer patches are absent or extremely
underdeveloped.

Table 152.1
Genetic Basis of SCID and SCID Variants

ADDITIONAL
DISEASE INHERITANCE PRESUMED PATHOGENESIS TREATMENT
FEATURES
Reticular AR Impaired mitochondrial energy Severe neutropenia, GCSF, HSCT
dysgenesis metabolism and leukocyte deafness. Mutations in
differentiation adenylate kinase 2
Adenosine AR Accumulation of toxic purine Neurologic, hepatic, renal, HSCT, PEG-
deaminase nucleosides lung, and skeletal and bone ADA, gene
deficiency marrow abnormalities therapy
IL-2Rγ X-linked Abnormal signaling through by None HSCT
deficiency IL-2 receptor and other receptors
containing γc (IL-4, -7, -9, -15,
-21)
Jak3 AR Abnormal signaling downstream None HSCT
deficiency of γc
RAG1 and AR Defective V(D)J recombination None HSCT
RAG2
deficiency
Artemis AR Defective V(D)J recombination, DCLERE1C gene defects HSCT
deficiency radiation sensitivity
DNA-PK AR Defective V(D)J recombination None HSCT
deficiency
DNA ligase AR Defective V(D)J recombination, Growth delay, HSCT
IV radiation sensitivity microcephaly, bone
 deficiency marrow abnormalities,
lymphoid malignancies
Cernunnos- AR Defective V(D)J recombination, Growth delay, HSCT
XLF radiation sensitivity microcephaly, birdlike
facies, bone defects
CD3δ AR Arrest of thymocytes Thymus size may be HSCT
deficiency differentiation at CD4− CD8− normal
stage
CD3ε AR Arrest of thymocytes γ/δ T cells absent HSCT
deficiency differentiation at CD4− CD8−
stage
CD3ζ AR Abnormal signaling None HSCT
deficiency
IL-7Rα AR Abnormal IL-7R signaling Thymus absent HSCT
deficiency
CD45 AR None HSCT
deficiency
Coronin-1A AR Abnormal T-cell egress from Normal thymus size. HSCT
deficiency thymus and lymph nodes Attention deficit disorder.
AR, Autosomal recessive; GCSF, granulocyte colony-stimulating factor; HSCT, hematopoietic
stem cell transplantation; IL, interleukin; Jak3, Janus kinase 3; PEG-ADA, polyethylene glycol-
modified adenosine deaminase; RAG1, RAG2, recombinase-activating genes 1 and 2; V(D)J,
variable, diversity, joining domains.
(Adapted from Roifman, CM. Grunebaum E: Primary T-cell immunodeficiencies. In Rich RR,
Fleisher TA, Shearer WT, et al, editors: Clinical immunology, ed 4. Philadelphia, 2013, Saunders,
pp 440–441).

FIG. 152.1 Relative frequencies of the different genetic types of severe combined
immunodeficiency (SCID). ADA, Adenosine deaminase; IL-7R, interleukin 7 receptor;
JAK, Janus kinase; RAG, recombinase-activating gene.
 Wu U, Holland SM. Host susceptibility to non-tuberculous
mycobacterial infections. Lancet Infect Dis . 2015;15(8):968–
980.

152.4
Treatment of Cellular or Combined
Immunodeficiency
Kathleen E. Sullivan, Rebecca H. Buckley

Good supportive care, including prevention and treatment of infections, is

critical while patients await more definitive therapy (Table 152.2 ). Having
knowledge of the pathogens causing disease with specific immune defects is also
useful.

Table 152.2
Infection in the Host Compromised by B- and T-Cell
Immunodeficiency Syndromes

APPROACH TO
IMMUNODEFICIENCY OPPORTUNISTIC ORGANISMS PREVENTION OF
TREATMENT OF
SYNDROME ISOLATED MOST FREQUENTLY INFECTIONS
INFECTIONS
B-cell immunodeficiencies Encapsulated bacteria (Streptococcus IVIG, 200-800 Maintenance
pneumoniae, Staphylococcus aureus, mg/kg IVIG for patients
Haemophilus influenzae , and Vigorous attempt with quantitative
Neisseria meningitidis ), to obtain and qualitative
Pseudomonas aeruginosa, specimens for defects in IgG
Campylobacter spp., enteroviruses, culture before metabolism (400-
rotaviruses, Giardia lamblia, antimicrobial 800 mg/kg every
Cryptosporidium spp., Pneumocystis therapy 3-5 wk)
jiroveci, Ureaplasma urealyticum , Incision and In chronic
and Mycoplasma pneumoniae drainage if recurrent
abscess present respiratory
Antibiotic disease, vigorous
selection on the attention to
 basis of postural drainage
sensitivity data In selected cases
(recurrent or
chronic
pulmonary or
middle ear),
prophylactic
administration of
ampicillin,
penicillin, or
trimethoprim-
sulfamethoxazole
T-cell immunodeficiencies Encapsulated bacteria (S. Vigorous attempt Prophylactic
pneumoniae, H. influenzae, S. aureus to obtain administration of
), facultative intracellular bacteria specimens for trimethoprim-
(Mycobacterium tuberculosis , other culture before sulfamethoxazole
Mycobacterium spp., and Listeria antimicrobial for prevention of
monocytogenes ); Escherichia coli; P. therapy P. jiroveci
aeruginosa; Enterobacter spp.; Incision and pneumonia
Klebsiella spp.; Serratia marcescens; drainage if Oral
Salmonella spp.; Nocardia spp.; abscess present nonadsorbable
viruses (cytomegalovirus, herpes Antibiotic antimicrobial
simplex virus, varicella-zoster virus, selection on the agents to lower
Epstein-Barr virus, rotaviruses, basis of concentration of
adenoviruses, enteroviruses, sensitivity data gut flora
respiratory syncytial virus, measles Early antiviral No live virus
virus, vaccinia virus, and treatment for vaccines or
parainfluenza viruses); protozoa herpes simplex, bacille Calmette-
(Toxoplasma gondii and cytomegalovirus, Guérin vaccine
Cryptosporidium spp.); and fungi and varicella- Careful
(Candida spp., Cryptococcus zoster viral tuberculosis
neoformans, Histoplasma capsulatum infections screening
, and P. jiroveci ) Topical and
nonadsorbable
antimicrobial
agents frequently
are useful
IVIG, Intravenous immune globulin.
From Stiehm ER, Ochs HD, Winkelstein JA: Immunologic disorders in infants and children , ed 5,
Philadelphia, 2004, Saunders.

Transplantation of major histocompatibility complex (MHC)–compatible

sibling or rigorously T-cell–depleted haploidentical (half-matched) parental
hematopoietic stem cells is the treatment of choice for patients with fatal T-cell
or combined T- and B-cell defects. The major risk to the recipient from
transplants of bone marrow or peripheral blood stem cells is GVHD from donor
T cells. Patients with less severe forms of cellular immunodeficiency, including
some forms of CID, Wiskott-Aldrich syndrome, cytokine deficiency, and MHC
antigen deficiency, reject even HLA-identical marrow grafts unless
chemoablative treatment is given before transplantation. Several patients with
 IPEX

Primary immunodeficiency diseases characterized by immune dysregulation,

autoimmunity, and autoinflammation are monogenic defects of the immune
system. These complex multisystem diseases often have a progressive phenotype
with organ-specific autoimmunity, specific infectious susceptibility, and
lymphoproliferation.

Autoimmune Lymphoproliferative
Syndrome
Autoimmune lymphoproliferative syndrome (ALPS ), also known as Canale-
Smith syndrome, is a disorder of abnormal lymphocyte apoptosis leading to
polyclonal populations of T cells (double-negative T cells), which express CD3
and α/β antigen receptors but do not have CD4 or CD8 co-receptors (CD3+ T-
cell receptor α/β+ , CD4− CD8− ). These T cells respond poorly to antigens or
mitogens and do not produce growth or survival factors (IL-2). The genetic
deficit in most patients is a germline or somatic mutation in the FAS gene, which
produces a cell surface receptor of the TNF receptor superfamily (TNFRSF6),
which, when stimulated by its ligand, will produce programmed cell death (Table
152.3 ). Persistent survival of these lymphocytes leads to immune dysregulation
and autoimmunity. ALPS is also caused by other genes in the Fas pathway
(FASLG and CASP10 ). In addition, ALPS-like disorders are associated with
other mutations: RAS-associated autoimmune lymphoproliferative disorder
(RALD), caspase-8 deficiency, Fas-associated protein with death domain
deficiency (FADD), and protein kinase C delta deficiency (PRKCD). These
disorders have varying degrees of immunodeficiency, autoimmunity, and
lymphoproliferation.

Table 152-3
Revised Diagnostic Criteria for Autoimmune
Lymphoproliferative Syndrome*
REQUIRED
1. Chronic (>6 months), nonmalignant, noninfectious lymphadenopathy, splenomegaly or both
2. Elevated CD3+TCRαβ+CD4-CD8- DNT cells (≥1.5% of total lymphocytes or 2.5% of CD3+ lymphocytes) in
 the setting of normal or elevated lymphocyte counts
ACCESSORY
Primary
1. Defective lymphocyte apoptosis (in 2 separate assays)
2. Somatic or Germline pathogenic mutation in FAS , FASLG , or CASP10
Secondary
1. Elevated plasma sFasL levels (>200 pg/mL) OR elevated plasma interleukin-10 levels (>20 pg/mL) OR
elevated serum or plasma vitamin B 12 levels (>1500 ng/L) OR elevated plasma interleukin-18 levels >500
pg/mL
2. Typical immunohistological findings as reviewed by an experienced hematopathologist
3. Autoimmune cytopenias (hemolytic anemia, thrombocytopenia, or neutropenia) AND elevated
immunoglobulin G levels (polyclonal hypergammaglobulinemia)
4. Family history of a nonmalignant/noninfectious lymphoproliferation with or without autoimmunity
*
A definitive diagnosis is based on the presence of both required criteria plus one primary
accessory criterion. A probable diagnosis is based on the presence of both required criteria plus
one secondary accessory criterion.
From Petty RE, Laxer RM, Lindsley CB, Wedderburn LR, editors: Textbook of pediatric
rheumatology, ed 7, Philadelphia, 2016, Elsevier, Box 46-2.

Clinical Manifestations
ALPS is characterized by autoimmunity, chronic persistent or recurrent
lymphadenopathy , splenomegaly, hepatomegaly (in 50%), and
hypergammaglobulinemia (IgG, IgA). Many patients present in the 1st yr of life,
and most are symptomatic by age 5 yr. Lymphadenopathy can be striking (Fig.
152.4 ). Splenomegaly may produce hypersplenism. Autoimmunity also
produces anemia (Coombs-positive hemolytic anemia) or thrombocytopenia or a
mild neutropenia. The lymphoproliferative process (lymphadenopathy,
splenomegaly) may regress over time, but autoimmunity does not regress and is
characterized by frequent exacerbations and recurrences. Other autoimmune
features include urticaria, uveitis, glomerulonephritis, hepatitis, vasculitis,
panniculitis, arthritis, and CNS involvement (seizures, headaches,
encephalopathy).
Treatment
Rapamycin (sirolimus) will often control the adenopathy and autoimmune
cytopenias. Malignancies can be treated with the usual protocols used in patients
unaffected by ALPS. Stem cell transplantation is another possible option in
treating the autoimmune manifestations of ALPS.

Immune Dysregulation,
Polyendocrinopathy, Enteropathy, X-
Linked Syndrome
This immune dysregulation syndrome is characterized by onset within the 1st
few wk or mo of life with watery diarrhea (autoimmune enteropathy), an
eczematous rash (erythroderma in neonates), insulin-dependent diabetes
mellitus, hyperthyroidism or more often hypothyroidism, severe allergies, and
other autoimmune disorders (Coombs-positive hemolytic anemia,
thrombocytopenia, neutropenia). Psoriasiform or ichthyosiform rashes and
alopecia have also been reported.
Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX )
syndrome is caused by a mutation in the FOXP3 gene, which encodes a
forkhead-winged helix transcription factor (scurfin) involved in the function and
development of CD4+ CD25+ regulatory T cells (Tregs). The absence of Tregs
may predispose to abnormal activation of effector T cells. Dominant gain-of-
function mutations in STAT1 and other gene mutations (Table 152.4 ) produce an
IPEX-like syndrome, also associated with compromised Tregs.

Table 152.4
Clinical and Laboratory Features of IPEX and IPEX-Like
Disorders

IPEX CD25 STAT5B STAT1 ITCH

AUTOIMMUNITY

Eczema +++ +++ ++ ++ ++

Enteropathy +++ +++ ++ ++ ++
Endocrinopathy +++ ++ + ++ ++
Allergic disease +++ + + ++ ++
 Cytopenias ++ ++ ++ –
Lung disease + ++ +++ + +++
INFECTIONS
Yeast – ++ – +++ –
Herpes virus – +++ ++ (VZV) ++ –
(EBV/CMV)
Bacterial +/– ++ ++ ++ +
Associated features None None Growth failure Vascular anomalies Dysmorphic growth
failure
Serum Elevated Elevated or Elevated or Low, normal, or Elevated
immunoglobulins normal normal high
Serum IgE Elevated Normal or Normal or Normal or mildly Elevated
elevated elevated elevated
CD25 expression Normal Absent Normal or low Normal Not tested
CD4+ CD45RO Elevated Elevated Elevated Normal or high Not tested
FOXP3 expression Absent or Normal or low Normal or low Normal Not tested
normal
IGF-1, IGFBP-3 Normal Normal Low Normal Not tested
Prolactin Normal Normal Elevated Normal Not tested
CMV, Cytomegalovirus; EBV, Epstein-Barr virus; IGF-1, insulin-like growth factor 1; IGFBP-3,
insulin-like growth factor–binding protein 3; IPEX, immune dysregulation, polyendocrinopathy,
enteropathy, X-linked; VZV, varicella-zoster virus; ITCH, ubiquitin ligase deficiency.
From Verbsky JW, Chatila TA: Immune dysregulation, polyendocrinopathy, enteropathy, X–linked
(IPEX) and IPEX–related disorders: an evolving web of heritable autoimmune diseases, Curr Opin
Pediatr 25:709, 2013.

Clinical Manifestations
Watery diarrhea with intestinal villous atrophy leads to failure to thrive in most
patients. Cutaneous lesions (usually eczema) and insulin-dependent diabetes
begin in infancy. Lymphadenopathy and splenomegaly are also present. Serious
bacterial infections (meningitis, sepsis, pneumonia, osteomyelitis) may be
related to neutropenia, malnutrition, or immune dysregulation. Laboratory
features reflect the associated autoimmune diseases, dehydration, and
malnutrition. In addition, serum IgE levels are elevated, with normal levels of
IgM, IgG, and IgA. The diagnosis is made clinically and by mutational analysis
of the FOXP3 gene.

Treatment
Inhibition of T-cell activation by cyclosporine, tacrolimus, or sirolimus with
corticosteroids is the treatment of choice, along with the specific care of the
endocrinopathy and other manifestations of autoimmunity. These agents are
transduction by type 1 and type 2 cytokine receptors within most hematopoietic
cells. Cytokines bind to their cognate receptor, triggering JAK-STAT pathways,
ultimately leading to the upregulation of genes involved in the immune response
against many pathogens. There are 4 JAK proteins (Jak1, Jak2, Jak3, Tyk2) and
6 STATs (1-6). Mutations in several JAKs and STATs cause immunodeficiency.
Table 152.5 includes diseases affecting STAT proteins characterized by immune
dysregulation. Chronic immunosuppression is necessary for control of STAT
defects. Ruxolitinib, a JAK-STAT inhibitor, has been used with some success.
With the advent of JAK-STAT immunomodulating therapies, more treatment
options will be available to patients.

Table 152.5
Defects of STAT Proteins Associated With
Immunodysregulation

AUTOIMMUNE OR
OTHER
PROTEIN LOF/GOF INFLAMMATORY IMMUNOPHENOTYPE
CHARACTERISTICS
COMPLICATIONS
STAT1 GOF IPEX-like enteropathy, Infections Variable lymphopenia,
enteropathy, endocrinopathy, CMC hypogammaglobulinemia,
dermatitis, cytopenias Viral infections abnormal T-cell function,
NTM reduced Th17 expression
Dimorphic mold
Respiratory
bacterial
STAT3 GOF Early onset enteropathy, Respiratory tract Increased DNT (CD3+
severe growth failure, infections CD4− CD8− )
lymphoproliferation, Herpes viral Hypogammaglobulinemia
autoimmune cytopenias, infections T-cell lymphopenia
inflammatory lung disease, T-cell LGL B-cell lymphopenia
type 1 diabetes, dermatitis, leukemia
arthritis NTM
STAT5B LOF Severe growth hormone Respiratory tract Lymphopenia
resistant growth failure, infections Reduced Treg cells
lymphocytic interstitial Viral infections Reduced γδ T cells
pneumonitis, atopic dermatitis Reduced NK cells
STAT, Signal transducer and activator of transcription; GOF, gain of function; LOF, loss of function;
IPEX, immunodysregulation, polyendocrinopathy, enteropathy, X-linked; CMC, chronic
mucocutaneous candidiasis; NTM, nontuberculous mycobacteria; DNT, double-negative T cell.

Nuclear Factor-κB Pathway Defects

The NF-κB pathways consists of canonical (NF-κB1) and noncanonical (NF-
κB2) pathways. On cellular activation, both pathways lead to activation and
translocation of NF-κB proteins into the nucleus, where they initiate downstream
inflammatory responses. Defects in many proteins in both pathways have been
described. Table 152.6 describes immune defects of the NF-κB pathways that
cause symptoms of immune dysregulation or autoimmunity. Treatment of NF-κB
defects includes prevention of infections and replacement of immunoglobulin
and has included HSCT.

Table 152.6
Defects of Nuclear Factor-κB Pathways Associated With
Immune Dysregulation

AUTOIMMUNE OR
OTHER IMMUNOLOGIC
PROTEIN INHERITANCE INFLAMMATORY
MANIFESTATIONS PHENOTYPE
COMPLICATIONS
IKBKG XL Colitis Ectodermal Hypogammaglobulinemia
(NEMO) dysplasia Hyper IgM
Osteopetrosis Hyper IgA
Lymphedema Hyper IgD
Bacterial Poor antibody responses
infections Decreased NK cell
Opportunistic function
infections Decreased TLR responses
DNA viral
infections
NF-κB1 AD Pyoderma Atrophic gastritis Hypogammaglobulinemia
gangrenosum Squamous cell IgA deficiency
Lymphoproliferation carcinoma
Cytopenia Respiratory tract
Hypothyroidism infections
Alopecia areata Superficial skin
Enteritis infections
LIP Lung
NRH adenocarcinoma
Respiratory
insufficiency
Aortic stenosis
Non-Hodgkin
lymphoma
NF-κB2 AD Alopecia totalis Viral respiratory Early-onset
Trachyonychia infections hypogammaglobulinemia
Vitiligo Pneumonias Low vaccine responses
Autoantibodies: Sinusitis Variable B-cell counts
thyroid peroxidase, Otitis media Low switched memory B
glutamate Recurrent herpes cells (CD19+ CD27+ IgD
decarboxylase, Asthma − )
thyroglobulin Type 1 Chiari Low marginal zone B
Central adrenal malformation
cells (CD19+ CD27+
 insufficiency Interstitial lung IgD+ )
disease
XL, X-linked; AD, autosomal dominant; LIP, lymphocytic interstitial pneumonitis; NRH,
nonregenerative hyperplasia.

Tetratricopeptide Repeat Domain 7A

(TTC7A) Deficiency
Combined immunodeficiency with T-cell and B-cell defects had long
accompanied hereditary multiple intestinal atresia . Mutations in TTC7A are
causative of the combined intestinal and immunologic defects. TTC7A is
involved in cell cycle control, cytoskeletal organization, cell shape and polarity,
and cell adhesion. Deficiency of TTC7A is inherited in an autosomal recessive
manner. Multiple intestinal atresia with disruption of intestinal architecture is a
universal feature. Often, early-onset severe enterocolitis occurs concurrently.
Immunodeficiency with severe T-cell lymphopenia has been described; B- and
NK-cell defects are variable. T-cell proliferative responses are also abnormal.
Severe hypogammaglobulinemia is common. Treatment includes removal of
atretic areas of the intestine and antimicrobial prophylaxis in immunodeficient
patients. Bowel transplant has also been performed with some success.

Deficiency of Adenosine Deaminase 2

(DADA2)
Deficiency in ADA2 is a cause of early vasculopathy, stroke , and
immunodeficiency. DADA2 is secondary to autosomal recessive mutations in
cat-eye syndrome chromosome region 1 (CECR1 ), mapped to chromosome
22q11.1. ADA2 is important in purine metabolism converting adenosine to
inosine and 2′-deoxyadenosine to 2′-deoxyinosine. The pathogenesis is not
exactly known, but ADA2 is mostly secreted by myeloid cells, and deficiency
leads to upregulation of proinflammatory genes and increased secretion of
proinflammatory cytokines. DADA2 is characterized by chronic or recurrent
inflammation with elevated acute-phase reactants and fever. Skin manifestations
include livedo reticularis, maculopapular rash, nodules, purpura, erythema
nodosum, Raynaud phenomenon, ulcerative lesions, and digital necrosis. CNS
CHAPTER 153

Neutrophils
Thomas D. Coates

The Phagocytic Inflammatory Response

The phagocyte system includes both granulocytes (neutrophils, eosinophils, and
basophils) and mononuclear phagocytes (monocytes and tissue macrophages).
Neutrophils and mononuclear phagocytes share primary functions, including the
defining properties of large-particle ingestion and microbial killing. Phagocytes
participate primarily in the innate immune response but also help initiate
acquired immunity. Mononuclear phagocytes, including tissue macrophages and
circulating monocytes, are discussed in Chapter 154 .
Neutrophils provide the rapid effector arm of the innate immune system. They
circulate in the bloodstream for only about 6 hr (Table 153.1 ), but on
encountering specific chemotactic signals, they adhere to the vascular
endothelium and transmigrate into tissues. There they ingest and kill microbes
and release chemotactic signals to recruit more neutrophils and to attract
dendritic cells and other initiators of the acquired immune response.

Table 153.1
Neutrophil and Monocyte Kinetics
NEUTROPHILS
Average time in mitosis (myeloblast to myelocyte) 7-9 days
Average time in postmitosis and storage (metamyelocyte to neutrophil) 3-7 days
Average half-life in the circulation 6 hr
Average total body pool 6.5 × 108 cells/kg
Average circulating pool 3.2 × 108 cells/kg
Average marginating pool 3.3 × 108 cells/kg
Average daily turnover rate 1.8 × 108 cells/kg
MONONUCLEAR PHAGOCYTES
 Average time in mitosis 30-48 hr
Average half-life in the circulation 36-104 hr
Average circulating pool (monocytes) 1.8 × 107 cells/kg
Average daily turnover rate 1.8 × 109 cells/kg
Average survival in tissues (macrophages) Months
From Boxer LA: Function of neutrophils and mononuclear phagocytes. In Bennett JC, Plum F,
editors: Cecil textbook of internal medicine, ed 20, Philadelphia, 1996, Saunders.

Hematopoiesis
The hematopoietic progenitor system can be viewed as a continuum of
functional compartments, with the most primitive compartment composed of
very rare pluripotential stem cells , which have high self-renewal capacity and
give rise to more mature stem cells, including cells that are committed to either
lymphoid or myeloid development (Fig. 153.1 ). Common lymphoid progenitor
cells give rise to T- and B-cell precursors and their mature progeny (see Chapter
149 ). Common myeloid progenitor cells eventually give rise to committed
single-lineage progenitors of the recognizable precursors through a random
process of lineage restriction in a stepwise process (see Chapter 473 ). The
capacity of lineage-specific committed progenitors to proliferate and
differentiate in response to demand provides the hematopoietic system with a
remarkable range of response to changing requirements for mature blood cell
production.
CHAPTER 154

Monocytes, Macrophages, and

Dendritic Cells
Richard B. Johnston Jr.

Mononuclear phagocytes (monocytes, macrophages) are distributed across all

body tissues and play a central role in maintaining immunologic and metabolic
homeostasis. They are essential for innate host defense against infection, tissue
repair and remodeling, and the antigen-specific adaptive immune response. No
human has been identified as having congenital absence of this cell line,
probably because macrophages are required to remove primitive tissues during
fetal development as new tissues develop to replace them. Monocytes and tissue
macrophages in their several forms have variable morphology, surface markers,
and transcriptional profiles but common functions, particularly phagocytosis
(Table 154.1 ). Dendritic cells (DCs) are specialized derivatives of this
mononuclear phagocyte system that develop from myeloid cell precursors or
monocytes themselves.
Table 154.1
Principal Sites of Macrophages in Tissues

Liver (Kupffer cells)

Lung (interstitial and alveolar macrophages)
Connective tissue, adipose tissue, and interstitium of major organs and skin
Serosal cavities (pleural and peritoneal macrophages)
Synovial membrane (type A synoviocytes)
Bone (osteoclasts)
Brain and retina (microglial cells)
Spleen, lymph nodes, bone marrow
 Intestinal wall
Breast milk
Placenta
Granulomas (multinucleated giant cells)

Development
Monocytes develop more rapidly during bone marrow hematopoiesis and
remain longer in the circulation than do neutrophils (see Table 153.1 ). The
monoblast is the first recognizable monocyte precursor, followed by the
promonocyte , with cytoplasmic granules and an indented nucleus, and finally
the fully developed monocyte with cytoplasmic granules filled with hydrolytic
enzymes. The transition from monoblast to mature circulating monocyte requires
about 6 days.
Three major subsets of human monocytes can be identified on the basis of
surface antigens: CD14++ CD16− classical monocytes that constitute the majority
of total monocytes in the resting state; the more mature CD14++ CD16+
proinflammatory (intermediate ) monocytes, which produce proinflammatory
hormone-like factors termed cytokines , such as tumor necrosis factor-α (TNF-
α), in response to microbial stimuli; and nonclassical (regulatory) monocytes
(CD14+ CD16++ ) that promote wound healing. Monocytes from these subsets
migrate into tissues in response to localized inflammation or injury and provide
proinflammatory host defense or antiinflammatory responses and wound
healing.
Tissue (organ)-specific macrophages arise from macrophage progenitors
that develop in the yolk sac and fetal liver before hematopoiesis occurs in the
bone marrow. These cells maintain their population through self-renewal. Tissue
macrophages can also be populated to some extent by circulating monocytes.
Monocytes or macrophages at sites of active inflammation mature into
proinflammatory (M1) macrophages or proresolving (M2) macrophages. In
ongoing tissue injury or inflammation, many (perhaps most) of the macrophages
will express a mix of the properties of the classic types.
Whether embryonic or blood derived, tissue macrophages are directed by
organ-specific factors to differentiate into macrophages characteristic of that
organ. Embryonic progenitors or monocytes in the liver become Kupffer cells
that bridge the sinusoids separating adjacent plates of hepatocytes. Those at the
Upregulated Functions in Macrophages
Activated in Response to Infection
Microbicidal and tumoricidal activity
Phagocytosis (of most particles) and pinocytosis
Phagocytosis-associated respiratory burst (O2 − , H2 O2 )
Generation of nitric oxide
Chemotaxis
Glucose transport and metabolism
Membrane expression of MHC, CD40, TNF receptor
Antigen presentation
Secretion:
Complement components
Lysozyme, acid hydrolases, and cytolytic proteinases
Collagenase
Plasminogen activator
Interleukins, including IL-1, IL-12, and IL-15
TNF-α
Interferons, including IFN-α and IFN-β
Antimicrobial peptides (cathelicidin, defensins)
Angiogenic factors

H2 O2 , Hydrogen peroxide; IFN, interferon; IL, interleukin; MHC, major

histocompatibility complex; O2 − , superoxide anion; TNF, tumor necrosis factor.

Classical macrophage activation is accomplished during infection with

intracellular pathogens (e.g., mycobacteria, Listeria ) through crosstalk between
Th1 lymphocytes and antigen-presenting macrophages mediated by the
engagement of a series of ligands and receptors on the 2 cell types, including
class II major histocompatibility complex (MHC) molecules and CD40 on
macrophages and CD40 ligand on Th1 cells, and through secretion of cytokines.
Macrophages encountering microorganisms release IL-12, which stimulates T
cells to release IFN-γ. These interactions constitute the basis of cell-mediated
immunity. IFN-γ is an especially important macrophage-activating cytokine; it is
currently used as a therapeutic agent.
more accurately reflect disease activity. Because prolonged eosinophilia is
associated with end-organ damage, especially involving the heart, patients with
persistently elevated AECs should undergo a thorough evaluation to search for
an underlying cause.
Table 155.1
Causes of Eosinophilia
Allergic Disorders

Allergic rhinitis
Asthma
Acute and chronic urticaria
Eczema
Angioedema
Hypersensitivity drug reactions (drug rash with eosinophilia and systemic
symptoms [DRESS])
Eosinophilic gastrointestinal disorders
Interstitial nephritis

Infectious Diseases
Tissue-Invasive Helminth Infections

Trichinosis
Toxocariasis
Strongyloidosis
Ascariasis
Filariasis
Schistosomiasis
Echinococcosis
Amebiasis
Malaria
Scabies
Toxoplasmosis

Other Infections
 Pneumocystis jirovecii
Scarlet fever
Allergic bronchopulmonary aspergillosis (ABPA)
Coccidioidomycosis
Human immunodeficiency virus (HIV)

Malignant Disorders

Hodgkin disease and T-cell lymphoma

Acute myelogenous leukemia
Myeloproliferative disorders
Eosinophilic leukemia
Brain tumors

Gastrointestinal Disorders

Inflammatory bowel disease

Peritoneal dialysis
Chronic active hepatitis
Eosinophilic gastrointestinal disorders:
Eosinophilic esophagitis
Eosinophilic gastroenteritis
Eosinophilic colitis

Rheumatologic Disease

Rheumatoid arthritis
Eosinophilic fasciitis
Scleroderma
Dermatomyositis
Systemic lupus erythematosus
IgG4-related disease
Eosinophilic granulomatosis with polyangiitis (Churg-Strauss vasculitis)

Immunodeficiency/Immune Dysregulation Disease

 Hyperimmunoglobulin E syndromes
Wiskott-Aldrich syndrome
Graft-versus-host disease
Omenn syndrome
Severe congenital neutropenia
Autoimmune lymphoproliferative syndromes (ALPS)
Immune dysregulation, polyendocrinopathy, X-linked (IPEX)
Transplant rejection (solid organ)

Miscellaneous

Thrombocytopenia with absent radii

Hypersensitivity pneumonitis
Adrenal insufficiency
Postirradiation of abdomen
Histiocytosis with cutaneous involvement
Hypereosinophilic syndromes
Cytokine infusion
Pemphigoid

Allergic Diseases
Allergy is the most common cause of eosinophilia in children in the United
States. Patients with allergic asthma typically have eosinophils in the blood,
sputum, and/or lung tissue. Hypersensitivity drug reactions can elicit
eosinophilia, and when associated with organ dysfunction (e.g., DRESS [drug
rash with eosinophilia and systemic symptoms]), these reactions can be serious
(see Chapter 177 ). If a drug is suspected of triggering eosinophilia, biochemical
evidence of organ dysfunction should be sought, and if found, the drug should be
discontinued. Various skin diseases have also been associated with eosinophilia,
including atopic dermatitis/eczema, pemphigus, urticaria, and toxic epidermal
necrolysis.
Eosinophilic gastrointestinal diseases are important emerging allergic causes
of eosinophilia in tissue and, in some cases, peripheral blood (see Chapter 363 ).
In these conditions, eosinophils are recruited to esophagus, stomach, and/or
intestine, where they cause tissue inflammation and clinical symptoms such as
dysphagia, food aversion, abdominal pain, vomiting, and diarrhea. Treatment
CHAPTER 156

Disorders of Phagocyte Function

Thomas D. Coates

Neutrophils are the first line of defense against microbial invasion. They arrive
at the site of inflammation during the critical 2-4 hr after microbial invasion to
contain the infection and prevent hematogenous dissemination. This well-
orchestrated process is one of the most interesting stories in modern cell biology.
In fact, much of our knowledge about neutrophil function derives from studies
done in patients with genetic errors in neutrophil function. These critical
functions and their associated disorders are depicted in Fig. 153.2 . Children
with phagocytic dysfunction present at a young age with recurrent infections that
often involve unusual organisms and are poorly responsive to treatment.
Primary defects of phagocytic function comprise <20% of
immunodeficiencies, and there is significant overlap in the presenting signs and
symptoms between phagocytic disorders and lymphocyte and humeral disorders.
Children with phagocytic defects present with deep tissue infection, pneumonia,
adenitis, or osteomyelitis rather than bloodstream infections (Tables 156.1 and
156.2 and Fig. 156.1 ). A few clinical features point to phagocyte defects rather
than other immunodeficiencies, but correct diagnosis relies on highly specialized
laboratory tests.

Table 156.1
Infections and White Blood Cell Defects: Features That Can
Be Seen in Phagocyte Disorders

UNUSUALLY
SEVERE INFECTIONS RECURRENT INFECTIONS SPECIFIC INFECTIONS LOCATED
INFECTIONS
Diagnosis
Type of Diagnosis to Site of Diagnosis to Diagnosis to Site of
Microorganism to
Infection Consider Infection Consider Consider Infection
 Consider
Cellulitis Neutropenia, Cutaneous Neutropenia, Staphylococcus Neutropenia, Umbilical LAD
LAD, CGD, CGD, LAD, epidermidis LAD cord
HIES HIES
Colitis Neutropenia, Gums LAD, Serratia CGD Liver CGD
CGD neutrophil marcescens, abscess
motility Nocardia,
disorders Burkholderia
cepacia
Osteomyelitis CGD, Upper and Neutropenia, Aspergillus Neutropenia, Gums LAD,
MSMD lower HIES, CGD, HIES neutrophil
pathway respiratory tract functional motility
defects neutrophil disorders
disorders
Gastrointestinal CGD, MSMD Nontuberculous MSMD
tract pathway mycobacteria, pathway
defects BCG defects,
(salmonella) SCID, CGD
Lymph nodes CGD, MSMD Candida Neutropenia,
pathway CGD, MPO
defects
(mycobacteria)
Osteomyelitis CGD, MSMD
BCG, Bacille Calmette-Guérin; CGD, chronic granulomatous disease; HIES, hyper-IgE syndrome;
LAD, leukocyte adhesion deficiency; MSMD, mendelian susceptibility to mycobacterial disease;
SCID, severe combined immunodeficiency.
From Leung DYM: Pediatric allergy principles and practice , ed 2, Philadelphia, 2010, Saunders, p
134.

Table 156.2
Clinical Disorders of Neutrophil Function

IMPAIRED CLINICAL
DISORDER ETIOLOGY
FUNCTION CONSEQUENCE
DEGRANULATION ABNORMALITIES
Chédiak-Higashi Autosomal recessive; disordered Decreased neutrophil Neutropenia; recurrent
syndrome (CHS) coalescence of lysosomal granules; chemotaxis, pyogenic infections;
responsible gene is CHSI/LYST , which degranulation, and propensity to develop
encodes a protein hypothesized to regulate bactericidal activity; marked
granule fusion platelet storage pool hepatosplenomegaly as a
defect; impaired NK manifestation of
function, failure to hemophagocytic
disperse melanosomes syndrome
Specific granule Autosomal recessive; functional loss of Impaired chemotaxis Recurrent deep-seated
deficiency myeloid transcription factor arising from a and bactericidal abscesses
mutation or arising from reduced activity; bilobed
expression of Gfi-1 or C/EBPε , which nuclei in neutrophils;
regulates specific granule formation defensins, gelatinase,
collagenase, vitamin
B12 –binding protein,
 and lactoferrin
ADHESION ABNORMALITIES
Leukocyte Autosomal recessive; absence of Decreased binding of Neutrophilia; recurrent
adhesion CD11/CD18 surface adhesive iC3b to neutrophils bacterial infection
deficiency 1 glycoproteins (β2 -integrins) on leukocyte and impaired adhesion associated with a lack of
(LAD-1) membranes most commonly arising from to ICAM-1 and pus formation
failure to express CD18 messenger RNA ICAM-2
Leukocyte Autosomal recessive; loss of fucosylation Decreased adhesion to Neutrophilia; recurrent
adhesion of ligands for selectins and other glycol activated endothelium bacterial infection
deficiency 2 conjugates arising from mutations of expressing ELAM without pus
(LAD-2) GDP-fucose transporter
Leukocyte Autosomal recessive; impaired integrin Impaired neutrophil Neutrophilia, recurrent
adhesion function arising from mutations of adhesion and platelet infections, bleeding
deficiency 3 FERMT3 , which encodes kindlin-3 in activation tendency
(LAD-1 variant hematopoietic cells; kindlin-3 binds to β-
syndrome) integrin and thereby transmits integrin
activation
DISORDERS OF CELL MOTILITY
Enhanced motile Autosomal recessive gene responsible for Excessive Recurrent fever,
responses; FMF FMF on chromosome 16, which encodes accumulation of peritonitis, pleuritis,
for a protein called pyrin; pyrin regulates neutrophils at arthritis, amyloidosis
caspase-1 and thereby IL-1β secretion; inflamed sites,
mutated pyrin may lead to heightened possibly the result of
sensitivity to endotoxin, excessive IL-1β excessive IL-1β
production, and impaired monocyte production
apoptosis
DEPRESSED MOTILE RESPONSES
Defects in the IgG deficiencies; C3 and properdin Deficiency of serum Recurrent pyogenic
generation of deficiency can arise from genetic or chemotaxis and infections
chemotactic acquired abnormalities; mannose-binding opsonic activities
signals protein deficiency predominantly in
neonates
Intrinsic defects In the neonatal neutrophil there is Diminished Propensity to develop
of the neutrophil, diminished ability to express β2 -integrins, chemotaxis pyogenic infections
e.g., LAD, CHS, and there is a qualitative impairment in β2
specific granule -integrin function
deficiency,
neutrophil actin
dysfunction,
neonatal
neutrophils
Direct inhibition Ethanol, glucocorticoids, cyclic AMP Impaired locomotion Possible cause for
of neutrophil and ingestion; frequent infections;
mobility, e.g., impaired adherence neutrophilia seen with
drugs epinephrine arises from
cyclic AMP release from
endothelium
Immune Bind to Fc receptors on neutrophils in Impaired chemotaxis Recurrent pyogenic
complexes patients with rheumatoid arthritis, infections
systemic lupus erythematosus, and other
inflammatory states
Hyper-IgE Autosomal dominant; responsible gene is Impaired chemotaxis Recurrent skin and
syndrome STAT3 at times; impaired sinopulmonary infections,
regulation of cytokine eczema, mucocutaneous
production candidiasis, eosinophilia,
 retained primary teeth,
minimal trauma fractures,
scoliosis, and
characteristic facies
Hyper-IgE Autosomal recessive; more than 1 gene High IgE levels, Recurrent pneumonia
syndrome–AR likely contributes to its etiology impaired lymphocyte without pneumatoceles
activation to sepsis, enzyme, boils,
staphylococcal mucocutaneous
antigens candidiasis, neurologic
symptoms, eosinophilia
MICROBICIDAL ACTIVITY
Chronic X-linked and autosomal recessive; Failure to activate Recurrent pyogenic
granulomatous failure to express functional gp91 phox neutrophil respiratory infections with catalase-
disease (CGD) in the phagocyte membrane in p22 burst, leading to positive microorganisms
phox (AR) failure to kill catalase-
Other AR forms of CGD arise from positive microbes
failure to express protein p47 phox or
p67 phox
G6PD deficiency <5% of normal activity of G6PD Failure to activate Infections with catalase-
NADPH-dependent positive microorganisms
oxidase; hemolytic
anemia
Myeloperoxidase Autosomal recessive; failure to process H2 O2 -dependent None
deficiency modified precursor protein arising from antimicrobial activity
missense mutation not potentiated by
myeloperoxidase
Rac2 deficiency Autosomal dominant; dominant negative Failure of membrane Neutrophilia, recurrent
inhibition by mutant protein of Rac2- receptor–mediated O2 bacterial infections
mediated functions − generation and
chemotaxis
Deficiencies of AR; failure to detoxify H2 O2 Excessive formation Minimal problems with
glutathione of H2 O2 recurrent pyogenic
reductase and infections
glutathione
synthetase
AMP, Adenosine monophosphate; AR, autosomal recessive; C, complement; CD, cluster of
differentiation; ELAM, endothelial-leukocyte adhesion molecule; FMF, familial Mediterranean
fever; G6PD, glucose-6-phosphate dehydrogenase; GDP, guanosine diphosphate; ICAM,
intracellular adhesion molecule; IL-1, interleukin-1; NADPH, nicotinamide adenine dinucleotide
phosphate; NK, natural killer.
Adapted from Curnutte JT, Boxer LA: Clinically significant phagocytic cell defects. In Remington
JS, Swartz MN, editors: Current clinical topics in infectious disease , ed 6, New York, 1985,
McGraw-Hill, p 144.
except in the most experienced hands. The assays must be done on freshly
obtained blood and are affected by many factors related to blood sampling itself.
It is best to assay other features of the suspected disorder, such as surface marker
expression, to establish a specific diagnosis.

Leukocyte Adhesion Deficiency

Leukocyte adhesion deficiency types 1 (LAD-1), 2 (LAD-2), and 3 (LAD-3) are
rare autosomal recessive disorders of leukocyte function. LAD-1 affects about 1
per 10 million individuals and is characterized by recurrent bacterial and fungal
infections and depressed inflammatory responses despite striking blood
neutrophilia (Table 156.3 ). The neutrophils have significant defects in adhesion,
motility, and ability to phagocytose bacteria.

Table 156.3
Leukocyte Adhesion Deficiency Syndromes

LEUKOCYTE
TYPE 1 TYPE 2 (LAD-2 TYPE 3 (LAD- E-SELECTIN Rac2
ADHESION
(LAD-1) or CDG-IIc) 3) DEFICIENCY DEFICIENCY
DEFICIENCY (LAD)
OMIM 116920 266265 612840 131210 602049
Inheritance pattern Autosomal Autosomal Autosomal Unknown Autosomal
recessive recessive recessive dominant
Affected protein(s) β2 -Integrin Fucosylated Kindlin 3 Endothelial E- Rac2
common proteins (e.g., selectin
chain sialyl-Lewisx , expression
(CD18) CD15s)
Neutrophil function Chemotaxis, Rolling, tethering Chemotaxis, Rolling, Chemotaxis,
affected tight adhesion, tethering superoxide
adherence superoxide production
production
Delayed umbilical cord Yes (severe Yes Yes Yes Yes
separation phenotype
only)
Leukocytosis/neutrophilia Yes Yes Yes No (mild Yes
neutropenia)
CDG-IIc, Congenital disorder of glycosylation IIc, OMIM, Online Mendelian Inheritance in Man.
From Leung DYM: Pediatric allergy principles and practice , ed 2, Philadelphia, 2010, Saunders, p
139.

Genetics and Pathogenesis

Laboratory Findings
Deficiency of neutrophil and monocyte MPO can be identified by histochemical
analysis. Severe MPO deficiency can cause the dihydrorhodamine (DHR) flow
cytometric assay for chronic granulomatous disease (CGD) to be falsely
positive. Unlike CGD, eosinophils in severe MPO deficiency will still reduce
DHR and yield a normal reaction.

Treatment
There is no specific therapy for MPO deficiency. Aggressive treatment with
antifungal agents should be provided for candidal infections. The prognosis is
usually excellent.

Chronic Granulomatous Disease

Chronic granulomatous disease is characterized by neutrophils and monocytes
capable of normal chemotaxis, ingestion, and degranulation, but unable to kill
catalase-positive microorganisms because of a defect in the generation of
microbicidal oxygen metabolites. CGD is a rare disease, affecting 4-5 per 1
million individuals; it is caused by 4 genes: 1 X-linked and 3 autosomal
recessive in inheritance (Table 156.4 ).

Table 156.4
Classification of Chronic Granulomatous Disease

NBT
COMPONENT FLAVOCYTOCHROME INCIDENCE
INHERITANCE SUBTYPE* SCORE (%
AFFECTED b SPECTRUM (% of Cases)
Positive)
gp91 phox X X910 0 0 60
X91− Low 80-100 5
(weak)
X91− Low 5-10 <1
X91+ 0 0 1
p22 phox A A220 0 0 4
A22+ N 0 <1
p47 phox A A470 N 0 † 25
p67 phox A A670 N 0 5
A67+ N 0 <1
p40 phox A A40− N 100 <1
CHAPTER 157

Leukopenia
Thomas F. Michniacki, Kelly J. Walkovich

Leukopenia refers to an abnormally low number of white blood cells (WBCs) in

the circulating blood secondary to a paucity of lymphocytes, granulocytes, or
both. Because there are marked developmental changes in normal values for
WBC counts during childhood (see Chapter 748 ), normal ranges must be
considered in the context of age. For newborns, the mean WBC count at birth is
high, followed by a rapid fall beginning at 12 hr through the 1st wk of life.
Thereafter, values are stable until 1 yr of age, after which a slow, steady decline
in the WBC count continues throughout childhood until adult values are reached
during adolescence. Evaluation of patients with leukopenia begins with a
thorough history, physical examination, and at least 1 confirmatory complete
blood count with differential. Further evaluation then depends on whether the
leukopenia represents a decreased number of neutrophils, lymphocytes, or both
cell populations (Table 157.1 ). Treatment depends on the etiology and clinical
manifestations of the leukopenia.

Table 157.1
Diagnostic Approach for Patients With Leukopenia

EVALUATION ASSOCIATED CLINICAL DIAGNOSES

INITIAL EVALUATION
• History of acute or chronic
leukopenia
• General medical history Congenital syndromes (severe congenital neutropenia, cyclic neutropenia,
including prior serious, Shwachman-Diamond, Wiskott-Aldrich, Fanconi anemia, dyskeratosis congenita,
recurrent or unusual glycogen storage disease type Ib, disorders of vesicular transport, GATA2
infections and malignancy haploinsufficiency, and primary immunodeficiencies)
• Physical examination:
stomatitis, gingivitis,
dental defects, warts,
 lymphedema, congenital
anomalies
• Spleen size Hypersplenism
• History of drug exposure Drug-associated neutropenia
• Complete blood count with Neutropenia, aplastic anemia, autoimmune cytopenias
differential and reticulocyte
counts
IF ANC <1,000/µL
Evaluation of Acute-Onset Neutropenia
• Repeat blood counts in 3-4 Transient myelosuppression (e.g., viral)
wk
• Serology and cultures for Active or chronic infection with viruses (e.g., EBV, CMV), bacteria, mycobacteria,
infectious agents rickettsia
• Discontinue drug(s) Drug-associated neutropenia
associated with
neutropenia
• Test for antineutrophil Autoimmune neutropenia
antibodies
• Measure quantitative Neutropenia associated with disorders of immune function
immunoglobulins (IgG,
IgA, IgM, IgE),
lymphocyte subsets
IF ANC <500/µL ON 3 SEPARATE TESTS
• Bone marrow aspiration Severe congenital neutropenia, cyclic neutropenia, Shwachman-Diamond
and biopsy, with syndrome, myelokathexis; chronic benign or idiopathic neutropenia; reticular
cytogenetics dysgenesis
• Glucocorticoid stimulation Chronic benign or idiopathic neutropenia, some autoimmune neutropenias
test
• Serial CBCs (3/wk for 6 Cyclic neutropenia
wk)
• Exocrine pancreatic Shwachman-Diamond syndrome
function
• Skeletal radiographs Shwachman-Diamond syndrome, cartilage-hair hypoplasia, Fanconi anemia
IF ALC <1000/µL
• Repeat blood counts in 3-4 Transient leukopenia (e.g., viral)
weeks
IF ALC <1000/µL ON 3 SEPARATE TESTS
• HIV-1 antibody or RNA HIV-1 infection, AIDS
test
• Quantitative Congenital or acquired disorders of immune function
immunoglobulins (IgG,
IgA, IgM, IgE), vaccine
titers, lymphocyte subsets
IF THERE IS PANCYTOPENIA
• Bone marrow aspiration Bone marrow replacement by malignancy, fibrosis, granulomata, storage cells;
and biopsy aplastic anemia
• Bone marrow cytogenetics Myelodysplasia, leukemia
and flow cytometry
• Vitamin B12 and folate Vitamin deficiencies
levels
ALC, Absolute lymphocyte count; ANC, absolute neutrophil count; CBC, complete blood count;
CMV, cytomegalovirus; EBV, Epstein-Barr virus.
Table 157.2

Causes of Neutropenia Extrinsic to Marrow Myeloid Cells

ETIOLOGIC
CAUSE ASSOCIATED FINDINGS
FACTORS/AGENTS
Infection Viruses, bacteria, protozoa, Clinical features and laboratory findings of the infectious
rickettsia, fungi agent
Drug induced Phenothiazines, Usually none; occasional hypersensitivity reaction (fever,
sulfonamides, lymphadenopathy, rash, hepatitis, nephritis, pneumonitis,
anticonvulsants, penicillins, aplastic anemia) or antineutrophil antibody
aminopyrine
Immune Alloimmune, autoimmune Myeloid hyperplasia with left shift in bone marrow (may
neutropenia appear to be “arrest” at metamyelocyte or band stage)
Reticuloendothelial Hypersplenism Anemia, thrombocytopenia
sequestration
Bone marrow Myelofibrosis, malignancy Anemia, thrombocytopenia, marrow fibrosis, malignant cells
replacement (leukemia, lymphoma, in bone marrow sites of extramedullary hematopoesis
metastatic solid tumor, etc.)
Cancer Suppression of myeloid cell Anemia, thrombocytopenia, bone marrow hypoplasia
chemotherapy or production
radiation therapy

Table 157.3

Acquired Disorders of Myeloid Cells

CAUSE ETIOLOGIC FACTORS/AGENTS ASSOCIATED FINDINGS
Aplastic anemia Stem cell destruction and depletion Pancytopenia
Vitamin B12 , copper, Malnutrition; congenital deficiency of B12 Megaloblastic anemia, hypersegmented
or folate deficiency absorption, transport, and storage; vitamin neutrophils
avoidance
Acute leukemia, Bone marrow replacement with malignant Pancytopenia, leukocytosis
chronic myelogenous cells
leukemia
Myelodysplasia Dysplastic maturation of stem cells Bone marrow hypoplasia with
megaloblastoid red cell precursors,
thrombocytopenia
Prematurity with Impaired regulation of myeloid proliferation Maternal preeclampsia
birthweight <2 kg and reduced size of postmitotic pool
Chronic idiopathic Impaired myeloid proliferation and/or None
neutropenia maturation
Paroxysmal nocturnal Acquired stem cell defect secondary to Pancytopenia, thrombosis (hepatic vein
hemoglobinuria mutation of PIGA gene thrombosis)

Clinical Manifestations of Neutropenia

Individuals with neutrophil counts <500/µL are at substantial risk for developing
maturation. Additional marrow studies, such as cytogenetic analysis and special
stains for detecting leukemia and other malignant disorders, should be obtained
for patients with suspected intrinsic defects in the myeloid progenitors and for
patients with suspected malignancy. Selection of further laboratory tests is
determined by the duration and severity of the neutropenia and the associated
findings on physical examination (see Table 157.1 ).

Table 157.4

Infections Associated With Neutropenia

Viral Cytomegalovirus, dengue, Epstein-Barr virus, hepatitis viruses, HIV, influenza, measles, parvovirus
B19, rubella, varicella, HHV-6
Bacterial Brucella, paratyphoid, pertussis, tuberculosis (disseminated), tularemia, Shigella, typhoid; any form
of sepsis
Fungal Histoplasmosis (disseminated)
Protozoan Malaria, leishmaniasis (kala-azar)
Rickettsial Anaplasma (formerly Ehrlichia ) phagocytophilum, psittacosis, Rocky Mountain spotted fever,
typhus, rickettsialpox

Table 157.5
Forms of Drug-Induced Neutropenia

IMMUNOLOGIC TOXIC HYPERSENSITIVITY

Paradigm Aminopyrine, propylthiouracil, Phenothiazines, Phenytoin, phenobarbital
drugs penicillins clozapine
Time to Days to weeks Weeks to months Weeks to months
onset
Clinical Acute, often explosive symptoms Often May be associated with fever, rash,
appearance asymptomatic or nephritis, pneumonitis, or aplastic
insidious onset anemia
Rechallenge Prompt recurrence with small test Latent period; high Latent period; high doses required
dose doses required
Laboratory Antineutrophil antibody may be Bone marrow Bone marrow myeloid hypoplasia
findings positive; bone marrow myeloid myeloid
hyperplasia hypoplasia

Acquired Neutropenia
Infection-Related Neutropenia
Transient neutropenia often accompanies or follows viral infections and is the
most frequent cause of neutropenia in childhood (Table 157.4 ). Viruses causing
mechanisms; select disorders are discussed next.

Table 157.6
Intrinsic Disorders of Myeloid Precursor Cells

CLINICAL FEATURES (INCLUDING STATIC

SYNDROME INHERITANCE (GENE) NEUTROPENIA UNLESS OTHERWISE
NOTED)
PRIMARY DISORDERS OF MYELOPOIESIS
Cyclic neutropenia AD (ELANE) Periodic oscillation (21-day cycles) in ANC
Severe congenital AD (primarily ELANE, also Risk of MDS/AML
neutropenia GFI and others)
AR (G6PC3, HAX1) (HAX1 = G6PC3: cardiac and urogenital anomalies, venous
Kostmann syndrome) angioectasias; HAX1: neurologic abnormalities, risk
of MDS/AML
XL (WAS) Neutropenic variant of Wiskott-Aldrich syndrome
DISORDERS OF MOLECULAR PROCESSING
Shwachman-Diamond Ribosomal defect: AR (SBDS, Pancreatic insufficiency, metaphyseal dysostosis,
syndrome DNAJC21, EFL1, SRP54) bone marrow failure, MDS/AML
Dyskeratosis congenita Telomerase defects: XL Nail dystrophy, leukoplakia, abnormal and carious
(DKC1), AD (TERC), AR teeth, lacey reticulated hyperpigmentation of the skin,
(TERT) bone marrow failure
DISORDERS OF VESICULAR TRAFFICKING
Chédiak-Higashi AR (LYST) Partial albinism, giant granules in myeloid cells,
syndrome platelet storage pool defect, impaired NK cell
function, HLH
Griscelli syndrome, type AR (RAB27a) Partial albinism, impaired NK cell function,
II neurologic impairment, HLH
Cohen syndrome AR (COH1) Partial albinism, pigmentary retinopathy,
developmental delay, facial dysmorphism
Hermansky-Pudlak AR (AP3B1) Cyclic neutropenia, partial albinism, HLH
syndrome, type II
p14 deficiency Probable AR (MAPBPIP) Partial albinism, decreased B and T cells
VPS45 defects AR (VPS45) Neutrophil dysfunction, bone marrow fibrosis,
nephromegaly
DISORDERS OF METABOLISM
Glycogen storage AR (G6PT1) Hepatic enlargement, growth retardation, impaired
disease, type 1b neutrophil motility
Methylmalonic/propionic AR Ketoacidosis, metabolic stroke, depressed
acidemias Mutase or cobalamin consciousness
transporters/propionyl
coenzyme A carboxylase
Barth syndrome XL (TAZ1) Episodic neutropenia, dilated cardiomyopathy,
methylglutaconic aciduria
Pearson syndrome Mitochondrial (DNA deletions) Episodic neutropenia, pancytopenia; defects in
exocrine pancreas, liver, and kidneys
NEUTROPENIA IN DISORDERS OF IMMUNE FUNCTION
Common variable Familial, sporadic Hypogammaglobulinemia, other immune system
immunodeficiency (TNFRSF13B) defects
IgA deficiency Unknown (Unknown or Decreased IgA
TNFRSF13B )
 Severe combined AR, XL (multiple loci) Absent humoral and cellular immune function
immunodeficiency
Hyper-IgM syndrome XL (HIGM1) Absent IgG, elevated IgM, autoimmune cytopenias
WHIM syndrome AD (CXCR4) Warts, hypogammaglobulinemia, infections,
myelokathexis
Cartilage-hair hypoplasia AR (RMRP) Lymphopenia, short-limbed dwarfism, metaphyseal
chondrodysplasia, fine sparse hair
Schimke immunoosseous Probable AR (SMARCAL1) Lymphopenia, pancytopenia, spondyloepiphyseal
dysplasia dysplasia, growth retardation, renal failure
X-linked Bruton tyrosine kinase (Btk) Agammaglobulinemia, neutropenia in ~25%
agammaglobulinemia
AD, Autosomal dominant; AML, acute myelogenous leukemia; ANC, absolute neutrophil count;
AR, autosomal recessive; HLH, hemophagocytic lymphohistiocytosis; MDS, myelodysplastic
syndrome; XL, X-linked.

Primary Disorders of Granulocytopoiesis

Cyclic neutropenia is an autosomal dominant congenital granulopoietic
disorder occurring with an estimated incidence of 0.5-1 cases per 1 million
population. The disorder is characterized by regular, periodic oscillations, with
the ANC ranging from normal to <200/µL, mirrored by reciprocal cycling of
monocytes. Cyclic neutropenia is sometimes termed cyclic hematopoiesis
because of the secondary cycling of other blood cells, such as platelets and
reticulocytes. The mean oscillatory period of the cycle is 21 days (±4 days).
During the neutropenic nadir, many patients develop malaise, fever, oral and
genital ulcers, gingivitis, periodontitis, or pharyngitis, and occasionally lymph
node enlargement. More serious infections occasionally occur, including
pneumonia, mastoiditis, and intestinal perforation with peritonitis leading to life-
threatening clostridial sepsis. Before the availability of G-CSF, approximately
10% of patients developed fatal clostridial or gram-negative infections. Cyclic
neutropenia arises from a regulatory abnormality involving early hematopoietic
precursor cells and is almost invariably associated with mutations in the
neutrophil elastase gene, ELANE , that lead to accelerated apoptosis as a result of
abnormal protein folding. Many patients experience abatement of symptoms
with age. The cycles tend to become less noticeable in older patients, and the
hematologic picture often begins to resemble that of chronic idiopathic
neutropenia.
Cyclic neutropenia is diagnosed by obtaining blood counts 3 times/wk for 6-8
wk. The requirement for repeated blood counts is necessary because some of the
elastase mutations overlap with those in patients who have severe congenital
neutropenia . Demonstrating oscillation or a lack thereof in the blood counts
recovery from chemotherapy and lymphocyte-specific immunosuppressive
agents may take several months to years. Prolonged lymphopenia (Table 157.7 )
may be caused by recurrent infection; persistent infections, mostly notably HIV;
malnutrition; mechanical loss of lymphocytes through protein-losing enteropathy
or thoracic duct leaks; or systemic diseases such as lupus erythematosus,
rheumatoid arthritis, sarcoidosis, renal failure, lymphoma, and aplastic anemia.

Table 157.7
Causes of Lymphocytopenia
ACQUIRED
Infectious diseases AIDS, hepatitis, influenza, sepsis, tuberculosis, typhoid
Iatrogenic Corticosteroids, cytotoxic chemotherapy, high-dose PUVA, immunosuppressive
therapy, radiation, thoracic duct drainage
Systemic diseases Hodgkin disease, lupus erythematosus, myasthenia gravis, protein-losing enteropathy,
renal failure, sarcoidosis
Other Aplastic anemia, dietary deficiencies, thermal injury
INHERITED
Aplasia of lymphopoietic Cartilage-hair hypoplasia, ataxia-telangiectasia, SCID, thymoma, Wiskott-Aldrich
stem cells syndrome
PUVA, Psoralen and ultraviolet A irradiation; SCID, severe combined immunodeficiency.

Inherited Lymphopenia
Primary immunodeficiencies and bone marrow failure syndromes are the main
cause of inherited lymphopenia in children (see Table 157.7 ). Primary
immunodeficiency may result in a severe quantitative defect, as in XLA and
severe combined immunodeficiency (SCID), or a qualitative or progressive
defect, as in Wiskott-Aldrich syndrome and CVID. XLA is characterized by a
near-absence of mature B cells because of a mutation in BTK that results in a
dysfunctional tyrosine kinase. SCIDs are a genetically heterogeneous group of
disorders characterized by abnormalities of thymopoiesis and T-cell maturation.
Newborn screening for severe T-cell deficiency, by analysis of T-cell receptor
excision circles from dried blood spot Guthrie cards, aids in the rapid
identification and treatment of infants with SCID and other T-cell disorders.
Quantitative defects in lymphocytes can also be appreciated in select forms of
inherited bone marrow failure such as reticular dysgenesis, SCN secondary to
GFI1 mutation, and dyskeratosis congenita.
Neutrophilia
Neutrophilia is an increase in the total number of blood neutrophils that is 2 SD
above the mean count for age (see Chapter 748 ). Elevated absolute neutrophil
counts represent disturbances of the normal equilibrium involving bone marrow
neutrophil production, migration out of the marrow compartments into the
circulation, and neutrophil destruction. Neutrophilia may arise either alone or in
combination with enhanced mobilization into the circulating pool from either
the bone marrow storage compartment or the peripheral blood marginating pool
, by impaired neutrophil egress into tissues, or by expansion of the circulating
neutrophil pool secondary to increased granulocytopoiesis. Myelocytes are not
released to the blood except under extreme circumstances.

Acute Acquired Neutrophilia

Neutrophilia is usually an acquired, secondary finding associated with
inflammation, infection, injury, or an acute physical or emotional stressor (Table
158.1 ). Bacterial infections, trauma (especially with hemorrhage), and surgery
are among the most common causes encountered in clinical practice.
Neutrophilia may also be associated with heat stroke, burns, diabetic
ketoacidosis, pregnancy, or cigarette use.

Table 158.1
Causes of Neutrophilia

TYPE CAUSE EXAMPLE

Acute Bacterial
acquired infections
Surgery
Acute stress Burns, diabetic ketoacidosis, heat stroke, postneutropenia rebound, exercise
Drugs Corticosteroids, epinephrine, hematopoietic growth factors, lithium
Chronic Chronic Inflammatory bowel disease, rheumatoid arthritis, vasculitis, cigarette exposure
acquired inflammation
Persistent Tuberculosis
infection
Persistent stress Chronic blood loss, hypoxia, sickle cell and other chronic hemolytic anemias
Drugs Corticosteroids, lithium; rarely ranitidine, quinidine
Other Postsplenectomy, tumors, Hodgkin disease, pregnancy, Sweet syndrome
Lifelong Congenital
asplenia
Hereditary Familial cold urticaria, hereditary neutrophilia, leukocyte adhesion deficiencies,
disorders periodic fever syndromes
Congenital or acquired asplenia is associated with lifelong neutrophilia. Some
patients with trisomy-21 also have neutrophilia. Uncommon genetic disorders
that present with neutrophilia include leukocyte function disorders such as
leukocyte adhesion deficiency and Rac2 deficiency (see Chapter 156 ) and
systemic disorders such as familial cold urticaria, periodic fever syndromes, and
familial myeloproliferative disease (see Table 158.1 ). Rare patients with an
autosomal dominant hereditary neutrophilia have been reported.
Evaluation of persistent neutrophilia requires a careful history, physical
examination, and laboratory studies to search for infectious, inflammatory, and
neoplastic conditions. The leukocyte alkaline phosphatase score of circulating
neutrophils can differentiate chronic myelogenous leukemia, in which the level
is uniformly almost zero, from reactive or secondary neutrophilia, which features
normal to elevated levels.

Additional Forms of Leukocytosis

Monocytosis
The average absolute blood monocyte count varies with age, which must be
considered in the assessment of monocytosis. Given the role of monocytes in
antigen presentation and cytokine secretion and as effectors of ingestion of
invading organisms, it is not surprising that many clinical disorders give rise to
monocytosis (Table 158.2 ). Typically, monocytosis occurs in patients recovering
from myelosuppressive chemotherapy and is a harbinger of the return of the
neutrophil count to normal. Monocytosis is occasionally a sign of an acute
bacterial, viral, protozoal, or rickettsial infection and may also occur in some
forms of chronic neutropenia and postsplenectomy states. Chronic inflammatory
conditions can stimulate sustained monocytosis, as can preleukemia, chronic
myelogenous leukemia, and lymphomas.

Table 158.2

Causes of Monocytosis
CAUSE EXAMPLE
Infections
Bacterial Brucellosis, subacute bacterial endocarditis, syphilis, tuberculosis, typhoid
infections
Nonbacterial Fungal infections, kala-azar, malaria, Rocky Mountain spotted fever, typhus
 infections
Hematologic Congenital and acquired neutropenias, hemolytic anemias
disorders
Malignant Acute myelogenous leukemia, chronic myelogenous leukemia, juvenile myelomonocytic
disorders leukemia, Hodgkin disease, non-Hodgkin lymphomas, preleukemia
Chronic Inflammatory bowel disease, polyarteritis nodosa, rheumatoid arthritis, sarcoidosis, systemic
inflammatory lupus erythematosus
diseases
Miscellaneous Cirrhosis, drug reaction, postsplenectomy, recovery from bone marrow suppression

Eosinophilia
Eosinophilia is defined as an absolute eosinophil count >1500 cells/µL. The
majority of eosinophilic conditions are reactive, including infections (especially
parasitic diseases), connective tissue disorders, allergic and hyperinflammatory
diseases, pulmonary disorders, and dermatologic conditions. Hypereosinophilic
syndrome and systemic mastocytosis are additional important causes of an
elevated eosinophil count. However, persistent eosinophilia can also herald a
malignancy such as leukemia, lymphoma, or carcinoma.

Basophilia
Basophilia is defined as an absolute basophil count >120 cells/µL. Basophilia is
a nonspecific sign of a wide variety of disorders and is usually of limited
diagnostic importance. Basophilia is most often present in hypersensitivity
reactions and frequently accompanies the leukocytosis of chronic myeloid
leukemia.

Lymphocytosis
The most common cause of lymphocytosis is an acute viral illness, as part of the
normal T-cell response to the infection. In infectious mononucleosis, the B cells
are infected with the Epstein-Barr virus, and the T cells react to the viral antigens
present in the B cells, resulting in atypical lymphocytes with characteristic
large, vacuolated morphology. Other viral infections classically associated with
lymphocytosis are cytomegalovirus and viral hepatitis. Chronic bacterial
infections such as tuberculosis and brucellosis may lead to a sustained
lymphocytosis. Pertussis is accompanied by marked lymphocytosis in
approximately 25% of infants infected before 6 mo of age. Thyrotoxicosis and
Addison disease are endocrine disorders associated with lymphocytosis.
CHAPTER 159

Complement Components and

Pathways
Richard B. Johnston Jr.

Complement is an exquisitely balanced, highly influential system that is

fundamental to the clinical expression of host defense and inflammation. The
complement system also has the capacity to perform functions beyond host
defense, such as promoting phagocytic removal of dying cells, molecular debris,
and weak or superfluous synapses during brain formation. Complement
components and receptors function within individual cells and can stabilize
intracellular homeostasis. However, complement activation can also cause harm
and has been implicated in many illnesses.
The complement system, an essential component of innate and adaptive
immunity, is broadly conceptualized as (1) the classical, lectin, and alternative
pathways , which interact and depend on each other for their full activity; (2)
the membrane attack complex (C5b6789), formed from activity of any
pathway; (3) cell membrane receptors that bind complement components or
fragments to mediate complement activity; and (4) a large array of serum and
membrane regulatory proteins (Table 159.1 and Fig. 159.1 ). The circulating
components and regulators together comprise approximately 15% of the globulin
fraction and 4% of the total proteins in serum. The normal concentrations of
serum complement components vary by age (see Chapter 748 ); newborn infants
have mild to moderate deficiencies of all components.
Table 159.1
Constituents of the Complement System
Serum Components That Are the Core of the Complement System
 Classical pathway: C1q, C1r, C1s, C4, C2, C3
Alternative pathway: factor B, factor D
Lectin pathway: Mannose-binding lectin (MBL), ficolins 1/2/3, MBL-
associated serine proteases (MASPs) 1/2/3
Membrane attack complex: C5, C6, C7, C8, C9
Regulatory protein, enhancing: properdin
Regulatory proteins, downregulating: C1 inhibitor (C1 INH), C4-binding
protein (C4-bp), factor H, factor I, vitronectin, clusterin,
carboxypeptidase N (anaphylatoxin inactivator)

Membrane Regulatory Proteins

CR1 (CD35), membrane cofactor protein (MCP; CD46), decay-

accelerating factor (DAF, CD55), CD59 (membrane inhibitor of reactive
lysis)

Membrane Receptors

CR1 (CD35), CR2 (CD21), CR3 (CD11b/CD18), CR4 (CD11c/CD18),

C3a receptor, C5a receptor, C1q receptors, complement receptor of the
immunoglobulin superfamily (CRIg)
Genetic Deficiencies of Complement
Components
Richard B. Johnston Jr.

Keywords
complement component deficiencies
C1q deficiency
C3 deficiency
MBL deficiency
complement deficiency and meningitis

Congenital deficiencies of all 11 components of the classical–membrane attack

pathway and of factors D and B and properdin of the alternative pathway are
described in Table 160.1 . All components of the classical and alternative
pathways except properdin and factor B are inherited as autosomal recessive co-
dominant traits. Each parent transmits a gene that codes for synthesis of half the
serum level of the component. Deficiency results from inheritance of 1 null gene
from each parent; the hemizygous parents typically have low normal CH50 levels
and no consequences of the partial deficiency. Properdin deficiency is
transmitted as an X-linked trait. Factor B is an autosomal recessive non–co-
dominant trait.

Table 160.1
Complement Defects

GENETIC
ASSOCIATED
DISEASE DEFECT/PRESUMED INHERITANCE FUNCTIONAL DEFECT
FEATURES
PATHOGENESIS
C1q Mutation in C1QA , AR Absent CH50 hemolytic SLE, infections with
deficiency C1QB , C1QC: classical activity; defective activation of encapsulated
complement pathway the classical pathway, organisms
 components diminished clearance of
apoptotic cells
C1r Mutation in C1R: AR Absent CH50 hemolytic SLE, infections with
deficiency classical complement activity; defective activation of encapsulated
pathway component the classical pathway organisms
C1s Mutation in C1S: AR Absent CH50 hemolytic SLE, infections with
deficiency classical complement activity; defective activation of encapsulated
pathway component the classical pathway organisms
C4 Mutation in C4A , C4B: AR Absent CH50 hemolytic SLE, infections with
deficiency classical complement activity; defective activation of encapsulated
pathway components the classical pathway, defective organisms
humoral immune response to
carbohydrate antigens in some
patients
C2 Mutation in C2: AR Absent CH50 hemolytic SLE, infections with
deficiency classical complement activity; defective activation of encapsulated
partway component the classical pathway organisms,
atherosclerosis
C3 Mutation in C3: central AR, gain-of- Absent CH50 and AH50 Infections;
deficiency complement component function AD hemolytic activity; defective glomerulonephritis,
opsonization, defective aHUS with gain-of-
humoral immune response function mutations
C5 Mutation in C5: AR Absent CH50 and AH50 Neisserial infections
deficiency terminal complement hemolytic activity; defective
component bactericidal activity
C6 Mutation in C6: AR Absent CH50 and AH50 Neisserial infections
deficiency terminal complement hemolytic activity; defective
component bactericidal activity
C7 Mutation in C7: AR Absent CH50 and AH50 Neisserial infections
deficiency terminal complement hemolytic activity; defective
component bactericidal activity
C8 α-γ Mutation in C8A, C8G: AR Absent CH50 and AH50 Neisserial infections
deficiency terminal complement hemolytic activity; defective
components bactericidal activity
C8b Mutation in C8B: AR Absent CH50 and AH50 Neisserial infections
deficiency terminal complement hemolytic activity. defective
component bactericidal activity
C9 Mutation in C9: AR Reduced CH50 and AH50 Mild susceptibility to
deficiency terminal complement hemolytic activity; deficient neisserial infections
component bactericidal activity
C1 Mutation in C1NH: AD Spontaneous activation of the Hereditary
inhibitor regulation of kinins and complement pathway with angioedema
deficiency complement activation consumption of C4/C2;
spontaneous activation of the
contact system with generation
of bradykinin from high-
molecular-weight kininogen
Factor B Mutation in CFB: AD Gain-of-function mutation with aHUS
activation of the increased spontaneous AH50
alternative pathway
Factor D Mutation in CFD: AR Absent AH50 hemolytic Neisserial infections
deficiency regulation of the activity
alternative complement
pathway
 Properdin Mutation in CFP: XL Absent AH50 hemolytic Neisserial infections
deficiency regulation of the activity
alternative complement
pathway
Factor I Mutation in CFI: AR Spontaneous activation of the Infections, neisserial
deficiency regulation of the alternative complement infections, aHUS,
alternative complement pathway with consumption of preeclampsia,
pathway C3 membranoproliferative
glomerulonephritis
Factor H Mutation in CFH: AR Spontaneous activation of the Infections, neisserial
deficiency regulation of the alternative complement infections, aHUS,
alternative complement pathway with consumption of preeclampsia,
pathway C3 membranoproliferative
glomerulonephritis
MASP-1 Mutation in MASP1: AR Deficient activation of the Infections, 3MC
deficiency cleaves C2 and activates lectin activation pathway, cell syndrome
MASP-2 migration
AD, Autosomal dominant; aHUS, atypical hemolytic-uremic syndrome; AR, autosomal recessive;
SLE, systemic lupus erythematosus; XL, X-linked; 3MC, previously Carnevale, Mingarelli,
Malpuech, and Michels syndromes.
From Kliegman RM, Lye PS, Bordini BJ, et al, editors: Nelson pediatric symptom-based diagnosis,
Philadelphia, 2018, Elsevier, Table 41.11, p 765.

Most patients with primary C1q deficiency have systemic lupus

erythematosus (SLE); some have an SLE-like syndrome without typical SLE
serology, a chronic rash with underlying vasculitis, or membranoproliferative
glomerulonephritis (MPGN). Some C1q-deficient children have serious
infections, including septicemia and meningitis. Individuals with C1r, C1s,
combined C1r/C1s, C4, C2, or C3 deficiency also have a high incidence of
autoimmune syndromes (see Table 160.1 ), especially SLE or an SLE-like
syndrome, without an elevated antinuclear antibody level.
C4 is encoded by 2 genes, C4A and C4B . C4 deficiency represents absence of
both gene products. Complete deficiency of only C4A, present in approximately
1% of the population, also predisposes to SLE, although C4 levels are only
partially reduced. Patients with only C4B deficiency may be predisposed to
infection. A few patients with C5, C6, C7, or C8 deficiency have SLE, but
recurrent meningococcal infections are much more likely to be the major
problem.
There are at least 2 possible reasons for the concurrence of complement
component deficiencies, especially C1, C4, C2, or C3 deficiency, and
autoimmune–immune complex diseases. First, deposition of C3 on autoimmune
complexes facilitates their removal from the circulation through binding to
complement receptor 1 (CR1) on erythrocytes and transport to the spleen and
matched recipient and donor in peptides that are presented by the same HLA
allotype. These antigens result from polymorphisms of non-HLA proteins,
differences in the level of expression of proteins, or genetic differences between
males and females. An example of the latter is represented by the H-Y antigens
encoded by the Y chromosome, which can stimulate GVHD when a female
donor is employed to transplant an HLA-identical male recipient. Thus, from
this evidence, it is clear that GVHD may occur even when the donor and
recipient are HLA identical.
The preferred donor for any patient undergoing HSCT is an HLA-identical
sibling. Because polymorphic HLA genes are closely linked and usually
constitute a single genetic locus, any pair of siblings has a 25% chance of
being HLA identical . Thus, also in view of the limited family size in the
developed countries, <25–30% of patients in need of an allograft can receive
their transplant from an HLA-identical sibling. This percentage is even lower in
patients with inherited disorders since affected siblings will not be considered
donor candidates.

HSCT From an HLA-Identical Sibling

Donor
Allogeneic HSCT from an HLA-compatible sibling is the treatment of choice for
children with hematologic malignancies and various congenital or acquired
diseases (Table 161.1 ). Best results are achieved in patients with congenital or
acquired nonmalignant disorders because the risk of disease recurrence is low
and the cumulative transplantation-related mortality is lower than in children
receiving transplants for hematologic malignancies.
Table 161.1
Indications for Allogeneic Hematopoietic Stem
Cell Transplantation for Pediatric Diseases
Malignancy

Acute lymphoblastic leukemia (ALL)

First complete remission for patients at very high risk of relapse
T-cell immunophenotype and poor response to corticosteroid
 therapy
Not in remission at the end of the induction phase
Marked hypodiploidy (<43 chromosomes)
Minimal residual disease at the end of consolidation therapy
High-risk infant ALL
Second complete remission
Third or later complete remission
Acute myeloid leukemia in 1st complete remission or in advanced-disease
phase
Philadelphia chromosome–positive chronic myeloid leukemia
Myelodysplastic syndromes
Hodgkin and non-Hodgkin lymphomas
Selected solid tumors
Metastatic neuroblastoma
Rhabdomyosarcoma refractory to conventional treatment
Very-high-risk Ewing sarcoma

Anemias

Severe acquired aplastic anemia

Fanconi anemia
Paroxysmal nocturnal hemoglobinemia
Congenital dyskeratosis
Diamond-Blackfan anemia
Thalassemia major
Sickle cell disease
Shwachman-Diamond syndrome

Immunologic Disorders

Variants of severe combined immunodeficiency

Hyper-IgM syndrome
Leukocyte adhesion deficiency
Omenn syndrome
Zap-70 kinase deficiency
Cartilage-hair hypoplasia
 PNP deficiency
CD40 ligand deficiency
MHC class II deficiency
Wiskott-Aldrich syndrome
Chédiak-Higashi syndrome
Kostmann syndrome (infantile malignant agranulocytosis)
Chronic granulomatous disease
Autoimmune lymphoproliferative syndrome
X-linked lymphoproliferative disease (Duncan syndrome)
IPEX syndrome
Interleukin-10 receptor deficiency
Hemophagocytic lymphohistiocytosis
Interferon-γ receptor deficiency
Griscelli disease
Granule deficiency

Other Disorders

Selected severe variants of platelet function disorders (e.g., Glanzmann

thromboasthenia, congenital amegakaryocytic thrombocytopenia)
Selected types of mucopolysaccharidosis (e.g., Hurler disease) or other
liposomal/peroxisomal disorders (e.g., Krabbe disease,
adrenoleukodystrophy)
Infantile malignant osteopetrosis
Life-threatening cytopenia unresponsive to conventional treatments

IPEX, Immune dysregulation, polyendocrinopathy, enteropathy, X-linked;

MHC, major histocompatibility complex; PNP, purine nucleoside
phosphorylase.

Acute Lymphoblastic Leukemia

Allogeneic HSCT is used for pediatric patients with acute lymphoblastic
leukemia (ALL ), either in the 1st complete remission when a child is considered
to be at high risk of leukemia recurrence (e.g., those carrying poor-risk
cytogenetic characteristics or with high levels of minimal residual disease), or in
lymphomas and select solid tumors (Table 162.1 ).
Table 162.1
Indications for Autologous Hematopoietic
Stem Cell Transplantation for Pediatric
Diseases
• Relapsed Hodgkin or non-Hodgkin lymphoma
• Stage IV or relapsed neuroblastoma
• High-risk, relapsed, or resistant brain tumors
• Stage IV Ewing sarcoma
• Life-threatening autoimmune diseases resistant to conventional treatments

Patients with sensitive lymphomas and minimal tumor burden have favorable
outcomes after autologous HSCT, with disease-free survival rates of 50–60%,
whereas high-risk patients with bulky tumor or poorly responsive disease have a
poor outcome, with survival rates of 10–20%.
Autologous HSCT in patients with high-risk neuroblastoma is associated with
a better outcome than conventional chemotherapy. A Children's Oncology Group
(COG) study demonstrated further survival advantage by performing 2
sequential, or tandem , transplants that use different chemotherapeutic agents.
Because of these improved outcomes, tandem autologous transplants are now
considered the standard recommended treatment. In these patients,
posttransplantation infusion of a monoclonal antibody directed against a
molecule (GD2) expressed on the surface of neuroblastoma cells confers a
protection against the risk of tumor recurrence.
For children with brain tumors at high risk of relapse, or resistant to
conventional chemotherapy and irradiation, the dose-limiting toxicity for
intensifying therapy is myelosuppression, thus providing a role for stem cell
rescue. Several studies provide encouraging results for patients with different
histologic types of brain tumors treated with autologous HSCT.

Bibliography
Chen Y-B, Wang T, Hemmer MT, et al. GvHD after umbilical

FIG. 163.2 Acute graft-versus-host disease. Almost confluent eruption of erythematous
macules and papules in an immunodeficient neonate treated with extracorporeal
membrane oxygenation (ECMO) and transfusion of nonirradiated blood. (From Paller
AS, Mancini AJ, editors: Hurwitz clinical pediatric dermatology, ed 5, Philadelphia,
2016, Elsevier, p 577.)

Table 163.1
Clinical Staging and Grading* of Graft-Versus-Host Disease
(GVHD)

SKIN (ACTIVE ERYTHEMA LIVER LOWER GI (STOOL

STAGE UPPER GI
ONLY) (BILIRUBIN) OUTPUT/DAY)
0 No active (erythematous) GVHD <2 mg/dL No or Adult: <500 mL/day or <3
rash intermittent episodes/day
nausea, Child: <10 mL/kg/day or <4
vomiting, or episodes/day
anorexia
1 Maculopapular rash <25% BSA 2-3 mg/dL Persistent Adult: 500-999 mL/day or
nausea, 3-4 episodes/day
vomiting or Child: 10-19.9 mL/kg/day
anorexia or 4-6 episodes/day
2 Maculopapular rash 25-50% BSA 3.1-6 mg/dL Adult: 1000-1500 mL/day
or 5-7 episodes/day
Child: 20-30 mL/kg/day or
7-10 episodes/day
3 Maculopapular rash >50% BSA 6.1-15 mg/dL Adult: >1500 mL/day or >7
episodes/day
Child: >30 mL/kg/day or
>10 episodes/day
4 Generalized erythroderma (>50% >15 mg/dL Severe abdominal pain with or
BSA) plus bullous formation and without ileus or grossly bloody
desquamation >5% BSA stool (regardless of stool
volume)
* Overall clinical grade (based on most severe target organ involvement):
and use of peripheral blood as the stem cell source have increased the incidence
and severity of chronic GVHD. Other factors that predict occurrence of chronic
GVHD include older donor and recipient ages, female donor for male recipient,
diagnosis of malignancy, and use of total body irradiation (TBI) as part of the
preparative regimen.
Chronic GVHD is a disorder of immune regulation characterized by
autoantibody production, increased collagen deposition and fibrosis, and clinical
symptoms similar to those seen in patients with autoimmune diseases (Table
163.2 ). The predominant cytokines involved in the pathophysiology of chronic
GVHD are usually type II cytokines such as IL-4, IL-5, and IL-13. IL-4 and IL-5
contribute to eosinophilia, B-cell hyperactivity with elevated IgM, IgG, and IgE
titers. Associated monoclonal gammopathies indicate clonal dysregulation.
Chronic GVHD is dependent on the development and persistence of donor T
cells that are not tolerant to the recipient. Maturation of transplanted stem cells
within a damaged thymus could lead to errors in negative selection and
production of cells that have not been tolerized to recipient antigens and are
therefore autoreactive or, more accurately, recipient reactive . This ongoing
immune reactivity results in clinical features resembling a systemic autoimmune
disease with lichenoid and sclerodermatous skin lesions, malar rash, sicca
syndrome, arthritis, joint contractures, bronchiolitis obliterans, and bile duct
degeneration with cholestasis.

Table 163.2

Clinical Findings in Chronic Graft-Versus-Host Disease

ORGAN
SYMPTOMS AND SIGNS
SYSTEM
Systemic Immunodeficiency and recurrent infections
Skin Lichen planus, scleroderma, hyperpigmentation or hypopigmentation, erythema, freckling,
ichthyosis, ulcerations
Flexion contractures
Vaginal scars
Onycholysis
Nail loss
Hair Alopecia; scarring or nonscarring
Mouth Sicca syndrome, lichen planus, depapillation of tongue with variegations, scalloping of lateral
margins, xerostomia, mucocele
Joints Diffuse myositis/tendonitis, arthritis, contractures
Eyes Decreased tearing, injected sclerae, scarring conjunctivitis, keratopathy
Liver Increased enzymes, cholestasis, hepatomegaly, cirrhosis
Gastrointestinal Failure to thrive, malabsorption, chronic diarrhea
Esophageal strictures
Lung Cough, dyspnea, wheezing
Bronchiolitis obliterans, chronic rales, pneumothorax, fibrosis
Hematology Thrombocytopenia, eosinophilia, Howell-Jolly bodies (splenic dysfunction)

Patients with chronic GVHD involving only the skin and liver have a
favorable course (Figs. 163.3 and 163.4 ). Extensive multiorgan disease may be
associated with a very poor quality of life, recurrent infections associated with
prolonged immunosuppressive regimens to control GVHD, and a high mortality
rate. Morbidity and mortality are highest in patients with a progressive onset of
chronic GVHD that directly follows acute GVHD, intermediate in those with a
quiescent onset after resolution of acute GVHD, and lowest in patients with de
novo onset in the absence of acute GVHD. Chronic GVHD can be classified as
mild, moderate, or severe depending on extent of involvement. Single-agent
prednisone is standard treatment at present, although other agents, including
extracorporeal photopheresis, MMF, anti-CD20 mAb, and pentostatin, have been
employed with variable success. Treatment with imatinib mesylate, which
inhibits the synthesis of collagen, has been effective in some patients with
chronic GVHD and sclerotic features. As a consequence of prolonged
immunosuppression, patients with chronic GVHD are particularly susceptible to
infections and should receive appropriate antibiotic prophylaxis, including
trimethoprim/sulfamethoxazole (TMP/SMX). Chronic GVHD resolves in most
pediatric patients but may require 1-3 yr of immunosuppressive therapy before
the drugs can be withdrawn without the disease recurring. Chronic GVHD
promotes the development of secondary neoplasms, in particular in patients with
Fanconi anemia, and has a significant impact on quality of life.

FIG. 163.3 Chronic graft-versus-host disease (GVHD), lichenoid. After bone marrow
transplantation, this boy had acute GVHD and subsequently developed cutaneous
scaling papules and plaques typical of lichen planus. (From Paller AS, Mancini AJ,
editors: Hurwitz clinical pediatric dermatology, ed 5, Philadelphia, 2016, Elsevier, p
577.)
underlying disease alone and require different types of monitoring.
Essentially, every organ system can be impacted by the long-term effects of
therapy, and each must be considered when undergoing late effects surveillance
(Table 165.1 ). As a result of growing evidence of the importance of lifelong
care for HSCT survivors, multiple groups have published recent consensus
guidelines to help in caring for this patient population. As the field of
survivorship continues to expand, we recommend the following reference for
real-time evidence-based recommendations from the Children's Oncology
Group : http://survivorshipguidelines.org .

Table 165.1
Summary of Late Effects After Hematopoietic Stem Cell
Transplantation (HSCT) in Childhood

EXPOSURE LATE EFFECT*

HSCT experience in general Dental abnormalities
Renal toxicity
Hepatic toxicity
Low BMD
Avascular necrosis
Increased risk of second cancers
Adverse psychosocial/quality-of-life effects
Mental health disorders, risk behaviors
Psychosocial disability caused by pain or fatigue
TRANSPLANTATION CONDITIONING
Alkylating agent Cataract (busulfan)
Pulmonary fibrosis (busulfan)
Renal toxicity
Urinary tract toxicity
Gonadal dysfunction
Therapy-related AML/MDS
Bladder cancer
Epipodophyllotoxin** Therapy-related AML/MDS
DNA intersecting and cross-linking agents (i.e., Ototoxicity
platinum, heavy metal) Renal toxicity
Gonadal toxicity
TBI † Neurocognitive deficits
Leukoencephalopathy
Cataract
Dental abnormalities
GH deficiency
Hypothyroidism, thyroid nodule
Pulmonary toxicity
Breast tissue hypoplasia
Cardiac toxicity
Renal toxicity
Gonadal dysfunction
 Uterine vascular insufficiency
Diabetes
Dyslipidemia
Musculoskeletal growth problems
Second cancers
PRETRANSPLANTATION EXPOSURES (Not Listed Above)
Anthracycline/anthraquinone Cardiac toxicity
Therapy-related AML/MDS
Bleomycin Pulmonary toxicity
Cytarabine Neurocognitive deficits
Leukoencephalopathy
Methotrexate Neurocognitive deficits
Leukoencephalopathy
Renal toxicity
Low BMD
Corticosteroid Cataract
Low BMD
Avascular necrosis
Cranial radiation ‡ Neurocognitive deficits
Leukoencephalopathy
Cerebrovascular disease
Cataract
Craniofacial abnormalities
Dental abnormalities, xerostomia
GH deficiency
Hypothyroidism thyroid nodule
Increased obesity
Precocious puberty
Brain tumor
Spinal radiation (in addition to cranial dose) Cardiac toxicity
Scoliosis/kyphosis, musculoskeletal problems
AFTER TRANSPLANTATION (Not Listed Above)
Chronic GVHD Xerophthalmia
Xerostomia, dental abnormalities
Pulmonary toxicity
Gastrointestinal strictures
Genitourinary strictures
Skin and joint changes
Immunodeficiency
Second cancers, especially skin, oral, cervical,
lymphoma
Tyrosine kinase inhibitor Acute cardiac toxicity reported, but not known to cause
late cardiotoxicity
OTHER EXPOSURES
Blood transfusions Hepatitis C, HIV
* Focused on those late effects that can develop or persist even after cessation of therapy.

† At given total dose, risks greater for single-fraction vs fractionated total body irradiation (TBI);
single-fraction myeloablative TBI (>500 cGy) now rarely used.
‡ Effects listed are those more likely to be associated with doses used in HSCT survivors (e.g.,
those given for leukemia treatment, <25 Gy); late effects are more likely if TBI also given.
** Include etoposide, teniposide.
urticaria/angioedema or atopic dermatitis. Xerosis , or dry skin, is the most
common skin abnormality of allergic children. Keratosis pilaris , often found on
facial cheeks and extensor surfaces of the upper arms and thighs, is a benign
condition characterized by skin-colored or slightly pink papules caused by
keratin plugs lodged in the openings of hair follicles. Examination of the skin of
the palms and soles may reveal thickened skin and exaggerated palmar and
plantar creases (hyperlinearity ) in children with moderate to severe atopic
dermatitis.

Diagnostic Testing
In Vitro Tests
Allergic diseases are often associated with increased numbers of eosinophils
circulating in the peripheral blood and invading the tissues and secretions of
target organs. Eosinophilia , defined as the presence of >500 eosinophils/µL in
peripheral blood, is the most common hematologic abnormality of allergic
patients. Seasonal increases in the number of circulating eosinophils may be
observed in sensitized patients after exposure to allergens such as tree, grass, and
weed pollens. The number of circulating eosinophils can be suppressed by
certain infections and systemic corticosteroids. In certain pathologic conditions,
such as drug reactions, eosinophilic pneumonias, and eosinophilic esophagitis,
significantly increased numbers of eosinophils may be present in the target organ
in the absence of peripheral blood eosinophilia. Increased numbers of
eosinophils are observed in a wide variety of disorders in addition to allergy;
eosinophil counts >1500 without an identifiable etiology should suggest 1 of the
2 hypereosinophilic syndromes (Table 167.1 ; see Chapter 155 ).
Table 167.1
Differential Diagnosis of Childhood
Eosinophilia
Physiologic

Prematurity
Infants receiving hyperalimentation
Hereditary
Infectious

Parasitic (with tissue-invasive helminths, e.g., trichinosis, strongyloidiasis,

pneumocystosis, filariasis, cysticercosis, cutaneous and visceral larva
migrans, echinococcosis)
Bacterial (brucellosis, tularemia, cat-scratch disease, Chlamydia )
Fungal (histoplasmosis, blastomycosis, coccidioidomycosis, allergic
bronchopulmonary aspergillosis)
Mycobacterial (tuberculosis, leprosy)
Viral (HIV-1, HTLV-1, hepatitis A, hepatitis B, hepatitis C, Epstein-Barr
virus)

Pulmonary

Allergic (rhinitis, asthma)

Eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome)
Loeffler syndrome
Hypersensitivity pneumonitis
Eosinophilic pneumonia (chronic, acute)
Pulmonary interstitial eosinophilia

Dermatologic

Atopic dermatitis
Pemphigus
Dermatitis herpetiformis
Infantile eosinophilic pustular folliculitis
Eosinophilic fasciitis (Schulman syndrome)
Eosinophilic cellulitis (Wells syndrome)
Kimura disease (angiolymphoid hyperplasia with eosinophilia)

Hematologic/Oncologic

Neoplasm (lung, gastrointestinal, uterine)

Leukemia/lymphoma
 Myelofibrosis
Myeloproliferative (FIP1L1-PDGFRA–positive) hypereosinophilic
syndrome
Lymphatic hypereosinophilic syndrome
Systemic mastocytosis

Immunologic

T-cell immunodeficiencies
Hyper-IgE (Job) syndrome
Wiskott-Aldrich syndrome
Graft-versus-host disease
Drug hypersensitivity
Postirradiation
Postsplenectomy

Endocrine

Addison disease
Hypopituitarism

Cardiovascular

Loeffler disease (fibroplastic endocarditis)

Congenital heart disease
Hypersensitivity vasculitis
Eosinophilic myocarditis

Gastrointestinal

Benign proctocolitis
Inflammatory bowel disease
Eosinophilic gastrointestinal diseases (EGID)

FIP1L1-PDGFRA, FIP1-like 1–platelet-derived growth factor receptor α.

 Nasal and bronchial secretions may be examined for the presence of
eosinophils. The presence of eosinophils in the sputum of asthmatic patients is
classic. An increased number of eosinophils in a smear of nasal mucus with
Hansel stain is a more sensitive indicator of nasal allergies than peripheral blood
eosinophilia and can aid in distinguishing allergic rhinitis from other causes of
rhinitis. An elevated IgE value is often found in the serum of allergic patients,
because IgE is the primary antibody associated with immediate hypersensitivity
reactions. IgE values are measured in international units (IU), with 1 IU equal to
2.4 ng of IgE. Maternal IgE (unlike IgG) does not cross the placenta. Serum IgE
levels gradually rise over the first years of life to peak in the teen years and
decrease steadily thereafter. Additional factors, such as genetic influences, race,
gender, certain diseases, and exposure to cigarette smoke and allergens, also
affect serum IgE levels. Total serum IgE levels may increase 2- to 4-fold during
and immediately after the pollen season and then gradually decline until the next
pollen season. Comparison of total IgE levels among patients with allergic
diseases reveals that those with atopic dermatitis tend to have the highest levels,
whereas patients with allergic asthma generally have higher levels than those
with allergic rhinitis. Although average total IgE levels are higher in populations
of allergic patients than in comparable populations without allergic disease, the
overlap in levels is such that the diagnostic value of a total IgE level is poor.
Approximately half of patients with allergic disease have total IgE levels in the
normal range. However, measurement of total IgE is indicated when the
diagnosis of allergic bronchopulmonary aspergillosis is suspected because
total serum IgE concentration >1,000 ng/mL is a criterion for diagnosis of this
disorder (see Chapter 264.1 ). Total serum IgE may also be elevated in several
nonallergic diseases (Table 167.2 ; see Chapter 152 ).
Table 167.2
Nonallergic Diseases Associated With
Increased Serum IgE Concentrations
Parasitic Infestations

Ascariasis
Capillariasis
Echinococcosis
Fascioliasis
 Filariasis
Hookworm
Onchocerciasis
Malaria
Paragonimiasis
Schistosomiasis
Strongyloidiasis
Trichinosis
Visceral larva migrans

Infections

Allergic bronchopulmonary aspergillosis

Candidiasis, systemic
Coccidioidomycosis
Cytomegalovirus mononucleosis
HIV type 1 infections
Infectious mononucleosis (Epstein-Barr virus)
Leprosy
Pertussis
Viral respiratory infections

Immunodeficiency

Autosomal dominant hyper-IgE syndrome (STAT3 mutations)

Autosomal recessive hyper-IgE syndrome (DOCK8, TYK2 mutations)
IgA deficiency, selective
Nezelof syndrome (cellular immunodeficiency with immunoglobulins)
Thymic hypoplasia (DiGeorge anomaly)
Wiskott-Aldrich syndrome

Neoplastic Diseases

Hodgkin disease
IgE myeloma
Bronchial carcinoma
Other Diseases and Disorders

Alopecia areata
Bone marrow transplantation
Burns
Cystic fibrosis
Dermatitis, chronic acral
Erythema nodosum, streptococcal infection
Guillain-Barré syndrome
Kawasaki disease
Liver disease
Medication related
Nephritis, drug-induced interstitial
Nephrotic syndrome
Pemphigus, bullous
Polyarteritis nodosa, infantile
Primary pulmonary hemosiderosis
Juvenile idiopathic arthritis

The presence of IgE specific for a particular allergen can be documented in

vivo by skin testing or in vitro by the measurement of allergen-specific IgE
(sIgE) levels in the serum (Table 167.3 ). The first test for documenting the
presence of sIgE was called the radioallergosorbent test (RAST) because it used
a radiolabeled anti-IgE antibody. The RAST has been replaced by an improved
generation of automated enzymatic sIgE immunoassays. These assays use solid-
phase supports to which allergens of an individual allergen extract are bound. A
small amount of the patient's serum is incubated with the allergen-coated
support. The allergen-coated support bound to the patient's sIgE is then
incubated with enzyme-conjugated antihuman IgE. Incubation of this sIgE–
antihuman IgE complex with a fluorescent substrate of the conjugated enzyme
results in the generation of fluorescence that is proportional to the amount of
sIgE in the serum sample. The amount of sIgE is calculated by interpolation
from a standard calibration curve and reported in arbitrary mass units (kilo-IU of
allergen-specific antibody per unit volume of sample, kUA /L). Laboratory
reports may specify classes, counts, or units, but quantification of results in kUA
/L is most useful. The 3 commercial detection systems approved by the U.S.
Food and Drug Administration have excellent performance characteristics, but
the individual systems do not measure sIgE antibodies with comparable
efficiencies and thus are not interchangeable. Component testing refers to
diagnostic tests where sIgE is measured to specific proteins that comprise
allergens (e.g., Ara h 2 from peanut, Bet v 1 from birch pollen), rather than to a
mixture of the allergens extracted from the source. Testing sIgE to component
allergens may add additional diagnostic value by differentiating immune
responses that are directed toward clinically relevant allergenic proteins.

Table 167.3

Determination of Allergen-Specific IgE by Skin Testing vs In Vitro Testing

VARIABLE SKIN TEST* sIgE ASSAY
Risk of allergic reaction Yes (especially ID) No
Relative sensitivity High High
Affected by antihistamines Yes No
Affected by corticosteroids Usually not No
Affected by extensive dermatitis or dermographism Yes No
Broad selection of antigens Fewer Yes
Immediate results Yes No
Expensive No Yes
Lability of allergens Yes No
Results evident to patient Yes No
* Skin testing may be the prick test or intradermal (ID) injection.

In Vivo Tests
Allergen skin testing is the primary in vivo procedure for the diagnosis of
allergic disease. Mast cells with sIgE antibodies attached to high-affinity
receptors on their surface reside in the skin of allergic patients. The introduction
of minute amounts of an allergen into the skin of the sensitized patient results in
cross-linking of IgE antibodies on the mast cell surface, thereby triggering local
mast cell activation. Once activated, these mast cells release a variety of
preformed and newly generated mediators that act on surrounding tissues.
Histamine is the mediator most responsible for the immediate wheal and flare
reactions observed in skin testing. Examination of the site of a positive skin test
result reveals a pruritic wheal surrounded by erythema. The time course of these
reactions is rapid in onset, reaching a peak within 10-20 min and usually
resolving over the next 30 min.
Evaluation of AR entails a thorough history, including details of the patient's
environment and diet and a family history of allergic conditions (e.g., eczema,
asthma, AR), physical examination, and laboratory evaluation. The history and
laboratory findings provide clues to the provoking factors. Symptoms such as
sneezing, rhinorrhea, nasal itching, and congestion and lab findings of elevated
IgE, sIgE antibodies, and positive allergy skin test results typify AR. Intermittent
AR differs from persistent AR by history and skin test results. Nonallergic
rhinitides give rise to sporadic symptoms; their causes are often unknown.
Nonallergic inflammatory rhinitis with eosinophils imitates AR in presentation
and response to treatment, but without elevated IgE antibodies. Vasomotor
rhinitis is characterized by excessive responsiveness of the nasal mucosa to
physical stimuli. Other nonallergic conditions, such as infectious rhinitis,
structural problems (e.g., nasal polyps, septal deviation), rhinitis
medicamentosa (caused by overuse of topical vasoconstrictors), hormonal
rhinitis associated with pregnancy or hypothyroidism, neoplasms, vasculitides,
and granulomatous disorders may mimic AR (Table 168.1 and Fig. 168.2 ).
Occupational risks for rhinitis include exposure to allergens (grain dust, insects,
latex, enzymes) and irritants (wood dust, paint, solvents, smoke, cold air).
Table 168.1
Causes of Rhinitis
ALLERGIC RHINITIS

Seasonal
Perennial
Perennial with seasonal exacerbations

NONALLERGIC RHINITIS
Structural/Mechanical Factors

Deviated septum/septal wall anomalies

Hypertrophic turbinates
Adenoidal hypertrophy
Foreign bodies
Nasal tumors
Benign
 Malignant
Choanal atresia

Infectious

Acute infections
Chronic infections

Inflammatory/Immunologic

Granulomatosis with polyangiitis

Sarcoidosis
Midline granuloma
Systemic lupus erythematosus
Sjögren syndrome
Nasal polyposis

Physiologic

Ciliary dyskinesia syndrome

Atrophic rhinitis
Hormonally induced
Hypothyroidism
Pregnancy
Oral contraceptives
Menstrual cycle
Exercise
Atrophic
Drug induced
Rhinitis medicamentosa
Oral contraceptives
Antihypertensive therapy
Aspirin
Nonsteroidal antiinflammatory drugs
Reflex induced
Gustatory rhinitis
 Chemical or irritant induced
Posture reflexes
Nasal cycle
Environmental factors
Odors
Temperature
Weather/barometric pressure
Occupational

NONALLERGIC RHINITIS WITH EOSINOPHILIA SYNDROME

PERENNIAL NONALLERGIC RHINITIS (VASOMOTOR RHINITIS)
EMOTIONAL FACTORS

From Skoner DP: Allergic rhinitis: definition, epidemiology, pathophysiology,

detection, and diagnosis, J Allergy Clin Immunol 108(1 Suppl);108:S2–S8, 2001
(original source).

FIG. 168.2 Diagnostic algorithm for rhinitis. Nasal allergen challenge is a research
procedure and is not undertaken routinely. CNS, Central nervous system; NSAID,
nonsteroidal antiinflammatory drug. (From Greiner AN, Hellings PW, Rotiroti G,
Scadding GK: Allergic rhinitis, Lancet 378:2112–2120, 2011.)
exposure to mite allergen. Bed linen and blankets should be washed every week
in hot water (>54.4°C [130°F]). The only effective measure for avoiding animal
allergens in the home is the removal of the pet. Avoidance of pollen and outdoor
molds can be accomplished by staying in a controlled environment. Air
conditioning allows for keeping windows and doors closed, reducing the pollen
exposure. High-efficiency particulate air (HEPA) filters lower the counts of
airborne mold spores.
Oral antihistamines help reduce sneezing, rhinorrhea, and ocular symptoms.
Administered as needed, antihistamines provide acceptable treatment for mild-
intermittent disease. Antihistamines have been classified as first generation
(relatively sedating) or second generation (relatively nonsedating).
Antihistamines usually are administered by mouth but are also available for
topical ophthalmic and intranasal use. Both first- and second-generation
antihistamines are available as nonprescription drugs. Second-generation
antihistamines are preferred because they cause less sedation . Preparations
containing pseudoephedrine , typically in combination with other agents, are
used for relief of nasal and sinus congestion and pressure and other symptoms
such as rhinorrhea, sneezing, lacrimation, itching eyes, oronasopharyngeal
itching, and cough. Pseudoephedrine is available without prescription (generally
in fixed combination with other agents such as first-generation antihistamines:
brompheniramine, chlorpheniramine, triprolidine; second-generation
antihistamines: desloratadine, fexofenadine, loratadine; antipyretics:
acetaminophen, ibuprofen; antitussives: guaifenesin, dextromethorphan;
anticholinergic: methscopolamine). Pseudoephedrine is an oral vasoconstrictor
distrusted for causing irritability and insomnia and for its association with infant
mortality. Because younger children (2-3 yr) are at increased risk of overdosage
and toxicity, some manufacturers of oral nonprescription cough and cold
preparations have voluntarily revised their product labeling to warn against the
use of preparations containing pseudoephedrine for children <4 yr old.
Pseudoephedrine is misused as a starting material for the synthesis of
methamphetamine and methcathinone. Tables 168.2 , 168.3 , and 168.4 provide
examples of prescription, nonprescription, and combined oral agents,
respectively, for treatment of AR.

Table 168.2
Oral Allergic Rhinitis Treatments (Prescription, Examples)
 GENERIC/BRAND STRENGTH FORMULATIONS DOSING
SECOND-GENERATION ANTIHISTAMINES
Desloratadine
Clarinex Reditabs* 2.5 mg, 5 mg Orally disintegrating Children 6-11 mo of age: 1 mg once daily
tablet
Clarinex Tablets 5 mg Tabs Children 12 mo-5 yr: 1.25 mg once daily
Clarinex Syrup 0.5 mg/mL Syrup Children 6-11 yr: 2.5 mg once daily
Adults and adolescents ≥12 yr: 5 mg once
daily
Levocetirizine
dihydrochloride
Xyzal Oral Solution 0.5 mg/mL Solution 6 mo-5 yr: max 1.25 mg once daily in the
PM
6-11 yr: max 2.5 mg once daily in the PM
LEUKOTRIENE ANTAGONIST
Montelukast
Singulair 10 mg Tablets 6 mo-5 yr: 4 mg daily
Singulair Chewables* 4 mg, 5 mg Chewable tablets 6-14 yr: 5 mg daily
Singulair Oral Granules 4 mg/packet Oral granules >14 yr: 10 mg daily
* Contains phenylalanine.

Dosing recommendations taken in part from Engorn B, Flerlage J, for the Johns Hopkins Hospital:
The Harriet Lane Handbook , ed 20, Philadelphia, 2015, Elsevier/Saunders.

Table 168.3
Oral Allergic Rhinitis Treatments (Nonprescription,
Examples)

GENERIC/BRAND STRENGTH FORMULATIONS DOSING

FIRST-GENERATION H1 ANTAGONISTS
Chlorpheniramine
maleate
Chlor-Trimeton 4 mg Tablets 2-5 yr: 1 mg every 4-6 hr (max 6 mg/day)
OTC (over the 6-11 yr: 2 mg every 4-6 hr (max 12 mg/day)
counter)
Chlor-Trimeton 2 mg/5 mL Syrup >12 yr: 4 mg every 4-6 hr (max 24 mg/day)
Syrup
OTC
SECOND-GENERATION H1 ANTAGONISTS
Cetirizine
Children's 1 mg/mL Syrup 6-12 mo: 2.5 mg once daily
Zyrtec Allergy
Syrup
OTC
Children's 5 mg, 10 mg Chewable tablets 12-23 mo: initial: 2.5 mg once daily; dosage may be
Zyrtec increased to 2.5 mg twice daily
Chewable
OTC
Zyrtec tablets 5 mg, 10 mg Tablets 2-5 yr: 2.5 mg/day; may be increased to max of 5
 OTC mg/day given either as a single dose or divided into 2
doses
Zyrtec Liquid 10 mg Liquid-filled gels ≥6 yr: 5-10 mg/day as a single dose or divided into 2
Gels doses
OTC
Levocetirizine 5 mg Tablet 2-5 yr: 1.25 mg once daily in the evening
Xyzal 0.5 Oral solution 6-11 yr: 2.5 mg orally once daily in the evening
mg/mL ≥12 yr: 5 mg orally once daily in the evening
Desloratadine 0.5 mg/mL Oral solution 6-11 mo: 2 mL once daily
Clarinex 12 mo-5 yr: 2.5 mL once daily
6-11 yr: 5 mL once daily
Desloratadine 5 mg Tablet 12-adult: 5 mg once daily
Clarinex
Fexofenadine 30 mg, 60 Tablet 6-11 yr: 30 mg twice daily
HCl mg, 180 mg 12-adult: 60 mg twice daily; 180 mg once daily
OTC
Children's 5 mg/5 mL Syrup 2-5 yr: 5 mg once daily
Claritin 6-adult: 10 mg once daily
OTC
Children's 30 mg Orally 6-11 yr: 30 mg twice daily
Allegra disintegrating
OTC tablets
ODT*
Children's 30 mg/5 mL Suspension >2-11 yr: 30 mg every 12 hr
Allegra Oral
Suspension
OTC
Allegra Tabs 30, 60, Tablet >12 yr-adult: 60 mg every 12 hr; 180 mg once daily
OTC 180 mg
Loratadine
Alavert 10 mg Orally 2-5 yr: 5 mg once daily
OTC 10 mg disintegrating >6 yr: 10 mg once daily or 5 mg twice daily
ODT* 10 mg tablets
5 mg Tablets
1 mg/mL Liquid-filled
caps
Chewable
tablets
Syrup
* Contains phenylalanine.

Dosing recommendations taken in part from Engorn B, Flerlage J, for the Johns Hopkins Hospital:
The Harriet Lane Handbook , ed 20. Philadelphia, 2015 Elsevier/Saunders.

Table 168.4
Combined Antihistamine + Sympathomimetic (Examples)

GENERIC STRENGTH FORMULATIONS DOSING

Chlorpheniramine 4 mg Tablets >12 yr: 1 tablet every 4 hr, not to
maleate 10 mg exceed 6 tablets per day
Phenylephrine
 HCl
Sudafed Sinus &
Allergy
Cetirizine + 5 mg cetirizine + 120 mg Extended-release >12 yr: 1 tablet every 12 hr
pseudoephedrine pseudoephedrine tablet
Zyrtec-D 12 hour
Dosing recommendations taken in part from Engorn B, MD, Flerlage J for the Johns Hopkins
Hospital: The Harriet Lane Handbook , ed 20. Philadelphia, 2015 Elsevier/Saunders.

The anticholinergic nasal spray ipratropium bromide is effective for the

treatment of serous rhinorrhea (Table 168.5 ). Intranasal decongestants
(oxymetazoline and phenylephrine) should be used for <5 days and should not to
be repeated more than once a month to avoid rebound nasal congestion. Sodium
cromoglycate (available as nonprescription drug) is effective but requires
frequent administration, every 4 hr. Leukotriene-modifying agents have a modest
effect on rhinorrhea and nasal blockage (see Chapter 169 for additional
indications and side effects). Nasal saline irrigation is a good adjunctive option
with all other treatments of AR. Patients with more persistent, severe symptoms
require intranasal corticosteroids , the most effective therapy for AR, which
may also be beneficial for concomitant allergic conjunctivitis (Table 168.6 ).
These agents reduce the symptoms of AR with eosinophilic inflammation, but
not those of rhinitis associated with neutrophils or free of inflammation.
Beclomethasone, triamcinolone, and flunisolide are absorbed from the
gastrointestinal tract, as well as from the respiratory tract; budesonide,
fluticasone, mometasone, and ciclesonide offer greater topical activity with
lower systemic exposure. More severely affected patients may benefit from
simultaneous treatment with oral antihistamines and intranasal corticosteroids.

Table 168.5
Miscellaneous Intranasal Sprays

INDICATIONS (I), MECHANISM(s) COMMENTS, CAUTIONS, ADVERSE

DRUG
OF ACTION (M), AND DOSING EVENTS, AND MONITORING
Ipratropium I: Symptomatic relief of rhinorrhea Atrovent inhalation aerosol is
bromide: M: Anticholinergic contraindicated in patients with
Atrovent nasal Colds (symptomatic relief of hypersensitivity to soy lecithin.
spray (0.06%) rhinorrhea): Safety and efficacy of use beyond 4 days in
5-12 yr: 2 sprays in each nostril tid patients with the common cold have not
≥12 yr and adults: 2 sprays in each been established.
nostril tid-qid Adverse effects: Epistaxis, nasal dryness,
nausea
Azelastine: I: Treatment of rhinorrhea, sneezing, May cause drowsiness
and nasal pruritus Adverse effects: Headache, somnolence,
 M: Antagonism of histamine H1 bitter taste
receptor
Astelin 6-12 yr: 1 spray bid
>12 yr: 1-2 sprays bid
Cromolyn sodium: I: AR. Not effective immediately; requires frequent
M: Inhibition of mast cell administration
degranulation
NasalCrom >2 yr: 1 spray tid-qid; max 6 times daily
Oxymetazoline: I: Symptomatic relief of nasal Excessive dosage may cause profound
Afrin mucosal congestion central nervous system (CNS) depression.
Nostrilla M: Adrenergic agonist, Use in excess of 3 days may result in
vasoconstricting agent severe rebound nasal congestion.
0.05% solution: instill 2-3 sprays into Do not repeat more than once a month.
each nostril bid; therapy should not Use with caution in patients with
exceed 3 days. hyperthyroidism, heart disease,
hypertension, or diabetes.
Adverse effects: Hypertension, palpitations,
reflex bradycardia, nervousness, dizziness,
insomnia, headache, CNS depression,
convulsions, hallucinations, nausea,
vomiting, mydriasis, elevated intraocular
pressure, blurred vision

Phenylephrine: I: Symptomatic relief of nasal Use in excess of 3 days may result in

mucosal congestion severe rebound nasal congestion.
M: Adrenergic, vasoconstricting Do not repeat more than once a month.
agent 0.16% and 0.125% solutions are not
Neo-Synephrine 2-6 yr: 1 drop every 2-4 hr of 0.125% commercially available.
solution as needed. Note: Therapy Adverse effects: Reflex bradycardia,
should not exceed 3 continuous days. excitability, headache, anxiety, dizziness
6-12 yr: 1-2 sprays or 1-2 drops every
4 hr of 0.25% solution as needed.
Note: Therapy should not exceed 3
continuous days.
>12 yr: 1-2 sprays or 1-2 drops every
4 hr of 0.25% to 0.5% solution as
needed; 1% solution may be used in
adults with extreme nasal congestion.
Note: Therapy should not exceed 3
continuous days.
bid, 2 times daily; tid, 3 times daily; qid, 4 times daily.

Table 168.6
Intranasal Inhaled Corticosteroids

INDICATIONS (I),
MECHANISM(s) OF COMMENTS, CAUTIONS, ADVERSE EVENTS,
DRUG
ACTION (M), AND AND MONITORING
DOSING
Beclomethasone: I: AR Shake container before use; blow nose; occlude 1
OTC (over the M: Antiinflammatory, nostril, administer dose to the other nostril.
counter) immune modulator Adverse effects: Burning and irritation of nasal
Beconase AQ (42 6-12 yr: 1 spray in each mucosa, epistaxis
µg/spray) nostril bid; may increase Monitor growth.
Qnasl (80 µg/spray) if needed to 2 sprays in
OTC each nostril bid
>12 yr: 1 or 2 sprays in
each nostril bid
Flunisolide 6-14 yr: 1 spray each Shake container before use; blow nose; occlude 1
OTC nostril tid or 2 sprays in nostril, administer dose to the other nostril.
each nostril bid; not to Adverse effects: Burning and irritation of nasal
exceed 4 sprays/day in mucosa, epistaxis
each nostril Monitor growth.
≥15 yr: 2 sprays each
nostril bid (morning and
evening); may increase
to 2 sprays tid;
maximum dose: 8
sprays/day in each
nostril (400 µg/day)
Triamcinolone I: AR Shake container before use; blow nose; occlude 1
Nasacort AQ (55 M: Antiinflammatory, nostril, administer dose to the other nostril.
µg/spray) immune modulator Adverse effects: Burning and irritation of nasal
OTC 2-6 yr: 1 spray in each mucosa, epistaxis
Fluticasone nostril qd Monitor growth.
propionate (available 6-12 yr: 1-2 sprays in
as generic each nostril qd
preparation): ≥12 yr: 2 sprays in each
OTC nostril qd
I: AR Shake container before use; blow nose; occlude 1
M: Antiinflammatory, nostril, administer dose to the other nostril.
immune modulator Ritonavir significantly increases fluticasone serum
concentrations and may result in systemic
corticosteroid effects.
Use fluticasone with caution in patients receiving
ketoconazole or other potent cytochrome P450
3A4 isoenzyme inhibitor.
Adverse effects: Burning and irritation of nasal
mucosa, epistaxis
Monitor growth.
Flonase (50 µg/spray) ≥4 yr: 1-2 sprays in each
OTC nostril qd
Fluticasone furoate: 2-12 yr:
Veramyst (27.5 Initial dose: 1 spray
µg/spray) (27.5 µg/spray) per
nostril qd (55 µg/day)
Patients who do not
show adequate response
may use 2 sprays per
nostril qd (110 µg/day)
Once symptoms are
controlled, dosage may
be reduced to 55 µg qd
Total daily dosage
should not exceed 2
sprays in each nostril
 (110 µg)/day
≥12 yr and adolescents:
Initial dose: 2 sprays
(27.5 µg/spray) per
nostril qd (110 µg/day)
Once symptoms are
controlled, dosage may
be reduced to 1 spray
per nostril qd (55
µg/day).
Total daily dosage
should not exceed 2
sprays in each nostril
(110 µg)/day.
Mometasone: I: AR Mometasone and its major metabolites are
M: Antiinflammatory, undetectable in plasma after nasal administration
immune modulator of recommended doses.
Nasonex (50 µg/spray) 2-12 yr: 1 spray in each Preventive treatment of seasonal AR should begin
nostril qd 2-4 wk prior to pollen season.
>12 yr: 2 sprays in each Shake container before use; blow nose; occlude 1
nostril qd nostril, administer dose to the other nostril.
Adverse effects: Burning and irritation of nasal
mucosa, epistaxis
Monitor growth.

Budesonide: I: AR Shake container before use; blow nose; occlude 1

OTC M: Antiinflammatory, nostril, administer dose to the other nostril.
immune modulator Adverse effects: Burning and irritation of nasal
Rhinocort Aqua (32 6-12 yr: 2 sprays in each mucosa, epistaxis
µg/spray) nostril qd Monitor growth.
OTC >12 yr: up to 4 sprays in
each nostril qd (max
dose)
Ciclesonide: I: AR Prior to initial use, gently shake, then prime the
M: Antiinflammatory, pump by actuating 8 times.
immune modulator If the product is not used for 4 consecutive days,
Omnaris 2-12 yr: 1-2 sprays in gently shake and reprime with 1 spray or until a
Zetonna (50 each nostril qd fine mist appears.
µg/spray) >12 yr: 2 sprays in each
nostril qd
Azelastine/fluticasone >12 yr: 1 spray in each Shake bottle gently before using. Blow nose to clear
(137 µg azelastine/50 nostril bid nostrils. Keep head tilted downward when spraying.
µg fluticasone) Insert applicator tip to inch into nostril, keeping
Dymista
bottle upright, and close off the other nostril. Breathe
in through nose. While inhaling, press pump to release
spray.
qd, Once daily; bid, 2 times daily; tid, 3 times daily.

Allergen-specific immunotherapy is a well-defined treatment for IgE-mediated

allergic disease. It may be administered by subcutaneous or sublingual routes.
Sublingual immunotherapy (SLIT) has been used successfully in Europe and
South America and is now approved by the U.S. Food and Drug Administration.
in 2006, childhood asthma accounted for 593,000 emergency department (ED)
visits, 155,000 hospitalizations, and 167 deaths. A disparity in asthma outcomes
links high rates of asthma hospitalization and death with poverty, ethnic
minorities, and urban living. In the past 2 decades, black children have had 2-7
times more ED visits, hospitalizations, and deaths as a result of asthma than
nonblack children. Although current asthma prevalence is higher in black than in
nonblack U.S. children (in 2011, 16.5% vs 8.1% for white and 9.8% for Latino
children), prevalence differences cannot fully account for this disparity in asthma
outcomes.
Worldwide, childhood asthma appears to be increasing in prevalence, despite
considerable improvements in our management and pharmacopeia to treat
asthma. Although childhood asthma may have plateaued in the United States
after 2008, numerous studies conducted in other countries have reported an
increase in asthma prevalence of approximately 50% per decade. Globally,
childhood asthma prevalence varies widely in different locales. A study of
childhood asthma prevalence in 233 centers in 97 countries (International Study
of Asthma and Allergies in Childhood, Phase 3) found a wide range in the
prevalence of current wheeze in 6-7 yr (2.4–37.6%) and 13-14 yr old children
(0.8–32.6%). Asthma prevalence correlated well with reported allergic
rhinoconjunctivitis and atopic eczema prevalence. Childhood asthma seems
more prevalent in modern metropolitan locales and more affluent nations, and is
strongly linked with other allergic conditions. In contrast, children living in rural
areas of developing countries and farming communities with domestic animals
are less likely to experience asthma and allergy.
Approximately 80% of all asthmatic patients report disease onset prior to 6 yr
of age. However, of all young children who experience recurrent wheezing, only
a minority go on to have persistent asthma in later childhood. Early childhood
risk factors for persistent asthma have been identified (Table 169.1 ) and have
been described as major (parent asthma, eczema, inhalant allergen sensitization)
and minor (allergic rhinitis, wheezing apart from colds, ≥4% peripheral blood
eosinophils, food allergen sensitization) risk factors. Allergy in young children
with recurrent cough and/or wheeze is the strongest identifiable factor for the
persistence of childhood asthma.
Table 169.1
Early Childhood Risk Factors for Persistent
Asthma
 Parental asthma*
Allergy:
• Atopic dermatitis (eczema)*
• Allergic rhinitis
• Food allergy
• Inhalant allergen sensitization*
• Food allergen sensitization
Severe lower respiratory tract infection:
• Pneumonia
• Bronchiolitis requiring hospitalization
Wheezing apart from colds
Male gender
Low birthweight
Environmental tobacco smoke exposure
Reduced lung function at birth
Formula feeding rather than breastfeeding

* Major risk factors.

Types of Childhood Asthma

There are 2 common types of childhood asthma based on different natural
courses: (1) recurrent wheezing in early childhood, primarily triggered by
common respiratory viral infections, usually resolves during the preschool/lower
school years; and (2) chronic asthma associated with allergy that persists into
later childhood and often adulthood (Table 169.2 ). School-age children with
mild-moderate persistent asthma generally improve as teenagers, with some
(about 40%) developing intermittent disease. Milder disease is more likely to
remit. Inhaled corticosteroid controller therapy for children with persistent
asthma does not alter the likelihood of outgrowing asthma in later childhood;
however, because children with asthma generally improve with age, their need
for controller therapy subsequently lessens and often resolves. Reduced growth
and progressive decline in lung function can be features of persistent,
problematic disease.
Table 169.2
Asthma Patterns in Childhood, Based on
Natural History and Asthma Management
Transient Nonatopic Wheezing

Common in early preschool years

Recurrent cough/wheeze, primarily triggered by common respiratory viral
infections
Usually resolves during the preschool and lower school years, without
increased risk for asthma in later life
Reduced airflow at birth, suggestive of relatively narrow airways; AHR
near birth; improves by school age

Persistent Atopy-Associated Asthma

Begins in early preschool years

Associated with atopy in early preschool years:
• Clinical (e.g., atopic dermatitis in infancy, allergic rhinitis, food
allergy)
• Biologic (e.g., early inhalant allergen sensitization, increased
serum IgE, increased blood eosinophils)
• Highest risk for persistence into later childhood and adulthood
Lung function abnormalities:
• Those with onset before 3 yr of age acquire reduced airflow by
school age.
• Those with later onset of symptoms, or with later onset of
allergen sensitization, are less likely to experience airflow
limitation in childhood.

Asthma With Declining Lung Function

Children with asthma with progressive increase in airflow limitation

Associated with hyperinflation in childhood, male gender

Asthma Management Types

 (From national and international asthma management guidelines)

Severity Classification*

• Intrinsic disease severity while not taking asthma medications

Intermittent
Persistent:
• Mild
• Moderate
• Severe

Control Classification*

• Clinical assessment while asthma being managed and treated

Well controlled
Not well controlled
Very poorly controlled

Management Patterns

• Easy-to-control: well controlled with low levels of daily controller therapy

• Difficult-to-control: well controlled with multiple and/or high levels of
controller therapies
• Exacerbators: despite being well controlled, continue to have severe
exacerbations
• Refractory: continue to have poorly controlled asthma despite multiple and
high levels of controller therapies

AHR, Airways hyperresponsiveness.

* From National Asthma Education and Prevention Program Expert Panel Report

3 (EPR3): Guideline for the diagnosis and management of asthma, NIH Pub No
07-4051, Bethesda, MD, 2007, US Department of Health and Human Services;
National Institutes of Health; National Heart, Lung, and Blood Institute;
National Asthma Education and Prevention Program.
https://www.nhlbi.nih.gov/health-pro/guidelines/current/asthma-guidelines/full-
report .

Asthma is also classified by disease severity (e.g., intermittent or persistent

[mild, moderate, or severe]) or control (e.g., well, not well, or very poorly
controlled), especially for asthma management purposes. Because most children
with asthma can be well controlled with conventional management guidelines,
children with asthma can also be characterized according to treatment response
and medication requirements as being (1) easy to control : well controlled with
low levels of controller therapy; (2) difficult to control : not as well controlled
with multiple and/or high levels of controller therapies; (3) exacerbators :
despite being controlled, continue to have severe exacerbations; and (4)
refractory asthma : continue to have poorly controlled asthma despite multiple
and high levels of controller therapies (Table 169.2 ). Different airways
pathologic processes, causing airways inflammation, AHR, and airways
congestion and blockage, are believed to underlie these different types of
asthma.

Pathogenesis
Airflow obstruction in asthma is the result of numerous pathologic processes. In
the small airways, airflow is regulated by smooth muscle encircling the airway
lumen; bronchoconstriction of these bronchiolar muscular bands restricts or
blocks airflow. A cellular inflammatory infiltrate and exudates distinguished by
eosinophils, but also including other inflammatory cell types (neutrophils,
monocytes, lymphocytes, mast cells, basophils), can fill and obstruct the airways
and induce epithelial damage and desquamation into the airways lumen. Helper
T lymphocytes and other immune cells that produce proallergic,
proinflammatory cytokines (interleukin [IL]-4, IL-5, IL-13), and chemokines
(eotaxins) mediate this inflammatory process (see Fig. 169.2 ). Pathogenic
immune responses and inflammation may also result from a breach in normal
immune regulatory processes (e.g., regulatory T lymphocytes that produce IL-10
and transforming growth factor-β) that dampen effector immunity and
inflammation when they are no longer needed. Hypersensitivity or susceptibility
to a variety of provocative exposures or triggers (Table 169.3 ) can lead to
airways inflammation, AHR, edema, basement membrane thickening,
subepithelial collagen deposition, smooth muscle and mucous gland
hypertrophy, and mucus hypersecretion—all processes that contribute to airflow
obstruction.
Table 169.3
Asthma Triggers
COMMON VIRAL INFECTIONS OF RESPIRATORY TRACT
AEROALLERGENS IN SENSITIZED ASTHMATIC PATIENTS
Indoor Allergens

• Animal dander
• Dust mites
• Cockroaches
• Molds

Seasonal Aeroallergens

• Pollens (trees, grasses, weeds)

• Seasonal molds

AIR POLLUTANTS

• Environmental tobacco smoke

• Ozone
• Nitrogen dioxide
• Sulfur dioxide
• Particulate matter
• Wood- or coal-burning smoke
• Mycotoxins
• Endotoxin
• Dust
 STRONG OR NOXIOUS ODORS OR FUMES

• Perfumes, hairsprays
• Cleaning agents

OCCUPATIONAL EXPOSURES

• Farm and barn exposures

• Formaldehydes, cedar, paint fumes

COLD DRY AIR

EXERCISE
CRYING, LAUGHTER, HYPERVENTILATION
COMORBID CONDITIONS

• Rhinitis
• Sinusitis
• Gastroesophageal reflux

DRUGS

• Aspirin and other nonsteroidal antiinflammatory drugs

• β-Blocking agents

Clinical Manifestations and Diagnosis

Intermittent dry coughing and expiratory wheezing are the most common
chronic symptoms of asthma. Older children and adults report associated
shortness of breath and chest congestion and tightness; younger children are
more likely to report intermittent, nonfocal chest pain. Respiratory symptoms
can be worse at night, associated with sleep, especially during prolonged
exacerbations triggered by respiratory infections or inhalant allergens. Daytime
symptoms, often linked with physical activities (exercise-induced) or play, are
reported with greatest frequency in children. Other asthma symptoms in children
can be subtle and nonspecific, including self-imposed limitation of physical
increased prolongation of exhalation, poor air entry, suprasternal and intercostal
retractions, nasal flaring, and accessory respiratory muscle use. In extremis,
airflow may be so limited that wheezing cannot be heard (silent chest ).

Table 169.4
Formal Evaluation of Asthma Exacerbation Severity in the
Urgent or Emergency Care Setting*

SUBSET:
RESPIRATORY
MILD MODERATE SEVERE
ARREST
IMMINENT
SYMPTOMS
Breathlessness While walking While at rest (infant— While at rest (infant Extreme dyspnea
softer, shorter cry, —stops feeding) Anxiety
difficulty feeding)
Can lie down Prefers sitting Sits upright Upright, leaning
forward
Talks in… Sentences Phrases Words Unable to talk
Alertness May be agitated Usually agitated Usually agitated Drowsy or confused
SIGNS
Respiratory rate † Increased Increased Often >30
breaths/min
Use of accessory Usually not Commonly Usually Paradoxical
muscles; suprasternal thoracoabdominal
retractions movement
Wheeze Moderate; often Loud; throughout Usually loud; Absence of wheeze
only end- exhalation throughout
expiratory inhalation and
exhalation
Pulse rate (beats/min) <100 100-120 >120 Bradycardia
‡
Pulsus paradoxus Absent May be present Often present Absence suggests
<10 mm 10-25 mm Hg >25 mm Hg respiratory muscle
Hg (adult) fatigue
20-40 mm Hg
(child)
FUNCTIONAL ASSESSMENT
Peak expiratory flow ≥70% Approx. 40–69% or <40% <25% §
(value predicted or response lasts <2 hr
personal best)
PaO 2 (breathing air) Normal (test not ≥60 mm Hg (test not <60 mm Hg;
usually usually necessary) possible cyanosis
necessary)
and/or
PCO 2 <42 mm Hg <42 mm Hg (test not ≥42 mm Hg;
(test not usually usually necessary) possible respiratory
necessary) failure
SaO 2 (breathing air) at >95% (test not 90–95% (test not usually <90% Hypoxia despite
 sea level usually necessary) oxygen therapy
necessary)
Hypercapnia (hypoventilation) develops more readily in young children than in adults
and adolescents.
* Notes:

† Normal breathing rates in awake children by age: <2 mo, <60 breaths/min; 2-12 mo, <50

breaths/min; 1-5 yr, <40 breaths/min; 6-8 yr, <30 breaths/min.

‡ Normal pulse rates in children by age: 2-12 mo, <160 beats/min; 1-2 yr, <120 beats/min; 2-8 yr,

<110 beats/min.
§ Peak expiratory flow testing may not be needed in very severe attacks.

• The presence of several parameters, but not necessarily all, indicates the general classification
of the exacerbation.
• Many of these parameters have not been systematically studied, especially as they correlate
with each other; thus they serve only as general guides.
• The emotional impact of asthma symptoms on the patient and family is variable but must be
recognized and addressed and can affect approaches to treatment and follow-up.
Adapted from National Asthma Education and Prevention Program Expert Panel Report 3
(EPR3): Guideline for the diagnosis and management of asthma, NIH Pub No 07-4051, Bethesda,
MD, 2007, US Department of Health and Human Services; National Institutes of Health; National
Heart, Lung, and Blood Institute; National Asthma Education and Prevention Program.
https://www.nhlbi.nih.gov/health-pro/guidelines/current/asthma-guidelines/full-report .

Differential Diagnosis
Many childhood respiratory conditions can present with symptoms and signs
similar to those of asthma (Table 169.5 ). Besides asthma, other common causes
of chronic, intermittent coughing include gastroesophageal reflux (GER) and
rhinosinusitis. Both GER and chronic sinusitis can be challeng spirometric lung
function testing ing to diagnose in children. Often, GER is clinically silent in
children, and children with chronic sinusitis do not report sinusitis-specific
symptoms, such as localized sinus pressure and tenderness. In addition, both
GER and rhinosinusitis are often comorbid with childhood asthma and, if not
specifically treated, may make asthma difficult to manage.
Table 169.5
Differential Diagnosis of Childhood Asthma
Upper Respiratory Tract Conditions
 Allergic rhinitis*
Chronic rhinitis*
Sinusitis*
Adenoidal or tonsillar hypertrophy
Nasal foreign body

Middle Respiratory Tract Conditions

Laryngotracheobronchomalacia*
Laryngotracheobronchitis (e.g., pertussis)*
Laryngeal web, cyst, or stenosis
Exercise-induced laryngeal obstruction
Vocal cord dysfunction*
Vocal cord paralysis
Tracheoesophageal fistula
Vascular ring, sling, or external mass compressing on the airway (e.g.,
tumor)
Endobronchial tumor
Foreign body aspiration*
Chronic bronchitis from environmental tobacco smoke exposure*
Repaired tracheoesophageal fistula
Toxic inhalations

Lower Respiratory Tract Conditions

Bronchopulmonary dysplasia (chronic lung disease of preterm infants)

Viral bronchiolitis*
Gastroesophageal reflux*
Causes of bronchiectasis:
• Cystic fibrosis
• Immunodeficiency
• Allergic bronchopulmonary mycoses (e.g., aspergillosis)
• Chronic aspiration
Primary ciliary dyskinesia, immotile cilia syndrome
Bronchiolitis obliterans
Interstitial lung diseases
 Hypersensitivity pneumonitis
Eosinophilic granulomatosis with angiitis
Eosinophilic pneumonia
Pulmonary hemosiderosis
Tuberculosis
Pneumonia
Pulmonary edema (e.g., congestive heart failure)
Vasculitis
Sarcoidosis
Medications associated with chronic cough:
• Acetylcholinesterase inhibitors
• β-Adrenergic antagonists
• Angiotensin-converting enzyme inhibitors

* More common asthma masqueraders.

In early life, chronic coughing and wheezing can indicate recurrent aspiration,
tracheobronchomalacia (congenital anatomic abnormality of airways), foreign
body aspiration, cystic fibrosis, or bronchopulmonary dysplasia.
In older children and adolescents, vocal cord dysfunction (VCD) can
manifest as intermittent daytime wheezing. The vocal cords involuntarily close
inappropriately during inspiration and sometimes exhalation, producing
shortness of breath, coughing, throat tightness, and often audible laryngeal
wheezing and/or stridor. In most cases of VCD, spirometric lung function testing
reveals truncated and inconsistent inspiratory and expiratory flow-volume loops,
a pattern that differs from the reproducible pattern of airflow limitation in
asthma that improves with bronchodilators. VCD can coexist with asthma.
Hypercarbia and severe hypoxia are uncommon in VCD. Flexible
rhinolaryngoscopy in the patient with symptomatic VCD can reveal paradoxical
vocal cord movements with anatomically normal vocal cords. Prior to the
diagnosis, patients with VCD are often treated unsuccessfully with multiple
different classes of asthma medications. This condition can be well managed
with specialized speech therapy training in the relaxation and control of vocal
cord movement. Furthermore, treatment of underlying causes of vocal cord
irritability (e.g., high GER/aspiration, allergic rhinitis, rhinosinusitis, asthma)
 FIG. 169.3 Spirometry. A, Spirometric flow-volume loops. Loop A is an expiratory flow-
volume loop of a nonasthmatic person without airflow limitation. B through E are
expiratory flow-volume loops in asthmatic patients with increasing degrees of airflow
limitation (B is mild; E is severe). Note the “scooped” or concave appearance of the
asthmatic expiratory flow-volume loops; with increasing obstruction, there is greater
“scooping.” B, Spirometric volume-time curves. Subject 1 is a nonasthmatic person;
subject 2 is an asthmatic patient. Note how the FEV1 and FVC lung volumes are
obtained. The FEV1 is the volume of air exhaled in the 1st sec of a forced expiratory
effort. The FVC is the total volume of air exhaled during a forced expiratory effort, or
forced vital capacity. Note that subject 2's FEV1 and FEV1 :FVC ratio are smaller than
subject 1's, demonstrating airflow limitation. Also, subject 2's FVC is very close to what
is expected.

In asthma, airways blockage results in reduced airflow with forced exhalation

(see Fig. 169.3 ). Because asthmatic patients typically have hyperinflated lungs,
forced expiratory volume in 1 sec (FEV1 ) can be simply adjusted for full
expiratory lung volume—the forced vital capacity (FVC)—with an FEV1 /FVC
ratio. Generally, an FEV1 /FVC ratio <0.80 indicates airflow obstruction (Table
169.6 ). Normative values for FEV1 have been determined for children by
height, gender, and ethnicity. Abnormally low FEV1 as a percentage of predicted
norms is 1 of 6 criteria used to determine asthma severity and control in asthma
management guidelines sponsored by the U.S. National Institutes of Health
(NIH) and the Global Initiative for Asthma (GINA) .
Table 169.6
Lung Function Abnormalities in Asthma and
Assessment of Airway Inflammation

Spirometry (in clinic) ‡ † :

Airflow limitation:
• Low FEV1 (relative to percentage of predicted norms)
• FEV1 /FVC ratio <0.80
Bronchodilator response (to inhaled β-agonist) assesses reversibility of
airflow limitation.
Reversibility is determined by an increase in either FEV1 >12% or
predicted FEV1 >10% after inhalation of a short-acting β-
agonist (SABA)*
Exercise challenge:
• Worsening in FEV1 ≥15%*
Daily peak expiratory flow (PEF) ‡ or FEV1 monitoring: day-to-day
and/or AM -to-PM variation ≥20%*
Exhaled nitric oxide (FeNO)
• A value of >20 ppb supports the clinical diagnosis of asthma in
children
• FeNO can be used to predict response to ICS therapy:
• <20 ppb: Unlikely to respond to ICS because eosinophilic
inflammation unlikely
• 20-35 ppb: Intermediate, may respond to ICS
• >35 ppb: Likely to respond to ICS because eosinophilic
inflammation is likely

FEV1 , forced expiratory volume in 1 sec; FVC, forced vital capacity; ICS,
inhaled corticosteroid; ppb, parts per billion.

‡ PEF variability is insensitive, while being highly specific for asthma.

† Of note, >50%of children with mild to moderate asthma will have a normal

FEV1 and will not have a significant bronchodilator response.

* Main criteria consistent with asthma.
assessment of asthma control is important in adjusting therapy and is categorized
in 3 levels: well controlled, not well controlled, and very poorly controlled.
Responsiveness to therapy is the ease or difficulty with which asthma control is
attained by treatment.
Classification of asthma severity and control is based on the domains of
impairment and risk . These domains do not necessarily correlate with each
other and may respond differently to treatment. Childhood asthma is
characterized by minimal day-to-day impairment, with the potential for frequent,
severe exacerbations most often triggered by viral infections, whereas adults
with asthma have greater impairment with less potential for risk. The NIH
guidelines have distinct criteria for 3 childhood age groups—0-4 yr, 5-11 yr, and
≥12 yr—for the evaluation of both severity (Table 169.7 ) and control (Table
169.8 ). The level of asthma severity or control is based on the most severe
impairment or risk category. In assessing asthma severity, impairment consists
of an assessment of the patient's recent symptom frequency (daytime and
nighttime, with subtle differences in numeric cutoffs between the 3 age-groups),
SABA use for quick relief, ability to engage in normal or desired activities, and
airflow compromise evaluated by spirometry in children ≥5 yr. Risk refers to the
likelihood of developing severe asthma exacerbations. Of note, even in the
absence of frequent symptoms, persistent asthma can be diagnosed and long-
term controller therapy initiated. For children ≥5 yr, 2 exacerbations requiring
oral corticosteroids in 1 yr, and for infants and preschool-aged children who
have risk factors for asthma (see earlier) and 4 or more episodes of wheezing
over the past year that lasted longer than 1 day and affected sleep, or 2 or more
exacerbations in 6 mo requiring systemic corticosteroids, qualifies them as
having persistent asthma.

Table 169.7
Assessing Asthma Severity and Initiating Treatment for
Patients Who Are Not Currently Taking Long-Term Control
Medications*

CLASSIFICATION OF ASTHMA SEVERITY

PERSISTENT
INTERMITTENT
Mild Moderate Severe
COMPONENTS OF SEVERITY
Impairment
Daytime symptoms ≤2 days/wk >2 days/wk but Daily Throughout the day
 not daily
Nighttime
awakenings:
Age 0-4 yr 0 1-2×/mo 3-4×/mo >1×/wk
Age ≥5 yr ≤2×/mo 3-4×/mo >1×/wk but not nightly Often 7×/wk
Short-acting β2 - ≤2 days/wk >2 days/wk but Daily Several times per day
agonist use for not daily, and not
symptoms (not for more than 1× on
EIB prevention) any day
Interference with None Minor limitation Some limitation Extreme limitation
normal activity
Lung function:
FEV1 % predicted, Normal FEV1 ≥80% predicted 60–80% predicted <60% predicted
age ≥5 yr between
exacerbations
>80%
predicted
FEV1 /FVC ratio † :
Age 5-11 yr >85% >80% 75-80% <75%
Age ≥12 yr Normal Normal Reduced 5% Reduced >5%
Risk
Exacerbations requiring systemic corticosteroids:
Age 0-4 yr 0-1/yr (see notes) ≥2 exacerbations in 6 mo requiring systemic CS
or
≥4 wheezing episodes/yr lasting >1 day and risk factors for
persistent asthma
Age ≥ 5 yr 0-1/yr (see notes) ≥2/yr (see notes) ≥2/yr (see notes) ≥2/yr (see notes)
Consider severity and interval since last exacerbation.
Frequency and severity may fluctuate over time for patients in any severity category.
Relative annual risk of exacerbations may be related to FEV1 .
RECOMMENDED STEP FOR INITIATING THERAPY
(See Table 169.11 for treatment steps.)
The stepwise approach is meant to assist, not replace, the clinical decision-making required to meet
individual patient needs.
All ages Step 1 Step 2
Age 0-4 yr Step 3 and consider a Step 3 and consider a
short course of short course of
systemic CS systemic CS
Age 5-11 yr Step 3: medium-dose Step 3: medium-dose
ICS option and ICS option or Step 4
consider a short course and consider a short
of systemic CS course of CS
In 2-6 wk, depending on severity, evaluate level of asthma control that is achieved.
• Children 0-4 yr old: If no clear benefit is observed in 4-6 wk, stop treatment and
consider alternative diagnoses or adjusting therapy accordingly.
• Children 5-11 yr old: Adjust therapy accordingly.
* Notes:

† Normal FEV /FVC: 8-19 yr, 85%; 20-39 yr, 80%.

1

• Level of severity is determined by both impairment and risk. Assess impairment domain by
patient's/caregiver's recall of previous 2-4 wk. Symptom assessment for longer periods should
reflect a global assessment, such as inquiring whether a patient's asthma is better or worse since
the last visit. Assign severity to the most severe category in which any feature occurs.
• At present, there are inadequate data to correspond frequencies of exacerbations with different
levels of asthma severity. For treatment purposes, patients who had ≥2 exacerbations requiring
oral systemic corticosteroids in the past 6 mo, or ≥4 wheezing episodes in the past year, and who
have risk factors for persistent asthma, may be considered the same as patients who have
persistent asthma, even in the absence of impairment levels consistent with persistent asthma.
FEV1 , Forced expiratory volume in 1 sec; FVC, forced vital capacity; CS corticosteroid; ICS,
inhaled corticosteroid: EIB, exercise-induced bronchospasm.
Adapted from the National Asthma Education and Prevention Program Expert Panel Report 3
(EPR3): Guidelines for the diagnosis and management of asthma—summary report 2007, J
Allergy Clin Immunol 120(Suppl):S94–S138, 2007.

Table 169.8
Assessing Asthma Control and Adjusting Therapy in
Children*

CLASSIFICATION OF ASTHMA CONTROL

Well-Controlled Not Well-Controlled Very Poorly Controlled
COMPONENTS OF CONTROL
Impairment
Symptoms ≤2 days/wk but not >2 days/wk or multiple times Throughout the day
more than once on on ≤2 days/wk
each day
Nighttime awakenings:
Age 0-4 yr ≤1×/mo >1×/mo >1×/wk
Age 5-11 yr ≤1×/mo ≥2×/mo ≥2×/wk
Age ≥12 yr ≤2×/mo 1-3×/wk ≥4×/wk
Short-acting β2 -agonist ≤2 days/wk >2 days/wk Several times per day
use for symptoms (not
for EIB pretreatment)
Interference with normal None Some limitation Extremely limited
activity
Lung function:
Age 5-11 yr:
FEV1 (% predicted or >80% predicted or 60-80% predicted or personal <60% predicted or personal
peak flow) personal best best best
FEV1 /FVC: >80% 75-80% <75%
Age ≥12 yr:
FEV1 (% predicted or >80% predicted or 60-80% predicted or personal <60% predicted or personal
peak flow) personal best best best
Validated questionnaires
† :
Age ≥12 yr:
ATAQ 0 1-2 3-4
ACQ ≤0.75 ≤1.5 N/A
ACT ≥20 16-19 ≤15
 Risk
Exacerbations requiring systemic corticosteroids:
Age 0-4 yr 0-1/yr 2-3/yr >3/yr
Age ≥5 yr 0-1/yr ≥2/yr (see notes)
Consider severity and interval since last exacerbation.
Treatment-related Medication side effects can vary in intensity from none to very troublesome and
adverse effects worrisome. The level of intensity does not correlate to specific levels of control but
should be considered in the overall assessment of risk.
Reduction in lung Evaluation requires long-term follow-up care.
growth or progressive
loss of lung function
RECOMMENDED ACTION FOR TREATMENT
Maintain current Step up ‡ (1 step) and Consider short course of
step. reevaluate in 2-6 wk. oral corticosteroids.
Regular follow- If no clear benefit in 4-6 Step up § (1-2 steps) and
up every 1-6 mo wk, consider alternative reevaluate in 2 wk.
to maintain diagnoses or adjusting If no clear benefit in 4-6
control. therapy. wk, consider alternative
Consider step For side effects, consider diagnoses or adjusting
down if well alternative options. therapy.
controlled for at For side effects, consider
least 3 mo. alternative options.
* Notes:

†
Validated questionnaires for the impairment domain (the questionnaires do not assess lung
function or the risk domain) and definition of minimal important difference (MID) for each:
‡ ACQ values of 0.76-1.40 are indeterminate regarding well-controlled asthma.

§ Before step-up therapy: (a) review adherence to medications, inhaler technique, and
environmental control; (b) if alternative treatment option was used in a step, discontinue it and use
preferred treatment for that step.
• The stepwise approach is meant to assist, not replace, the clinical decision making required to
meet individual patient needs.
• The level of control is based on the most severe impairment or risk category. Assess impairment
domain by caregiver's recall of previous 2-4 wk. Symptom assessment for longer periods should
reflect a global assessment, such as inquiring whether the patient's asthma is better or worse
since the last visit.
• At present, there are inadequate data to correspond frequencies of exacerbations with different
levels of asthma control. In general, more frequent and intense exacerbations (e.g., requiring
urgent, unscheduled care, hospitalization, or intensive care unit admission) indicate poorer
disease control. For treatment purposes, patients who had ≥2 exacerbations requiring oral
systemic corticosteroids in the past year may be considered the same as patients who have not-
well-controlled asthma, even in the absence of impairment levels consistent with not-well-
controlled asthma.
• ATAQ, Asthma Therapy Assessment Questionnaire; MID = 1.0.
• ACQ, Asthma Control Questionnaire; MID = 0.5.
• ACT, Asthma Control Test; MID not determined.
FEV1 , Forced expiratory volume in 1 sec; FVC, forced vital capacity; EIB, exercise-induced
at home can be helpful in the assessment of asthmatic children with poor
symptom perception, moderate to severe asthma, or a history of severe asthma
exacerbations. PEF monitoring is feasible in children as young as 4 yr who are
able to master this skill. Use of a stoplight zone system tailored to each child's
“personal best” PEF values can optimize effectiveness and interest (see Fig.
169.4 ): The green zone (80–100% of personal best) indicates good control; the
yellow zone (50–80%) indicates less-than-optimal control and necessitates
increased awareness and treatment; and the red zone (<50%) indicates poor
control and greater likelihood of an exacerbation, requiring immediate
intervention. In actuality, these ranges are approximate and may need to be
adjusted for many asthmatic children by raising the ranges that indicate
inadequate control (e.g., yellow zone, 70–90% in children with poor perception
and those with lung hyperinflation). Once-daily PEF monitoring is preferable in
the morning when peak flows are typically lower. Adherence to PEF monitoring
is difficult, results may be variable and PEF monitoring alone is not more
effective than symptoms monitoring on influencing asthma outcomes. Therefore,
although PEF may be helpful in some circumstances to monitor those who are
poor perceivers of airway obstruction, PEF monitoring is no longer generally
recommended.

Component 2: Patient Education

Specific educational elements in the clinical care of children with asthma are
believed to make an important difference in home management and in adherence
of families to an optimal plan of care, eventually impacting patient outcomes
(Table 169.9 ). Every visit presents an important opportunity to educate the child
and family, allowing them to become knowledgeable partners in asthma
management, because optimal management depends on their daily assessments
and implementation of any management plan. Effective communications take
into account sociocultural and ethnic factors of children and their families,
provide an open forum for concerns about asthma and its treatment to be raised
and addressed, and include patients and families as active participants in the
development of treatment goals and selection of medications. Self-management
skills should be reevaluated regularly (e.g., inhaler medication technique).
Table 169.9
Key Elements of Productive Clinic Visits for
Asthma

Standardize assessment of asthma control (e.g., Asthma Control Test,

exacerbations in past 12 mo)
Specify goals of asthma management
Explain basic facts about asthma:
• Contrast normal vs asthmatic airways.
• Link airways inflammation, “twitchiness,” and
bronchoconstriction.
• Long-term-control and quick-relief medications
• Address concerns about potential adverse effects of asthma
pharmacotherapy.
Teach, demonstrate, and have patient show proper technique for:
• Inhaled medication use (spacer use with metered-dose inhaler)
Investigate and manage factors that contribute to asthma severity:
• Environmental exposures
• Comorbid conditions
Create written 2-part Asthma Action Plan (see Fig. 169.7 ):
• Daily management
• Action plan for asthma exacerbations
Regular follow-up visits:
• Twice yearly (more often if asthma not well controlled)
• Monitor lung function at least annually

During initial patient visits, a basic understanding of the pathogenesis of

asthma (chronic inflammation and AHR underlying a clinically intermittent
presentation) can help children with asthma and their parents understand the
importance of recommendations aimed at reducing airways inflammation to
achieve and maintain good asthma control. It is helpful to specify the
expectations of good asthma control resulting from optimal asthma management
(see Fig. 169.6 ). Addressing concerns about potential adverse effects of asthma
pharmacotherapeutic agents, especially their risks relative to their benefits, is
essential in achieving long-term adherence with asthma pharmacotherapy and
environmental control measures.
All children with asthma should benefit from a written Asthma Action Plan
(Fig. 169.7 ). This plan has two main components: (1) a daily “routine”
 FIG. 169.7 Asthma action plan for home use. This plan has two main components: (1) a
daily management plan to keep asthma in good control; and (2) an action plan to
recognize and manage worsening asthma. (From US Department of Health and Human
Services, National Institutes of Health, National Heart, Lung, and Blood Institute, NIH
Pub No 07-5251, April 2007. https://www.nhlbi.nih.gov/health/resources/lung/asthma-
action-plan ).

Regular follow-up visits are recommended to help to maintain optimal asthma

control. In addition to determining disease control level, revising PEF values
daily and exacerbation management plans accordingly, follow-up visits are
important teaching opportunities to encourage open communication of concerns
with asthma management recommendations (e.g., daily administration of
controller medications). Reassessing patients’ and parents’ understanding of the
role of different medications in asthma management and control, and their
technique in using inhaled medications, can be insightful and can help guide
teaching to improve adherence to a management plan that might not have been
adequately or properly implemented.

Adherence
Asthma is a chronic condition that is usually best managed with daily controller
medication. However, symptoms wax and wane, severe exacerbations are
infrequent, and when asthma is asymptomatic, a natural tendency is to reduce or
discontinue daily controller therapies. As such, adherence to a daily controller
regimen is frequently suboptimal; ICSs are underused 60% of the time. In one
study, children with asthma who required an oral corticosteroid course for an
asthma exacerbation had used their daily controller ICS 15% of the time.
Misconceptions about controller medication time to onset, efficacy, and safety
often underlie poor adherence and can be addressed by asking about such
concerns at each visit.

Component 3: Control of Factors Contributing to

Asthma Severity
Controllable factors that can worsen asthma can be generally grouped as (1)
environmental exposures and (2) comorbid conditions (Table 169.10 ).
Table 169.10
Control of Factors Contributing to Asthma
Severity
Eliminate or Reduce Problematic Environmental Exposures

Environmental tobacco smoke elimination or reduction in home and

automobiles
Allergen exposure elimination or reduction in sensitized asthmatic patients:
• Animal danders: pets (cats, dogs, rodents, birds)
• Pests (mice, rats)
• Dust mites
• Cockroaches
• Molds
Other airway irritants:
• Wood- or coal-burning smoke
• Strong chemical odors and perfumes (e.g., household cleaners)
• Dusts

Treat Comorbid Conditions

• Rhinitis
• Sinusitis
• Gastroesophageal reflux

Eliminating and Reducing Problematic Environmental

Exposures
Most children with asthma have an allergic component to their disease; steps
should be taken to investigate and minimize allergen exposures in sensitized
asthmatic patients. The medical history should identify exposure to smoke,
pollutant, and potential allergen triggers (see later), especially in the patient's
home. Since often patients have chronic symptoms and cannot identify potential
triggers, allergy testing should be considered for at least those with persistent
asthma. For asthmatic patients who are allergic to allergens in their homes and/or
schools or daycare centers, reducing or eliminating these indoor allergen
exposures can reduce asthma symptoms, medication requirements, AHR, severe
exacerbations, and disease persistence. Common home, school, and daycare
Children with severe persistent asthma are at Treatment Steps 5 and 6 . The
goals of therapy are to achieve a well-controlled state by reducing the
components of both impairment (e.g., preventing or minimizing symptoms,
infrequently needing quick-reliever medications, maintaining “normal” lung
function and normal activity levels) and risk (e.g., preventing recurrent
exacerbations, reduced lung growth, and medication adverse effects). The
recommendations for initial therapy are based on assessment of asthma severity,
while level of control determines any modifications of treatment in children who
are already using controller therapy. A major objective of this approach is to
identify and treat all “persistent” and inadequately controlled asthma with
antiinflammatory controller medication. Management of Treatment Step 1
(intermittent asthma) is simply the use of a SABA as needed for symptoms and
for pretreatment in those with exercise-induced bronchospasm (see Table 169.11
).

Table 169.11
Stepwise Approach for Managing Asthma in Children*

THERAPY INTERMITTENT
AGE PERSISTENT ASTHMA: DAILY MEDICATION
† ASTHMA

Step 1 Step 2 Step 3 Step 4 Step 5 Step 6

0-4 Preferred SABA prn Low-dose Medium-dose Medium- High-dose
yr ICS ICS dose ICS + ICS + either
either LABA
LABA or
or LTRA
LTRA

Alternative Cromolyn
or
montelukast
5-11 Preferred SABA prn Low-dose Either low- Medium-dose High-dose ICS +
yr ICS dose ICS ± ICS + LABA LABA
LABA,
LTRA, or
theophylline
or
 Medium-
dose ICS
Alternative Cromolyn, Medium- High-dose
LTRA, dose ICS + ICS + either
nedocromil, either LTRA
or LTRA or
theophylline or Theophylline
Theophylline

≥12 Preferred SABA prn Low-dose Low-dose Medium-dose High-dose

yr ICS ICS + ICS + LABA ICS +
LABA LABA
or and
Medium- Consider
dose ICS omalizumab
for patients
with
allergies

Alternative Cromolyn, Low-dose ICS + Medium-dose

LTRA, LTRA, ICS + LTRA,
nedocromil, theophylline, or theophylline, or
or zileuton zileuton
theophylline
Each step: Patient education, environmental control, and management of comorbidities.
Age ≥5 yr: Steps 2-4: Consider subcutaneous allergen immunotherapy for patients who have allergic asthma.
QUICK-RELIEF MEDICATION FOR ALL PATIENTS
SABA as needed for symptoms. Intensity of treatment depends on severity of symptoms: up to 3 treatments at 20-min
intervals as needed. Short course of oral systemic corticosteroids may be needed.
Caution: Use of SABA >2 days/wk for symptom relief (not prevention of exercise-induced bronchospasm) generally
indicates inadequate control and the need to step up treatment.
For ages 0-4 yr: With viral respiratory infection: SABA q4-6h up to 24 hr (longer with physician consult). Consider
short course of systemic corticosteroids if exacerbation is severe or patient has history of previous severe
exacerbations.
* Notes:

† Alphabetical order is used when more than 1 treatment option is listed within either preferred or
alternative therapy.
• The stepwise approach is meant to assist, not replace, the clinical decision making required to
meet individual patient needs.
• If alternative treatment is used and response is inadequate, discontinue it and use the preferred
treatment before stepping up.
• If clear benefit is not observed within 4-6 wk and patient/family medication technique and
adherence are satisfactory, consider adjusting therapy or alternative diagnosis.
• Studies on children age 0-4 yr are limited.
• Clinicians who administer immunotherapy or omalizumab should be prepared and equipped to
identify and treat anaphylaxis that may occur.
Long-Term Controller Medications
All levels of persistent asthma should be treated with ICS therapy to reduce
airway inflammation and improve long-term control (see Table 169.11 ). Other
long-term controller medications include LABAs, leukotriene modifiers,
cromolyn, sustained-release theophylline, and tiotropium in adolescents.
Omalizumab (Xolair) and mepolizumab (Nucala) are approved by the U.S. Food
and Drug Administration (FDA) for use as an add-on therapy in children ≥6 yr
and ≥12 yr who have severe allergic asthma or eosinophilic asthma, respectively,
that remains difficult to control. Corticosteroids are the most potent and most
effective medications used to treat both the acute (administered systemically)
and the chronic (administered by inhalation) manifestations of asthma. They are
available in inhaled, oral, and parenteral forms (Tables 169.12 and 169.13 ).

Table 169.12
Usual Dosages for Long-Term Control Medications

AGE
MEDICATION
0-4 yr 5-11 yr ≥12 yr
INHALED CORTICOSTEROIDS (see Table 169.13 )
Methylprednisolone: 0.25-2 mg/kg 0.25-2 mg/kg daily in 7.5-60 mg daily in a
2, 4, 8, 16, 32 mg daily in single single dose in AM or qod single dose in AM or
tablets dose in AM or as needed for control qod as needed for
Prednisolone: qod as needed Short-course “burst”: 1-2 control
5 mg tablets; 5 mg/5 for control mg/kg/day; maximum 60 Short-course “burst” to
mL, 15 mg/5 mL Short-course mg/day for 3-10 days achieve control: 40-60
Prednisone: “burst”: 1-2 mg/day as single or 2
1, 2.5, 5, 10, 20, 50 mg mg/kg/day; divided doses for 3-10
tablets; 5 mg/mL, 5 maximum 30 days
mg/5 mL mg/day for 3-10
days
Fluticasone/salmeterol N/A
(Advair):
DPI: 100, 250, or 500 µg/50 1 inhalation bid; dose depends 1 inhalation bid; dose
µg on level of severity or control depends on level of severity
(the 100/50 dosage is indicated or control
in children ≥4 yr)
HFA: 45 µg/21 µg, 115 2 inhalations bid; dose
µg/21 µg, 230 µg/21 µg depends on level of severity
or control
Budesonide/formoterol N/A 2 inhalations bid; dose
(Symbicort): depends on level of severity
HFA: 80 µg/4.5 µg, 160 or control
µg/4.5 µg
Mometasone/formoterol 2 inhalations bid; dose
(Dulera): depends on level of severity
 HFA: 100 µg/5 µg, 200 or control
µg/5 µg
Leukotriene receptor
antagonists:
Montelukast 4 mg qhs (1-5 yr of 5 mg qhs (6-14 yr) 10 mg qhs (indicated in
(Singulair): age) children ≥15 yr)
4 or 5 mg chewable
tablet
4 mg granule packets
10 mg tablet
Zafirlukast (Accolate): N/A 10 mg bid (7-11 yr) 40 mg daily (20 mg tablet
10 or 20 mg tablet bid)
5-Lipoxygenase N/A N/A 1,200 mg bid (give 2 tablets
inhibitor: bid)
(Zileuton CR): 600 mg
tablet
Immunomodulators:
Omalizumab (anti-IgE; N/A N/A 150-375 mg SC q 2-4 wk,
Xolair): depending on body weight
SC injection, 150 and pretreatment serum IgE
mg/1.2 mL after level
reconstitution with 1.4
mL sterile water for
injection
Mepolizumab (anti–IL- N/A N/A 100 mg SC q 4 wk
5; Nucala):
SC injection, 100 mg
after reconstitution with
1.2 mL sterile water for
injection
bid, 2 times daily; DPI, dry powder inhaler; HFA, hydrofluoroalkane; MDI, metered-dose inhaler; q,
every; qhs, every night; qid, 4 times daily; qod, every other day; SC, subcutaneous(ly).

Table 169.13
Estimated Comparative Inhaled Corticosteroid Doses

LOW DAILY MEDIUM DAILY HIGH DAILY

GLUCOCORTICOID DOSE DOSE DOSE
Beclomethasone (Qvar) 80-160 µg 160-320 µg >320 µg
MDI: 40 or 80 µg
(Approved for children ≥5 yr)
Budesonide (Pulmicort Flexhaler) 200 µg 200-400 µg >400 µg
DPI: 90, 180 µg
(Approved for children ≥6 yr)
Budesonide suspension for nebulization 0.5 mg 1.0 mg 2.0 mg
(Generic and Pulmicort Respules)
0.25 mg, 0.5 mg, 1 mg
(Approved for children 1-8 yr)
Ciclesonide (Alvesco) 80 µg 80-160 µg 160 µg
MDI: 80, 160 µg
 (Approved for children ≥12 yr)
Flunisolide (Aerospan) 80 µg 80-160 µg 160 µg
MDI: 80 µg/puff
(Approved for children ≥6 yr)

Fluticasone propionate (Flovent, Flovent 88-176 µg 176-440 µg >440 µg

Diskus) 100-200 µg 200-500 µg >500 µg
MDI: 44, 110, 220 µg
DPI: 50, 100, 250 µg
(44 and 50 µg approved for children ≥4 yr)
Fluticasone furoate (Arnuity Ellipta) 100 µg 100-200 µg 200 µg
DPI: 100, 200 µg
(Approved for children ≥12 yr)
Mometasone Furoate (Asmanex, Asmanex 110 µg 110 µg 110 µg
Twisthaler) 100 µg 100 µg 100 µg
MDI: 100, 200 µg
DPI: 110, 220 µg
(Approved for children ≥4 yr)
DPI, Dry powder inhaler; MDI, metered-dose inhaler.
Adapted from National Asthma Education and Prevention Program Expert Panel Report 3
(EPR3): Guidelines for the diagnosis and management of asthma—summary report 2007, J
Allergy Clin Immunol 120(Suppl):S94–S138, 2007.

Inhaled Corticosteroids
ICS therapy improves lung function; reduces asthma symptoms, AHR, and use
of “rescue” medications; improves quality of life; and most importantly reduces
the need for prednisone, urgent care visits, and hospitalizations by approximately
50%. Epidemiologic studies have also shown that ICS therapy substantially
lowers the risk of death attributable to asthma if used regularly. Because ICS
therapy can achieve all the goals of asthma management, it is viewed as first-line
treatment for persistent asthma.
Seven ICSs are FDA approved for use in children. The NIH and GINA
guidelines provide equivalence classifications (see Table 169.13 ), although
direct comparisons of efficacy and safety outcomes are lacking. ICSs are
available in metered-dose inhalers (MDIs) using hydrofluoroalkane (HFA) as
their propellant, in dry powder inhalers (DPIs), or in suspension for nebulization.
Fluticasone propionate, fluticasone furoate, mometasone furoate, ciclesonide,
and to a lesser extent budesonide are considered “second-generation” ICSs, in
that they have greater antiinflammatory potency and less systemic bioavailability
(and thus potential for systemic adverse effects) because of their extensive first-
pass hepatic metabolism. The selection of the initial ICS dose is based on the
determination of disease severity.
Even though ICSs can be very effective, there has been some reluctance to
treat children with ICSs due to parental and occasionally physician concerns
regarding their potential for adverse effects with chronic use. The adverse effects
that occur with long-term systemic corticosteroid therapy have not been seen or
have only rarely been reported in children receiving ICSs in recommended
doses. The risk of adverse effects from ICS therapy is related to the dose and
frequency of administration (Table 169.14 ). High doses (≥1,000 µg/day in
children) and frequent administration (4 times/day) are more likely to have both
local and systemic adverse effects. Children who receive maintenance therapy
with higher ICS doses are also likely to require frequent systemic corticosteroid
courses for asthma exacerbations, further increasing their risk of corticosteroid
adverse effects.

Table 169.14

Risk Assessment for Corticosteroid Adverse Effects

CONDITIONS RECOMMENDATIONS
Low (≤1 risk factor* ) Monitor blood pressure and weight with each physician visit.
risk Low- to medium-dose Measure height annually (stadiometry); monitor periodically for
ICS (see Table 169.13 ) declining growth rate and pubertal developmental delay.
Encourage regular physical exercise.
Ensure adequate dietary calcium and vitamin D with additional
supplements for daily calcium if needed.
Avoid smoking and alcohol.
Ensure TSH status if patient has history of thyroid abnormality.
Medium (If >1 risk factor,* As above, plus :
risk consider evaluating as Yearly ophthalmologic evaluations to monitor for cataracts or
high risk) glaucoma
High-dose ICS (see Table Baseline bone densitometry (DEXA scan)
169.13 ) Consider patient at increased risk for adrenal insufficiency,
At least 4 courses of especially with physiologic stressors (e.g., surgery, accident,
OCS/yr significant illness).
High Chronic systemic As above, plus :
risk corticosteroids (>7.5 mg DEXA scan: if DEXA z score ≤1.0, recommend close monitoring
daily or equivalent for >1 (every 12 mo)
mo) Consider referral to a bone or endocrine specialist.
≥7 OCS burst Bone age assessment
treatments/year Complete blood count
Very-high-dose ICS (e.g., Serum calcium, phosphorus, and alkaline phosphatase
fluticasone propionate determinations
≥800 µg/day) Urine calcium and creatinine measurements
Measurements of testosterone in males, estradiol in amenorrheic
premenopausal women, vitamin D (25-OH and 1,25-OH vitamin
D), parathyroid hormone, and osteocalcin
Urine telopeptides for those receiving long-term systemic or
frequent OCS treatment
Assume adrenal insufficiency for physiologic stressors (e.g.,
surgery, accident, significant illness).
Mepolizumab, an anti–IL-5 antibody that blocks IL-5-mediated
eosinophilopoiesis, reduces severe asthma exacerbations and lowers sputum and
blood eosinophils while allowing for a significant reduction in OCS dose in
adults with severe exacerbation-prone eosinophilic asthma. It is administered
subcutaneously every 4 wk and is FDA approved for severe eosinophilic
asthmatic children ≥12 yr old. Reslizumab , another anti–IL-5 antibody
therapeutic, is administered intravenously and is FDA approved for severe
asthmatics ≥18 yr old (i.e., not currently approved for use in children).

Dupilumab (Anti–IL-4 Receptor α Antibody).

Dupilumab, an anti–IL-4 receptor antibody that inhibits both IL-4 and IL-13
production (both cytokines share the same IL-4 receptor) and atopic immune
responses, reduces exacerbations and symptoms and improves lung function in
moderate to severe asthmatic patients with persistent eosinophilia. Although not
yet FDA approved, studies are ongoing in both children and adults.

Quick-Reliever Medications
Quick-reliever or “rescue” medications (SABAs, inhaled anticholinergics, and
short-course systemic corticosteroids) are used in the management of acute
asthma symptoms (Table 169.15 ).

Table 169.15
Management of Asthma Exacerbation (Status Asthmaticus)
RISK ASSESSMENT ON ADMISSION
Focused history Onset of current exacerbation
Frequency and severity of daytime and nighttime symptoms and activity limitation
Frequency of rescue bronchodilator use
Current medications and allergies
Potential triggers
History of systemic steroid courses, emergency department visits, hospitalization,
intubation, or life-threatening episodes
Clinical assessment Physical examination findings: vital signs, breathlessness, air movement, use of
accessory muscles, retractions, anxiety level, alteration in mental status
Pulse oximetry
Lung function (defer in patients with moderate to severe distress or history of labile
disease)
Risk factors for asthma See Table 169.16 .
morbidity and death
TREATMENT
Drug and Trade Name Mechanisms of Action and Dosing Cautions and Adverse Effects
Oxygen (mask or nasal Treats hypoxia Monitor pulse oximetry to
cannula) maintain O2 saturation >92%
Cardiorespiratory monitoring
Inhaled short-acting β- Bronchodilator During exacerbations, frequent
agonists: or continuous doses can cause
pulmonary vasodilation, V̇/Q̇
mismatch, and hypoxemia.
Adverse effects: palpitations,
tachycardia, arrhythmias,
tremor, hypoxemia
Albuterol nebulizer Nebulizer: 0.15 mg/kg (minimum 2.5 mg) as Nebulizer: when giving concentrated
solution (5 mg/mL often as every 20 min for 3 doses as needed, then forms, dilute with saline to 3 mL
concentrate; 2.5 mg/3 0.15-0.3 mg/kg up to 10 mg every 1-4 hr as total nebulized volume.
mL, 1.25 mg/3 mL, 0.63 needed, or up to 0.5 mg/kg/hr by continuous
mg/3 mL) nebulization
Albuterol MDI (90 2-8 puffs up to every 20 min for 3 doses as For MDI: use spacer/holding
µg/puff) needed, then every 1-4 hr as needed chamber
Levalbuterol (Xopenex) 0.075 mg/kg (minimum 1.25 mg) every 20 min Levalbuterol 0.63 mg is equivalent
nebulizer solution (1.25 for 3 doses, then 0.075-0.15 mg/kg up to 5 mg to 1.25 mg of standard albuterol for
mg/0.5 mL concentrate; every 1-4 hr as needed, or 0.25 mg/kg/hr by both efficacy and side effects.
0.31 mg/3 mL, 0.63 continuous nebulization
mg/3 mL, 1.25 mg/3
mL)
Systemic Antiinflammatory If patient has been exposed to
corticosteroids: chickenpox or measles,
consider passive
immunoglobulin prophylaxis;
also, risk of complications with
herpes simplex and
tuberculosis.
For daily dosing, 8 AM
administration minimizes
adrenal suppression.
Children may benefit from
dosage tapering if course
exceeds 7 days.
Adverse effects monitoring:
frequent therapy bursts risk
numerous corticosteroid
adverse effects (see Chapter 595
); see Table 169.14 for adverse
effects screening
recommendations.
Prednisone: 1, 2.5, 0.5-1 mg/kg every 6-12 hr for 48 hr, then 1-2
5, 10, 20, 50 mg mg/kg/day bid (maximum 60 mg/day)
tablets
Methylprednisolone
(Medrol): 2, 4, 8,
16, 24, 32 mg
tablets
Prednisolone: 5 mg
tablets; 5 mg/5 mL
and 15 mg/5 mL
solution
Depo-Medrol (IM); Short-course “burst” for exacerbation: 1-2
Solu-Medrol (IV) mg/kg/day qd or bid for 3-7 days
Dexamethasone See text See text
Anticholinergics: Mucolytic/bronchodilator Should not be used as first-line
therapy; added to β2 -agonist
therapy
Ipratropium:
Atrovent (nebulizer Nebulizer: 0.5 mg q6-8h (tid-qid) as needed
solution 0.5 mg/2.5 mL; MDI: 2 puffs qid
MDI 18 µg/inhalation)
Ipratropium with
albuterol:
DuoNeb nebulizer 1 vial by nebulizer qid Nebulizer: may mix ipratropium
solution (0.5 mg with albuterol
ipratropium + 2.5 mg
albuterol/3 mL vial)
Injectable Bronchodilator For extreme circumstances (e.g.,
sympathomimetic impending respiratory failure despite
epinephrine: high-dose inhaled SABA,
respiratory failure)
Adrenalin 1 mg/mL SC or IM: 0.01 mg/kg (max dose 0.5 mg); may
(1 : 1000) repeat after 15-30 min
EpiPen
autoinjection device
(0.3 mg; EpiPen Jr
0.15 mg)
Terbutaline: Terbutaline is β-agonist–
selective relative to
epinephrine.
Monitoring with continuous
infusion: cardiorespiratory
monitor, pulse oximetry, blood
pressure, serum potassium
Adverse effects: tremor,
tachycardia, palpitations,
arrhythmia, hypertension,
headaches, nervousness, nausea,
vomiting, hypoxemia
Brethine 1 mg/mL Continuous IV infusion (terbutaline only): 2-
10 µg/kg loading dose, followed by 0.1-0.4
µg/kg/min
Titrate in 0.1-0.2 µg/kg/min increments
every 30 min, depending on clinical
response.
RISK ASSESSMENT FOR DISCHARGE
Medical stability Discharge home if there has been sustained
improvement in symptoms and bronchodilator
treatments are at least 3 hr apart, physical
findings are normal, PEF >70% of predicted or
personal best, and oxygen saturation >92% when
breathing room air.
Home supervision Capability to administer intervention and to
observe and respond appropriately to clinical
deterioration
Asthma education See Table 169.8 .
 (Courtesy of BJC Healthcare/Washington University School of Medicine,
Community Asthma Program, January 2000.)

Table 169.16
Risk Factors for Asthma Morbidity and
Mortality
Biologic

Previous severe asthma exacerbation (intensive care unit admission,

intubation for asthma)
Sudden asphyxia episodes (respiratory failure, arrest)
Two or more hospitalizations for asthma in past year
Three or more emergency department visits for asthma in past year
Increasing and large diurnal variation in peak flows
Use of >2 canisters of short-acting β-agonists per month
Poor response to systemic corticosteroid therapy
Male gender
Low birthweight
Nonwhite (especially black) ethnicity
Sensitivity to Alternaria

Environmental

Allergen exposure
Environmental tobacco smoke exposure
Air pollution exposure
Urban environment

Economic and Psychosocial

Poverty
Crowding
Mother <20 yr old
Mother with less than high school education
Inadequate medical care:
 Inaccessible
Unaffordable
No regular medical care (only emergency)
Lack of written Asthma Action Plan
No care sought for chronic asthma symptoms
Delay in care of asthma exacerbations
Inadequate hospital care for asthma exacerbation
Psychopathology in the parent or child
Poor perception of asthma symptoms or severity
Alcohol or substance abuse

Asthma exacerbations characteristically vary among individuals but tend to be

similar in the same patient. Severe asthma exacerbations, resulting in respiratory
distress, hypoxia, hospitalization, and respiratory failure, are the best predictors
of future life-threatening exacerbations or a fatal asthma episode. In addition to
distinguishing such high-risk children, some experience exacerbations that
develop over days, with airflow obstruction resulting from progressive
inflammation, epithelial sloughing, and cast impaction of small airways. When
such a process is extreme, respiratory failure as a result of fatigue can ensue,
necessitating mechanical ventilation for numerous days. In contrast, some
children experience abrupt-onset exacerbations that may result from extreme
AHR and physiologic susceptibility to airways closure. Such exacerbations,
when extreme, are asphyxial in nature, often occur outside medical settings, are
initially associated with very high arterial partial pressure of carbon dioxide (PCO
2 ) levels, and tend to require only brief periods of supportive ventilation.
Recognizing the characteristic differences in asthma exacerbations is important
for optimizing their early management.

Home Management of Asthma Exacerbations

Families of all children with asthma should have a written Asthma Action Plan
(see Fig. 169.7 ) to guide their recognition and management of exacerbations,
along with the necessary medications and tools to manage them. Early
recognition of asthma exacerbations in order to intensify treatment early can
often prevent further worsening and keep exacerbations from becoming severe.
A written home action plan can reduce the risk of asthma death by 70%. The
NIH guidelines recommend immediate treatment with “rescue” medication
Laboratory Findings
There are no specific laboratory tests to diagnose AD. Many patients have
peripheral blood eosinophilia and increased serum IgE levels. Serum IgE
measurement or skin-prick testing can identify the allergens (foods,
inhalant/microbial allergens) to which patients are sensitized. The diagnosis of
clinical allergy to these allergens requires confirmation by history and
environmental challenges.

Diagnosis and Differential Diagnosis

AD is diagnosed on the basis of 3 major features: pruritus, an eczematous
dermatitis that fits into a typical pattern of skin inflammation, and a chronic or
chronically relapsing course (Table 170.1 ). Associated features, such as a family
history of asthma, hay fever, elevated IgE, and immediate skin test reactivity,
reinforce the diagnosis of AD.
Table 170.1
Clinical Features of Atopic Dermatitis
Major Features

Pruritus
Facial and extensor eczema in infants and children
Flexural eczema in adolescents
Chronic or relapsing dermatitis
Personal or family history of atopic disease

Associated Features

Xerosis
Cutaneous infections (Staphylococcus aureus, group A streptococcus,
herpes simplex, coxsackievirus, vaccinia, molluscum, warts)
Nonspecific dermatitis of the hands or feet
Ichthyosis, palmar hyperlinearity, keratosis pilaris
Nipple eczema
 White dermatographism and delayed blanch response
Anterior subcapsular cataracts, keratoconus
Elevated serum IgE levels
Positive results of immediate-type allergy skin tests
Early age at onset
Dennie lines (Dennie-Morgan infraorbital folds)
Facial erythema or pallor
Course influenced by environmental and/or emotional factors

Many inflammatory skin diseases, immunodeficiencies, skin malignancies,

genetic disorders, infectious diseases, and infestations share symptoms with AD
and should be considered and excluded before a diagnosis of AD is established
(Tables 170.2 and 170.3 ). Severe combined immunodeficiency (see Chapter
152.1 ) should be considered for infants presenting in the first yr of life with
diarrhea, failure to thrive, generalized scaling rash, and recurrent cutaneous
and/or systemic infection. Histiocytosis should be excluded in any infant with
AD and failure to thrive (see Chapter 534 ). Wiskott-Aldrich syndrome, an X-
linked recessive disorder associated with thrombocytopenia, immune defects,
and recurrent severe bacterial infections, is characterized by a rash almost
indistinguishable from that in AD (see Chapter 152.2 ). One of the hyper-IgE
syndromes is characterized by markedly elevated serum IgE values, recurrent
deep-seated bacterial infections, chronic dermatitis, and refractory
dermatophytosis. Many of these patients have disease as a result of autosomal
dominant STAT3 mutations. In contrast, some patients with hyper-IgE syndrome
present with increased susceptibility to viral infections and an autosomal
recessive pattern of disease inheritance. These patients may have a DOCK8
(dedicator of cytokinesis 8 gene) mutation. This diagnosis should be considered
in young children with severe eczema, food allergy, and disseminated skin viral
infections.

Table 170.2
Differential Diagnosis of Atopic Dermatitis (AD)

MAIN AGE
GROUP FREQUENCY* CHARACTERISTICS AND CLINICAL FEATURES
AFFECTED
OTHER TYPES OF DERMATITIS
Seborrheic Infants Common Salmon-red greasy scaly lesions, often on the scalp (cradle
dermatitis cap) and napkin area; generally presents in the 1st 6 wk of
life; typically clears within weeks
Seborrheic Adults Common Erythematous patches with yellow, white, or grayish scales
dermatitis in seborrheic areas, particularly the scalp, central face, and
anterior chest
Nummular Children and Common Coin-shaped scaly patches, mostly on legs and buttocks;
dermatitis adults usually no itch
Irritant contact Children and Common Acute to chronic eczematous lesions, mostly confined to the
dermatitis adults site of exposure; history of locally applied irritants is a risk
factor; might coexist with AD
Allergic contact Children and Common Eczematous rash with maximum expression at sites of direct
dermatitis adults exposure but might spread; history of locally applied
irritants is a risk factor; might coexist with AD
Lichen simplex Adults Uncommon One or more localized, circumscribed, lichenified plaques
chronicus that result from repetitive scratching or rubbing because of
intense itch
Asteatotic eczema Adults Common Scaly, fissured patches of dermatitis overlying dry skin,
most often on lower legs
INFECTIOUS SKIN DISEASES
Dermatophyte Children and Common One or more demarcated scaly plaques with central clearing
infection adults and slightly raised reddened edge; variable itch
Impetigo Children Common Demarcated erythematous patches with blisters or honey-
yellow crusting
Scabies Children Common † Itchy superficial burrows and pustules on palms and soles,
between fingers, and on genitalia; might produce secondary
eczematous changes
HIV Children and Uncommon Seborrhea-like rash
adults
CONGENITAL IMMUNODEFICIENCIES (see Table 170.3 )
Keratinization Disorders
Ichthyosis Infants and Uncommon Dry skin with fine scaling, particularly on the lower
vulgaris adults abdomen and extensor areas; perifollicular skin roughening;
palmar hyperlinearity; full form (i.e., 2 FLG mutations) is
uncommon; often coexists with AD
NUTRITIONAL DEFICIENCY–METABOLIC DISORDERS
Zinc deficiency Children Uncommon Erythematous scaly patches and plaques, most often around
(acrodermatitis the mouth and anus; rare congenital form accompanied by
enteropathica) diarrhea and alopecia
Biotin deficiency Infants Uncommon Scaly periorofacial dermatitis, alopecia, conjunctivitis,
(nutritional or lethargy, hypotonia
biotinidase
deficiency)
Pellagra (niacin All ages Uncommon Scaly crusted epidermis, desquamation, sun-exposed areas,
deficiency) diarrhea
Kwashiorkor Infants and Geographic Flaky scaly dermatitis, swollen limbs with cracked peeling
children dependent patches
Phenylketonuria Infants Uncommon Eczematous rash, hypopigmentation, blonde hair,
developmental delay
NEOPLASTIC DISEASE
Cutaneous T-cell Adults Uncommon Erythematous pink-brown macules and plaques with a fine
lymphoma scale; poorly responsive to topical corticosteroids; variable
itch (in early stages)
Langerhans cell Infants Uncommon Scaly and purpuric dermatosis, hepatosplenomegaly,
histiocytosis cytopenias
* Common = approximately 1 in 10 to 1 in 100; uncommon = 1 in 100 to 1 in 1000; rare = 1 in

1000 to 1 in 10,000; very rare = <1 in 10,000.

† Especially in developing countries.

FLG, filaggrin gene.

Table 170.3
Features of Primary Immunodeficiencies Associated With
Eczematous Dermatitis

DISEASE GENE INHERITANCE CLINICAL FEATURES LAB ABNORMALITIES

AD-HIES STAT3 AD, less Cold abscesses High IgE (>2000 IU/µL)
commonly Recurrent sinopulmonary Eosinophilia
sporadic infections
Mucocutaneous candidiasis
Coarse facies
Minimal trauma fractures
Scoliosis
Joint hyperextensibility
Retained primary teeth
Coronary artery tortuosity or
dilation
Lymphoma
DOCK8 DOCK8 AR Severe mucocutaneous viral High IgE
deficiency infections Eosinophilia
Mucocutaneous candidiasis With or without decreased
Atopic features (asthma, IgM
allergies)
Squamous cell carcinoma
Lymphoma
PGM3 PGM3 AR Neurologic abnormalities High IgE
deficiency Leukocytoclastic vasculitis Eosinophilia
Atopic features (asthma,
allergies)
Sinopulmonary infections
Mucocutaneous viral
infections
WAS WASP XLR Hepatosplenomegaly Thrombocytopenia
Lymphadenopathy (<80,000/µL)
Atopic diathesis Low mean platelet volume
Autoimmune conditions Eosinophilia is common
(especially hemolytic anemia) Lymphopenia
Lymphoreticular malignancies Low IgM, variable IgG
SCID Variable, XLR and AR Recurrent, severe infections Lymphopenia common
depends most common Failure to thrive Variable patterns of reduced
on type Persistent diarrhea lymphocyte subsets (T, B,
Recalcitrant oral candidiasis natural killer cells)
Omenn syndrome: Omenn syndrome: high
lymphadenopathy, lymphocytes, eosinophilia,
hepatosplenomegaly, high IgE
 erythroderma
IPEX FOXP3 XLR Severe diarrhea (autoimmune High IgE
enteropathy) Eosinophilia
Various autoimmune Various autoantibodies
endocrinopathies (especially
diabetes mellitus, thyroiditis)
Food allergies
Netherton SPINK5 AR Hair shaft abnormalities High IgE
syndrome Erythroderma Eosinophilia
Ichthyosis linearis circumflexa
Food allergies
Recurrent gastroenteritis
Neonatal hypernatremic
dehydration
Upper and lower respiratory
infections
AD, Autosomal dominant; AD-HIES, autosomal-dominant hyper-IgE syndrome; AR, autosomal
recessive; DOCK8 , dedicator of cytokinesis 8 gene; IPEX, immune dysregulation,
polyendocrinopathy, enteropathy, X-linked syndrome; PGM3, phosphoglucomutase 3; SCID,
severe combined immunodeficiency; WAS, Wiskott-Aldrich syndrome.
From Kliegman RM, Bordini BJ, editors: Undiagnosed and Rare Diseases in Children 64(1):41–
42, 2017.

Adolescents who present with an eczematous dermatitis but no history of

childhood eczema, respiratory allergy, or atopic family history may have allergic
contact dermatitis (see Chapter 674.1 ). A contact allergen may be the problem
in any patient whose AD does not respond to appropriate therapy. Sensitizing
chemicals, such as parabens and lanolin, can be irritants for patients with AD
and are commonly found as vehicles in therapeutic topical agents. Topical
glucocorticoid contact allergy has been reported in patients with chronic
dermatitis receiving topical corticosteroid therapy. Eczematous dermatitis has
also been reported with HIV infection as well as with a variety of infestations
such as scabies. Other conditions that can be confused with AD include
psoriasis, ichthyosis, and seborrheic dermatitis.

Treatment
The treatment of AD requires a systematic, multifaceted approach that
incorporates skin moisturization, topical antiinflammatory therapy, identification
and elimination of flare factors (Table 170.4 ), and, if necessary, systemic
therapy. Assessment of the severity also helps direct therapy (Table 170.5 ).
Table 170.4
Counseling and Aggravating Factors for
Patients With Atopic Dermatitis (AD)
Maintain cool temperature in bedroom, and avoid too many bed covers.
Increase emollient use with cold weather.
Avoid exposure to herpes sores; urgent visit if flare of unusual aspect.
Clothing: Avoid skin contact with irritating fibers (wool, large-fiber
textiles).
Do not use tight and too-warm clothing, to avoid excessive
sweating.
New, nonirritating clothing designed for AD children is being
evaluated.
Tobacco: Avoid exposure.
Vaccines: Normal schedule in noninvolved skin, including egg-allergic
patients (see text).
Sun exposure: No specific restriction.
Usually helpful because of improvement of epidermal barrier.
Encourage summer holidays in altitude or at beach resorts.
Physical exercise, sports: no restriction.
If sweating induces flares of AD, progressive adaptation to
exercise.
Shower and emollients after swimming pool.
Food allergens:
Maintain breastfeeding exclusively to 4-6 mo if possible.
Consider evaluation for early introduction of allergens (see
Chapter 176 ).
Otherwise normal diet, unless an allergy workup has proved the
need to exclude a specific food.
Indoor aeroallergens: House dust mites
Use adequate ventilation of housing; keep the rooms well aerated
even in winter.
Avoid wall-to-wall carpeting.
Remove dust with a wet sponge.
Vacuum floors and upholstery with an adequately filtered cleaner
once a week.
Avoid soft toys in bed (cradle), except washable ones.
 Wash bedsheets at a temperature higher than 55°C (131°F) every
10 days.
Use bed and pillow encasings made of Gore-Tex or similar
material.
Furred pets: Advise to avoid. If allergy is demonstrated, be firm on
avoidance measures, such as pet removal.
Pollen: Close windows during peak pollen season on warm and dry
weather days, and restrict, if possible, time outdoors.
Windows may be open at night and early in the morning or during
rainy weather.
Avoid exposure to risk situations (lawn mowing).
Use pollen filters in motor vehicles.
Clothes and pets can vectorize aeroallergens, including pollen.

Adapted from Darsow U, Wollenberg A, Simon D, et al: ETFAD/EADV Eczema

Task Force 2009 position paper on diagnosis and treatment of atopic dermatitis,
J Eur Acad Dermatol Venereol 24:321, 2010.
Table 170.5
Categorization of Physical Severity of Atopic
Eczema

Clear —Normal skin, with no evidence of atopic eczema

Mild —Areas of dry skin, infrequent itching (with or without small areas of
redness)
Moderate —Areas of dry skin, frequent itching, redness (with or without
excoriation and localized skin thickening)
Severe —Widespread areas of dry skin, incessant itching, redness (with or
without excoriation, extensive skin thickening, bleeding, oozing,
cracking, and alteration of pigmentation)

From Lewis-Jones S, Mugglestone MA; Guideline Development Group:

Management of atopic eczema in children aged up to 12 years: summary of
NICE guidance, BMJ 335:1263–1264, 2007.

Cutaneous Hydration
ointments have a greater potential to occlude the epidermis, resulting in
enhanced systemic absorption.
Table 170.6
Selected Topical Corticosteroid Preparations*
Group 1

Clobetasol propionate (Temovate) 0.05% ointment/cream

Betamethasone dipropionate (Diprolene) 0.05% ointment/lotion/gel
Fluocinonide (Vanos) 0.1% cream

Group 2

Mometasone furoate (Elocon) 0.1% ointment

Halcinonide (Halog) 0.1% cream
Fluocinonide (Lidex) 0.05% ointment/cream
Desoximetasone (Topicort) 0.25% ointment/cream
Betamethasone dipropionate (Diprolene) 0.05% cream

Group 3

Fluticasone propionate (Cutivate) 0.005% ointment

Halcinonide (Halog) 0.1% ointment
Betamethasone valerate (Valisone) 0.1% ointment

Group 4

Mometasone furoate (Elocon) 0.1% cream

Triamcinolone acetonide (Kenalog) 0.1% ointment/cream
Fluocinolone acetonide (Synalar) 0.025% ointment

Group 5

Fluocinolone acetonide (Synalar) 0.025% cream

 Hydrocortisone valerate (Westcort) 0.2% ointment

Group 6

Desonide (DesOwen) 05% ointment/cream/lotion

Alclometasone dipropionate (Aclovate) 0.05% ointment/cream

Group 7

Hydrocortisone (Hytone) 2.5%, 1%, 0.5% ointment/cream/lotion

* Representative corticosteroids are listed by group from 1 (superpotent) through

7 (least potent).

Adapted from Stoughton RB: Vasoconstrictor assay-specific applications. In

Malbach HI, Surber C, editors: Topical corticosteroids, Basel, Switzerland,
1992, Karger, pp 42–53.

Adverse effects of topical glucocorticoids can be divided into local adverse

effects and systemic adverse effects, the latter resulting from suppression of the
hypothalamic-pituitary-adrenal axis. Local adverse effects include the
development of striae and skin atrophy. Systemic adverse effects are related to
the potency of the topical corticosteroid, site of application, occlusiveness of the
preparation, percentage of the body surface area covered, and length of use. The
potential for adrenal suppression from potent topical corticosteroids is greatest in
infants and young children with severe AD requiring intensive therapy.

Topical Calcineurin Inhibitors

The nonsteroidal topical calcineurin inhibitors are effective in reducing AD skin
inflammation. Pimecrolimus cream 1% (Elidel) is indicated for mild to moderate
AD. Tacrolimus ointment 0.1% and 0.03% (Protopic) is indicated for moderate
to severe AD. Both are approved for short-term or intermittent long-term
treatment of AD in patients ≥2 yr whose disease is unresponsive to or who are
intolerant of other conventional therapies or for whom these therapies are
candidates for VIT. The risk of a systemic reaction for those who experienced a
large, local reaction is approximately 7%; testing or VIT is usually not
recommended, and prescription of self-injectable epinephrine is considered
optional but usually not necessary. There is growing evidence that VIT can
reduce the size and duration of large, local reactions, and therefore VIT may be
considered for those with frequent or unavoidable large, local reactions. Those
who experience severe systemic reactions, such as airway involvement or
hypotension, and who have specific IgE to venom allergens should receive
immunotherapy. Immunotherapy against winged Hymenoptera is generally not
required when stings have caused only generalized urticaria or angioedema,
because the risk for a systemic reaction after a subsequent sting is approximately
10% and the chance of a more severe reaction is <3%. VIT may be considered if
there are potential high-risk cofactors such as comorbid cardiovascular disease
or use of specific cardiovascular medications (e.g., ACE inhibitors, β-blockers),
elevated basal tryptase level, or high likelihood of future stings. VIT is usually
not indicated if there is no evidence of IgE to venom.

Table 171.1
Indications for Venom Immunotherapy (VIT) Against
Winged Hymenoptera

SKIN TEST/IN RISK OF SYSTEMIC REACTION IF VIT

SYMPTOMS
VITRO TEST UNTREATED* RECOMMENDED
Large local reaction Usually not indicated ~7% Usually not
indicated
Generalized cutaneous Usually not indicated 10% Usually not
reaction indicated
Systemic reaction Positive result Child: 40% Yes
Adult: 30–60%
Negative result — Usually not
indicated
* Risks generally decrease after 10 yr.

The incidence of adverse effects in the course of treatment is not trivial in

adults; 50% experience large, local reactions, and about 10% experience
systemic reactions. The incidence of both local and systemic reactions is much
lower in children. Patients treated with honeybee venom are at higher risk for
systemic reactions to VIT than those receiving treatment with vespid venom.
Individuals with mast cell disorders are at increased risk for severe anaphylaxis
and more frequent systemic reactions with VIT; thus some experts recommend
Treatment
Primary treatment of ocular allergies includes avoidance of allergens, cold
compresses, and lubrication. Secondary treatment regimens include the use of
oral or topical antihistamines and, if necessary, topical decongestants, mast cell
stabilizers, and antiinflammatory agents (Table 172.1 ). Drugs with dual
antihistamine and mast cell–blocking activities provide the most advantageous
approach in treating allergic conjunctivitis, with both fast-acting symptomatic
relief and disease-modifying action. Children often complain of stinging or
burning with use of topical ophthalmic preparations and usually prefer oral
antihistamines for allergic conjunctivitis. It is important not to contaminate
topical ocular medications by allowing the applicator tip to contact the eye or
eyelid. Using refrigerated medications may decrease some of the discomfort
associated with their use. Topical decongestants act as vasoconstrictors, reducing
erythema, vascular congestion, and eyelid edema, but do not diminish the
allergic response. Adverse effects of topical vasoconstrictors include burning or
stinging and rebound hyperemia or conjunctivitis medicamentosa with chronic
use. Combined use of an antihistamine and a vasoconstrictor is more effective
than use of either agent alone. Use of topical nasal corticosteroids for allergic
rhinoconjunctivitis decreases ocular symptoms, presumably through a
nasoocular reflex.

Table 172.1
Topical Ophthalmic Medications for Allergic Conjunctivitis
DRUG AND MECHANISM OF ACTION
CAUTIONS AND ADVERSE EVENTS
TRADE NAMES AND DOSING
Azelastine Antihistamine Not for treatment of contact lens–related irritation; the
hydrochloride Children ≥3 yr: 1 gtt bid preservative may be absorbed by soft contact lenses.
0.05% Wait at least 10 min after administration before
Optivar inserting soft contact lenses.
Emedastine Antihistamine Soft contact lenses should not be worn if the eye is
difumarate Children ≥3 yr: 1 gtt qid red. Wait at least 10 min after administration before
0.05% inserting soft contact lenses.
Emadine
Levocabastine Antihistamine Not for use in patients wearing soft contact lenses
hydrochloride Children ≥12 yr: 1 gtt bid-qid during treatment.
0.05% up to 2 wk
Livostin
Pheniramine maleate Antihistamine/vasoconstrictor Avoid prolonged use (>3-4 days) to avoid rebound
symptoms. Not for use with contact lenses.
0.3% Naphazoline Children >6 yr: 1-2 gtt qid
hydrochloride
0.025%
Naphcon-A, Opcon-
A
Cromolyn Mast cell stabilizer Can be used to treat giant papillary conjunctivitis and
sodium 4% Children >4 yr: 1-2 gtt q4-6h vernal keratitis. Not for use with contact lenses.
Crolom,
Opticrom
Lodoxamide Mast cell stabilizer Can be used to treat vernal keratoconjunctivitis. Not
tromethamine Children ≥2 yr: 1-2 gtt qid up for use in patients wearing soft contact lenses during
0.1% to 3 mo treatment.
Alomide
Nedocromil sodium Mast cell stabilizer Avoid wearing contact lenses while exhibiting the
2% Alocril Children ≥3 yr: 1-2 gtt bid signs and symptoms of allergic conjunctivitis.
Pemirolast Mast cell stabilizer Not for treatment of contact lens–related irritation; the
potassium 0.1% Children >3 yr: 1-2 gtt qid preservative may be absorbed by soft contact lenses.
Alamast Wait at least 10 min after administration before
inserting soft contact lenses.
Epinastine Antihistamine/mast cell Contact lenses should be removed before use. Wait at
hydrochloride stabilizer least 15 min after administration before inserting soft
0.05% Children ≥3 yr: 1 gtt bid contact lenses. Not for the treatment of contact lens
Elestat irritation.
Ketotifen Antihistamine/mast cell Not for treatment of contact lens–related irritation; the
fumarate 0.025% stabilizer preservative may be absorbed by soft contact lenses.
Zaditor Children ≥3 yr: 1 gtt bid q8- Wait at least 10 min after administration before
12h inserting soft contact lenses.
Olopatadine Antihistamine/mast cell Not for treatment of contact lens–related irritation; the
hydrochloride stabilizer preservative may be absorbed by soft contact lenses.
0.1%, 0.2%, Children ≥3 yr: 1 gtt bid (8 hr Wait at least 10 min after administration before
0.7% apart) inserting soft contact lenses.
Patanol Children≥2 yr: 1 gtt qd
Pataday
Pazeo
Alcaftadine, Antihistamine/mast cell Contact lenses should be removed before application;
0.25% stabilizer may be inserted after 10 min. Not for the treatment of
Lastacaft Children > 2 yr: 1 gtt bid q8- contact lens irritation.
12h
Bepotastine Antihistamine/mast cell Contact lenses should be removed before application,
besilate 1.5% stabilizer may be inserted after 10 min. Not for the treatment of
Bepreve Children >2 yr: 1 gtt bid q8- contact lens irritation.
12h
Ketorolac NSAID Avoid with aspirin or NSAID sensitivity. Use ocular
tromethamine Children ≥3 yr: 1 gtt qid product with caution in patients with complicated
0.5% ocular surgeries, corneal denervation or epithelial
Acular defects, ocular surface diseases (e.g., dry eye
syndrome), repeated ocular surgeries within a short
period, diabetes mellitus, or rheumatoid arthritis; these
patients may be at risk for corneal adverse events that
may be sight threatening. Do not use while wearing
contact lenses.
Fluorometholone Fluorinated corticosteroid If improvement does not occur after 2 days, patient
0.1%, 0.25% Children ≥2 yr, 1 gtt into should be reevaluated. Patient should remove soft
suspension conjunctival sac of affected contact lenses before administering (contains
(0.1%, 0.25%) eye(s) bid-qid. During initial benzalkonium chloride) and delay reinsertion of lenses
and ointment 24-48 hr, dosage may be for ≥15 min after administration. Close monitoring for
 (0.1%) increased to 1 gtt q4h. development of glaucoma and cataracts.
FML, FML Ointment (~1.3 cm in length)
Forte, Flarex into conjunctival sac of
affected eye(s) 1-3 times
daily. May be applied q4h
during initial 24-48 hr of
therapy.

NSAID, Nonsteroidal antiinflammatory drug; bid, 2 times daily; gtt, drops; qid, 4 times daily; q4-6h;
every 4-6 hr; qd, every day.

Tertiary treatment of ocular allergy includes topical (or rarely oral)

corticosteroids and should be conducted in conjunction with an ophthalmologist.
Local administration of topical corticosteroids may be associated with increased
intraocular pressure, viral infections, and cataract formation. Other
immunomodulatory medications, such as topical tacrolimus or topical
cyclosporine, are used as steroid-sparing agents by ophthalmologists. Allergen
immunotherapy can be very effective in seasonal and perennial allergic
conjunctivitis, especially when associated with rhinitis, and can decrease the
need for oral or topical medications to control allergy symptoms.
Because vernal and atopic keratoconjunctivitis can be associated with visual
morbidity, if these diagnoses are suspected, the patient should be referred to an
ophthalmologist. Symptoms that should prompt referral to an ophthalmologist
include unilateral red eye with pain, photophobia, change in vision, refractory
dry eyes, or corneal abnormality.

Bibliography
Bielory BP, Shah SP, O'Brien TP, et al. Emerging therapeutics
for ocular surface disease. Curr Opin Allergy Clin Immunol .
2016;16(5):477–486.
Castillo M, Scott NW, Mustafa MZ, et al. Topical
antihistamines and mast cell stabilisers for treating seasonal
and perennial allergic conjunctivitis. Cochrane Database Syst
Rev . 2015;(6) [CD009566].
Chen JJ, Applebaum DS, Sun GS, et al. Atopic
keratoconjunctivitis: a review. J Am Acad Dermatol .
2014;70(3):569–575.
Esposito S, Fior G, Mori A, et al. An update on the therapeutic
CHAPTER 173

Urticaria (Hives) and Angioedema

Amy P. Stallings, Stephen C. Dreskin, Michael M. Frank, Scott H. Sicherer

Urticaria and angioedema affect 20% of individuals at some point in their life.
Episodes of hives that last for <6 wk are considered acute, whereas those that
occur on most days of the week for >6 wk are designated chronic. The
distinction is important, because the causes and mechanisms of urticaria
formation and the therapeutic approaches are different in each instance.

Etiology and Pathogenesis

Acute urticaria and angioedema are often caused by an allergic IgE–mediated
reaction (Table 173.1 ). This form of urticaria is a self-limited process that
occurs when an allergen activates mast cells in the skin. Common causes of
acute generalized urticaria include foods, drugs (particularly antibiotics), and
stinging-insect venoms. If an allergen (latex, animal dander) penetrates the skin
locally, hives often can develop at the site of exposure. Acute urticaria can also
result from non–IgE-mediated stimulation of mast cells, caused by radiocontrast
agents, viral agents (including hepatitis B and Epstein-Barr virus), opiates, and
nonsteroidal antiinflammatory drugs (NSAIDs). The diagnosis of chronic
urticaria is established when lesions occur on most days of the week for >6 wk
and are not physical urticaria or recurrent acute urticaria with repeated exposures
to a specific agent (Tables 173.2 and 173.3 ). In about half the cases, chronic
urticaria is accompanied by angioedema. Rarely, angioedema occurs without
urticaria. Angioedema without urticaria is often a result of allergy, but recurrent
angioedema suggests other diagnoses.

Table 173.1

Etiology of Acute Urticaria

Etiology of Acute Urticaria
Foods Egg, milk, wheat, peanuts, tree nuts, soy, shellfish, fish, (direct mast cell degranulation)
Medications Suspect all medications, even nonprescription or homeopathic
Insect stings Hymenoptera (honeybee, yellow jacket, hornets, wasp, fire ants), biting insects (papular urticaria)
Infections Bacterial (streptococcal pharyngitis, Mycoplasma , sinusitis); viral (hepatitis, mononucleosis
[Epstein-Barr virus], coxsackieviruses A and B); Parasitic (Ascaris, Ancylostoma, Echinococcus,
Fasciola, Filaria, Schistosoma, Strongyloides, Toxocara, Trichinella); Fungal (dermatophytes,
Candida )
Contact Latex, pollen, animal saliva, nettle plants, caterpillars
allergy
Transfusion Blood, blood products, or IV immune globulin administration
reactions
From Lasley MV, Kennedy MS, Altman LC: Urticaria and angioedema. In Altman LC, Becker JW,
Williams PV, editors: Allergy in primary care , Philadelphia, 2000, Saunders, p 232.

Table 173.2
Etiology of Chronic Urticaria
Idiopathic/autoimmune Approximately 30% of chronic urticaria cases are physical urticaria, and 60–70% are
idiopathic. Of the idiopathic cases approximately 35–40% have anti-IgE or anti-
FcεRI (high-affinity IgE receptor α chain) autoantibodies (autoimmune chronic
urticaria)
Physical Dermatographism
Cholinergic urticaria
Cold urticaria (see Table 173.5 )
Delayed pressure urticaria
Solar urticaria
Vibratory urticaria
Aquagenic urticaria
Autoimmune diseases Systemic lupus erythematosus
Juvenile idiopathic arthritis
Thyroid disease (Graves, Hashimoto)
Celiac disease
Inflammatory bowel disease
Leukocytoclastic vasculitis
Autoinflammatory/periodic See Tables 173.3 and 173.5 .
fever syndromes
Neoplastic Lymphoma
Mastocytosis
Leukemia
Angioedema Hereditary angioedema (autosomal dominant inherited deficiency of C1-esterase
inhibitor)
Acquired angioedema
Angiotensin-converting enzyme inhibitors
From Lasley MV, Kennedy MS, Altman LC: Urticaria and angioedema. In Altman LC, Becker JW,
Williams PV, editors: Allergy in primary care , Philadelphia, 2000, Saunders, p 234.
Table 173.3
Febrile Autoinflammatory Diseases Causing Urticaria in
Children

TIMING
GENE ATTACK CUTANEOUS EXTRACUTANEOUS
DISEASE INHERITANCE OF
(PROTEIN) LENGTH FEATURES CLINICAL FEATURES
ONSET
FCAS NLRP3 AD Brief; Neonatal Cold-induced Arthralgia
(cryopyrin) minutes to or urticaria Conjunctivitis
3 days infantile Headache
Muckle- NLRP3 AD 1-3 days Neonatal, Widespread urticaria Arthralgia/arthritis
Wells (cryopyrin) infantile, Sensorineural hearing
syndrome childhood loss
(can be Conjunctivitis/episcleritis
later) Headache
Amyloidosis
Chronic NLRP3 AD Continuous Neonatal Widespread urticaria Deforming
infantile (cryopyrin) flares or osteoarthropathy,
neurologic infantile epiphyseal overgrowth
cutaneous Sensorineural hearing
articular loss
syndrome; Dysmorphic facies
neonatal- Chronic aseptic
onset meningitis, headaches,
multisystem papilledema, seizures
inflammatory Conjunctivitis/uveitis,
disease optic atrophy
Growth retardation
Developmental delay
Amyloidosis
HIDS MVK AR 3-7 days Infancy Intermittent Arthralgia/arthritis
(mevalonate (<2 yr) morbilliform or Cervical
kinase) urticarial rash lymphadenopathy
Aphthous Severe abdominal pain
mucosal ulcers Diarrhea/vomiting
Erythema Headache
nodosum Elevated IgD and IgA
antibody levels
Elevated urine mevalonic
acid during attacks
Tumor TNFRSF1A AD >7 days Childhood Intermittent Migratory myalgia
necrosis (TNFR1) migratory Conjunctivitis
factor erythematous Serositis
receptor– macules and Amyloidosis
associated edematous
periodic plaques
syndrome overlying areas
of myalgia, often
on limbs
Periorbital
edema
Systemic- Polygenic Varies Daily Peak Nonfixed Polyarthritis
 onset (quotidian) onset at 1- erythematous Myalgia
juvenile 6 yr rash; may be Hepatosplenomegaly
idiopathic urticarial Lymphadenopathy
arthritis With or without Serositis
(SoJIA) dermatographism
With or without
periorbital edema
PLAID PLCG2 AD N/A Infancy Urticaria induced Allergies
by evaporative Autoimmune disease
cooling Recurrent sinopulmonary
Ulcers in cold- infections
exposed areas Elevated IgE antibody
levels
Decreased IgA and IgM
antibody levels
Often elevated
antinuclear antibody
titers
AD, Autosomal dominant; AR, autosomal recessive; HIDS, hyperimmunoglobulinemia D
syndrome; FCAS, familial cold-induced autoinflammatory syndrome; N/A, not available; PLAID,
PLCγ2-associated antibody deficiency and immune dysregulation.
From Youseff MJ, Chiu YE: Eczema and urticaria as manifestations of undiagnosed and rare
diseases, Pediatr Clin North Am 64:39–56, 2017 (Table 2, pp 49–50).

A typical hive is an erythematous, pruritic, raised wheal that blanches with

pressure, is transient, and resolves without residual lesions, unless the area was
intensely scratched. In contrast, urticaria associated with serum sickness
reactions, systemic lupus erythematosus (SLE), or other vasculitides in which a
skin biopsy reveals a small-vessel vasculitis, often have distinguishing clinical
features. Lesions that burn more than itch, last >24 hr, do not blanch, blister, heal
with scarring, or that are associated with bleeding into the skin (purpura) suggest
urticarial vasculitis. Atypical aspects of the gross appearance of the hives or
associated symptoms should heighten concern that the urticaria or angioedema
may be the manifestation of a systemic disease process (Table 173.4 ).

Table 173.4

Distinguishing Features Between Urticaria and Systemic Urticarial Syndromes

COMMON URTICARIA URTICARIAL SYNDROMES (≥1 of following)
Only typical wheals: Atypical “wheals”:
Erythematous edematous lesions Infiltrated plaques
Transient (<24-36 hr) Persistent (>24-36 hr)
Asymmetric distribution Symmetric distribution
Resolution without signs Resolution with signs (hypo/hyperpigmentation, bruising, or
No associated different elementary scarring)
lesions (papules, vesicles, purpura, Associated different elementary lesions (papules, vesicles, purpura,
crustae) scaling, crustae)
 Pruritic (rarely stinging/burning) Not pruritic; rather painful or burning
Possibly associated with Usually no associated angioedema
angioedema Often associated with systemic symptoms (fever, malaise, arthralgia,
No associated systemic symptoms abdominal pain, weight loss, acral circulatory abnormalities,
neurologic signs
From Peroni A, Colato C, Zanoni G, Girolomoni G: Urticarial lesions: if not urticaria, what else?
The differential diagnosis of urticaria, J Am Acad Dermatol 62(4):559, 2009.

Physical Urticaria
Physically induced urticaria and angioedema share the common property of
being induced by an environmental stimulus, such as a change in temperature or
direct stimulation of the skin with pressure, stroking, vibration, or light (see
Table 173.2 ).

Cold-Dependent Disorders
Cold urticaria is characterized by the development of localized pruritus,
erythema, and urticaria/angioedema after exposure to a cold stimulus. Total body
exposure, as seen with swimming in cold water, can cause massive release of
vasoactive mediators, resulting in hypotension, loss of consciousness, and even
death if not promptly treated. The diagnosis is confirmed by challenge testing for
an isomorphic cold reaction by holding an ice cube in place on the patient's skin
for 5 min. In patients with cold urticaria, an urticarial lesion develops about 10
min after removal of the ice cube and on rewarming of the chilled skin. Cold
urticaria can be associated with the presence of cryoproteins such as cold
agglutinins, cryoglobulins, cryofibrinogen, and the Donath-Landsteiner antibody
seen in secondary syphilis (paroxysmal cold hemoglobinuria). In patients with
cryoglobulins the isolated proteins appear to transfer cold sensitivity and activate
the complement cascade on in vitro incubation with normal plasma. The term
idiopathic cold urticaria generally applies to patients without abnormal
circulating plasma proteins such as cryoglobulins. Cold urticaria has also been
reported after viral infections. Cold urticaria must be distinguished from the
familial cold autoinflammatory syndrome (see later, Diagnosis) (Table 173.5 ;
see also Table 173.3 and Chapter 188 ).

Table 173.5
Hereditary Diseases With Cold-Induced Urticaria
 EPISODIC SYMPTOMS SUSTAINED/PROGRESSIVE SYMPTOMS
CAPS FCAS Urticarial rash, arthralgia, myalgia, chills, Renal amyloidosis
fever, swelling of extremities
MWS Urticarial rash, arthralgia, chills, fever Sensorineural deafness, renal amyloidosis
CINCA Fever Rash, arthritis, chronic meningitis, visual defect,
deafness, growth retardation, renal amyloidosis
NAPS12 Fever, arthralgia, myalgia, urticaria, Sensorineural deafness
(FCAS2) abdominal pain, aphthous ulcers,
lymphadenopathy
PLAID Urticaria induced by evaporative cooling, Serum low IgM and IgA levels; high IgE levels;
(FCAS3) sinopulmonary infections decreased B and NK cells; granulomata; antinuclear
antibodies
CAPS, Cryopyrin-associated periodic syndromes; FCAS, familial cold-induced autoinflammatory
syndrome; MWS, Muckle-Wells syndrome; CINCA, chronic infantile neurologic cutaneous articular
syndrome; NAPS, NLRP-12–associated periodic syndrome; PLAID, PLCG2-associated antibody
deficiency and immune dysregulation.
From Kanazawa N: Hereditary disorders presenting with urticaria, Immunol Allergy Clin NORTH
Am 34:169–179, 2014 (Table 4, p 176).

Cholinergic Urticaria
Cholinergic urticaria is characterized by the onset of small, punctate pruritic
wheals surrounded by a prominent erythematous flare and associated with
exercise, hot showers, and sweating. Once the patient cools down, the rash
usually subsides in 30-60 min. Occasionally, symptoms of more generalized
cholinergic stimulation, such as lacrimation, wheezing, salivation, and syncope,
are observed. These symptoms are mediated by cholinergic nerve fibers that
innervate the musculature via parasympathetic neurons and innervate the sweat
glands by cholinergic fibers that travel with the sympathetic nerves. Elevated
plasma histamine values parallel the onset of urticaria triggered by changes in
body temperature.

Dermatographism
The ability to write on skin, dermatographism (also called dermographism or
urticaria factitia ) may occur as an isolated disorder or may accompany chronic
urticaria or other physical urticaria. It can be diagnosed by observing the skin
after stroking it with a tongue depressor. In patients with dermatographism, a
linear response occurs secondary to reflex vasoconstriction, followed by
pruritus, erythema, and a linear flare caused by secondary dilation of the vessel
and extravasation of plasma.
complexes, malignancies, mixed connective tissue diseases, and cutaneous
blistering disorders (e.g., bullous pemphigoid; see Table 173.2 ). In general,
laboratory testing should be limited to a complete blood cell count with
differential, ESR determination, urinalysis, thyroid autoantibody testing, and
liver function tests. Further studies are warranted if the patient has fever,
arthralgias, or elevated ESR (Table 173.6 ; see also Table 173.4 ). Testing for
antibodies directed at the high-affinity IgE receptor may be warranted in patients
with intractable urticaria. Hereditary angioedema is potentially life threatening,
usually associated with deficient C1 inhibitor activity, and the most important
familial form of angioedema (see Chapter 160.3 ), but it is not associated with
typical urticaria. In patients with eosinophilia, stools should be obtained for ova
and parasite testing, because infection with helminthic parasites has been
associated with urticaria. A syndrome of episodic angioedema/urticaria and fever
with associated eosinophilia has been described in both adults and children. In
contrast to other hypereosinophilic syndromes, this entity has a benign course.

Table 173.6

Diagnostic Testing for Urticaria and Angioedema

DIAGNOSIS DIAGNOSTIC TESTING
Food and drug reactions Elimination of offending agent, skin testing, and challenge with suspected foods
Autoimmune urticaria Autologous serum skin test; antithyroid antibodies; antibodies against the high-
affinity IgE receptor
Thyroiditis Thyroid-stimulating hormone; antithyroid antibodies
Infections Appropriate cultures or serology
Collagen vascular diseases and Skin biopsy, CH50 , C1q, C4, C3, factor B, immunofluorescence of tissues,
cutaneous vasculitis antinuclear antibodies, cryoglobulins
Malignancy with angioedema CH50 , C1q, C4, C1-INH determinations
Cold urticaria Ice cube test usually positive but may be negative in some familial
autoinflammatory disorders
Solar urticaria Exposure to defined wavelengths of light, red blood cell protoporphyrin, fecal
protoporphyrin, and coproporphyrin
Dermatographism Stroking with narrow object (e.g., tongue blade, fingernail)
Pressure urticaria Application of pressure for defined time and intensity
Vibratory urticaria Vibration for 4 min
Aquagenic urticaria Challenge with tap water at various temperatures
Urticaria pigmentosa Skin biopsy, test for dermatographism
Hereditary angioedema C4, C2, CH50 , C1-INH testing by protein and function
Familial cold urticaria Challenge by cold exposure, measurement of temperature, white blood cell
count, erythrocyte sedimentation rate, skin biopsy
C3b inactivator deficiency C3, factor B, C3b inactivator determinations
Chronic idiopathic urticaria Skin biopsy, immunofluorescence (negative result), autologous skin test

Skin biopsy for diagnosis of possible urticarial vasculitis is recommended

symptoms such as conjunctivitis, sweating, headache, and nausea. Patient
longevity is usually normal.

Treatment
Acute urticaria is a self-limited illness requiring little treatment other than
antihistamines and avoidance of any identified trigger. Hydroxyzine and
diphenhydramine are sedating but are effective and frequently used for treatment
of urticaria. Loratadine, fexofenadine, and cetirizine are also effective and are
preferable because of reduced frequency of drowsiness and longer duration of
action (Table 173.7 ). Epinephrine 1 : 1,000, 0.01 mL/kg (maximum 0.3 mL)
intramuscularly, usually provides rapid relief of acute, severe
urticaria/angioedema but is seldom required. A short course of oral
corticosteroids should be given only for severe episodes of urticaria and
angioedema that are unresponsive to antihistamines.

Table 173.7
Treatment of Urticaria and Angioedema

CLASS/DRUG DOSE FREQUENCY

ANTIHISTAMINES, TYPE H1 (SECOND GENERATION)
Fexofenadine 6-11 yr: 30 mg Twice daily
>12 yr: 60 mg
Adult: 180 mg Once daily
Loratadine 2-5 yr: 5 mg Once daily
>6 yr: 10 mg
Desloratadine 6-11 mo: 1 mg Once daily
12 mo-5 yr: 1.25 mg
6-11 yr: 2.5 mg
>12 yr: 5 mg
Cetirizine 6-23 mo: 2.5 mg Once daily
2-6 yr: 2.5-5 mg
>6 yr: 5-10 mg
Levocetirizine 6 mo-5 yr: 1.25 mg Once daily
6-11 yr: 2.5 mg Once daily
>12 yr: 5 mg Once daily
ANTIHISTAMINES, TYPE H2
Cimetidine Infants: 10-20 mg/kg/day Divided q6-12h
Children: 20-40 mg/kg/day
Ranitidine 1 mo-16 yr: 5-10 mg/kg/day Divided q12h
Famotidine 3-12 mo: 1 mg/kg/day Divided q12h
1-16 yr: 1-2 mg/kg/day
LEUKOTRIENE PATHWAY MODIFIERS
 Montelukast 12 mo-5 yr: 4 mg Once daily
6-14 yr: 5 mg
>14 yr: 10 mg
Zafirlukast 5-11 yr: 10 mg Twice daily
IMMUNOMODULATORY DRUGS
Omalizumab (anti IgE) >11 yr: 150 mg or 300 mg Every 28 days
Cyclosporine 3-4 mg/kg/day Divided q12h*
Sulfasalazine >6 yr: 30 mg/kg/day Divided q6h †
Intravenous immune globulin (IVIG) 400 mg/kg/day 5 consecutive days
* Monitor blood pressure and serum creatinine, potassium, and magnesium levels monthly.

† Monitor complete blood count and liver function tests at baseline, every 2 wk for 3 mo, and then

every 1-3 mo.

The best treatment of physical urticaria is avoidance of the stimulus.

Antihistamines are also helpful. Cyproheptadine in divided doses is the drug of
choice for cold-induced urticaria. Treatment of dermatographism consists of
local skin care and antihistamines; for severe symptoms, high doses may be
needed. The initial objective of therapy is to decrease pruritus so that the
stimulation for scratching is diminished. A combination of antihistamines,
sunscreens, and avoidance of sunlight is helpful for most patients.
Chronic urticaria only rarely responds favorably to dietary manipulation. The
mainstay of therapy is the use of nonsedating or low-sedating H1 antihistamines.
In those patients not showing response to standard doses, pushing the H1
blockade with higher than the usual recommended doses of these agents is a
common next approach. The 3-drug combination of H1 and H2 antihistamine
with a leukotriene receptor antagonist (montelukast) is helpful for many patients.
If hives persist after maximal H1 - and/or H2 -receptor blockade has been
achieved, a brief course of oral corticosteroids may be considered, but long-term
steroid use is best avoided. The monoclonal antibody omalizumab (anti-IgE) is
FDA approved for the treatment of chronic urticaria in children 12 years and
older. Other agents that have been used for chronic urticaria but are not approved
by the U.S. Food and Drug Administration (FDA) for this condition include
cyclosporine, hydroxychloroquine, sulfasalazine, colchicine, dapsone,
mycophenolate, intravenous immune globulin (IVIG), and plasmapheresis.

Hereditary Angioedema
Hereditary angioedema (HAE , types 1 and 2) is an inherited autosomal
dominant disease caused by low functional levels of the plasma protein C1
CHAPTER 174

Anaphylaxis
Hugh A. Sampson, Julie Wang, Scott H. Sicherer

Anaphylaxis is defined as a serious allergic reaction that is rapid in onset and

may cause death. Anaphylaxis in children, particularly infants, is
underdiagnosed. Anaphylaxis occurs when there is a sudden release of potent,
biologically active mediators from mast cells and basophils, leading to cutaneous
(urticaria, angioedema, flushing), respiratory (bronchospasm, laryngeal edema),
cardiovascular (hypotension, dysrhythmias, myocardial ischemia), and
gastrointestinal (nausea, colicky abdominal pain, vomiting, diarrhea) symptoms
(Table 174.1 and Fig. 174.1 ).

Table 174.1
Symptoms and Signs of Anaphylaxis in Infants

ANAPHYLAXIS
SYMPTOMS ANAPHYLAXIS SIGNS THAT MAY BE DIFFICULT
ANAPHYLAXIS SIGNS IN
THAT INFANTS TO INTERPRET/UNHELPFUL IN INFANTS, AND
INFANTS
CANNOT WHY
DESCRIBE
GENERAL
Feeling of Nonspecific behavioral changes such as persistent crying,
warmth, fussing, irritability, fright, suddenly becoming quiet
weakness,
anxiety,
apprehension,
impending doom
SKIN/MUCOUS MEMBRANES
Itching of lips, Flushing (may also occur with fever, hyperthermia, or Rapid onset of hives (potentially
tongue, palate, crying spells) difficult to discern in infants with
uvula, ears, throat, acute atopic dermatitis; scratching
nose, eyes, etc.; and excoriations will be absent in
mouth-tingling or young infants); angioedema (face,
metallic taste tongue, oropharynx)
RESPIRATORY SYSTEM
 Nasal congestion, Hoarseness, dysphonia (common after a crying spell); Rapid onset of coughing,
throat tightness; drooling or increased secretions (common in infants) choking, stridor, wheezing,
chest tightness; dyspnea, apnea, cyanosis
shortness of
breath
GASTROINTESTINAL SYSTEM
Dysphagia, Spitting up/regurgitation (common after feeds), loose Sudden, profuse vomiting
nausea, stools (normal in infants, especially if breastfed); colicky
abdominal abdominal pain
pain/cramping
CARDIOVASCULAR SYSTEM
Feeling faint, Hypotension (need appropriate-size blood pressure cuff; Weak pulse, arrhythmia,
presyncope, low systolic blood pressure for children is defined as <70 diaphoresis/sweating,
dizziness, mm Hg from 1 mo to 1 yr, and less than (70 mm Hg + [2 collapse/unconsciousness
confusion, blurred × age in yr]) from 1-10 yr; tachycardia, defined as >140
vision, difficulty beats/min from 3 mo to 2 yr, inclusive; loss of bowel and
in hearing bladder control (ubiquitous in infants)
CENTRAL NERVOUS SYSTEM
Headache Drowsiness, somnolence (common in infants after feeds) Rapid onset of unresponsiveness,
lethargy, or hypotonia; seizures
Adapted from Simons FER: Anaphylaxis in infants: can recognition and management be
improved? J Allergy Clin Immunol 120:537–540, 2007.
products. Patients with latex allergy may also experience food-allergic reactions
from homologous proteins in foods such as bananas, kiwi, avocado, chestnut,
and passion fruit. Anaphylaxis to galactose-α-1,3-galactose has been reported 3-
6 hr after eating red meat.
Table 174.2
Anaphylaxis Triggers in the Community*
Allergen Triggers (IgE-Dependent Immunologic Mechanism)*

Foods (e.g., peanut, tree nuts, shellfish, fish, milk, egg, wheat, soy, sesame,
meat [galactose-α-1,3-galactose])
Food additives (e.g., spices, colorants, vegetable gums, contaminants)
Stinging insects: Hymenoptera species (e.g., bees, yellow jackets, wasps,
hornets, fire ants)
Medications (e.g., β-lactam antibiotics, ibuprofen)
Biologic agents (e.g., monoclonal antibodies [infliximab, omalizumab] and
allergens [challenge tests, specific immunotherapy])
Natural rubber latex
Vaccines
Inhalants (rare) (e.g., horse or hamster dander, grass pollen)
Previously unrecognized allergens (foods, venoms, biting insect saliva,
medications, biologic agents)

Other Immune Mechanisms (IgE Independent)

IgG mediated (infliximab, high-molecular-weight dextrans)

Immune aggregates (IVIG)
Drugs (aspirin, NSAID, opiates, contrast material, ethylene oxide/dialysis
tubing)
Complement activation
Physical factors (e.g., exercise, † cold, heat, sunlight/ultraviolet radiation)
Ethanol
Idiopathic*

IVIG, Intravenous immune globulin; NSAID, nonsteroidal antiinflammatory

drug.
* In the pediatric population, some anaphylaxis triggers, such as hormones

(progesterone), seminal fluid, and occupational allergens, are uncommon, as is

idiopathic anaphylaxis.
† Exercise with or without a co-trigger, such as a food or medication, cold air, or

cold water.

Adapted from Leung DYM, Sampson HA, Geha RS, et al: Pediatric allergy
principles and practice , Philadelphia, 2010, Elsevier, p 652.

Epidemiology
The overall annual incidence of anaphylaxis in the United States is estimated at
42 cases per 100,000 person-years, totaling >150,000 cases/yr. Food allergens
are the most common trigger in children, with an incidence rate of
approximately 20 per 100,000 person-years. An Australian parental survey
found that 0.59% of children 3-17 yr of age had experienced at least 1
anaphylactic event. Having asthma and the severity of asthma are important
anaphylaxis risk factors (Table 174.3 ). In addition, patients with systemic
mastocytosis or monoclonal mast cell–activating syndrome are at increased risk
for anaphylaxis, as are patients with an elevated baseline serum tryptase level.
Table 174.3
Patient Risk Factors for Anaphylaxis
Age-Related Factors

Infants: anaphylaxis can be difficult to recognize, especially if the first

episode; patients cannot describe symptoms.
Adolescents and young adults: increased risk-taking behaviors, such as
failure to avoid known triggers and to carry an epinephrine autoinjector
consistently
Pregnancy: risk of iatrogenic anaphylaxis, as from β lactam antibiotics to
prevent neonatal group B streptococcal infection, agents used
perioperatively during caesarean sections, and natural rubber latex
Older people: increased risk of death because of concomitant disease and
drugs
Concomitant Diseases

Asthma and other chronic respiratory diseases

Cardiovascular diseases
Systemic mastocytosis or monoclonal mast cell–activating syndrome
Allergic rhinitis and eczema*
Depression, cognitive dysfunction, substance misuse

Drugs

β-Adrenergic blockers †
Angiotensin-converting enzyme (ACE) inhibitors †
Sedatives, antidepressants, narcotics, recreational drugs, and alcohol may
decrease the patient's ability to recognize triggers and symptoms.

Factors That May Increase Risk for Anaphylaxis or Make It More

Difficult to Treat

Age
Asthma
Atopy
Drugs
Alcohol
Other cofactors such as exercise, infection, menses

* Atopic diseases are a risk factor for anaphylaxis triggered by food, latex, and

exercise, but not for anaphylaxis triggered by most drugs or by insect stings.
† Patients taking β-blockers or ACE inhibitors seem to be at increased risk for

severe anaphylaxis. In addition, those taking β-blockers may not respond

optimally to epinephrine treatment and may need glucagon, a polypeptide with
non–catecholamine-dependent inotropic and chronotropic cardiac effects,
atropine for persistent bradycardia, or ipratropium for persistent bronchospasm.
Adapted from Lieberman P, Nicklas RA, Randolph C, et al: Anaphylaxis—a
practice parameter update 2015, Ann Allergy Asthma Immunol 115(5):341–384,
2015, Table I-9.

Pathogenesis
Principal pathologic features in fatal anaphylaxis include acute bronchial
obstruction with pulmonary hyperinflation, pulmonary edema, intraalveolar
hemorrhaging, visceral congestion, laryngeal edema, and urticaria and
angioedema. Acute hypotension is attributed to vasomotor dilation and cardiac
dysrhythmias.
Most cases of anaphylaxis are believed to be the result of activation of mast
cells and basophils via cell-bound allergen-specific IgE molecules (see Fig.
174.1 ). Patients initially must be exposed to the responsible allergen to generate
allergen-specific antibodies. In many cases the child and the parent are unaware
of the initial exposure, which may be from passage of food proteins in maternal
breast milk or exposure to inflamed skin (e.g., eczematous lesions). When the
child is reexposed to the sensitizing allergen, mast cells and basophils, and
possibly other cells such as macrophages, release a variety of mediators
(histamine, tryptase) and cytokines that can produce allergic symptoms in any or
all target organs. Clinical anaphylaxis may also be caused by mechanisms other
than IgE-mediated reactions, including direct release of mediators from mast
cells by medications and physical factors (morphine, exercise, cold),
disturbances of leukotriene metabolism (aspirin and nonsteroidal
antiinflammatory drugs), immune aggregates and complement activation (blood
products), probable complement activation (radiocontrast dyes, dialysis
membranes), and IgG-mediated reactions (high-molecular-weight dextran,
chimeric or humanized monoclonal antibodies) (see Table 174.2 ).
Idiopathic anaphylaxis is a diagnosis of exclusion when no inciting agent is
identified and other disorders have been excluded (see Chapter 678.1 ).
Symptoms are similar to IgE mediated causes of anaphylaxis; episodes often
recur.

Clinical Manifestations
The onset of symptoms may vary depending on the cause of the reaction.
man syndrome (caused by vancomycin) should be considered.
Table 174.4
Diagnosis of Anaphylaxis
Anaphylaxis is highly likely when any 1 of the following 3 criteria is
fulfilled:
1. Acute onset of an illness (minutes to several hours) with
involvement of the skin and/or mucosal tissue (e.g., generalized
hives, pruritus or flushing, swollen lips/tongue/uvula)
AND at least 1 of the following :
a. Respiratory compromise (e.g., dyspnea,
wheeze/bronchospasm, stridor, reduced peak PEF,
hypoxemia)
b. Reduced BP or associated symptoms of end-organ
dysfunction (e.g., hypotonia [collapse], syncope,
incontinence)
2. Two or more of the following that occur rapidly after exposure
to a likely allergen for that patient (minutes to several hours):
a. Involvement of the skin/mucosal tissue (e.g.,
generalized hives, itch/flush, swollen
lips/tongue/uvula)
b. Respiratory compromise (e.g., dyspnea,
wheeze/bronchospasm, stridor, reduced PEF,
hypoxemia)
c. Reduced BP or associated symptoms (e.g., hypotonia
[collapse], syncope, incontinence)
d. Persistent gastrointestinal symptoms (e.g., crampy
abdominal pain, vomiting)
3. Reduced BP following exposure to known allergen for that
patient (minutes to several hours):
a. Infants and children: low systolic BP (age specific) or
>30% drop in systolic BP
b. Adults: systolic BP <90 mm Hg or >30% drop from
patient's baseline

BP, Blood pressure; PEF, peak expiratory flow.

Adapted from Sampson HA, Muñoz-Furlong A, Campbell RL, et al: Second
Symposium on the Definition and Management of Anaphylaxis: summary
report, Second National Institute of Allergy and Infectious Disease/Food Allergy
and Anaphylaxis Network Symposium, J Allergy Clin Immunol 117:391–397,
2006.

Treatment
Anaphylaxis is a medical emergency requiring aggressive management with
intramuscular (IM, first line) or intravenous (IV) epinephrine, IM or IV H1 and
H2 antihistamine antagonists, oxygen, IV fluids, inhaled β-agonists, and
corticosteroids (Table 174.5 and Fig. 174.2 ). The initial assessment should
ensure an adequate airway with effective respiration, circulation, and perfusion.
Epinephrine is the most important medication, and there should be no delay in
its administration. Epinephrine should be given by the IM route to the lateral
thigh (1 : 1000 dilution, 0.01 mg/kg; maximum 0.5 mg). For children ≥12 yr,
many recommend the 0.5 mg IM dose. The IM dose can be repeated at intervals
of 5-15 min if symptoms persist or worsen. If there is no response to multiple
doses of epinephrine, IV epinephrine using the 1 : 10,000 dilution may be
needed. If IV access is not readily available, epinephrine can be administered via
the endotracheal or intraosseous routes.

Table 174.5
Management of a Patient With Anaphylaxis

MECHANISM(S)
TREATMENT DOSAGE(S) COMMENTS; ADVERSE REACTIONS
OF EFFECT
PATIENT EMERGENCY MANAGEMENT (dependent on severity of symptoms)
Epinephrine α1 -, β1 -, β2 - 0.01 mg/kg, up to Tachycardia, hypertension, nervousness,
(adrenaline) Adrenergic effects 0.5 mg IM in headache, nausea, irritability, tremor
lateral thigh
Adrenaclick,
Auvi-Q, EpiPen
Jr/EpiPen:
0.15 mg IM for 8-
25 kg
0.3 mg IM for 25
kg or more
Epinephrine
autoinjector:
0.1 mg for 7.5-15
 kg
0.15 mg for 15 to
25 kg
0.3 mg for 25 kg
or more
Cetirizine (liquid) Antihistamine Cetirizine liquid: 5 Hypotension, tachycardia, somnolence
(competitive of H1 mg/5 mL
receptor) 0.25 mg/kg, up to
10 mg PO
Alternative: Antihistamine 1.25 mg/kg up to 50 Hypotension, tachycardia, somnolence,
Diphenhydramine (competitive of H1 mg PO or IM paradoxical excitement
receptor)
Transport to an emergency facility
EMERGENCY PERSONNEL MANAGEMENT (dependent on severity of symptoms)
Epinephrine α1 -, β1 -, β2 - 0.01 mg/kg, up to Tachycardia, hypertension, nervousness,
(adrenaline) Adrenergic effects 0.5 mg IM in headache, nausea, irritability, tremor
lateral thigh
Epinephrine
autoinjector:
0.1 mg for 7.5-15
kg
0.15 mg for 15 to
25 kg
0.3 mg for 25 kg
or more
0.01 mL/kg/dose
of 1 : 1,000 (vial)
solution, up to 0.5
mL IM
May repeat every
10-15 min
For severe
hypotension: 0.01
mL/kg/dose of 1 :
10,000 slow IV
push
Supplemental oxygen and airway management
Volume Expanders
Crystalloids 30 mL/kg in 1st hr Rate titrated against BP response
(normal saline or If tolerated, place patient supine with legs
Ringer lactate) raised.
Colloids 10 mL/kg rapidly Rate titrated against BP response
(hydroxyethyl followed by slow If tolerated, place patient supine with legs
starch) infusion raised.
Antihistamines
Cetirizine (liquid) Antihistamine Cetirizine liquid: 5 Hypotension, tachycardia, somnolence
(competitive of H1 mg/5 mL
receptor) 0.25 mg/kg, up to
10 mg PO
Alternative: Antihistamine 1.25 mg/kg, up to 50 Hypotension, tachycardia, somnolence,
Diphenhydramine (competitive of H1 mg PO, IM, or IV paradoxical excitement
receptor)

Ranitidine Antihistamine 1 mg/kg, up to 50 Headache, mental confusion

(competitive of H2 mg IV
 receptor) Should be
administered
slowly
Alternative: Antihistamine 4 mg/kg, up to 200 Headache, mental confusion
Cimetidine (competitive of H2 mg IV
receptor) Should be
administered
slowly
Corticosteroids
Methylprednisolone Antiinflammatory Solu-Medrol (IV): Hypertension, edema, nervousness, agitation
1-2 mg/kg, up to
125 mg IV
Depo-Medrol
(IM): 1 mg/kg, up
to 80 mg IM
Prednisone Antiinflammatory 1 mg/kg up, to 75 mg Hypertension, edema, nervousness, agitation
PO
Nebulized albuterol β-Agonist 0.83 mg/mL (3 mL) via Palpitations, nervousness, CNS stimulation,
mask with O2 tachycardia; use to supplement epinephrine
when bronchospasm appears unresponsive;
may repeat
POSTEMERGENCY MANAGEMENT
Antihistamine Cetirizine (5-10 mg
qd) or loratadine (5-10
mg qd) for 3 days
Corticosteroids Optional: Oral
prednisone (1 mg/kg
up to 75 mg) daily for
3 days
Preventive Treatment
Prescription for epinephrine autoinjector and antihistamine
Provide written plan outlining patient emergency management (may download form from http://www.aap.org or
http://www.foodallergy.org )
Follow-up evaluation to determine/confirm etiology
Immunotherapy for insect sting allergy
Patient Education
Instruction on avoidance of causative agent
Information on recognizing early signs of anaphylaxis
Stress early treatment of allergic symptoms to avoid systemic anaphylaxis
Encourage wearing medical identification jewelry
BP, Blood pressure; CNS, central nervous system; IM, Intramuscularly; IV, intravenously; PO,
orally; qd, every day.
patients with suspected reactions to previous radiocontrast dye. Nonlatex gloves
and materials should be used in children undergoing multiple operations.
Any child at risk for anaphylaxis should receive emergency medications
(including epinephrine autoinjector), education on identification of signs and
symptoms of anaphylaxis and proper administration of medications (Table 174.6
), and a written emergency plan in case of accidental exposure. They should be
encouraged to wear medical identification jewelry.
Table 174.6
Considerations With Epinephrine Injection
for Anaphylaxis
Why Healthcare Professionals Fail to Inject Epinephrine Promptly

• Lack of recognition of anaphylaxis symptoms; failure to diagnose

anaphylaxis
• Episode appears mild, or there is a history of previous mild episode(s)*
• Inappropriate concern about transient mild pharmacologic effects of
epinephrine (e.g., tremor)
• Lack of awareness that serious adverse effects are almost always attributable
to epinephrine overdose or IV administration, especially IV bolus, rapid IV
infusion, or IV infusion of a 1 : 1,000 epinephrine solution instead of an
appropriately diluted solution (1 : 10,000 or 1 : 100,000 concentration)

Why Patients and Caregivers Fail to Inject Epinephrine Promptly

• Lack of recognition of anaphylaxis symptoms; failure to diagnose

anaphylaxis
• Episode appears mild, or there is a history of previous mild episode(s)*
• H1 antihistamine or asthma puffer is used initially instead, relieving early
warning signs such as itch or cough, respectively.
• Prescription for epinephrine autoinjectors (EAIs) is not provided by
physician.
• Prescription for EAIs is provided but not filled at pharmacy (e.g., not
affordable).
 • Patients do not carry EAIs consistently (due to size and bulk, or “don't think
they’ll need it”).
• Patients and caregivers are afraid to use EAIs (concern about making an
error when giving the injection or about a bad outcome).
• Patients and caregivers are concerned about injury from EAIs.
• Competence in using EAIs is associated with regular allergy clinic visits; it
decreases as time elapses from first EAI instruction; regular retraining is
needed.
• Difficulty in understanding how to use EAIs (15% of mothers with no EAI
experience could not fire an EAI immediately after a one-on-one
demonstration)
• Errors in EAI use can occur despite education, possibly related to the design
of some EAIs.

Why Patients Occasionally Fail to Respond to Epinephrine Injection

• Delayed recognition of anaphylaxis symptoms; delayed diagnosis

• Error in diagnosis: problem being treated (e.g., foreign body inhalation) is
not anaphylaxis.
• Rapid progression of anaphylaxis †
Epinephrine † :
• Injected too late; dose too low on mg/kg basis; dose too low
because epinephrine solution has degraded (e.g., past the
expiration date, stored in a hot place)
• Injection route or site not optimal; dose took too long to be
absorbed.
• Patient suddenly sits up or walks or runs, leading to the
empty ventricle syndrome.
• Concurrent use of certain medications (e.g., β-adrenergic
blockers)

* Subsequent anaphylaxis episodes can be more severe, less severe, or similar in

severity.
† Median times to respiratory or cardiac arrest are 5 min in iatrogenic

anaphylaxis, 15 min in stinging-insect venom anaphylaxis, and 30 min in food

anaphylaxis; however, regardless of the trigger, respiratory or cardiac arrest can
occur within 1 min in anaphylaxis.

Adapted from Leung DYM, Szefler SJ, Bonilla FA Akdis CA, Sampson HA,
editors: Pediatric allergy principles and practice, Philadelphia, 2016, Elsevier, p
531.

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Boyce JA, Assa'ad A, Burks AW, et al. Guidelines for the
diagnosis and management of food allergy in the United
States: report of the NIAID-sponsored expert panel. J Allergy
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Brown JC, Tuuri RE, Akhter S, et al. Lacerations and embedded
needles caused by epinephrine autoinjector use in children.
Ann Emerg Med . 2017;67(3):307–315.
Dahdah L, Ceccarelli S, Amendola S, et al. IgE
immunoadsorption knocks down the risk of food-related
anaphylaxis. Pediatrics . 2015;136(6):e1617–e1620.
Dhami S, Panesar SS, Roberts G, et al. Management of
anaphylaxis: a systematic review. Allergy . 2014;69(2):168–
175.
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Opin Pediatr . 2016;28:294–297.
Fellinger C, Hemmer W, Wohrl S, et al. Clinical characteristics
and risk profile of patients with elevated baseline serum
CHAPTER 175

Serum Sickness
Anna Nowak-Węgrzyn, Scott H. Sicherer

Serum sickness is a systemic, immune complex–mediated hypersensitivity

vasculitis classically attributed to the therapeutic administration of foreign serum
proteins or other medications (Table 175.1 ).
Table 175.1
Proteins and Medications That Cause Serum
Sickness*
Proteins From Other Species

Antibotulinum globulin
Antithymocyte globulin
Antitetanus toxoid
Antivenin (Crotalidae) polyvalent (horse serum based)
Crotalidae polyvalent immune Fab (ovine serum based)
Antirabies globulin
Infliximab
Rituximab
Etanercept
Anti-HIV antibodies ([PE]HRG214)
Hymenoptera stings
Streptokinase
H1N1 influenza vaccine

Drugs
Antibiotics
 Cefaclor
Penicillins
Trimethoprim sulfate
Minocycline
Meropenem

Neurologic

Bupropion
Carbamazepine
Phenytoin
Sulfonamides
Barbiturates

HIV, Human immunodeficiency virus.

* Based on review of most current literature. Other medications that are not

listed might also cause serum sickness.

From Aceves SS: Serum sickness. In Burg FD, Ingelfinger JR, Polin RA,
Gershon AA, editors: Current pediatric therapy , ed 18, Philadelphia, 2006,
Elsevier, p 1138.

Etiology
Immune complexes involving heterologous (animal) serum proteins and
complement activation are important pathogenic mechanisms in serum sickness.
Antibody therapies derived from the horse, sheep, or rabbit are available for
treatment of envenomation by the black widow spider and a variety of snakes,
for treatment of botulism, and for immunosuppression (antithymocyte globulin
, ATG). The availability of alternative medical therapies, modified or
bioengineered antibodies, and biologics of human origin have supplanted the use
of nonhuman antisera, reducing the risk of serum sickness. However, rabbit-
generated ATGs, which target human T cells, continue to be widely used as
immunosuppressive agents during treatment of kidney allograft recipients; serum
CHAPTER 176

Food Allergy and Adverse Reactions

to Foods
Anna Nowak-Węgrzyn, Hugh A. Sampson, Scott H. Sicherer

Adverse reactions to foods consist of any untoward reaction following the

ingestion of a food or food additive and are classically divided into food
intolerances (e.g., lactose intolerance ), which are adverse physiologic
responses, and food allergies, which are adverse immunologic responses and can
be IgE mediated or non–IgE mediated (Tables 176.1 and 176.2 ). As with other
atopic disorders, food allergies appear to have increased over the past 3 decades,
primarily in countries with a Western lifestyle. Worldwide, estimates of food
allergy prevalence range from 1–10%; food allergies affect an estimated 3.5% of
the U.S. population. Up to 6% of children experience food allergic reactions in
the 1st 3 yr of life, including approximately 2.5% with cow's milk allergy, 2%
with egg allergy, and 2–3% with peanut allergy. Peanut allergy prevalence
tripled over the past decade. Most children “outgrow” milk and egg allergies,
with approximately 50% doing so by school-age. In contrast, 80–90% of
children with peanut, tree nut, or seafood allergy retain their allergy for life.
Table 176.1
Adverse Food Reactions
Food Intolerance (non–immune system mediated, nontoxic,
noninfectious)
Host Factors

Enzyme deficiencies—lactase (primary or secondary), sucrase/isomaltase,

hereditary fructose intolerance, galactosemia
Gastrointestinal disorders—inflammatory bowel disease, irritable bowel
 syndrome, pseudoobstruction, colic
Idiosyncratic reactions—caffeine in soft drinks (“hyperactivity”)
Psychologic—food phobias, obsessive/compulsive disorder
Migraines (rare)

Food Factors (Toxic or Infectious or Pharmacologic)

Infectious organisms—Escherichia coli, Staphylococcus aureus,

Clostridium perfringens, Shigella, botulism, Salmonella, Yersinia,
Campylobacter
Toxins—histamine (scombroid poisoning), saxitoxin (shellfish)
Pharmacologic agents—caffeine, theobromine (chocolate, tea), tryptamine
(tomatoes), tyramine (cheese), benzoic acid in citrus fruits (perioral flare)
Contaminants—heavy metals, pesticides, antibiotics

Food Allergy
IgE Mediated

Cutaneous—urticaria, angioedema, morbilliform rashes, flushing, contact

urticarial
Gastrointestinal—oral allergy syndrome, gastrointestinal anaphylaxis
Respiratory—acute rhinoconjunctivitis, bronchospasm
Generalized—anaphylactic shock, exercise-induced anaphylaxis

Mixed IgE Mediated and Non–IgE Mediated

Cutaneous—atopic dermatitis, contact dermatitis

Gastrointestinal—allergic eosinophilic esophagitis and gastroenteritis
Respiratory—asthma

Non–IgE Mediated

Cutaneous—contact dermatitis, dermatitis herpetiformis (celiac disease)

Gastrointestinal—food protein–induced enterocolitis, proctocolitis, and
enteropathy syndromes, celiac disease
 Respiratory—food-induced pulmonary hemosiderosis (Heiner syndrome)
Unclassified

IgE, Immunoglobulin E.
Table 176.2
Differential Diagnosis of Adverse Food
Reactions
Gastrointestinal Disorders (with vomiting and/or diarrhea)

Structural abnormalities (pyloric stenosis, Hirschsprung disease, reflux)

Enzyme deficiencies (primary or secondary) :
Disaccharidase deficiency—lactase, fructase, sucrase-isomaltase
Galactosemia
Malignancy with obstruction
Other: pancreatic insufficiency (cystic fibrosis), peptic disease

Contaminants and Additives

Flavorings and preservatives—rarely cause symptoms:

Sodium metabisulfite, monosodium glutamate, nitrites
Dyes and colorings—very rarely cause symptoms (urticaria, eczema):
Tartrazine
Toxins:
Bacterial, fungal (aflatoxin), fish related (scombroid, ciguatera)
Infectious organisms:
Bacteria (Salmonella, Escherichia coli, Shigella)
Virus (rotavirus, enterovirus)
Parasites (Giardia, Akis simplex [in fish])
Accidental contaminants:
Heavy metals, pesticides
Pharmacologic agents:
Caffeine, glycosidal alkaloid solanine (potato spuds), histamine
(fish), serotonin (banana, tomato), tryptamine (tomato),
tyramine (cheese)
Psychologic Reactions

Food phobias

Genetics
Genetic factors play an important role in the development of food allergy.
Family and twin studies show that family history confers a 2-10–fold increased
risk, depending on the study setting, population, specific food, and diagnostic
test. Candidate gene studies suggest that genetic variants in the HLA-DQ locus
(HLA-DQB1*02 and DQB1*06:03P), filaggrin, interleukin-10, STAT6, and
FOXP3 genes are associated with food allergy, although the results are
inconsistent across different populations. In a genome-wide association study,
differential methylation at the HLA-DR and -DQ regions was associated with
food allergy. Epigenetic studies implicate DNA methylation effects on
interleukins 4, 5, and 10 and interferon (IFN)-γ genes and in the mitogen-
activated protein kinase (MAPK) pathway.

Pathogenesis
Food intolerances are the result of a variety of mechanisms, whereas food allergy
is predominantly caused by IgE-mediated and cell-mediated immune
mechanisms. In susceptible individuals exposed to certain allergens, food-
specific IgE antibodies are formed that bind to Fcε receptors on mast cells,
basophils, macrophages, and dendritic cells. When food allergens penetrate
mucosal barriers and reach cell-bound IgE antibodies, mediators are released
that induce vasodilation, smooth muscle contraction, and mucus secretion, which
result in symptoms of immediate hypersensitivity (allergy). Activated mast cells
and macrophages may release several cytokines that attract and activate other
cells, such as eosinophils and lymphocytes, leading to prolonged inflammation.
Symptoms elicited during acute IgE-mediated reactions can affect the skin
(urticaria, angioedema, flushing), gastrointestinal (GI) tract (oral pruritus,
angioedema, nausea, abdominal pain, vomiting, diarrhea), respiratory tract (nasal
congestion, rhinorrhea, nasal pruritus, sneezing, laryngeal edema, dyspnea,
wheezing), and cardiovascular system (dysrhythmias, hypotension, loss of
consciousness). In non-IgE food allergies, lymphocytes, primarily food allergen–
specific T cells, secrete excessive amounts of various cytokines that lead to a
“delayed,” more chronic inflammatory process affecting the skin (pruritus,
erythematous rash), GI tract (failure to thrive, early satiety, abdominal pain,
vomiting, diarrhea), and respiratory tract (food-induced pulmonary
hemosiderosis). Mixed IgE and cellular responses to food allergens can also lead
to chronic disorders, such as atopic dermatitis, asthma, eosinophilic esophagitis,
and gastroenteritis.
Children who develop IgE-mediated food allergies may be sensitized by food
allergens penetrating the GI barrier, referred to as class 1 food allergens , or by
food allergens that are partially homologous to plant pollens penetrating the
respiratory tract, referred to as class 2 food allergens . Any food may serve as a
class 1 food allergen, but egg, milk, peanuts, tree nuts, fish, soy, and wheat
account for 90% of food allergies during childhood. Many of the major
allergenic proteins of these foods have been characterized. There is variable but
significant cross-reactivity with other proteins within an individual food group.
Exposure and sensitization to these proteins often occur very early in life.
Virtually all milk allergies develop by 12 mo of age and all egg allergies by 18
mo, and the median age of 1st peanut allergic reactions is 14 mo. Class 2 food
allergens are typically vegetable, fruit, or nut proteins that are partially
homologous with pollen proteins (Table 176.3 ). With the development of
seasonal allergic rhinitis from birch, grass, or ragweed pollens, subsequent
ingestion of certain uncooked fruits or vegetables provokes the oral allergy
syndrome . Intermittent ingestion of allergenic foods may lead to acute
symptoms such as urticaria or anaphylaxis, whereas prolonged exposure may
lead to chronic disorders such as atopic dermatitis and asthma. Cell-mediated
sensitivity typically develops to class 1 allergens.

Table 176.3
Natural History of Food Allergy and Cross-Reactivity
Between Common Food Allergies

USUAL AGE AT ONSET OF USUAL AGE AT

FOOD CROSS REACTIVITY
ALLERGY RESOLUTION
Hen's egg white 0-1 yr Other avian eggs 7 yr (75% of cases
resolve)*
Cow's milk 0-1 yr Goat's milk, sheep's milk, 5 yr (76% of cases
buffalo milk resolve)*
Peanuts 1-2 yr Other legumes, peas, lentils; Persistent (20% of
coreactivity with tree nuts cases resolve)
 Tree nuts 1-2 yr; in adults, onset occurs after Other tree nuts; co-reactivity Persistent (9% of
cross reactivity to birch pollen with peanuts cases resolve)
Fish Late childhood and adulthood Other fish (low cross-reactivity Persistent †
with tuna and swordfish)
Shellfish Adulthood (in 60% of patients with Other shellfish Persistent
this allergy)
Wheat* 6-24 mo Other grains containing gluten 5 yr (80% of cases
(rye, barley) resolve)
Soybeans* 6-24 mo Other legumes 2 yr (67% of cases
resolve)
Kiwi Any age Banana, avocado, latex Unknown
Apples, carrots, Late childhood and adulthood Birch pollen, other fruits, nuts Unknown
and peaches §
*
Recent studies suggest that resolution may occur at a later age, especially in children with
multiple food allergies and lifetime peak food-specific IgE >50 kUA /L.
† Fish allergy that is acquired in childhood can resolve.

§ Allergy to fresh apples, carrots, and peaches (oral allergy syndrome ) is typically caused by
heat-labile proteins. Fresh fruit causes oral pruritus, but cooked fruit is tolerated. There is
generally no risk of anaphylaxis, although in rare cases, allergies to cross-reactive lipid transfer
protein can cause anaphylaxis after ingestion of fruits (e.g., peach) and vegetables.
Adapted from Lack G: Food allergy, N Engl J Med 359:1252–1260, 2008.

Clinical Manifestations
From a clinical and diagnostic standpoint, it is most useful to subdivide food
hypersensitivity disorders according to the predominant target organ (Table
176.4 ) and immune mechanism (see Table 176.1 ).

Table 176.4

Symptoms of Food-Induced Allergic Reactions

TARGET
IMMEDIATE SYMPTOMS DELAYED SYMPTOMS
ORGAN
Cutaneous Erythema Erythema
Pruritus Flushing
Urticaria Pruritus
Morbilliform eruption Morbilliform eruption
Angioedema Angioedema
Eczematous rash
Ocular Pruritus Pruritus
Conjunctival erythema Conjunctival erythema
Tearing Tearing
Periorbital edema Periorbital edema
Upper Nasal congestion
 respiratory Pruritus
Rhinorrhea
Sneezing
Laryngeal edema
Hoarseness
Dry staccato cough
Lower Cough Cough, dyspnea, wheezing
respiratory Chest tightness
Dyspnea
Wheezing
Intercostal retractions
Accessory muscle use
Gastrointestinal Angioedema of the lips, tongue, or
(oral) palate
Oral pruritus
Tongue swelling
Gastrointestinal Nausea Nausea
(lower) Colicky abdominal pain Abdominal pain
Reflux Reflux
Vomiting Vomiting
Diarrhea Diarrhea
Hematochezia
Irritability and food refusal with weight loss
(young children)
Cardiovascular Tachycardia (occasionally bradycardia
in anaphylaxis)
Hypotension
Dizziness
Fainting
Loss of consciousness
Miscellaneous Uterine contractions
Sense of “impending doom”
From Boyce JA, Assa'ad A, Burks AW, et al: Guideline for the diagnosis and management of food
allergy in the United States: report of the NIAID-sponsored expert panel, J Allergy Clin Immunol
126(6):S1–S58, 2010 (Table IV, p S19).

Gastrointestinal Manifestations
GI food allergies are often the 1st form of allergy to affect infants and young
children and typically manifest as irritability, vomiting or “spitting-up,” diarrhea,
and poor weight gain. Cell-mediated hypersensitivities without IgE involvement
predominate, making standard allergy tests such as skin-prick tests and in vitro
tests for food-specific IgE antibodies of little diagnostic value.
Food protein–induced enterocolitis syndrome (FPIES) typically manifests
in the 1st several mo of life as irritability, intermittent vomiting, and protracted
diarrhea and may result in dehydration (Table 176.5 ). Vomiting generally occurs
1-4 hr after feeding, and continued exposure may result in abdominal distention,
bloody diarrhea, anemia, and failure to thrive. Symptoms are most often
provoked by cow's milk or soy protein–based formulas. A similar enterocolitis
syndrome occurs in older infants and children from rice, oat, wheat, egg, peanut,
nut, chicken, turkey, or fish. Hypotension occurs in approximately 15% of
patients after allergen ingestion and may initially be thought to be caused by
sepsis. FPIES usually resolves by age 3-5 yr.

Table 176.5
Food Protein–Induced Gastrointestinal Syndromes

EOSINOPHILIC
FPIES PROCTOCOLITIS ENTEROPATHY
GASTROENTEROPATHIES*
Age at onset 1 day–1 year 1 day–6 months Dependent of age Infant to adolescent
of exposure to
antigen, cow's
milk and soy up to
2 yr
Food proteins
implicated
Most common Cow's milk, Cow's milk, soy Cow's milk, soy Cow's milk, soy, egg white,
soy wheat, peanut
Less common Rice, Egg, corn, chocolate Wheat, egg Meats, corn, rice, fruits,
chicken, vegetables, fish
turkey, fish,
pea
Multiple food >50% both 40% both cow's milk Rare Common
hypersensitivities cow's milk and soy
and soy
Feeding at the time Formula >50% exclusive Formula Formula
of onset breastfeeding
Atopic background
Family history of 40–70% 25% Unknown ~50% (often history of
atopy eosinophilic esophagitis)
Personal history of 30% 22% 22% ~50%
atopy
Symptoms
Emesis Prominent No Intermittent Intermittent
Diarrhea Severe No Moderate Moderate
Bloody stools Severe Moderate Rare Moderate
Edema Acute, severe No Moderate Moderate
Shock 15% No No No
Failure to thrive Moderate No Moderate Moderate
Laboratory
findings
Anemia Moderate Mild Moderate Mild-moderate
Hypoalbuminemia Acute Rare Moderate Mild-severe
Methemoglobinemia May be No No No
present
Allergy evaluation
Food skin-prick test Negative † Negative Negative Positive in ~50%
 Serum food allergen Negative † Negative Negative Positive in ~50%
IgE
Total IgE Normal Negative Normal Normal to elevated
Peripheral blood No Occasional No Present in <50%
eosinophilia
Biopsy findings
Colitis Prominent Focal No May be present
Lymph nodular No Common No Yes
hyperplasia
Eosinophils Prominent Prominent Few Prominent; also neutrophilic
infiltrates, papillary elongation,
and basal zone hyperplasia
Food challenge Vomiting in Rectal bleeding in 6- Vomiting, Vomiting and diarrhea in hours
1-4 hr; 72 hr diarrhea, or both to days
diarrhea in 5- in 40-72 hr
8 hr
Treatment Protein Protein elimination, Protein Protein elimination, good
elimination, symptoms clear in 3 elimination, response to casein hydrolysate,
80% respond days with casein symptoms clear in excellent response to elemental
to casein hydrolysate; 1-3 wk; diet; symptoms clear in 2-3 wk,
hydrolysate resume/continue rechallenge and excellent acute response to
and breastfeeding on biopsy in 1-2 yr steroids; rechallenge by
symptoms maternal antigen- introducing food at home and
clear in 3-10 restricted diet; biopsy in 1-2 yr
days; reintroduce at home
rechallenge after 9-12 mo of age
under
supervision
in 1.5-2 yr
Natural history Cow's Resolved by 9-12 mo Most cases resolve Typically a prolonged, relapsing
milk: in 2-3 yr course
60%
resolved
by 2 yr
Soy:
25%
resolved
by 2 yr
Reintroduction of Supervised At home, gradually Home, gradually Home, gradually advancing
the food food advancing from 1 oz advancing
challenge to full feedings over
2 wk
* Eosinophilic gastroenteropathies encompass esophagitis, gastritis, and gastroenterocolitis.

† If positive, may be a risk factor for persistent disease.

FPIES, Food protein–induced enterocolitis syndrome.

From Nowak-Węgrzyn A, Muraro A: Food protein-induced enterocolitis syndrome, Curr Opin
Allergy Immunol 9:371–377, 2009 (Table 1, p 372).

Food protein–induced allergic proctocolitis (FPIAP) presents in the 1st few

mo of life as blood-streaked stools in otherwise healthy infants (Table 176.5 ).
Approximately 60% of cases occur among breastfed infants, with the remainder
ingested, so more definitive tests, such as quantitative IgE tests or food
elimination and challenge, are often necessary to establish a diagnosis of food
allergy. Serum food-specific IgE levels ≥15 kUA /L for milk (≥5 kUA /L for
children ≤1 yr), ≥7 kUA /L for egg (≥2 kUA /L for children <2 yr), and ≥14 kUA
/L for peanut are associated with a >95% likelihood of clinical reactivity to these
foods in children with suspected reactivity. In the absence of a clear history of
reactivity to a food and evidence of food-specific IgE antibodies, definitive
studies must be performed before recommendations are made for avoidance or
the use of highly restrictive diets that may be nutritionally deficient, logistically
impractical, disruptive to the family, expensive, or a potential source of future
feeding disorders. IgE-mediated food allergic reactions are generally very food
specific, so the use of broad exclusionary diets, such as avoidance of all
legumes, cereal grains, or animal products, is not warranted (Table 176.6 ; see
also Table 176.3 ).

Table 176.6

Clinical Implications of Cross-Reactive Proteins in IgE-Mediated Allergy

RISK OF ALLERGY TO
FOOD FAMILY ≥1 MEMBER (%; FEATURE(S)
approximate)
Legumes 5 Main causes of reactions are peanut, soybean, lentil,
lupine, and garbanzo (chickpea).
Tree nuts (e.g., almond, 35 Reactions are often severe.
cashew, hazelnut, walnut,
brazil)
Fish 50 Reactions can be severe.
Shellfish 75 Reactions can be severe.
Grains 20
Mammalian milks 90 Cow's milk is highly cross-reactive with goat's or
sheep's milk (92%) but not with mare's milk (4%).
Rosaceae (pitted fruits) 55 Risk of reactions to >3 related foods is very low
(<10%); symptoms are usually mild (oral allergy
syndrome).
Latex-food 35 For individuals allergic to latex, banana, kiwi, fig,
chestnut, and avocado are the main causes of
reactions.
Food-latex 11 Individuals allergic to banana, kiwi, fig, chestnut, and
avocado may be at an increased risk of reactions to
latex.
Modified from Sicherer SH: Food allergy, Lancet 360:701–710, 2002.

There are no laboratory studies to help identify foods responsible for cell-
mediated reactions. Consequently, elimination diets followed by oral food
challenges are the only way to establish the diagnosis. Allergists experienced in
dealing with food allergic reactions and able to treat anaphylaxis should perform
food challenges. Before a food challenge is initiated, the suspected food should
be eliminated from the diet for 10-14 days for IgE-mediated food allergy and up
to 8 wk for some cell-mediated disorders, such as EoE. Some children with cell-
mediated reactions to cow's milk do not tolerate hydrolysate formulas and must
receive amino acid–derived formulas. If symptoms remain unchanged despite
appropriate elimination diets, it is unlikely that food allergy is responsible for the
child's disorder.

Treatment
Appropriate identification and elimination of foods responsible for food
hypersensitivity reactions are the only validated treatments for food allergies.
Complete elimination of common foods (milk, egg, soy, wheat, rice, chicken,
fish, peanut, nuts) is very difficult because of their widespread use in a variety of
processed foods. The lay organization Food Allergy Research and Education
(FARE , www.foodallergy.org ) provides excellent information to help parents
deal with both the practical and emotional issues surrounding these diets.
Validated educational materials are also available through the Consortium of
Food Allergy Research (www.cofargroup.org ).
Children with asthma and IgE-mediated food allergy, peanut or nut allergy, or
a history of a previous severe reaction should be given self-injectable
epinephrine and a written emergency plan in case of accidental ingestion (see
Chapter 174 ). Because many food allergies are outgrown, children should be
reevaluated periodically by an allergist to determine whether they have lost their
clinical reactivity. A number of clinical trials are evaluating the efficacy of oral,
sublingual, and epicutaneous (patch) immunotherapy for the treatment of IgE-
mediated food allergies (milk, egg, peanut). Combining oral immunotherapy
with anti-IgE treatment (omalizumab) may improve safety compared to oral
immunotherapy alone. Furthermore, extensively heated milk or egg in baked
products are tolerated by the majority of milk and egg–allergic children. Regular
ingestion of baked products with milk and egg appears to accelerate resolution of
milk and egg allergy. Table 176.7 provides vaccination recommendations for
egg-allergic children who require immunization.

Table 176.7
ACIP and AAP Recommendations for Administering Vaccines to Patients With Egg
Allergy
VACCINE ACIP, CDC, 2016 AAP, 2016
MMR/MMRV May be used May be used
Influenza Receive with no special precautions* Receive with no special precautions*
Rabies Use caution No specific recommendation
Yellow fever Contraindicated, but desensitization protocols Contraindicated, but desensitization protocols
may be followed to administer vaccine if may be followed to administer vaccine if
necessary (citing PI) necessary (citing PI)
*
In 2016, recommendations changed to suggest all children with any severity of egg allergy
receive the injectable influenza vaccine as appropriate for age in a medical setting without any
special testing and with the same precautions as those suggested for other vaccinations,
including a 15 minute observation period and being in a setting where personnel and equipment
are available to recognize and treat allergic reactions and anaphylaxis.
ACIP, Advisory Committee on Immunization Practices, Centers for Disease Control and
Prevention; AAP, American Academy of Pediatrics; PI, product insert.
From Boyce JA, Assa'ad A, Burks AW, et al: Guideline for the diagnosis and management of food
allergy in the United States: report of the NIAID-sponsored expert panel, J Allergy Clin Immunol
126(6):S1–S58, 2010 (Table V, p S31).

Prevention
It was once thought that avoidance of allergenic foods and delayed introduction
to the diet would prevent allergy, but the opposite is probably true; delayed
introduction of these foods may increase the risk of allergy, especially in children
with atopic dermatitis. A trial of early introduction of dietary peanut randomized
640 infants age 4-11 mo with severe eczema, egg allergy, or both to consume or
avoid peanut until age 60 mo. The early introduction of peanut dramatically
decreased the development of peanut allergy among children at high risk for this
allergy. A theory behind this approach is that early oral introduction of peanut
induces oral tolerance that precedes the potential sensitization to peanut via the
disrupted skin barrier. Infants with early-onset atopic disease (e.g., severe
eczema) or egg allergy in the 1st 4 to 6 mo of life might benefit from evaluation
by an allergist or physician trained in management of allergic diseases to
diagnose any food allergy and assist in implementing appropriate early peanut
introduction. The clinician can perform an observed peanut challenge for those
with evidence of a positive peanut skin test response or serum peanut-specific
IgE >0.35 kUA /L to determine whether they are clinically reactive before
initiating at-home introduction of infant-safe forms of peanut. Additional details
for the early introduction of peanut are available from the National Institute of
Allergy and Infectious Diseases (NIAID).*
There is no compelling evidence to support the practice of restricting the
maternal diet during pregnancy or while breastfeeding, or of delaying
introduction of various allergenic foods to infants from atopic families (Table
176.8 ). Exclusive breastfeeding for the 1st 4-6 mo of life may reduce allergic
disorders in the 1st few yr of life in infants at high risk for development of
allergic disease. Potentially allergenic foods (eggs, milk, wheat, soy, peanut/tree
nut products, fish) should be introduced after this period of exclusive
breastfeeding and may prevent the development of allergies later in life. Use of
hydrolyzed formulas may be beneficial if breastfeeding cannot be continued for
4-6 mo or after weaning, especially to prevent eczema in high-risk families, but
this approach remains controversial. Probiotic supplements may also reduce the
incidence and severity of eczema. Because some skin preparations contain
peanut oil, which may sensitize young infants, especially those with cutaneous
inflammation, such preparations should be avoided. Since inflamed/disrupted
skin barrier is a risk factor for food allergy, trials are underway to enhance the
skin barrier from birth, using emollients and decreasing bathing frequency, to
reduce the incidence of atopic dermatitis in high-risk neonates.
Table 176.8
Prevention of Food Allergy
Breastfeed exclusively for 4-6 mo.
Introduce solid (complementary) foods after 4-6 mo of exclusive
breastfeeding.
Introduce low-risk complementary foods 1 at a time.
Introduce potentially highly allergenic foods (fish, eggs, peanut, milk,
wheat) soon after the lower-risk foods (no need to avoid or delay).
Infants with early-onset atopic disease (e.g., severe eczema) or
egg allergy in the 1st 4-6 mo of life.
Do not avoid allergenic foods during pregnancy or nursing.
Soy-based formulas do not prevent allergic disease.

Bibliography
U.S. Food and Drug Administration (FDA) MedWatch program
(http://www.fda.gov/medwatch/index.html ) likely suffer from underreporting.
Cutaneous reactions are the most common form of ADRs, with ampicillin,
amoxicillin, penicillin, and trimethoprim/sulfamethoxazole (TMP/SMX) being
the most frequently implicated drugs (Tables 177.1 and 177.2 ). Although the
majority of ADRs do not appear to be allergic in nature, 6–10% can be attributed
to an allergic or immunologic mechanism. Importantly, given the high
probability of recurrence of allergic reactions, these reactions should be
preventable, and information technology–based interventions may be especially
useful to reduce risk of reexposure.

Table 177.1
Heterogeneity of Drug-Induced Allergic Reactions

ORGAN-
EXAMPLES OF CAUSATIVE
SPECIFIC CLINICAL FEATURES
AGENTS
REACTIONS
CUTANEOUS
Exanthems Diffuse fine macules and papules evolve over Allopurinol, aminopenicillins,
days after drug initiation cephalosporins, antiepileptic agents, and
Delayed-type hypersensitivity antibacterial sulfonamides
Urticaria, Onset within minutes of drug initiation IgE mediated: β-lactam antibiotics
angioedema Potential for anaphylaxis Bradykinin mediated: ACEI
Often IgE mediated
Fixed drug Hyperpigmented plaques Tetracycline, sulfonamides, NSAIDs, and
eruption Recur at same skin or mucosal site carbamazepine
Pustules Acneiform Acneiform: corticosteroids, sirolimus
Acute generalized exanthematous pustulosis AGEP: antibiotics, calcium-channel
(AGEP) blockers
Bullous Tense blisters Furosemide, vancomycin
Flaccid blisters Captopril, penicillamine
SJS Fever, erosive stomatitis, ocular involvement, Antibacterial sulfonamides,
purpuric macules on face and trunk with <10% anticonvulsants, oxicam NSAIDs, and
epidermal detachment allopurinol
TEN Similar features as SJS but >30% epidermal Same as SJS
detachment
Mortality as high as 50%
Cutaneous Erythematous/scaly plaques in photodistribution Hydrochlorothiazide, calcium channel
lupus blockers, ACEIs
Hematologic Hemolytic anemia, thrombocytopenia, Penicillin, quinine, sulfonamides
granulocytopenia
Hepatic Hepatitis, cholestatic jaundice Paraaminosalicylic acid, sulfonamides,
phenothiazines
Pulmonary Pneumonitis, fibrosis Nitrofurantoin, bleomycin, methotrexate
Renal Interstitial nephritis, membranous Penicillin, sulfonamides, gold,
glomerulonephritis penicillamine, allopurinol
MULTIORGAN REACTIONS
 Anaphylaxis Urticaria/angioedema, bronchospasm, β-Lactam antibiotics, monoclonal
gastrointestinal symptoms, hypotension antibodies
IgE- and non–IgE-dependent reactions
DRESS Cutaneous eruption, fever, eosinophilia, hepatic Anticonvulsants, sulfonamides,
dysfunction, lymphadenopathy minocycline, allopurinol
Serum sickness Urticaria, arthralgias, fever Heterologous antibodies, infliximab
Systemic lupus Arthralgias, myalgias, fever, malaise Hydralazine, procainamide, isoniazid
erythematosus
Vasculitis Cutaneous or visceral vasculitis Hydralazine, penicillamine,
propylthiouracil
ACEI, Angiotensin-converting enzyme inhibitor; DRESS, drug rash with eosinophilia and systemic
symptoms; NSAID, nonsteroidal antiinflammatory drug; SJS, Stevens-Johnson syndrome; TEN,
toxic epidermal necrolysis.
From Khan DA, Solensky R: Drug allergy, J Allergy Clin Immunol 125:S126–S137, 2010 (Table 1,
p S127).

Table 177.2

Delayed Hypersensitivity Drug Rashes by Category

MACULOPAPULAR EXANTHEMS—ANY DRUG CAN PRODUCE A RASH 7-10 DAYS AFTER THE
FIRST DOSE
Allopurinol
Antibiotics: penicillin, sulfonamides
Antiepileptics: phenytoin, phenobarbital
Antihypertensives: captopril, thiazide diuretics
Contrast dye: iodine
Gold salts
Hypoglycemic drugs
Meprobamate
Phenothiazines
Quinine
DRUG RASH WITH EOSINOPHILIA AND SYSTEMIC SYMPTOMS (DRESS)
Anticonvulsants: phenytoin, phenobarbital, valproate, lamotrigine
Antibiotics: sulfonamides, minocycline, dapsone, ampicillin, ethambutol, isoniazid, linezolid, metronidazole,
rifampin, streptomycin, vancomycin
Antihypertensives: amlodipine, captopril
Antidepressants: bupropion, fluoxetine
Allopurinol
Celecoxib
Ibuprofen
Phenothiazines
 ERYTHEMA MULTIFORME/STEVENS-JOHNSON SYNDROME
Sulfonamides, phenytoin, barbiturates, carbamazepine, allopurinol, amikacin, phenothiazines
Toxic epidermal necrolysis: same as for erythema multiforme but also acetazolamide, gold, nitrofurantoin,
pentazocine, tetracycline, quinidine
ACUTE GENERALIZED EXANTHEMIC PUSTULOSIS
Antibiotics: penicillins, macrolides, cephalosporins, clindamycin, imipenem, fluoroquinolones, isoniazid,
vancomycin, minocycline, doxycycline, linezolid
Antimalarials: chloroquine, hydroxychloroquine
Antifungals: terbinafine, nystatin
Anticonvulsants: carbamazepine
Calcium-channel blockers
Furosemide
Systemic corticosteroids
Protease inhibitors
COLLAGEN VASCULAR OR LUPUS-LIKE REACTIONS
Procainamide, hydralazine, phenytoin, penicillamine, trimethadione, methyldopa, carbamazepine, griseofulvin,
nalidixic acid, oral contraceptives, propranolol
ERYTHEMA NODOSUM
Oral contraceptives, penicillin, sulfonamides, diuretics, gold, clonidine, propranolol, opiates
FIXED DRUG REACTIONS
Phenolphthalein, barbiturates, gold, sulfonamides, meprobamate, penicillin, tetracycline, analgesics
See Chapter 664 and Table 664.3 .

From Duvic M: Urticaria, drug hypersensitivity rashes, nodules and tumors, and
atrophic diseases. In Goldman L, Schafer AI, editors: Goldman-Cecil medicine,
ed 25, Philadelphia, 2016, Elsevier, Table 440.3.

Pathogenesis and Clinical Manifestations

Immunologically mediated ADRs have been classified according to the Gell and
Coombs classification: immediate hypersensitivity reactions (type I ), cytotoxic
antibody reactions (type II ), immune complex reactions (type III ), and
delayed-type hypersensitivity reactions (type IV ). Immediate hypersensitivity
reactions occur when a drug or drug metabolite interacts with preformed drug-
specific IgE antibodies that are bound to the surfaces of tissue mast cells and/or
circulating basophils. The cross-linking of adjacent receptor-bound IgE by
antigen causes the release of preformed and newly synthesized mediators, such
 Varying degrees of in vitro cross-reactivity have been documented between
cephalosporins and penicillins. Although the risk of allergic reactions to
cephalosporins in patients with positive skin test responses to penicillin appears
to be low (<2%), anaphylactic reactions have occurred after administration of
cephalosporins in patients with a history of penicillin anaphylaxis. If a patient
has a history of penicillin allergy and requires a cephalosporin, skin testing for
major and minor determinants of penicillin should preferably be performed to
determine whether the patient has penicillin-specific IgE antibodies. If skin test
results are negative, the patient can receive a cephalosporin with no greater risk
than found in the general population. If skin test results are positive for
penicillin, recommendations may include administration of an alternative
antibiotic; cautious graded challenge with appropriate monitoring, with the
recognition that there is a 2% chance of inducing an anaphylactic reaction; and
desensitization to the required cephalosporin. Cross-reactivity is most likely
when the cephalosporin shares the same side chain as the penicillin (Table 177.3
).

Table 177.3
Groups of β-Lactam Antibiotics That Share Identical R1-
Group Side Chains*
Amoxicillin Ampicillin Ceftriaxone Cefoxitin Cefamandole Ceftazidime
Cefadroxil Cefaclor Cefotaxime Cephaloridine Cefonicid Aztreonam
Cefprozil Cephalexin Cefpodoxime Cephalothin
Cefatrizine Cephradine Cefditoren
Cephaloglycin Ceftizoxime
Loracarbef Cefmenoxime
* Each column represents a group with identical R1 side chains.

From Solensky R, Khan DA: Drug allergy: an updated practice parameter, Ann Allergy Asthma
Immunol 105:273e1–273e78, 2010 (Table 16, p 273e49).

Conversely, patients who require penicillin and have a history of an IgE-

mediated reaction to a cephalosporin should also undergo penicillin skin testing.
Patients with a negative result can receive penicillin. Patients with a positive
result should either receive an alternative medication or undergo desensitization
to penicillin. In patients with a history of allergic reaction to one cephalosporin
who require another cephalosporin, skin testing with the required cephalosporin
can be performed, with the recognition that the NPV of such testing is unknown.
If the skin test response to the cephalosporin is positive, the significance of the
pediatric rheumatologists. Arthralgias without physical findings for arthritis
suggest infection, malignancy, orthopedic conditions, benign syndromes, or pain
syndromes such as fibromyalgia (Table 178.1 ). Although rheumatic diseases
may manifest as arthralgias, arthritis is a stronger predictor of the presence of
rheumatic disease and a reason for referral to a pediatric rheumatologist. The
timing of joint pain along with associated symptoms, including poor sleep and
interference with normal activities, provides important clues. Poor sleep,
debilitating generalized joint pain that worsens with activity, school absences,
and normal physical and laboratory findings in an adolescent suggest a pain
syndrome (e.g., fibromyalgia). If arthralgia is accompanied by a history of dry
skin, hair loss, fatigue, growth disturbance, or cold intolerance, testing for
thyroid disease is merited. Nighttime awakenings because of severe pain along
with decreased platelet or white blood cell count or, alternatively, a very high
WBC count, may lead to the diagnosis of malignancy, especially marrow-
occupying lesions such as acute lymphocytic leukemia and neuroblastoma .
Pain with physical activity suggests a mechanical problem such as an overuse
syndrome or orthopedic condition. An adolescent girl presenting with knee pain
aggravated by walking up stairs and on patellar distraction likely has
patellofemoral syndrome . Children age 3-10 yr who have a history of episodic
pain that occurs at night after increased daytime physical activity that is relieved
by rubbing, but who have no limp or complaints in the morning, likely have
growing pains . There is often a positive family history for growing pains,
which may aid in this diagnosis. Intermittent pain in a child, especially a girl 3-
10 yr old, that is increased with activity and is associated with hyperextensible
joints on examination, is likely benign hypermobility syndrome . Many febrile
illnesses cause arthralgias that improve when the temperature normalizes, and
arthralgias are part of the diagnostic criteria for acute rheumatic fever (ARF ;
see Chapter 210.1 ).

Table 178.1

Symptoms Suggestive of Rheumatic Disease

RHEUMATIC POSSIBLE NONRHEUMATIC DISEASES CAUSING
SYMPTOM
DISEASE(S) SIMILAR SYMPTOMS
Fevers Systemic JIA, SLE, Malignancies, infections and postinfectious syndromes,
vasculitis, acute rheumatic inflammatory bowel disease, periodic fever (autoinflammatory)
fever, sarcoidosis, MCTD syndromes, Kawasaki disease, HSP
Arthralgias JIA, SLE, rheumatic fever, Hypothyroidism, trauma, endocarditis, other infections, pain
JDM, vasculitis, scleroderma, syndromes, growing pains, malignancies, overuse syndromes
 sarcoidosis
Weakness JDM, myositis secondary to Muscular dystrophies, metabolic and other myopathies,
SLE, MCTD, and deep hypothyroidism
localized scleroderma
Chest pain Juvenile idiopathic arthritis, Costochondritis (isolated), rib fracture, viral pericarditis, panic
SLE (with associated attack, hyperventilation
pericarditis or
costochondritis)
Back pain Enthesitis-related arthritis, Vertebral compression fracture, diskitis, intraspinal tumor,
juvenile ankylosing spondylolysis, spondylolisthesis, bone marrow–occupying
spondylitis malignancy, pain syndromes, osteomyelitis, muscle spasm, injury
Fatigue SLE, JDM, MCTD, Pain syndromes, chronic infections, chronic fatigue syndrome,
vasculitis, JIA depression
HSP, Henoch-Schönlein purpura; JDM, juvenile dermatomyositis; JIA, juvenile idiopathic arthritis;
MCTD, mixed connective tissue disease; SLE, systemic lupus erythematosus.

Arthralgia may also be a presenting symptom of pediatric systemic lupus

erythematosus (SLE ) and chronic childhood arthritis such as juvenile
idiopathic arthritis (JIA). Interestingly, many children with JIA do not
complain of joint symptoms at presentation. Other symptoms more suggestive of
arthritis include morning stiffness, joint swelling, limited range of motion, pain
with joint motion, gait disturbance, fever, and fatigue or stiffness after physical
inactivity (gelling phenomenon) . A diagnosis of JIA cannot be made without the
finding of arthritis on physical examination (see Chapters 180 and 181 ). No
laboratory test is diagnostic of JIA or any other chronic inflammatory arthritis in
childhood.
Fatigue is a nonspecific symptom that may point to the presence of a
rheumatic disease but is also common in nonrheumatic causes, such as viral
infections, pain syndromes, depression, and malignancy. Fatigue, rather than the
specific complaints of muscle weakness, is a common presenting complaint in
juvenile dermatomyositis (JDM) . It is also frequently present in SLE,
vasculitis, and the chronic childhood arthritides. Overwhelming fatigue with
inability to attend school is more suggestive of chronic fatigue syndrome,
pediatric fibromyalgia, or other amplified pain syndrome.

Signs Suggestive of Rheumatic Disease

A complete physical examination is mandated in any child with suspected
rheumatic disease, because many diseases have associated subtle physical
findings that will further refine the differential diagnosis. In addition, many
rheumatic diseases have multisystem effects, and a stepped assessment should
focus on delineating the extent of organ system involvement (e.g., skin, joints,
muscle, hepatic, renal, cardiopulmonary).
Presence of a photosensitive malar rash that spares the nasolabial folds is
suggestive of SLE (Table 178.2 ; see Fig. 183.1A ), especially in an adolescent
girl. Diffuse facial rash is more indicative of JDM. A hyperkeratotic rash on the
face or around the ears of an adolescent black girl may represent discoid lupus
(see Fig. 183.1D ). A palpable purpuric rash on the extensor surfaces of the
lower extremities points to Henoch-Schönlein purpura (see Fig. 192.2A ). Less
localized purpuric rashes and petechiae are present in systemic vasculitis or
blood dyscrasias, including coagulopathies. Nonblanching erythematous papules
on the palms are seen in vasculitis and SLE as well as endocarditis. Gottron
papules (see Fig. 184.2 ) and heliotrope rashes (see Fig. 184.1 ) along with
erythematous rashes on the elbows and knees are pathognomonic of JDM.
Dilated capillary loops in the nail beds (periungual telangiectasias; see Fig.
184.3 ) are common in JDM, scleroderma, and secondary Raynaud phenomenon.
An evanescent macular rash associated with fever is part of the diagnostic
criteria for systemic-onset arthritis (see Fig. 180.12 ). Sun sensitivity or
photosensitive rashes are indicative of SLE or JDM but can also be caused by
antibiotics.

Table 178.2
Signs Suggestive of Rheumatic Disease

SIGN RHEUMATIC DISEASES COMMENTS NONRHEUMATIC CAUSES

Malar SLE, JDM SLE classically spares nasolabial Sunburn, parvovirus B19 (fifth
rash folds disease), Kawasaki disease
Oral SLE, Behçet disease Behçet disease also associated with HSV infection, PFAPA
ulcers genital ulcers syndrome
Purpuric Vasculitis, e.g., ANCA- HSP typically starts as small lesions Meningococcemia,
rash associated vasculitis, HSP on lower extremities and buttocks thrombocytopenia, clotting
that coalesce disorders
Gottron JDM Look for associated heliotrope rash, Psoriasis, eczema
papules periungual telangiectasias
Arthritis Juvenile idiopathic arthritis, Chronic joint swelling (>6 wk) Postviral arthritis, reactive
SLE, vasculitis, HSP, MCTD, required for diagnosis of chronic arthritis, trauma, infection, Lyme
scleroderma, acute rheumatic arthritis of childhood; MCTD disease, Kawasaki disease,
fever, reactive arthritis associated with diffuse puffiness of malignancy, overuse syndromes
hands
ANCA, Antineutrophil cytoplasmic antibody; HSP, Henoch-Schönlein purpura; HSV, herpes
simplex virus; JDM, juvenile dermatomyositis; MCTD, mixed connective tissue disease; PFAPA,
periodic fever, aphthous stomatitis, pharyngitis, and adenitis; SLE, systemic lupus erythematosus.

Mouth ulcers are part of the diagnostic criteria for SLE and Behçet disease
Laboratory Testing
There are no specific screening tests for rheumatologic disease. Once a
differential diagnosis is determined, appropriate testing can be performed (Tables
178.3 and 178.4 ). Initial studies are generally performed in standard local
laboratories. Screening for specific autoantibodies can be performed in
commercial laboratories, but confirmation of results in a tertiary care center
immunology laboratory is often necessary.

Table 178.3
Autoantibody Specificity and Disease Associations

PREVALENCE
ANTIBODY DISEASE SPECIFICITY
(%)
Antinuclear antibody SLE, juvenile — Associated with increased risk of uveitis
(ANA) rheumatoid arthritis, in JIA and psoriatic arthritis
dermatomyositis, Up to 30% of children testing positive for
scleroderma, psoriatic ANAs have no underlying rheumatic
arthritis, MCTD disease
Double-stranded SLE 60-70 High specificity for SLE; associated with
DNA (dsDNA) lupus nephritis
Smith (Sm) SLE 20-30 Highly specific for SLE; associated with lupus
nephritis
Smooth muscle (Sm) Autoimmune hepatitis — —
Pm-Scl Sclerodermatomyositis — —
(polymyositis-
scleroderma)
SSA (Ro) SLE, Sjögren 25-30 Associated with neonatal lupus syndrome,
syndrome subacute cutaneous lupus, thrombocytopenia
SSB (La) SLE, Sjögren 25-30 Usually coexists with anti-SSA antibody
syndrome
Ribonuclease protein MCTD, SLE 30-40 Suggestive of MCTD unless meets criteria for
(RNP) SLE
Histone Drug-induced lupus, — —
SLE
Centromere Limited cutaneous 70 Nonspecific for systemic sclerosis
systemic sclerosis
Topoisomerase I (Scl- Systemic sclerosis — Rare in childhood
70)
Antineutrophil Vasculitis — —
cytoplasmic
antibodies (ANCAs)
Cytoplasmic — cANCAs associated with granulomatosis with
(cANCAs)/PR3- polyangiitis (Wegener), cystic fibrosis
ANCA
Perinuclear — pANCAs associated with microscopic
(pANCAs)/MPO- polyangiitis, polyarteritis nodosa, SLE,
ANCA inflammatory bowel disease, cystic fibrosis,
 primary sclerosing cholangitis, Henoch-
Schönlein purpura, Kawasaki disease, Churg-
Strauss syndrome
Anticitrullinated RF-positive JIA 50-90 Specific for JIA (RF+), may be positive before
protein (ACPA); also RF
called anti–cyclic
citrullinated protein
(anti-CCP)
MCTD, Mixed connective tissue disease; MPO-ANCA, antimyeloperoxidase; PR3-ANCA,
antiproteinase 3; RF, rheumatoid factor; SLE, systemic lupus erythematosus.
Adapted from Aggerwal A: Clinical application of tests used in rheumatology, Indian J Pediatr
69:889–892, 2002.

Table 178.4
Evaluation Based on Suspected Diagnosis of Rheumatic
Disease

SUSPECTED
FURTHER SUBSPECIALTY
RHEUMATIC INITIAL EVALUATION
EVALUATION EVALUATION
DISEASE(S)
Systemic CBC, ESR, ANA, ALT, AST, If ANA test result is Antiphospholipid Abs, lupus
lupus CPK, creatinine, albumin, total positive: anti-SSA (Ro), anticoagulant, anti–β2 -
erythematosus protein, urinalysis, BP, thyroid anti-SSB (La), anti-Smith, glycoprotein,
(SLE) profile and anti-RNP Abs; anti- echocardiogram; consider
Mixed dsDNA Ab, C3, C4, renal biopsy, PFTs,
connective Coombs, spot urine bronchoscopy with lavage,
tissue disease protein/creatinine ratio, HRCT of chest; consider
(MCTD) CXR lung biopsy
Juvenile CBC, CPK, ALT, AST, LDH, Consider MRI of muscle Consider electromyography
dermatomyositis aldolase, ANA; check gag reflex and possible muscle biopsy,
(JDM) PFTs, swallowing study,
serum neopterin
Juvenile idiopathic CBC, ESR, creatinine, ALT, Consider Ab titers to MRI
arthritis (JIA) AST, consider anti–streptolysin unusual infectious agents,
O/anti–DNAase B for purified protein derivative,
streptococcus-induced arthritis, RF, ANA, HLA-B27, anti-
Epstein-Barr virus titers, Lyme CCP
titer, parvovirus B19 titer, plain
radiograph of joints
Granulomatosis CBC, ANCA, AST, ALT, Spot urine Bronchoscopy with lavage,
with polyangiitis albumin, creatinine, ESR, protein/creatinine ratio, HRCT chest; consider lung
(Wegener urinalysis, CXR, BP anti–myeloperoxidase and and kidney biopsies
granulomatosis) anti–proteinase-3 Abs,
PFTs
Sarcoidosis CBC, electrolytes, AST, ALT, CXR, PFTs Consider testing for Blau
albumin, creatinine, calcium, syndrome in infants (see
phosphorous, ACE, BP Chapter 184 ); HRCT of
chest; consider renal and lung
biopsy
 Localized Skin biopsy, CBC, ESR Serum IgG, ANA, RF,
scleroderma single-stranded DNA Ab,
antihistone Ab, CPK

Systemic ANA, CBC, ESR, BP, AST, Anti-Scl70, PFTs HRCT of chest,
scleroderma ALT, CPK, creatinine, CXR echocardiogram, upper GI
radiography series
Ab, Antibody; ACE, angiotensin-converting enzyme (normally elevated in childhood; interpret with
caution); ALT, alanine transaminase; ANA, antinuclear antibody; anti-dsDNA Ab, anti–double-
stranded DNA antibody; AST, aspartate transaminase; BP, blood pressure; CBCD, complete blood
count with differential; CCP, cyclic citrullinated protein; CPK, creatine phosphokinase; CXR, chest
radiograph; ESR, erythrocyte sedimentation rate; GI, gastrointestinal; HRCT, high-resolution CT;
LDH, lactate dehydrogenase; PFTs, pulmonary function tests; RF, rheumatoid factor; RNP,
ribonucleoprotein.

One essential laboratory test for rheumatic disease assessment is the complete
blood count (CBC), since it yields many diagnostic clues. Elevated WBC count
is compatible with malignancy, infection, systemic JIA, and vasculitis.
Leukopenia can be postinfectious, especially viral, or caused by SLE or
malignancy. Lymphopenia is more specific for SLE than is leukopenia. Platelets
are acute-phase reactants and are therefore elevated with inflammatory markers.
Exceptions are a bone marrow–occupying malignancy, such as leukemia or
neuroblastoma, SLE, and early Kawasaki disease. Anemia is nonspecific and
may be caused by any chronic illness, but hemolytic anemia (positive Coombs
test result) may point to SLE or MCTD. Rheumatoid factor (RF) is present in
<10% of children with JIA and thus has poor sensitivity as a diagnostic tool; RF
may be elevated by infections such as endocarditis, tuberculosis, syphilis, and
viruses (parvovirus B19, hepatitides B and C, mycoplasma), as well as primary
biliary cirrhosis and malignancies. In a child with chronic arthritis, RF serves as
a prognostic indicator.
Inflammatory markers (erythrocyte sedimentation rate, C-reactive protein) are
nonspecific and are elevated in infections and malignancies as well as rheumatic
diseases (Tables 178.5 and 178.6 ). Their levels may also be normal in rheumatic
diseases such as arthritis, scleroderma, and dermatomyositis. Inflammatory
marker measurements are more useful in rheumatic diseases for following
response to treatment than as diagnostic tests. Muscle enzymes include aspartate
transaminase (AST), alanine transaminase (ALT), creatinine phosphokinase
(CPK), aldolase, and lactate dehydrogenase (LDH), any of which may be
elevated in JDM as well as in other diseases causing muscle breakdown. Muscle-
building supplements, medications, and extreme physical activity may also cause
muscle breakdown and enzyme elevations. AST, ALT, and aldolase are also
elevated secondary to liver disease, and a γ-glutamyltransferase (GGT)
measurement may help differentiate whether the source is muscle or liver.

Table 178.5

Comparison of Erythrocyte Sedimentation Rate and C-Reactive Protein

ERYTHROCYTE SEDIMENTATION RATE C-REACTIVE PROTEIN
Advantages Much clinical information in the literature Rapid response to inflammatory
May reflect overall health status stimuli
Wide range of clinically relevant
values are detectable
Unaffected by age and gender
Reflects value of a single acute-
phase protein
Can be measured on stored sera
Quantitation is precise and
reproducible
Disadvantages Affected by red blood cell morphology Not sensitive to changes in SLE
Affected by anemia and polycythemia disease activity
Reflects levels of many plasma proteins, not all of
which are acute-phase proteins
Responds slowly to inflammatory stimuli
Requires fresh sample
May be affected by drugs (IVIG)
IVIG, Intravenous immune globulin; SLE, systemic lupus erythematosus.
From Firestein GS, Budd RC, Gabriel SE, et al, editors: Kelley & Firestein's textbook of
rheumatology, ed 10, Philadelphia, 2017, Elsevier (Table 57.3 , p 849).

Table 178.6
Conditions Associated With Elevated C-
Reactive Protein Levels
Normal Or Minor Elevation (<1 mg/dL)

1. Vigorous exercise
2. Common cold
3. Pregnancy
4. Gingivitis
5. Seizures
6. Depression
7. Insulin resistance and diabetes
8. Several genetic polymorphisms
 9. Obesity

Moderate Elevation (1-10 mg/dL)

1. Myocardial infarction
2. Malignancies
3. Pancreatitis
4. Mucosal infection (bronchitis, cystitis)
5. Most systemic autoimmune diseases
6. Rheumatoid arthritis

Marked Elevation (>10 mg/dL)

1. Acute bacterial infection (80–85%)

2. Major trauma, surgery
3. Systemic vasculitis

From Firestein GS, Budd RC, Gabriel SE, et al, editors: Kelley & Firestein's
textbook of rheumatology, ed 10, Philadelphia, 2017, Elsevier (Table 57-4, p
849).

The use of an antinuclear antibody (ANA) measurement as a screening test is

not recommended because it has low specificity. A positive ANA test result may
be induced by infection, especially EBV infection, endocarditis, and parvovirus
B19 infection. The ANA test result is also positive in up to 30% of normal
children, and ANA level is increased in those with a first-degree relative with a
known rheumatic disease. In the majority of children with a positive ANA test
result without signs of a rheumatic disease on initial evaluation, autoimmune
disease does not develop over time, so this finding does not necessitate referral
to a pediatric rheumatologist. A positive ANA test result is found in many
rheumatic diseases, including JIA, in which it serves as a predictor of the risk for
inflammatory eye disease (Table 178.7 ). Once a positive ANA test result is
discovered in a child, the need for specific autoantibody testing is directed by the
presence of clinical signs and symptoms (see Table 178.3 ).
Table 178.7
Other Nonrheumatic Conditions With
Elevated Acute Phase Responses
Neuroendocrine Changes

Fever, somnolence, and anorexia

Increased secretion of corticotropin-releasing hormone, corticotropin, and
cortisol
Increased secretion of arginine vasopressin
Decreased production of insulin-like growth factor I
Increased adrenal secretion of catecholamines

Hematopoietic Changes

Anemia of chronic disease

Leukocytosis
Thrombocytosis

Metabolic Changes

Loss of muscle and negative nitrogen balance

Decreased gluconeogenesis
Osteoporosis
Increased hepatic lipogenesis
Increased lipolysis in adipose tissue
Decreased lipoprotein lipase activity in muscle and adipose tissue
Cachexia

Hepatic Changes

Increased metallothionein, inducible nitric oxide synthase, heme

oxygenase, manganese superoxide dismutase, and tissue inhibitor of
metalloproteinase 1
Decreased phosphoenolpyruvate carboxykinase activity
coordination of subspecialty care and rehabilitation services with communication
of clinical information; and child- and family-centered chronic illness care,
including self-management support, alliance with community resources,
partnership with schools, resources for dealing with the financial burdens of
disease, and connection with advocacy groups. Planning for transition to adult
care providers needs to start in adolescence. Central to effective care is
partnership with the primary care provider, who helps coordinate care, monitor
compliance with treatment plans, ensure appropriate immunization, monitor for
medication toxicities, and identify disease exacerbations and concomitant
infections. Communication between the primary care provider and subspecialty
team permits timely intervention when needed.

Table 179.1
Multidisciplinary Treatment of Rheumatic Diseases in
Childhood
Accurate diagnosis and Pediatric rheumatologist
education of family Pediatrician
Nurse:
• Disease-related education
• Medication administration (injection teaching)
• Safety monitoring
Social worker:
• Facilitation of school services
• Resource identification (community, government, financial, advocacy groups,
vocational rehabilitation)
Physical medicine and Physical therapy:
rehabilitation • Addressing deficits in joint or muscle mobility, limb length discrepancies, gait
abnormalities, and weakness
Occupational therapy:
• Splinting to reduce joint contractures/deformities and lessen stress on joints;
adaptive devices for activities of daily living
Consultant team Ophthalmology:
• Eye screening for uveitis (see Table 180.4 )
• Screening for medication-related ocular toxicity (hydroxychloroquine,
glucocorticoids)
Nephrology
Orthopedics
Dermatology
Gastroenterology
Physical and psychosocial Nutrition:
growth and development • Addressing undernourishment from systemic illness and
obesity/overnourishment from glucocorticoids
School integration:
• Individualized educational plan (IEP) or 504 plan
Peer-group relationships
 Individual and family counseling
Coordination of care Involvement of patient and family as active team members
Communication among healthcare providers
Involvement of school (school nurse) and community (social worker) resources

Therapeutics
A key principle of pharmacologic management of rheumatic diseases is that
early disease control, striving for induction of remission, leads to less tissue and
organ damage with improved short- and long-term outcomes. Medications are
chosen from broad therapeutic classes on the basis of diagnosis, disease severity,
anthropometrics, and adverse effect profile. Many drug therapies used do not
have U.S. Food and Drug Administration (FDA) indications for pediatric
rheumatic diseases given the relative rarity of these conditions. The evidence
base may be limited to case series, uncontrolled studies, or extrapolation from
use in adults. The exception is JIA, for which there is a growing body of
randomized controlled trial (RCT) evidence, particularly for newer therapeutics.
Therapeutic agents used for treatment of childhood rheumatic diseases have
various mechanisms of action, but all suppress inflammation (Table 179.2 ).
Both biologic and nonbiologic disease-modifying antirheumatic drugs
(DMARDs ) directly affect the immune system. DMARDs should be prescribed
by specialists. Live vaccines are contraindicated in patients taking
immunosuppressive glucocorticoids or DMARDs. A negative test result for
tuberculosis (purified protein derivative and/or QuantiFERON-TB Gold) should
be verified and the patient's immunization status updated, if possible, before
such treatment is initiated. Killed vaccines are not contraindicated, and annual
injectable influenza vaccine is recommended.

Table 179.2
Therapeutics for Childhood Rheumatic Diseases*

ADVERSE
CLASSIFICATION THERAPEUTIC † DOSE INDICATION † REACTIONS
Nonsteroidal Etodolac a PO once-daily JIA GI intolerance
antiinflammatory dose: Spondyloarthropathy (abdominal pain,
drugs (NSAIDs) ‡ 20-30 kg: 400 Pain nausea), gastritis,
mg Serositis hepatitis, tinnitus,
31-45 kg: 600 Cutaneous vasculitis anemia,
mg Uveitis pseudoporphyria,
46-60 kg: 800 aseptic meningitis,
 mg headache, renal
>60 kg: 1,000 disease
mg
Ibuprofen a 40 mg/kg/day
PO in 3 divided
doses
Max: 2400
mg/day
Naproxen a 15 mg/kg/day
PO in 2 divided
doses
Max 1,000
mg/day
Celecoxib a 10-25 kg: 50
mg PO bid
>25 kg: 100 mg
PO bid
Meloxicam a 0.125 mg/kg
PO qd
Max 7.5 mg
Disease-modifying Methotrexate a 10-20 mg/m2 JIA GI intolerance
antirheumatic drugs /wk (0.35-0.65 Uveitis (nausea,
(DMARDs) mg/kg/wk) PO vomiting),
20-30 mg/m2 hepatitis,
/wk (0.65-1 myelosuppression,
mg/kg/wk) SC; mucositis,
higher doses teratogenesis,
better absorbed lymphoma,
by SC injection interstitial
pneumonitis
Leflunomide PO once daily: JIA Hepatitis, hepatic
10 to <20 kg: necrosis,
10 mg cytopenias,
20-40 kg: 15 mucositis,
mg teratogenesis,
>40 kg: 20 mg peripheral
neuropathy
Hydroxychloroquine 5 mg/kg PO qd; SLE Retinal toxicity,
do not exceed 5 JDMS GI intolerance,
mg/kg/daily Antiphospholipid rash, skin
Max 400 mg antibody syndrome discoloration,
daily anemia,
cytopenias,
myopathy, CNS
stimulation, death
(overdose)
Sulfasalazine a 30-50 Spondyloarthropathy, GI intolerance,
mg/kg/day in 2 JIA rash,
divided doses hypersensitivity
Adult max 3 reactions, Stevens-
g/day Johnson
syndrome,
cytopenias,
hepatitis,
headache
Tumor necrosis Adalimumab a SC once every JIA Injection site
factor (TNF)-α other wk: Spondyloarthropathy reaction, infection,
antagonists 10 to <15 kg: Psoriatic arthritis rash, cytopenias,
10 mg Uveitis lupus-like
15 to <30 kg: syndrome,
20 mg potential increased
≥30 kg: 40 mg malignancy risk
Etanercept a 0.8 mg/kg SC once JIA Injection site
weekly (max 50 reactions,
mg/dose) or 0.4 infections, rash,
mg/kg SC twice demyelinating
weekly (max 25 disorders,
mg/dose) cytopenias,
potential increased
malignancy risk
Infliximab 5-10 mg/kg IV JIA Infusion reactions,
every 4-8 wk Spondyloarthropathy hepatitis, potential
Uveitis increased
Sarcoidosis malignancy risk
Modulate T-cell Abatacept a IV every 2 wk JIA Infection,
activation ×3 doses, then headache,
monthly for ≥6 potential increased
yr of age: malignancy risk
<75 kg: 10
mg/kg
75-100 kg: 750
mg
>100 kg: 1,000
mg
SC once
weekly:
10 to <25 kg:
50 mg
≥25 to <50 kg:
87.5 mg
≥50 kg: 125 mg
Anti-CD20 (B-cell) Rituximab 575 mg/m2 , max SLE Infusion reactions,
antibody 1,000 mg, IV on lymphopenia,
days 1 and 15 reactivation
hepatitis B, rash,
serum sickness,
arthritis, PML
Anti-BLyS antibody Belimumab e 10 mg/kg IV every 2 SLE Infusion reactions,
wk ×3 doses, then infection,
every 4 wk depression
Interleukin (IL)-1 Anakinra 1-2 mg/kg/daily Systemic JIA Injection site
antagonist Adult max 100 CAPS reactions,
mg infection
Canakinumab b Given SC every CAPS Injection site
8 wk (CAPS) Systemic JIA reaction, infection,
every 4 wk diarrhea, nausea,
(systemic JIA): vertigo, headache
15-40 kg: 2
mg/kg (up to 3
mg/kg if
 needed)
>40 kg: 150 mg
IV: Polyarticular JIA
<30 kg: 10
mg/kg/dose
every 4 wk
≥30 kg: 8
mg/kg/dose
every 4 wk;
maximum dose:
800 mg/dose
SC:
<30 kg: 162
mg/dose once
every 3 wk
≥30 kg: 162
mg/dose once
every 2 wk
IL-6 antagonist Tocilizumab a ≥2 yr and ≥30 Systemic JIA Infusion reactions,
kg: 8 elevated LFTs,
mg/kg/dose elevated lipids,
every 2 wk thrombocytopenia,
≥2 yr and ≤30 infections
kg: 12
mg/kg/dose
every 2 wk
Intravenous immune IVIG c 1,000-2,000 Kawasaki disease Infusion reaction,
globulin mg/kg IV JDMS aseptic meningitis,
infusion SLE renal failure
For JDMS, give
monthly
Cytotoxic Cyclophosphamide 0.5-1 g/m2 IV SLE Nausea, vomiting,
(max 1.5 g) Vasculitis myelosuppression,
monthly for 6 JDMS mucositis,
mo induction, Pulmonary hyponatremia,
then every 2-3 hemorrhage alopecia,
mo hemorrhagic
Oral regimen: cystitis, gonadal
1-2 failure,
mg/kg/daily; teratogenesis,
max 150 secondary
mg/daily malignancy
Immunosuppressive Mycophenolate Oral SLE GI intolerance
mofetil suspension: Uveitis (diarrhea, nausea,
max 1,200 vomiting), renal
mg/m2 /day PO impairment,
(up to 2 g/day) neutropenia,
divided bid teratogenesis,
Capsules: max secondary
1,500 mg/day malignancy, PML
PO for BSA
1.25-1.5 m2 , 2
g/day PO for
BSA >1.5 m2
divided bid
 Glucocorticoids Prednisone a , d - f 0.05-2 SLE Cushing
mg/kg/day PO JDMS syndrome,
given in 1-4 Vasculitis osteoporosis,
divided doses; JIA increased appetite,
max varies by Uveitis weight gain,
individual (80 Sarcoidosis striae,
mg/daily) hypertension,
Adverse effects adrenal
are dose suppression,
dependent; hyperglycemia,
lowest effective infection,
dose should be avascular necrosis
used
Methylprednisolone 0.5-1.7 SLE
a , d - g mg/kg/day or 5- JDMS
2
25 mg/m /day Vasculitis
IM/IV in Sarcoidosis
divided doses Localized
every 6-12 hr scleroderma
For severe
manifestations:
30 mg/kg/dose
(max 1 g) daily
for 1-5 days
Intraarticular Dose varies by joint JIA Subcutaneous
and formulation atrophy, skin
hypopigmentation,
calcification,
infection
Prednisolone 1-2 drops into Uveitis Ocular
ophthalmic eye up to every hypertension,
suspension hr while awake glaucoma, nerve
Needs damage, cataract,
monitoring by infection
ophthalmologist
* Consult a clinical pharmacology reference for current dosing and monitoring guidelines, and

complete list of known adverse effects.

† Therapeutics used in practice may not have a FDA-approved indication. Individual therapeutics
annotated with FDA-approved indication as follows: a , JIA; b , CAPS; c , Kawasaki disease; d ,
sarcoidosis; e , SLE; f , uveitis; g , dermatomyositis.
‡ Many more products available in this class.

qd, Once daily; bid, twice daily; Blys, B-lymphocyte stimulator; BMP, basic metabolic panel; BSA,
body surface area; BUN, blood urea nitrogen; CAPS, cryopyrin-associated periodic syndrome;
CBC, complete blood count; CNS, central nervous system; dsDNA, double-stranded DNA; GI,
gastrointestinal; IM, intramuscular(ly); IV, intravenous(ly); IVIG, intravenous immune globulin;
JDMS, juvenile dermatomyositis; JIA, juvenile idiopathic arthritis; LFTs, liver function tests; PML,
progressive multifocal leukoencephalopathy; PO, by mouth; SC, subcutaneous(ly); SLE, systemic
lupus erythematosus; TB, tuberculosis.
Biologic Agents
Biologic agents are proteins that have been engineered to target and modulate
specific components of the immune system, with the goal of decreasing the
inflammatory response. Antibodies have been developed to target specific
cytokines such as IL-1 and IL-6 or to interfere with specific immune cell
function through depletion of B cells or suppression of T-cell activation (Table
179.3 ). The availability of biologic agents has dramatically increased the
therapeutic options for treating rheumatic disease recalcitrant to nonbiologic
therapies, and in some cases biologics are becoming first-line interventions. A
primary concern is the increased risk of malignancy when biologics are
combined with other immunosuppressants.

Table 179.3

Method of Action of Biologic Therapies Studied in Juvenile Idiopathic Arthritis

DRUG METHOD OF ACTION
Etanercept Soluble TNF p75 receptor fusion protein that binds to and inactivates TNF-α
Infliximab Chimeric human/mouse monoclonal antibody that binds to soluble TNF-α and its membrane-bound
precursor, neutralizing its action
Adalimumab A humanized IgG1 monoclonal antibody that binds to TNF-α
Abatacept Soluble, fully human fusion protein of the extracellular domain of (CTLA-4, linked to a modified
Fc portion of the human IgG1 . It acts as a co-stimulatory signal inhibitor by binding competitively
to CD80 or CD86, where it selectively inhibits T-cell activation
Tocilizumab A humanized anti–human IL-6 receptor monoclonal antibody
Anakinra An IL-1 receptor antagonist (IL-1RA)
CTLA, Cytotoxic T lymphocyte–associated antigen; IL, interleukin; TNF, tumor necrosis factor.
From Beresford MW, Baildam EM: New advances in the management of juvenile idiopathic
arthritis. Part 2. The era of biologicals, Arch Dis Child Educ Pract Ed 94:151–156, 2009.

Tumor Necrosis Factor-α Antagonists

Two TNF antagonists have an FDA indication for treatment of children with
moderate to severe polyarticular JIA (etanercept and adalimumab). Etanercept is
a genetically engineered fusion protein consisting of 2 identical chains of the
recombinant extracellular TNF receptor monomer fused with the Fc domain of
human immunoglobulin G1 . Etanercept binds both TNF-α and lymphotoxin-α
(formerly called TNF-β) and inhibits their activity. Three fourths of children
with active polyarticular JIA that fails to respond to MTX demonstrate response
to etanercept after 3 mo of therapy. Dosing is 0.8 mg/kg subcutaneously weekly
Nigrovic PA, Mannion M, Prince F, et al. Anakinra as first-line
disease-modifying therapy in systemic juvenile idiopathic
arthritis. Arthritis Rheum . 2011;63:545–555.
Shum K, Askanase A. Belimumab and the clinical data. Curr
Rheumatol Rep . 2012;14:310–317.
Sobel RE, Lovell DJ, Brunner HI, et al. Safety of celecoxib and
nonselective nonsteroidal anti-inflammatory drugs in juvenile
idiopathic arthritis: results of the Phase 4 registry. Pediatr
Rheumatol Online J . 2014;12:29.
Sterba Y, Ilowite N. Biologics in pediatric rheumatology: quo
vadis. Curr Rheumatol Rep . 2016;18(7):45.
CHAPTER 180

Juvenile Idiopathic Arthritis

Eveline Y. Wu, C. Egla Rabinovich

Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in

children and one of the more common chronic illnesses of childhood. JIA
represents a heterogeneous group of disorders sharing the clinical manifestation
of arthritis. The etiology and pathogenesis of JIA are largely unknown, and the
genetic component is complex, making clear distinction among various subtypes
difficult. As a result, several classification schemes exist, each with its own
limitations. The former classification of the American College of
Rheumatology (ACR) uses the term juvenile rheumatoid arthritis and
categorizes the disease into 3 onset types (Table 180.1 ). Attempting to
standardize nomenclature, the International League of Associations for
Rheumatology (ILAR) proposed a different classification using the term
juvenile idiopathic arthritis (Table 180.2 ), inclusive of all subtypes of chronic
juvenile arthritis. We refer to the ILAR classification criteria; see Chapter 181
for enthesitis-related arthritis (ERA) and psoriatic JIA (Tables 180.3 and 180.4 ).
Table 180.1
Criteria for the Classification of Juvenile
Rheumatoid Arthritis

Age at onset: <16 yr

Arthritis (swelling or effusion, or the presence of ≥2 of the following signs:
limitation of range of motion, tenderness or pain on motion, increased
heat) in ≥1 joint
Duration of disease: ≥6 wk
Onset type defined by type of articular involvement in the 1st 6 mo after
onset:
 Polyarthritis: ≥5 inflamed joints
Oligoarthritis: ≤4 inflamed joints
Systemic-onset disease: arthritis with rash and a characteristic
quotidian fever
Exclusion of other forms of juvenile arthritis

Adapted from Cassidy JT, Levison JE, Bass JC, et al: A study of classification
criteria for a diagnosis of juvenile rheumatoid arthritis, Arthritis Rheum 29:174–
181, 1986.

Table 180.2
International League of Associations for Rheumatology
Classification of Juvenile Idiopathic Arthritis (JIA)

CATEGORY DEFINITION EXCLUSIONS

Systemic JIA Arthritis in ≥1 joint with, or preceded by, a. Psoriasis or a history of psoriasis in patient
fever of at least 2 wk in duration that is or first-degree relative
documented to be daily (quotidian* ) for at b. Arthritis in an HLA-B27–positive boy
least 3 days and accompanied by ≥1 of the beginning after 6th birthday
following: c. Ankylosing spondylitis, enthesitis-related
1. Evanescent (nonfixed) erythematous rash arthritis, sacroiliitis with IBD, Reiter
2. Generalized lymph node enlargement syndrome, or acute anterior uveitis, or
3. Hepatomegaly or splenomegaly or both history of 1 of these disorders in first-degree
4. Serositis † relative
d. Presence of IgM RF on at least 2 occasions
at least 3 mo apart
Oligoarthritis Arthritis affecting 1-4 joints during 1st 6 a, b, c, d (above)
mo of disease; 2 subcategories are plus
recognized: e. Presence of systemic JIA in the patient
1. Persistent oligoarthritis—affecting ≤4 joints
throughout the disease course
2. Extended oligoarthritis—affecting >4 joints
after 1st 6 mo of disease
Polyarthritis Arthritis affecting ≥5 joints during 1st 6 mo of a, b, c, d, e
(RF negative) disease; a test for RF is negative
Polyarthritis Arthritis affecting ≥5 joints during 1st 6 mo of a, b, c, e
(RF positive) disease; ≥2 tests for RF at least 3 mo apart
during 1st 6 mo of disease are positive
Psoriatic Arthritis and psoriasis, or arthritis and at least 2 b, c, d, e
arthritis of the following:
1. Dactylitis ‡
2. Nail pitting § and onycholysis
3. Psoriasis in first-degree relative
Enthesitis- Arthritis and enthesitis, ǁ or arthritis or enthesitis a, d, e
related arthritis with at least 2 of the following:
1. Presence of or history of sacroiliac joint
 tenderness or inflammatory lumbosacral pain,
or both ¶
2. Presence of HLA-B27 antigen
3. Onset of arthritis in a male >6 yr old
4. Acute (symptomatic) anterior uveitis
5. History of ankylosing spondylitis, enthesitis-
related arthritis, sacroiliitis with IBD, Reiter
syndrome, or acute anterior uveitis in first-
degree relative
Undifferentiated Arthritis that fulfills criteria in no category or in
arthritis ≥2 of the above categories.
* Quotidian fever is defined as a fever that rises to 39°C (102.2°F) once daily and returns to 37°C

(98.6°F) between fever peaks.

† Serositis refers to pericarditis, pleuritis, or peritonitis, or some combination of the 3.

‡ Dactylitis is swelling of ≥1 digit(s), usually in an asymmetric distribution, that extends beyond the

joint margin.
§ A minimum of 2 pits on any 1 or more nails at any time.
ǁ
Enthesitis is defined as tenderness at the insertion of a tendon, ligament, joint capsule, or fascia
to bone.
¶ Inflammatory lumbosacral pain refers to lumbosacral pain at rest with morning stiffness that

improves on movement.
IBD, Inflammatory bowel disease; RF, rheumatoid factor.
From Firestein GS, Budd RC, Harris ED Jr, et al, editors: Kelley's textbook of rheumatology, ed 8,
Philadelphia, 2009, Saunders.

Table 180.3
Characteristics of ACR and ILAR Classifications of
Childhood Chronic Arthritis

PARAMETER ACR (1977) ILAR (1997)

Term Juvenile rheumatoid Juvenile idiopathic arthritis
arthritis (JRA) (JIA)
Minimum duration ≥6 wk ≥6 wk
Age at onset <16 yr <16 yr
≤4 joints in 1st 6 mo after presentation Pauciarticular Oligoarthritis:
Persistent: <4 joints for
course of disease
Extended: >4 joints after 6
mo
>4 joints in 1st 6 mo after presentation Polyarticular Polyarthritis, RF
negative
Polyarthritis, RF
positive
Fever, rash, arthritis Systemic onset Systemic
 Other categories included Exclusion of other Psoriatic arthritis
forms Enthesitis-related
arthritis
Undifferentiated:
Fits no other category
Fits >1 category
Inclusion of psoriatic arthritis, inflammatory bowel No (see Chapter 181 ) Yes
disease, ankylosing spondylitis
ACR, American College of Rheumatology; ILAR, International League of Associations for
Rheumatology; RF, rheumatoid factor.

Table 180.4
Overview of Main Features of Subtypes of Juvenile
Idiopathic Arthritis (JIA)

PEAK
% of
ILAR AGE at FEMALE:MALE ARTHRITIS EXTRAARTICULAR LABORATORY
ALL JIA
SUBTYPE ONSET RATIO PATTERN FEATURES INVESTIGATIONS
CASES
(yr)
Systemic 1-5 1 : 1 5-15 Polyarticular, often Daily fever; evanescent Anemia; WBC ↑↑;
arthritis affecting knees, rash; pericarditis; ESR ↑↑; CRP ↑↑;
wrists, and ankles; pleuritis ferritin ↑; platelets ↑↑
also fingers, neck, (normal or ↓ in
and hips MAS)

Oligoarthritis 2-4 3 : 1 40-50 Knees ++; ankles, Uveitis in 30% of cases ANA positive in
(but fingers + 60%; other test
ethnic results usually
variation) normal; may have
mildly ↑ ESR/CRP

Polyarthritis:
RF negative 2-4 and 3 : 1 and 10 : 1 20-35 Symmetric or Uveitis in 10% ANA positive in
10-14 asymmetric; small 40%; RF negative;
and large joints; ESR ↑ or ↑↑; CRP ↑
cervical spine; or normal; mild
temporomandibular anemia
joint
 RF positive 9-12 9 : 1 <10 Aggressive Rheumatoid nodules in RF positive; ESR ↑↑;
symmetric 10%; low-grade fever CRP ↑/normal; mild
polyarthritis anemia

Psoriatic 2-4 and 2 : 1 5-10 Asymmetric Uveitis in 10%; ANA positive in

arthritis 9-11 arthritis of small or psoriasis in 50% 50%; ESR ↑; CRP ↑
medium-sized or normal; mild
joints anemia

Enthesitis- 9-12 1 : 7 5-10 Predominantly Acute anterior uveitis; 80% of patients

related lower limb joints association with positive for HLA-
arthritis affected; reactive arthritis and B27
sometimes axial inflammatory bowel
skeleton (but less disease
than in adult,
ankylosing
spondylitis)
ILAR, International League of Associations for Rheumatology; ANA, antinuclear antibody; CRP, C-
reactive protein; ESR, erythrocyte sedimentation rate; MAS, macrophage activation syndrome;
MTX, methotrexate; NSAIDs, nonsteroidal antiinflammatory drugs; RF, rheumatoid factor; TNF,
tumor necrosis factor; WBC, white blood cell count.
From Firestein GS, Budd RC, Harris ED Jr, et al, editors: Kelley's textbook of rheumatology, ed 8,
Philadelphia, 2009, Saunders.

Epidemiology
The worldwide incidence of JIA ranges from 0.8-22.6 per 100,000 children per
year, with prevalence ranges from 7-401 per 100,000. These wide-ranging
numbers reflect population differences, particularly environmental exposure and
immunogenetic susceptibility, along with variations in diagnostic criteria,
difficulty in case ascertainment, and lack of population-based data. An estimated
300,000 U.S. children have arthritis, including 100,000 with a form of JIA.
Oligoarthritis is the most common subtype (40–50%), followed by
polyarthritis (25–30%) and systemic JIA (5–15%) (see Table 180.4 ). There is
no sex predominance in systemic JIA (sJIA ), but more girls than boys are
affected in both oligoarticular (3 : 1) and polyarticular (5 : 1) JIA. The peak age
at onset is 2-4 yr for oligoarticular disease. Age of onset has a bimodal
distribution in polyarthritis, with peaks at 2-4 yr and 10-14 yr. sJIA occurs
throughout childhood, with a peak at 1-5 yr.

FIG. 180.4 Oligoarticular juvenile idiopathic arthritis with swelling and
flexion contracture of the right knee.

Table 180.5
Frequency of Ophthalmologic Examination in Patients With
Juvenile Idiopathic Arthritis
Referral
• Patients should be referred at time of diagnosis, or suspicion, of JIA
Initial screening examination
• Should occur as soon as possible and no later than 6 wk from referral
• Symptomatic ocular patients should be seen within a week of referral
Ongoing screening
• Screening at two monthly intervals from onset of arthritis for 6 mo
• Followed by 3-4 monthly screening for time outlined below
Oligoarticular JIA, psoriatic arthritis, and enthesitis-related arthritis irrespective of ANA status, onset under 11 yr
AGE AT ONSET (YR) LENGTH OF SCREENING (YR)
<3 8
3-4 6
5-8 3
9-10 1
 Polyarticular, ANA-positive JIA, onset <10 yr
AGE AT ONSET (YR) LENGTH OF SCREENING (YR)
<6 5
6-9 2
• Polyarticular, ANA-negative JIA, onset <7 yr
• 5-yr screening for all children
• Systemic JIA and rheumatoid factor–positive polyarticular JIA
Uveitis risk very low; however, diagnostic uncertainty in the early stages and overlap of symptoms may mean
initial screening is indicated
• All categories, onset >11 yr
1-yr screening for all children
• After stopping immunosuppression (eg, methotrexate)
Two monthly screening for 6 mo, then revert to previous screening frequency as above
• After discharge from screening
Patients should receive advice about regular self-monitoring by checking vision uniocularly once weekly and
when to seek medical advice
Screening may need to continue indefinitely in situations where a young person may be unable to detect a change
in vision or be unwilling to seek re-referral
Annual check by optometrist as a useful adjunct
From Clarke SLN, Sen ES, Ramanan AV: Juvenile idiopathic arthritis-associated uveitis. Pediatr
Rheumatol 14:27, 2016. p. 3.

Polyarthritis is characterized by inflammation of ≥5 joints in both upper and

lower extremities (Figs. 180.5 and 180.6 ). Rheumatoid factor (RF)–positive
polyarthritis resembles the characteristic symmetric presentation of adult
rheumatoid arthritis. Rheumatoid nodules on the extensor surfaces of the
elbows, spine, and over the Achilles tendons, although unusual, are associated
with a more severe course and almost exclusively occur in RF-positive
individuals (Fig. 180.7 ). Micrognathia reflects chronic temporomandibular
joint disease (Fig. 180.8 ). Cervical spine involvement (Fig. 180.9 ), manifesting
as decreased neck extension, occurs with a risk of atlantoaxial subluxation and
neurologic sequelae. Hip disease may be subtle, with findings of decreased or
painful ROM on examination (Fig. 180.10 ).
encephalopathy. Laboratory evaluation shows thrombocytopenia and leukopenia
with elevated liver enzymes, lactate dehydrogenase, ferritin, and triglycerides.
Patients may have purpura and mucosal bleeding, as well as elevated fibrin split
product values and prolonged prothrombin and partial prothromboplastin times.
The erythrocyte sedimentation rate (ESR) falls because of hypofibrinogenemia
and hepatic dysfunction, a feature useful in distinguishing MAS from a flare of
systemic disease (Table 180.6 ). An international consensus panel developed a
set of classification criteria for sJIA-associated MAS, including
hyperferritinemia (>684 ng/mL) and any 2 of the following: thrombocytopenia
(≤181 × 109 /L), elevated liver enzymes (aspartate transaminase >48 U/L),
hypertriglyceridemia (>156 mg/dL), and hypofibrinogenemia (≤360 mg/dL)
(Table 180.6 ). These criteria apply to a febrile patient suspected of sJIA and in
the absence of disorders such as immune-mediated thrombocytopenia, infectious
hepatitis, familial hypertriglyceridemia or visceral leishmaniasis. A relative
change in laboratory values is likely more relevant in making an early diagnosis
than are absolute normal values . A bone marrow aspiration and biopsy may be
helpful in diagnosis, but evidence of hemophagocytosis is not always evident.
Emergency treatment with high-dose intravenous methylprednisolone,
cyclosporine, or anakinra may be effective. Severe cases may require therapy
similar to that for primary HLH (see Chapter 534.2 ).
Table 180.6
Macrophage Activation Syndrome (MAS)
Laboratory Features*

1. Cytopenias
2. Abnormal liver function tests
3. Coagulopathy (hypofibrinogenemia)
4. Decreased erythrocyte sedimentation rate
5. Hypertriglyceridemia
6. Hyponatremia
7. Hypoalbuminemia
8. Hyperferritinemia
9. Elevated sCD25 and sCD163

Clinical Features*
 1. Nonremitting fever
2. Hepatomegaly
3. Splenomegaly
4. Lymphadenopathy
5. Hemorrhages
6. Central nervous system dysfunction (headache, seizures, lethargy, coma,
disorientation)

Histopathologic Features*

1. Macrophage hemophagocytosis in the bone marrow aspirate

2. Increased CD163 staining of the bone marrow

Proposed Criteria for MAS in sJIA †

• Serum ferritin >684 ng/mL and

• Any 2 of the following:
• Thrombocytopenia (≤181 × 109 /L)
• Elevated liver enzymes (aspartate transaminase >48 U/L)
• Hypertriglyceridemia (>156 mg/dL)
• Hypofibrinogenemia (≤360 mg/dL)

* From Ravelli A, Grom A, Behrens E, Cron R: Macrophage activation

syndrome as part of systemic juvenile idiopathic arthritis: diagnosis, genetics,

pathophysiology and treatment, Genes Immun 13:289–298, 2012.
† From Ravelli A, Minoia F, Davì S, et al: 2016 Classification criteria for

macrophage activation syndrome complicating systemic juvenile idiopathic

arthritis: a European League Against Rheumatism/American College of
Rheumatology/Paediatric Rheumatology International Trials Organisation
collaborative initiative, Arthritis Rheumatol 68:566-576, 2016.

Bone mineral metabolism and skeletal maturation are adversely affected in

children with JIA, regardless of subtype. Children with JIA have decreased bone
mass (osteopenia), which appears to be associated with increased disease
activity. Increased levels of cytokines such as TNF-α and IL-6, both key
regulators in bone metabolism, have deleterious effects on bone within the joint
as well as systemically in the axial and appendicular bones. Abnormalities of
skeletal maturation become most prominent during the pubertal growth spurt.

Diagnosis
JIA is a clinical diagnosis without any diagnostic laboratory tests. The
meticulous clinical exclusion of other diseases and many mimics is therefore
essential. Laboratory studies, including tests for ANA and RF, are only
supportive or prognostic, and their results may be normal in patients with JIA
(see Tables 180.1 , 180.3 , and 180.4 ).

Differential Diagnosis
The differential diagnosis for arthritis is broad and a careful, thorough
investigation for other underlying etiology is imperative (Table 180.7 ). History,
physical examination, laboratory tests, and radiography may help exclude other
possible causes. Arthritis can be a presenting manifestation for any of the
multisystem rheumatic diseases of childhood, including systemic lupus
erythematosus (see Chapter 183 ), juvenile dermatomyositis (see Chapter 184 ),
sarcoidosis (see Chapter 190 ), and the vasculitic syndromes (see Chapter 192 ).
In scleroderma (see Chapter 185 ), limited ROM caused by sclerotic skin
overlying a joint may be confused with sequelae from chronic inflammatory
arthritis. Acute rheumatic fever is characterized by exquisite joint pain and
tenderness, remittent fever, and migratory polyarthritis. Autoimmune hepatitis
can also be associated with an acute arthritis.
Table 180.7
Conditions Causing Arthritis or Extremity
Pain
Rheumatic and Inflammatory Diseases

Juvenile idiopathic arthritis

 Systemic lupus erythematosus
Juvenile dermatomyositis
Polyarteritis nodosa
Scleroderma
Sjögren syndrome
Behçet disease
Overlap syndromes
Antineutrophilic cytoplasmic antibody (ANCA)–associated vasculitis
Sarcoidosis
Kawasaki syndrome
Henoch-Schönlein purpura
Chronic recurrent multifocal osteomyelitis

Seronegative Spondyloarthropathies

Juvenile ankylosing spondylitis

Inflammatory bowel disease
Psoriatic arthritis
Reactive arthritis associated with urethritis, iridocyclitis, and
mucocutaneous lesions

Infectious Illnesses

Bacterial arthritis (septic arthritis, Staphylococcus aureus, Kingella kingae,

pneumococcal, gonococcal, Haemophilus influenzae )
Lyme disease
Viral illness (parvovirus, rubella, mumps, Epstein-Barr, hepatitis B,
chikungunya)
Fungal arthritis
Mycobacterial infection
Spirochetal infection
Endocarditis

Reactive Arthritis

Acute rheumatic fever

 Reactive arthritis (postinfectious caused by Shigella, Salmonella, Yersinia,
Chlamydia, or meningococcus)
Serum sickness
Toxic synovitis of the hip
Postimmunization

Immunodeficiencies

Hypogammaglobulinemia
Immunoglobulin A deficiency
Common variable immunodeficiency disease (CVID)
Human immunodeficiency virus (HIV)

Congenital and Metabolic Disorders

Gout
Pseudogout
Mucopolysaccharidoses
Thyroid disease (hypothyroidism, hyperthyroidism)
Hyperparathyroidism
Vitamin C deficiency (scurvy)
Hereditary connective tissue disease (Marfan syndrome, Ehlers-Danlos
syndrome)
Fabry disease
Farber disease
Amyloidosis (familial Mediterranean fever)

Bone and Cartilage Disorders

Trauma
Patellofemoral syndrome
Hypermobility syndromes
Osteochondritis dissecans
Avascular necrosis (including Legg-Calvé-Perthes disease)
Hypertrophic osteoarthropathy
Slipped capital femoral epiphysis
 Osteolysis
Benign bone tumors (including osteoid osteoma)
Langerhans cell histiocytosis
Rickets

Neuropathic Disorders

Peripheral neuropathies
Carpal tunnel syndrome
Charcot joints

Neoplastic Disorders

Leukemia
Neuroblastoma
Lymphoma
Bone tumors (osteosarcoma, Ewing sarcoma)
Histiocytic syndromes
Synovial tumors

Hematologic Disorders

Hemophilia
Hemoglobinopathies (including sickle cell disease)

Miscellaneous Disorders

Autoinflammatory diseases
Recurrent multifocal osteomyelitis
Pigmented villonodular synovitis
Plant-thorn synovitis (foreign body arthritis)
Myositis ossificans
Eosinophilic fasciitis
Tendinitis (overuse injury)
Raynaud phenomenon
 Hemophagocytic syndromes

Pain Syndromes

Fibromyalgia
Growing pains
Depression (with somatization)
Complex regional pain syndrome

Many infections are associated with arthritis, and a recent history of infectious
symptoms may help make a distinction. Viruses, including parvovirus B19,
rubella, Epstein-Barr virus, hepatitis B virus, and HIV, can induce a transient
arthritis. Arthritis may follow enteric infections (see Chapter 182 ). Lyme
disease should be considered in children with oligoarthritis living in or visiting
endemic areas (see Chapter 249 ). Although a history of tick exposure, preceding
flulike illness, and subsequent rash should be sought, these are not always
present. Monoarticular arthritis unresponsive to antiinflammatory treatment may
be the result of chronic mycobacterial or other infection, such as Kingella kingae
, and the diagnosis is established by synovial fluid analysis (PCR) or biopsy.
Acute onset of fever and a painful, erythematous, hot joint suggests septic
arthritis (see Chapter 705 ). Isolated hip pain with limited ROM suggests
suppurative arthritis, osteomyelitis (see Chapter 704 ), toxic synovitis, Legg-
Calvé-Perthes disease, slipped capital femoral epiphysis, and chondrolysis of the
hip (see Chapter 698 ).
Lower-extremity arthritis and tenderness over insertion of ligaments and
tendons, especially in a boy, suggests ERA (see Chapter 181 ). Psoriatic
arthritis can manifest as limited joint involvement in an unusual distribution
(e.g., small joints of hand and ankle) years before onset of cutaneous disease.
Inflammatory bowel disease may manifest as oligoarthritis, usually affecting
joints in the lower extremities, as well as gastrointestinal symptoms, elevations
in ESR, and microcytic anemia.
Many conditions present solely with arthralgia (i.e., joint pain). Hypermobility
may cause joint pain, especially in the lower extremities. Growing pains should
be suspected in a child age 4-12 yr complaining of leg pain in the evening with
normal investigative studies and no morning symptoms. Nocturnal pain that
awakens the child also alerts to the possibility of a malignancy. An adolescent
modifying antirheumatic drugs (DMARDs), including methotrexate, and, if no
response, TNF inhibitors.

Table 180.8
Pharmacologic Treatment of Juvenile Idiopathic Arthritis
(JIA)

TYPICAL
TYPICAL DOSES JIA SUBTYPE SIDE EFFECT(S)
MEDICATIONS
NONSTEROIDAL ANTIINFLAMMATORY DRUGS
Naproxen 15 mg/kg/day PO divided bid Polyarthritis Gastritis, renal and hepatic toxicity,
(maximum dose 500 mg bid) Systemic pseudoporphyria
Oligoarthritis
Ibuprofen 40 mg/kg/day PO divided tid Same as above Same as above
(maximum dose 800 mg tid)
Meloxicam 0.125 mg/kg PO once daily Same as above Same as above
(maximum dose 15 mg daily)
DISEASE-MODIFYING ANTIRHEUMATIC DRUGS
Methotrexate 0.5-1 mg/kg PO or SC weekly Polyarthritis Nausea, vomiting, oral ulcerations,
(maximum dose 25 mg/wk) Systemic hepatic toxicity, blood count dyscrasias,
Persistent or immunosuppression, teratogenicity
extended
oligoarthritis
Sulfasalazine Initial 12.5 mg/kg PO Polyarthritis GI upset, allergic reaction, pancytopenia,
daily; increase by 10 renal and hepatic toxicity, Stevens-
mg/kg/day Johnson syndrome
Maintenance: 40-50 mg/kg
divided bid (maximum
dose 2 g/day)
Leflunomide* 10-20 mg PO daily Polyarthritis GI upset, hepatic toxicity, allergic rash,
alopecia (reversible), teratogenicity
(needs washout with cholestyramine)
BIOLOGIC AGENTS
Anti–Tumor Necrosis Factor-α
Etanercept 0.8 mg/kg SC weekly or 0.4 Polyarthritis Immunosuppressant, concern for
mg/kg SC twice weekly Systemic malignancy, demyelinating disease,
(maximum dose 50 mg/wk) Persistent or lupus-like reaction, injection site reaction
extended
oligoarthritis
Infliximab* 3-10 mg/kg IV q4-8 wk Same as above Same as above, infusion reaction
Adalimumab 10 to <15 kg: 10 mg SC Same as above Same as above
every other week
15 to <30 kg: 20 mg SC
every other week
>30 kg: 40 mg SC every
other week
Anticytotoxic T-Lymphocyte–Associated Antigen-4 Immunoglobulin
Abatacept <75 kg: 10 mg/kg/dose IV Polyarthritis Immunosuppressant, concern for
q4wk malignancy, infusion reaction
75-100 kg: 750 mg/dose
 IV q4wk
>100 kg: 1,000 mg/dose
IV q4wk
SC once weekly:
10 to <25 kg: 50 mg
≥25 to <50 kg: 87.5 mg
≥50 kg: 125 mg
Anti-CD20
Rituximab* 750 mg/m2 IV 2 wk × 2 Polyarthritis Immunosuppressant, infusion reaction,
(maximum dose 1,000 mg) progressive multifocal encephalopathy
Interleukin-1 Inhibitors
Anakinra* 1-2 mg/kg SC daily (maximum Systemic Immunosuppressant, GI upset, injection
dose 100 mg/day) site reaction
Canakinumab 15-40 kg: 2 mg/kg/dose Systemic Immunosuppressant, headache, GI upset,
SC q8wk injection site reaction
>40 kg: 150 mg SC q8wk
Rilonacept* 2.2 mg/kg/dose SC weekly Systemic Immunosuppressant, allergic reaction,
(maximum dose 160 mg) dyslipidemia, injection site reaction
Interleukin-6 Receptor Antagonist
Tocilizumab IV q2 wk: Systemic Immunosuppressant, hepatic toxicity,
<30 kg: 12 mg/kg/dose Polyarthritis dyslipidemia, cytopenias, GI upset,
q2wk infusion reaction
>30 kg: 8 mg/kg/dose
q2wk (maximum dose 800
mg)
SC: Polyarthritis
<30 kg: 162 mg/dose
q3wk
≥30 kg: 162 mg/dose
q2wk
* Not indicated by the U.S. Food and Drug Administration for use in JIA as of 2018.

bid, Twice daily; GI, gastrointestinal; IV, intravenous; PO, oral; q, every; SC, subcutaneous; tid, 3
times daily.

NSAIDs alone rarely induce remission in children with polyarthritis or sJIA.

Methotrexate is the oldest and least toxic of the DMARDs available for
adjunctive therapy. It may take 6-12 wk to see the effects of methotrexate.
Failure of methotrexate monotherapy warrants the addition of a biologic
DMARD. Biologic medications that inhibit proinflammatory cytokines, such as
TNF-α, IL-1, and IL-6, demonstrated excellent disease control. TNF-α
antagonists (e.g., etanercept, adalimumab ) are used to treat children with an
inadequate response to methotrexate, with poor prognostic factors, or with
severe disease onset. Early aggressive therapy with a combination of
methotrexate and a TNF-α antagonist may result in earlier achievement of
clinically inactive disease. Abatacept, a selective inhibitor of T-cell activation,
and tocilizumab, an IL-6 receptor antagonist, have demonstrated efficacy in and
are approved for treatment of polyarticular JIA (Table 180.8 ).
CHAPTER 181

Ankylosing Spondylitis and Other

Spondyloarthritides
Pamela F. Weiss, Robert A. Colbert

The diseases collectively referred to as spondyloarthritides include ankylosing

spondylitis (AS) , arthritis associated with inflammatory bowel disease (IBD) or
psoriasis, and reactive arthritis following gastrointestinal (GI) or genitourinary
(GU) infections (Table 181.1 and Table 181.2 ). Spondyloarthritis is more
common in adults, but all forms can present during childhood with varying
symptoms and signs. Many children with spondyloarthritis are classified in the
juvenile idiopathic arthritis (JIA) categories of enthesitis-related arthritis
(ERA) or psoriatic arthritis. Children and adolescents with spondyloarthritis who
may not meet JIA criteria include arthritis associated with IBD, juvenile
ankylosing spondylitis (JAS), and reactive arthritis.

Table 181.1
Overlapping Characteristics of the Spondyloarthritides*

JUVENILE JUVENILE
INFLAMMATORY REACTIVE
CHARACTERISTIC ANKYLOSING PSORIATIC
BOWEL DISEASE ARTHRITIS
SPONDYLITIS ARTHRITIS
Enthesitis +++ + + ++
Axial arthritis +++ ++ ++ +
Peripheral arthritis +++ +++ +++ +++
HLA-B27 positive +++ + ++ +++
Antinuclear antibody − ++ − −
positive
Rheumatoid factor − − − −
positive
SYSTEMIC DISEASE:
Eyes + + + +
Skin − +++ + +
Mucous membranes − − + +
 Gastrointestinal tract − − ++++ +++
* Frequency of characteristics: −, absent; +, <25%; ++, 25–50%; +++, 50–75%; ++++, ≥75%.

From Cassidy JT, Petty RE: Textbook of pediatric rheumatology, ed 6, Philadelphia, 2011,
Elsevier/Saunders.

Table 181.2
Etiologic Microorganisms of Reactive
Arthritis
Probable

Chlamydia trachomatis
Shigella species
Salmonella enteritidis
Salmonella typhimurium
Yersinia enterocolitica
Yersinia pseudotuberculosis
Campylobacter jejuni and coli

Possible

Neisseria gonorrhoeae
Mycoplasma fermentans
Mycoplasma genitalium
Ureaplasma urealyticum
Escherichia coli
Cryptosporidium
Entamoeba histolytica
Giardia lamblia
Brucella abortus
Clostridium difficile
Streptococcus pyogenes
Chlamydia pneumoniae
Chlamydia psittaci

From Kim PS, Klausmeier TL, Orr DP: Reactive arthritis: a review, J Adolesc
Health 44:309–315, 2009 (Table 2, p 311).

Epidemiology
JIA is diagnosed in 90 per 100,000 U.S. children every year (see Chapter 180 ).
ERA accounts for 10–20% of JIA, and has a mean age at onset of 12 yr. In India,
ERA is the most common category of JIA, accounting for 35% of cases. Unlike
other JIA categories, males are affected more often than females, accounting for
60% of ERA cases. AS occurs in 0.2–0.5% of adults, with approximately 15% of
cases beginning in childhood. These disorders can be familial, largely as a result
of the influence of human leukocyte antigen (HLA )-B27 , which is found in
90% of JAS and 50% of ERA patients compared to 7% of healthy individuals.
Approximately 20% of children with ERA have a family history of HLA-B27–
associated disease, such as reactive arthritis, AS, or IBD with sacroiliitis.

Etiology and Pathogenesis

Spondyloarthritides are complex diseases in which susceptibility is largely
genetically determined. Only 30% of heritability has been defined, with HLA-
B27 responsible for two thirds of the total, and >100 additional genetic loci
accounting for only one third. Genes that influence interleukin (IL)-23 responses
(e.g., CARD9 , IL23R, JAK2, TYK2 , STAT3 ) and the function of HLA-B27
(ERAP1) are particularly important. Unusual properties of HLA-B27, such as its
tendency to misfold and form abnormal cell surface structures, may have a role.
Infection with certain GI or GU pathogens can trigger reactive arthritis (see
Table 181.2 and Chapter 182 ). Altered gut microbiota and an abnormal immune
response to normal microbiota may also play a role in pathogenesis. Inflamed
joints and entheses in spondyloarthritis contain T and B cells, macrophages,
osteoclasts, proliferating fibroblasts, and osteoblasts, with activation of the IL-
23/IL-17 pathway. Bone loss and osteoproliferation in and around vertebral
bodies and facet joints in long-standing AS contribute to significant morbidity.

Clinical Manifestations and Diagnosis

Clinical manifestations that help distinguish spondyloarthritis from other forms
of juvenile arthritis include arthritis of the axial skeleton (sacroiliac joints) and
hips, enthesitis (inflammation at the site of tendon, ligament, or joint capsule
attachment to bone), symptomatic eye inflammation (acute anterior uveitis), and
GI inflammation (even in the absence of IBD) (Tables 181.1 and 181.3 ).

Table 181.3
Assessment in Spondyloarthritis International Society
(ASAS) Classification Criteria for Spondyloarthritis (SpA)

AXIAL SpA PERIPHERAL SpA

In patients with ≥3 mo back pain and age at onset <45 yr In patients with peripheral
symptoms ONLY
Sacroiliitis on imaging * plus ≥1 SpA or HLA-B27 plus ≥2 other SpA Arthritis or enthesitis or dactylitis
feature(s) features plus
SpA features ≥1 SpA feature(s)
• Inflammatory back pain (IBP) • Uveitis
• Arthritis • Psoriasis
• Enthesitis (heel) • Crohn disease/ulcerative colitis
• Uveitis • Preceding infection
• Dactylitis • HLA-B27
• Psoriasis • Sacroiliitis on imaging*
• Crohn disease/ulcerative colitis or
• Good response to NSAIDs ≥2 other SpA features
• Family history for SpA • Arthritis
• HLA-B27 • Enthesitis
• Elevated CRP • Dactylitis
• IBP ever
• Family history for SpA
* Active (acute) inflammation on MRI highly suggestive of sacroiliitis associated with SpA. Definite

radiographic sacroiliitis according to modified NY criteria.

CRP, C-reactive protein; NSAIDs, nonsteroidal antiinflammatory drugs.
Adapted from Rudwaleit M, van der Heijde D, Landewé R, et al: The development of Assessment
of Spondyloarthritis International Society classification criteria for axial spondyloarthritis. Part II.
Validation and final selection, Ann Rheum Dis 68(6):777–783, 2009; and The Assessment of
Spondyloarthritis International Society classification criteria for peripheral spondyloarthritis and for
spondyloarthritis in general, Ann Rheum Dis 70(1):25–31, 2011.

Enthesitis-Related Arthritis
Children have ERA if they have either arthritis and enthesitis or arthritis or
enthesitis, with at least 2 of the following characteristics: (1) sacroiliac joint
tenderness or inflammatory lumbosacral pain, (2) presence of HLA-B27, (3)
onset of arthritis in a male older than 6 yr, (4) acute anterior uveitis, and (5) a
family history of an HLA-B27–associated disease (ERA, sacroiliitis with IBD,
reactive arthritis, or acute anterior uveitis) in a first-degree relative. Patients with
psoriasis (or a family history of psoriasis in a first-degree relative), a positive–
rheumatoid factor (RF) test result, or systemic arthritis are excluded from this
group. During the 1st 6 mo of disease the arthritis is typically asymmetric and
involves ≤4 joints. most frequently the knees, ankles, and hips. Inflammation of
the small joints of the foot, or tarsitis, is highly suggestive of ERA. Enthesitis is
typically symmetric and typically affects the lower limbs. Up to 40% of children
develop clinical or radiographic evidence of sacroiliac joint arthritis as part of
their disease; approximately 20% have evidence of sacroiliac joint arthritis at
diagnosis. When the sacroiliac or other axial joints are involved, children may
experience inflammatory back pain (Table 181.4 ), hip pain, and alternating
buttock pain. Patients may also experience pain with palpation of the lower back
or with pelvic compression. The risk of sacroiliac joint arthritis is highest in
children who are HLA-B27 positive and have an elevated C-reactive protein
(CRP). Untreated sacroiliitis may, but does not always, evolve into AS;
additional risk factors for progression are unclear.
Table 181.4
Symptoms Characteristic of Inflammatory
Back Pain

Pain at night with morning stiffness (and improvement on arising)

No improvement with rest
Improvement with exercise
Insidious onset
Good response to nonsteroidal antiinflammatory drugs

Psoriatic Arthritis
Psoriatic arthritis accounts for approximately 5% of JIA. Common clinical
features of psoriatic arthritis are nail pitting (Fig. 181.1 ), onycholysis, and
dactylitis (sausage-like swelling of fingers or toes).
 1976. Image #6950.)

Familiarity with other causes of postinfectious arthritis is vital when a

diagnosis of reactive arthritis is being considered. Numerous viruses are
associated with postinfectious arthritis and may result in particular patterns of
joint involvement (Table 182.1 ). Rubella and hepatitis B virus typically affect
the small joints, whereas mumps and varicella often involve large joints,
especially the knees. The hepatitis B arthritis–dermatitis syndrome is
characterized by urticarial rash and a symmetric migratory polyarthritis
resembling that of serum sickness. Rubella-associated arthropathy may follow
natural rubella infection and, infrequently, rubella immunization. It typically
occurs in young women, with an increased frequency with advancing age, and is
uncommon in preadolescent children and in males. Arthralgia of the knees and
hands usually begins within 7 days of onset of the rash or 10-28 days after
immunization. Parvovirus B19, which is responsible for erythema infectiosum
(fifth disease), can cause arthralgia, symmetric joint swelling, and morning
stiffness, particularly in adult women and less frequently in children. Arthritis
occurs occasionally during cytomegalovirus infection and may occur during
varicella infections but is rare after Epstein-Barr virus infection. Varicella may
also be complicated by suppurative arthritis, usually secondary to group A
streptococcus infection. HIV is associated with an arthritis that resembles
psoriatic arthritis more than JIA (see Chapter 180 ).
Table 182.1
Viruses Associated With Arthritis
TOGAVIRUSES
Rubivirus

Rubella

Alphaviruses

Ross River
Chikungunya
O'nyong-nyong
Mayaro
 Sindbis
Ockelbo
Pogosta

Orthopoxviruses

Variola virus (smallpox)

Vaccinia virus
Parvoviruses

Adenoviruses

Adenovirus 7

Herpesviruses

Epstein-Barr
Cytomegalovirus
Varicella-zoster
Herpes simplex

Paramyxoviruses

Mumps

Flavivirus

Zika virus

Hepadnavirus

Hepatitis B

Enteroviruses
 Echovirus
Coxsackievirus B

Adapted from Infectious arthritis and osteomyelitis. In Petty RE, Laxer R,

Lindsley CB, et al: Textbook of pediatric rheumatology, ed 7, Philadelphia, 2015,
Saunders Elsevier.

Poststreptococcal arthritis may follow infection with either group A or

group G streptococcus. It is typically oligoarticular, affecting lower-extremity
joints, and mild symptoms can persist for months. Poststreptococcal arthritis
differs from rheumatic fever, which typically manifests with painful migratory
polyarthritis of brief duration. Because valvular lesions have occasionally been
documented by echocardiography after the acute illness, some clinicians
consider poststreptococcal arthritis to be an incomplete form of acute rheumatic
fever (see Chapter 210.1 ). Certain HLA-DRB1 types may predispose children to
development of either poststreptococcal arthritis (HLA-DRB1*01) or acute
rheumatic fever (HLA-DRB1*16).
Transient synovitis (toxic synovitis) , another form of postinfectious arthritis,
typically affects the hip, often after an upper respiratory tract infection (see
Chapter 698.2 ). Boys 3-10 yr of age are most often affected and have acute
onset of severe pain in the hip (groin), with referred pain to the thigh or knee,
lasting approximately 1 wk. ESR and white blood cell count are usually normal.
Radiologic or ultrasound examination may confirm widening of the joint space
secondary to an effusion. Aspiration of joint fluid is often necessary to exclude
septic arthritis and typically results in dramatic clinical improvement. The
trigger is presumed to be viral, although responsible microbes have not been
identified.
Nonsuppurative arthritis has been reported in children, usually adolescent
boys, in association with s evere truncal acne. Patients often have fever and
persistent infection of the pustular lesions. Pyogenic (sterile) arthritis,
pyoderma gangrenosum, and acne (cystic) syndrome , an autosomal dominant
disorder caused by a mutation in the PSTPIP1 gene, is a difficult-to-treat but rare
autoinflammatory disorder that has responded to anakinra or anti–tumor necrosis
factor antibody therapy in a few patients. Recurrent episodes of erosive arthritis
begin in childhood; cystic acne and the painful ulcerating lesions of pyoderma
gangrenosum begin during adolescence. Recurrent episodes may also be
associated with a sterile myopathy and may last for several months.
Table 183.1

Potential Clinical Manifestations of Systemic Lupus Erythematosus

TARGET
POTENTIAL CLINICAL MANIFESTATIONS
ORGAN
Constitutional Fatigue, anorexia, weight loss, fever, lymphadenopathy
Musculoskeletal Arthritis, myositis, tendonitis, arthralgias, myalgias, avascular necrosis, osteoporosis
Skin Malar rash, discoid (annular) rash, photosensitive rash, cutaneous vasculitis (petechiae,
palpable purpura, digit ulcers, gangrene, urticaria), livedo reticularis, periungual capillary
abnormalities, Raynaud phenomenon, alopecia, oral and nasal ulcers, panniculitis, chilblains,
alopecia
Renal Hypertension, proteinuria, hematuria, edema, nephrotic syndrome, renal failure
Cardiovascular Pericarditis, myocarditis, conduction system abnormalities, Libman-Sacks endocarditis
Neuropsychiatric Seizures, psychosis, cerebritis, stroke, transverse myelitis, depression, cognitive impairment,
headaches, migraines, pseudotumor, peripheral neuropathy (mononeuritis multiplex),
polyneuropathy, myasthenia gravis, chorea, optic neuritis, cranial nerve palsies, plexopathy,
acute confusional states, dural sinus thrombosis, aseptic meningitis, depression, psychosis,
anxiety disorder
Pulmonary Pleuritis, interstitial lung disease, pulmonary hemorrhage, pulmonary hypertension, pulmonary
embolism
Hematologic Immune-mediated cytopenias (hemolytic anemia, thrombocytopenia or leukopenia), anemia of
chronic inflammation, hypercoagulability, thrombocytopenic thrombotic microangiopathy
Gastroenterology Hepatosplenomegaly, pancreatitis, vasculitis affecting bowel, protein-losing enteropathy,
peritonitis
Ocular Retinal vasculitis, scleritis, episcleritis, papilledema, dry eyes, optic neuritis
Other Macrophage activation syndrome

Table 183.2

Frequency of Clinical Features of Children and Adolescents With Systemic Lupus

Erythematosus
CLINICAL FEATURE* WITHIN 1 YR OF DIAGNOSIS (%) ANY TIME (%)
Fever 35-90 37-100
Lymphadenopathy 11-45 13-45
Hepatosplenomegaly 16-42 19-43
Weight loss 20-30 21-32
Arthritis 60-88 60-90
Myositis <5 <5
Any skin involvement 60-80 60-90
Malar rash 22-68 30-80
Discoid rash <5 <5
Photosensitivity 12-45 17-58
Mucosal ulceration 25-32 30-40
Alopecia 10-30 15-35
Other rashes 40-52 42-55
Nephritis 20-80 48-100
Neuropsychiatric disease 5-30 † 15-95 ‡
 Psychosis 5-12 8-18
Seizures 5-15 5-47
Headache 5-22 10-95
Cognitive dysfunction 6-15 12-55
Acute confusional state 5-15 8-35
Peripheral nerve involvement <5 <5
Cardiovascular disease 5-30 25-60
Pericarditis 12-20 20-30
* Not all reports commented on all features or incidence in 1st yr.

† Had highest prevalence of central nervous system disease but did not describe incidence in 1st

yr.
‡ Headache reported in 95% of patients.

From Petty RE, Laxer RM, Lindsley CB, Wedderburn LR, editors: Textbook of pediatric
rheumatology, ed 7, Philadelphia, 2016, Elsevier (Table 23.5, p 291).

Renal disease in SLE is often asymptomatic, underscoring the need for careful
monitoring of blood pressure and urinalyses; in adolescents, SLE can present
with nephrotic syndrome and/or renal failure with the predominant symptoms
being edema, fatigue, changes in urine color, and nausea/vomiting. Because SLE
symptoms and findings may develop serially over several years, and not all may
be present simultaneously, the diagnosis may require longitudinal follow up.
SLE is often characterized by periods of flare and disease quiescence but may
follow a more smoldering disease course. The neuropsychiatric complications
of SLE may occur with or without apparently active SLE, posing a particularly
difficult diagnostic challenge in adolescents, who are already at high risk for
mood disorders (Fig. 183.2 ). Long-term complications of SLE and its therapy,
including accelerated atherosclerosis and osteoporosis, become clinically evident
in young to middle adulthood. SLE is a disease that evolves over time in each
affected individual, and new manifestations arise even many years after
diagnosis.

FIG. 183.2 Overlapping neuropsychiatric symptoms in pediatric SLE. Patients with
pediatric SLE typically have >1 neuropsychiatric symptom—in particular for seizures.
(From Silverman E, Eddy A: Systemic lupus erythematosus. In Cassidy JT, Petty RE,
Laxer RM, et al, editors, Textbook of pediatric rheumatology, ed 6, Philadelphia, 2011,
Saunders Elsevier, Fig 21-17, p 329.)

Diagnosis
The diagnosis of SLE requires a comprehensive clinical and laboratory
assessment revealing characteristic multisystem disease and excluding other
etiologies, including infection and malignancy. Presence of 4 of the 11
American College of Rheumatology (ACR) 1997 revised classification criteria
for SLE simultaneously or cumulatively over time establishes the diagnosis
(Table 183.3 ). Of note, although a positive antinuclear antibody (ANA) test
result is not required for the diagnosis of SLE, ANA-negative lupus is extremely
rare. ANA is very sensitive for SLE (95–99%), but it is not very specific (50%).
The ANA may be positive many years before a diagnosis of SLE is established.
However, most asymptomatic, ANA-positive patients do not have SLE or other
autoimmune disease.
Table 183.3
American College of Rheumatology (ACR)
1997 Revised Classification Criteria for
Systemic Lupus Erythematosus*
Malar rash
Discoid rash
Photosensitivity
Oral or nasal ulcers
Arthritis
Nonerosive, ≥2 joints
Serositis
Pleuritis, pericarditis, or peritonitis
Renal manifestations †
Consistent renal biopsy
Persistent proteinuria or renal casts
Seizure or psychosis
Hematologic manifestations †
Hemolytic anemia
Leukopenia (<4,000 leukocytes/mm3 )
Lymphopenia (<1,500 leukocytes/mm3 )
Thrombocytopenia (<100,000 thrombocytes/mm3 )
Immunologic abnormalities †
Positive anti–double-stranded DNA or anti-Smith antibody
False-positive rapid plasma reagin test result, positive lupus
anticoagulant test result, or elevated anticardiolipin IgG or IgM
antibody
Positive antinuclear antibody test result

* The presence of 4 of 11 criteria establishes the diagnosis of SLE. These criteria

were developed for classification in clinical trials and not for clinical diagnosis.
† Each of these criteria counts as a single criterion whether 1 or more definitions

are satisfied.

Adapted from Hochberg MC: Updating the American College of Rheumatology

revised criteria for the classification of systemic lupus erythematosus, Arthritis
Rheum 40:1725, 1997.

Antibodies against dsDNA and anti-Smith are specific for SLE (98%) but not
as sensitive (40–65%). Hypocomplementemia , although common in SLE, is
not one of the ACR classification criteria; however, hypocomplementemia has
been added to updated criteria validated by the Systemic Lupus International
Collaborating Clinics (SLICC) in 2012 (Table 183.4 ). Other differences in the
SLICC criteria include the addition of nonscarring alopecia, additional cutaneous
and neurologic manifestations of lupus, and a positive direct Coombs test in the
absence of hemolytic anemia. The SLICC criteria have been validated in
pediatric SLE and have been shown to have higher sensitivity (93% vs 77%) but
lower specificity (85% vs 99%) than the ACR criteria.
Table 183.4
Systemic Lupus International Collaborating
Clinics (SLICC) Classification Criteria for
Systemic Lupus Erythematosus*
Clinical Criteria

Acute cutaneous lupus

Malar rash, bullous lupus, toxic epidermal necrolysis variant of
SLE, maculopapular lupus rash, photosensitive lupus rash, or
subacute cutaneous lupus
Chronic cutaneous lupus
Classic discoid rash, lupus panniculitis, mucosal lupus, lupus
erythematous tumidus, chilblains lupus, discoid lupus/lichen
planus overlap
Oral or nasal ulcers
Nonscarring alopecia
Synovitis (≥2 joints)
Serositis
Pleurisy or pericardial pain ≥1 day, pleural effusion or rub,
pericardial effusion or rub, ECG evidence of pericarditis
Renal
Presence of red blood cell casts or urine protein/creatinine ratio
 representing >500 mg protein/24 hr
Neurologic
Seizures, psychosis, mononeuritis multiplex, myelitis, peripheral
or cranial neuropathy, or acute confusional state
Hemolytic anemia
Leukopenia (<4,000/mm3 ) or lymphopenia (<1,000/mm3 )
Thrombocytopenia (<100,000/mm3 )

Immunologic Criteria

Positive antinuclear antibody

Positive double-stranded DNA antibody
Positive anti-Smith antibody
Antiphospholipid antibody positivity
Positive lupus anticoagulant, false-positive test for rapid plasma
regain, medium- to high-titer anticardiolipin antibody level
(IgA, IgG, IgM), or positive anti–β2 -glycoprotein-1 antibody
(IgA, IgG, IgM)
Low complement
Low C3, C4, or CH50 level
Positive direct Coombs test

* The presence of 4 criteria (including at least 1 clinical and 1 immunologic

criterion) establishes the diagnosis of SLE. Biopsy-proven lupus nephritis with

positive ANA or anti–double-stranded DNA also satisfies the diagnosis of SLE.
These criteria were developed for classification in clinical trials and not for
clinical diagnosis.

Adapted from Petri M: Derivation and validation of the Systemic Lupus

International Collaborating Clinics classification criteria for systemic lupus
erythematosus, Arthritis Rheum 64(8):2677–2686, 2012.

Differential Diagnosis
Multiorgan disease is the hallmark of SLE. Given its wide array of potential
clinical manifestations, SLE is in the differential diagnosis of many clinical
scenarios, including unexplained fevers, joint pain or arthritis, rash, cytopenias,
nephritis, nephrotic syndrome, pleural or pericardial effusions or other
cardiopulmonary abnormalities, and new-onset psychosis, movement disorders,
or seizures. For patients ultimately diagnosed with pediatric SLE, the initial
differential diagnosis often includes infections (sepsis, EBV, parvovirus B19,
endocarditis), malignancies (leukemia, lymphoma), poststreptococcal
glomerulonephritis, other rheumatologic conditions (juvenile idiopathic arthritis,
vasculitides), and drug-induced lupus.
Drug-induced lupus refers to the presence of SLE manifestations triggered
by exposure to specific medications, including hydralazine, minocycline, many
anticonvulsants, sulfonamides, and antiarrhythmic agents (Table 183.5 ). In
individuals prone to SLE, these agents may act as a trigger for true SLE, but
more often these agents provoke a reversible lupus-like syndrome. Unlike SLE,
drug-induced lupus affects males and females equally. A genetic predisposition
toward slow drug acetylation may increase the risk of drug-induced lupus.
Circulating antihistone antibodies are often present in drug-induced SLE; these
antibodies are only detected in up to 20% of individuals with SLE. Hepatitis,
which is rare in SLE, is more common in drug-induced lupus. Individuals with
drug-induced lupus are less likely to demonstrate antibodies to dsDNA,
hypocomplementemia, and significant renal or neurologic disease. In contrast to
SLE, manifestations of drug-induced lupus typically resolve after withdrawal of
the offending medication; however, complete recovery may take several months
to years, requiring treatment with hydroxychloroquine, NSAIDs, and/or
corticosteroids.
Table 183.5
Medications Associated With Drug-Induced
Lupus
Definite Association

Minocycline, procainamide, hydralazine, isoniazid, penicillamine,

diltiazem, interferon-α, methyldopa, chlorpromazine, etanercept,
infliximab, adalimumab
Probable Association

Phenytoin, ethosuximide, carbamazepine, sulfasalazine, amiodarone,

quinidine, rifampin, nitrofurantoin, β-blockers, lithium, captopril,
interferon-γ, hydrochlorothiazide, glyburide, docetaxel, penicillin,
tetracycline, statins, gold, valproate, griseofulvin, gemfibrozil,
propylthiouracil

Laboratory Findings
A positive ANA test is present in 95–99% of SLE patients. ANA has poor
specificity for SLE, however, because up to 20% of healthy individuals also have
a positive ANA test result, making the ANA a poor screen for SLE when used in
isolation. High titers are more suggestive of underlying autoimmune disease, but
ANA titers do not correlate with disease activity, so repeating ANA titers after
diagnosis is not helpful. Antibodies to dsDNA are specific for SLE, and in many
individuals, anti-dsDNA levels correlate with disease activity, particularly in
those with significant nephritis. Anti-Smith antibody, although found specifically
in patients with SLE, does not correlate with disease activity. Serum levels of
total hemolytic complement (CH50 ), C3, and C4 are typically decreased in
active disease and often improve with treatment. Table 183.6 lists autoantibodies
found in SLE along with their clinical associations. Hypergammaglobulinemia is
a common but nonspecific finding. Inflammatory markers, particularly
erythrocyte sedimentation rate, are often elevated in active disease. C-reactive
protein (CRP) correlates less well with disease activity; significantly elevated
CRP values often reflect infection, whereas chronic mild elevation may indicate
increased cardiovascular risk.

Table 183.6

Autoantibodies Typically Associated With Systemic Lupus Erythematosus

ANTIBODY CLINICAL ASSOCIATION
Anti–double-stranded DNA Specific for the diagnosis of SLE
Correlates with disease activity, especially nephritis, in some
with SLE
Anti-Smith antibody Specific for the diagnosis of SLE
Antiribonucleoprotein (anti-RNP) antibody Increased risk for Raynaud phenomenon, insterstitial lung disease,
and pulmonary hypertension
 Anti-Ro antibody (anti-SSA antibody) Associated with sicca syndrome
Anti-La antibody (anti-SSB antibody) May suggest diagnosis of Sjögren syndrome
Increased risk of neonatal lupus in offspring (congenital heart
block)
May be associated with cutaneous and pulmonary
manifestations of SLE
May be associated with isolated discoid lupus
Antiphospholipid antibodies (including Increased risk for venous and arterial thrombotic events
anticardiolipin antibodies)
Antihistone antibodies Present in a majority of patients with drug-induced lupus
May be present in SLE

Antiphospholipid antibodies , which increase clotting risk, can be found in

up to 66% of children and adolescents with SLE. Antiphospholipid laboratory
findings include the presence of anticardiolipin or anti–β2 -glycoprotein
antibodies, prolonged phospholipid-dependent coagulation test results (partial
thromboplastin time, dilute Russell viper-venom time), and circulating lupus
anticoagulant (which confirms that a prolonged PPT is not corrected with
mixing studies). When an arterial or venous clotting event occurs in the presence
of an antiphospholipid antibody, antiphospholipid antibody syndrome is
diagnosed, which can occur in the context of SLE (secondary) or independent of
SLE (primary) (see Chapter 479 ).

Treatment
Treatment of SLE is tailored to the individual and is based on specific disease
manifestations and medication tolerability. For all patients, sunscreen and
avoidance of prolonged direct sun exposure and other UV light may help control
disease and should be reinforced at every visit with the patient.
Hydroxychloroquine is recommended for all individuals with SLE when
tolerated. In addition to treating mild SLE manifestations such as rash and mild
arthritis, hydroxychloroquine prevents SLE flares, improves lipid profiles, and
may improve mortality and renal outcomes. Potential toxicities include retinal
deposition and subsequent vision impairment; therefore, annual ophthalmology
exams are recommended for patients taking hydroxychloroquine, including
automated visual field testing as well as spectral-domain optical coherence
tomography (SD-OCT). Given that risk factors for ocular toxicity include
duration of use and dose, hydroxychloroquine in SLE should never be prescribed
at doses >6.5 mg/kg (maximum 400 mg daily), and newer ophthalmology
guidelines recommend limiting maintenance dosing to 4-5 mg/kg.
Corticosteroids are a treatment mainstay for significant manifestations of
Table 183.7

Morbidity in Childhood Lupus

SYSTEM MORBIDITY
Renal Hypertension, dialysis, transplantation
Central nervous Organic brain syndrome, seizures, psychosis, neurocognitive dysfunction
Cardiovascular Atherosclerosis, myocardial infarction, cardiomyopathy, valvular disease
Immune Recurrent infection, functional asplenia, malignancy
Musculoskeletal Osteopenia, compression fractures, avascular necrosis
Ocular Cataracts, glaucoma, retinal detachment, blindness
Endocrine Diabetes, obesity, growth failure, infertility, fetal wastage
From Cassidy JT, Petty RE: Textbook of pediatric rheumatology, ed 6, Philadelphia, 2011, Elsevier
Saunders.

Prognosis
The severity of pediatric SLE is notably worse than the typical course for adult-
onset SLE. However, because of advances in the diagnosis and treatment of
SLE, survival has improved dramatically over the past 50 yr. Currently, the 5 yr
survival rate for pediatric SLE is approximately 95%, although the 10 yr survival
rate remains 80–90%. Given their long burden of disease, children and
adolescents with SLE face high risks of future morbidity and mortality from the
disease and its complications, as well as medication side effects (see Table 183.7
). Given the complex and chronic nature of SLE, it is optimal for children and
adolescents with SLE to be treated by pediatric rheumatologists in a
multidisciplinary clinic with access to a full complement of pediatric
subspecialists.

183.1
Neonatal Lupus
Deborah M. Friedman, Jill P. Buyon, Rebecca E. Sadun, Stacy P. Ardoin, Laura
E. Schanberg
cells (CD56), T-cell subsets (CD4, CD8, Th17), monocytes/macrophages
(CD14), and plasmacytoid DCs. Neopterin, IFN-inducible protein 10, monocyte
chemoattractant protein, myxovirus resistance protein, and von Willebrand factor
products, as well as other markers of vascular inflammation, may be elevated in
patients with JDM who have active inflammation.

Clinical Manifestations
Children with JDM present with either rash, insidious onset of weakness, or
both. Fevers, dysphagia or dysphonia, arthritis, muscle tenderness, and fatigue
are also commonly reported at diagnosis (Tables 184.1 and 184.2 ).

Table 184.1
Diagnostic Criteria for Juvenile Dermatomyositis
Classic rash Heliotrope rash of the eyelids
Gottron papules
Plus 3 of the following:
Weakness Symmetric
Proximal
Muscle enzyme elevation (≥1) Creatine kinase
Aspartate transaminase
Lactate dehydrogenase
Aldolase
Electromyographic changes Short, small polyphasic motor unit potentials
Fibrillations
Positive sharp waves
Insertional irritability
Bizarre, high-frequency repetitive discharges
Muscle biopsy Necrosis
Inflammation
Data from Bohan A, Peter JB: Polymyositis and dermatomyositis (2nd of 2 parts), N Engl J Med
292:403–407, 1975.

Table 184.2

Clinical Features of Juvenile Dermatomyositis During Disease Course

FEATURE %
Muscle weakness 90-100
Dysphagia or dysphonia 13-40
Muscle atrophy 10
Muscle pain and tenderness 30-75
 Skin lesions 85-100
Heliotrope rash of eyelids 66-95
Gottron papules 57-95
Erythematous rash of malar/facial area 42-100
Periungual (nail fold) capillary changes 80-90
Photosensitive rash 5-42
Ulcerations 22-30
Calcinosis 12-30
Lipodystrophy 11-14
Raynaud phenomenon 2-15
Arthritis and arthralgia 22-58
Joint contractures 26-27
Fever 16-65
Gastrointestinal signs and symptoms 8-37
Restrictive pulmonary disease 4-32
Interstitial lung disease 1-7
Cardiac involvement 0-3
From Rider LG, Lindsley CB, Cassidy JT: Juvenile dermatomyositis. In Cassidy JT, Petty RE,
Laxer RM, et al, editors: Textbook of pediatric rheumatology, ed 6, Philadelphia, 2011, Saunders
(Table 24.20, p 410).

Rash develops as the first symptom in 50% of patients and appears

concomitant with weakness only 25% of the time. Children often exhibit
extreme photosensitivity to ultraviolet (UV) light exposure with generalized
erythema in sun-exposed areas. If seen over the chest and neck, this erythema is
known as the shawl sign . Erythema is also commonly seen over the knees and
elbows. The characteristic heliotrope rash is a blue-violet discoloration of the
eyelids that may be associated with periorbital edema (Fig. 184.1 ). Facial
erythema crossing the nasolabial folds is also common, in contrast to the malar
rash without nasolabial involvement typical of systemic lupus erythematosus
(SLE). Classic Gottron papules are bright-pink or pale, shiny, thickened or
atrophic plaques over the proximal interphalangeal joints and distal
interphalangeal joints and occasionally on the knees, elbows, small joints of the
toes, and ankle malleoli (Fig. 184.2 ). The rash of JDM is sometimes mistaken
for eczema or psoriasis. Rarely, a thickened erythematous and scaly rash
develops in children over the palms (known as mechanic's hands ) and soles
along the flexor tendons, which is associated with anti–Jo-1 antibodies.
Barré syndrome, endocrinopathies (hyperthyroidism, hypothyroidism, Cushing
syndrome, Addison disease, parathyroid disorders), mitochondrial myopathies,
TNF receptor–associated periodic syndrome (TRAPS), and metabolic disorders
(glycogen and lipid storage diseases). Infections associated with prominent
muscular symptoms include trichinosis, Bartonella infection, toxoplasmosis, and
staphylococcal pyomyositis. Blunt trauma and crush injuries may lead to
transient rhabdomyolysis with myoglobinuria. Myositis in children may also be
associated with vaccinations, drugs, growth hormone, and GVHD. The rash of
JDM may be confused with eczema, dyshidrosis, psoriasis, erythema nodosa,
malar rash from SLE, capillary telangiectasias from Raynaud phenomenon, and
other rheumatic diseases. Muscle inflammation is also seen in children with
SLE, juvenile idiopathic arthritis, mixed connective tissue disease, inflammatory
bowel disease, and antineutrophil cytoplasmic antibody–positive vasculitides.
Necrotizing immune-mediated myopathies are characterized by muscle necrosis
without lymphocytic infiltration. Antibodies to signal recognition particle (SRP)
or 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) distinguish two types
from each other and from JDM. Table 184.3 compares other juvenile idiopathic
inflammatory myositis disorders: JDM, juvenile polymyositis, and juvenile
connective tissue myositis.

Table 184.3
Frequency of Manifestations of Juvenile Dermatomyositis,
Juvenile Polymyositis, and Overlap Myositis

FREQUENCY AT ONSET (%)

Manifestation
JDM JPM Overlap Myositis
Progressive proximal muscle weakness 82-100 100 100
Easy fatigue 80-100 85 84
Gottron papules 57-91 0 74-80
Heliotrope rash 66-87 0 40-59
Erythematous rash of malar/facial area 42-100 0-6 20-51
Periungual nailfold capillary changes 35-91 33 67-80
Muscle pain or tenderness 25-83 61-66 55
Weight loss 33-36 52 53
Falling episodes 40 59 29

Arthritis 10-65 0-45 69-80

Fever 16-65 0-41 0-49
Lymphadenopathy 8-75 0-12 20-22
Dysphagia or dysphonia 15-44 39 40
Joint contractures 9-55 17-42 57-60
V- or shawl-sign rashes 19-29 3-6 8-14
 Dyspnea on exertion 5-43 17-42 40
Gastrointestinal symptoms 5-37 9-33 6-53
Photosensitive rashes 5-51 0-6 22-40
Raynaud phenomenon 9-28 0-24 41-60
Edema 11-34 15 20
Gingivitis 6-30 9 0-37
Cutaneous ulceration 5-30 3 20-22
Calcinosis 3-34 6 24
Cardiac involvement 2-13 36 19
Interstitial lung disease 5 15 26
Lipodystrophy 4-14 3 0-6
Gastrointestinal bleeding or ulceration 3-4 3 4-10
JDM, Juvenile dermatomyositis; JPM, juvenile polymyositis.
From Rider LG, Lindsley CB, Miller FW: Juvenile Dermatomyositis. IN Petty RE, Laxer RM,
Lindsley CB, Wedderburn L, editors: Textbook of pediatric rheumatology, ed 7, Philadelphia, 2016,
Elsevier, Table 26.4.

Laboratory Findings
Elevated serum levels of muscle-derived enzymes (creatine kinase [CK],
aldolase, aspartate transaminase, alanine transaminase [ALT], lactate
dehydrogenase) reflect muscle inflammation. Not all enzyme levels rise with
inflammation in a specific individual; ALT is usually elevated on initial
presentation, whereas CK level may be normal. The erythrocyte sedimentation
rate (ESR) is often normal, and the rheumatoid factor (RF) test result is typically
negative. There may be anemia consistent with chronic disease. Antinuclear
antibody (ANA) is present in >80% of children with JDM. Serologic testing
results are divided into 2 groups: myositis-associated antibodies (MAAs) and
myositis-specific antibodies (MSAs) . MAAs are associated with JDM, but are
not specific and can be seen in both overlap conditions and other rheumatic
diseases. MSAs are specific for myositis. Presence of MAAs such as SSA, SSB,
Sm, ribonucleoprotein (RNP), and double-stranded (ds) DNA may increase the
likelihood of overlap disease or connective tissue myositis. Antibodies to Pm/Scl
identify a small, distinct subgroup of myopathies with a protracted disease
course, often complicated by pulmonary interstitial fibrosis and cardiac
involvement. Similar to what is seen in adults, the presence of MSAs in JDM
such as anti–Jo-1, anti–Mi-2, anti-p155/140, anti-NXP2, and other myositis-
specific autoantibodies help define distinct clinical subsets and may predict the
development of complications, although differences remain in certain aspects
such as malignancy between adults and children. Anti-p155/140 antibodies also
fibers.
Autoimmunity is believed to be a key process in the pathogenesis of both
localized and systemic scleroderma, given the high percentage of affected
children with autoantibodies. Children with localized disease often have a
positive antinuclear antibody (ANA) test result (42%), and 47% of this subgroup
have antihistone antibodies. Children with JSSc have higher rates of ANA
positivity (80.7%) and may have anti–Scl-70 antibody (34%, antitopoisomerase
I). The relationship between specific autoantibodies and the various forms of
scleroderma is not well understood, and all antibody test results may be negative,
especially in JLS.

Classification
Localized scleroderma is distinct from systemic scleroderma and rarely
progresses to systemic disease. The category of JLS includes several subtypes
differentiated by both the distribution of the lesions and the depth of
involvement (Tables 185.1 and 185.2 ). Up to 15% of children have a
combination of 2 or more subtypes.
Table 185.1
Classification of Pediatric Scleroderma
(Morphea)
Localized Scleroderma
Plaque Morphea

Confined to dermis, occasionally superficial panniculus

Well-circumscribed circular area of induration, often a central waxy, ivory-
colored area surrounded by a violaceous halo; unilateral

Generalized Morphea

Involves dermis primarily, occasionally panniculus

Defined as confluence of individual morphea plaques or lesions in ≥3
anatomic sites; more likely to be bilateral
Bullous Morphea

Bullous lesions that can occur with any of the subtypes of morphea

Linear Scleroderma

Linear lesions can extend through the dermis, subcutaneous tissue, and
muscle to underlying bone; more likely unilateral
Limbs/trunk:
One or more linear streaks of the extremities or trunk
Flexion contracture occurs when lesion extends over a joint; limb
length discrepancies
En coup de sabre:
Involves the scalp and/or face; lesions can extend into the central
nervous system, resulting in neurologic sequelae, most
commonly seizures and headaches
Parry-Romberg syndrome:
Hemifacial atrophy without a clearly definable en coup de sabre
lesion; can also have neurologic involvement

Deep Morphea

Involves deeper layers, including panniculus, fascia, and muscle; more

likely to be bilateral
Subcutaneous morphea:
Primarily involves the panniculus or subcutaneous tissue
Plaques are hyperpigmented and symmetric
Eosinophilic fasciitis:
Fasciitis with marked blood eosinophilia
Fascia is the primary site of involvement; typically involves
extremities
Classic description is “peau d'orange” or orange peel texture, but
early disease manifests as edema (see Fig. 185.2 )
Morphea profunda:
Deep lesion extending to fascia and sometimes muscle, but may
be limited to a single plaque, often on trunk
 Disabling pansclerotic morphea of childhood:
Generalized full-thickness involvement of skin on the trunk, face
and extremities, sparing fingertips and toes

Systemic Sclerosis
Diffuse

Most common type in childhood

Symmetric thickening and hardening of the skin (sclerosis) with fibrous
and degenerative changes of viscera

Limited

Rare in childhood
Previously known as CREST (calcinosis cutis, Raynaud phenomenon,
esophageal dysfunction, sclerodactyly, and telangiectasia) syndrome
Table 185.2
Provisional Criteria for Classification of
Juvenile Systemic Sclerosis (JSSc)
Major Criterion (Required)*

Proximal skin sclerosis/induration of the skin proximal to

metacarpophalangeal or metatarsophalangeal joints

Minor Criteria (at Least 2 Required)

Cutaneous: Sclerodactyly
Peripheral vascular: Raynaud phenomenon, nail fold capillary
abnormalities (telangiectasias), digital tip ulcers
Gastrointestinal: Dysphagia, gastroesophageal reflux
Cardiac: Arrhythmias, heart failure
Renal: Renal crisis, new-onset arterial hypertension
Respiratory: Pulmonary fibrosis (high-resolution CT/radiography),
 decreased diffusing capacity for carbon monoxide, pulmonary arterial
hypertension
Neurologic: Neuropathy, carpal tunnel syndrome
Musculoskeletal: Tendon friction rubs, arthritis, myositis
Serologic: Antinuclear antibodies—SSc-selective autoantibodies
(anticentromere, antitopoisomerase I [Scl-70], antifibrillarin, anti-
PM/Scl, antifibrillin, or anti-RNA polymerase I or III

* Diagnosis requires at least 1 major and at least 2 minor criteria.

From Zulian F, Woo P, Athreya BH, et al: The Pediatric Rheumatology European
Society/American College of Rheumatology/European League against
Rheumatism provisional classification criteria for juvenile systemic sclerosis,
Arthritis Rheum 57:203–212, 2007.

Epidemiology
Juvenile scleroderma is rare, with an estimated prevalence of 1 in 100,000
children. LS is much more common than SSc in children, by a 10 : 1 ratio, with
linear scleroderma being the most common subtype. LS is predominantly a
pediatric condition, with 65% of patients diagnosed before age 18 yr. After age 8
yr the female/male ratio for both LS and SSc is approximately 3 : 1, whereas in
patients younger than 8 yr, there is no sex predilection.

Clinical Manifestations
Localized Scleroderma
The onset of scleroderma is generally insidious, and manifestations vary
according to disease subtype. The initial skin manifestations of localized disease
usually include erythema or a bluish hue seen around an area of waxy
induration; subtle erythema may be the only presenting sign (Fig. 185.1 ).
Edema and erythema are followed by indurated, hypopigmented or
hyperpigmented atrophic lesions (Fig. 185.2 ). LS varies in size from a few
centimeters to the entire length of the extremity, with varying depth. Patients
late in the course, are subtle, and include cough and dyspnea on exertion.
Pulmonary evaluation should include pulmonary function tests (PFTs) such as
diffusion capacity of carbon monoxide (DLCO ), bronchoalveolar lavage (BAL),
and high-resolution chest computed tomography (HRCT). PFTs reveal decreased
vital capacity and decreased DLCO , whereas neutrophilia or eosinophilia on
BAL suggest active alveolitis. Chest CT is much more sensitive than chest
radiographs, which are often normal, showing typical basilar ground-glass
abnormalities, reticular linear opacities, nodules, honeycombing, and mediastinal
adenopathy.
Gastrointestinal tract disease is seen in 25% of children with SSc. Common
manifestations include esophageal and intestinal dysmotility resulting in
dysphagia, reflux, dyspepsia, gastroparesis, bacterial overgrowth, dilated bowel
loops and pseudoobstruction, and dental caries, as well as malabsorption and
failure to thrive. Renal arterial disease can cause chronic or severe episodic
hypertension; unlike adult disease, renal crisis is rare. Cardiac fibrosis is
associated with arrhythmias, ventricular hypertrophy, and decreased cardiac
function. Mortality from JSSc is usually a result of cardiopulmonary disease. A
scoring system helps identify the severity of the multiorgan involvement (Table
185.3 ).

Table 185.3
Medsger Systemic Sclerosis Severity Scale*

ORGAN 2
0 (NORMAL) 1 (MILD) 3 (SEVERE) 4 (END STAGE)
SYSTEM (MODERATE)
General Wt loss <5% Wt loss 5–10% Wt loss 10– Wt loss 15–20% Wt loss 20%+
15%
Hct 37%+ Hct 33–37% Hct 29–33% Hct 25–29% Hct 25%
Hb 12.3+ g/dL Hb 11.0-12.2 g/dL Hb 9.7-10.9 Hb 8.3-9.6 g/dL Hb <8.3 g/dL
g/dL
Peripheral No RP; RP not RP requiring Digital pitting Digital tip Digital gangrene
vascular requiring vasodilators scars ulcerations
vasodilators
Skin TSS 0 TSS 1-14 TSS 15-29 TSS 30-39 TSS 40+
Joint/tendon FTP 0-0.9 cm FTP 1.0-1.9 cm FTP 2.0-3.9 cm FTP 4.0-4.9 cm FTP 5.0+ cm
Muscle Normal Proximal Proximal Proximal Ambulation aids
proximal weakness, mild weakness, weakness, severe required
muscle strength moderate
Gastrointestinal Normal Distal esophageal Antibiotics Malabsorption Hyperalimentation
tract esophagogram; hypoperistalsis; required for syndrome; required
normal small small bowel series bacterial episodes of
bowel series abnormal overgrowth pseudoobstruction
Lung DLCO DLCO 70– DLCO 50– DLCO <50% Oxygen required
 80%+ 79% 69% FVC <50%
FVC 80%+ FVC 70–79% FVC 50– sPAP 65+
No fibrosis Basilar rales; 69% mm Hg
on fibrosis on sPAP 50-64
radiograph radiograph mm Hg
sPAP <35 sPAP 35-49
mm Hg mm Hg
Heart ECG normal ECG conduction ECG ECG arrhythmia CHF
defect arrhythmia requiring therapy
LVEF 50%+ LVEF 45–49% LVEF 40–44% LVEF 30–40% LVEF <30%
Kidney No history of History of SRC History of SRC History of SRC History of SRC with
SRC with with serum with serum with serum serum creatinine
serum creatinine <1.5 creatinine 1.5- creatinine 2.5-5.0 >5.0 mg/dL or
creatinine <1.3 mg/dL 2.4 mg/dL mg/dL dialysis required
mg/dL
* If 2 items are included for a severity grade, only 1 is required for the patient to be scored as
having disease of that severity level.
CHF, Congestive heart failure; DLCO , diffusing capacity for carbon monoxide, % predicted; ECG,
electrocardiogram; FTP, fingertip-to-palm distance in flexion; FVC, forced vital capacity, %
predicted; Hb, hemoglobin; Hct, hematocrit; LVEF, left ventricular ejection fraction; RP, Raynaud
phenomenon; sPAP, estimated pulmonary artery pressure by Doppler echo; SRC, scleroderma
renal crisis; TSS, total skin score; Wt, weight.
Modified from Medsger TA Jr, Bombardieri S, Czirjak L, et al: Assessment of disease severity and
prognosis, Clin Exp Rheumatol 21(3 Suppl 29):S51, 2003 (Table 1, p S-43).

Raynaud Phenomenon
Raynaud phenomenon (RP) is the most frequent initial symptom in pediatric
systemic sclerosis, present in 70% of affected children months to years before
other manifestations. RP refers to the classic triphasic sequence of blanching,
cyanosis, and erythema of the digits induced by cold exposure and/or emotional
stress. RP is typically independent of an underlying rheumatic disease (Raynaud
disease) but can result from rheumatic diseases such as scleroderma, systemic
lupus erythematosus (SLE), and mixed connective tissue disease (Fig. 185.6 ).
The color changes are brought about by (1) initial arterial vasoconstriction,
resulting in hypoperfusion and pallor (blanching), (2) venous stasis (cyanosis),
and (3) reflex vasodilation caused by the factors released from the ischemic
phase (erythema). The color change is classically reproduced by immersing the
hands in iced water and reversed by warming. During the blanching phase, there
is inadequate tissue perfusion in the affected area, associated with pain and
paresthesias and resulting in ischemic damage only when associated with a
rheumatic disease. The blanching usually affects the distal fingers but may also
involve thumbs, toes, ears, and tip of the nose. The affected area is usually well
among people along the Silk Road, evidence for genetic anticipation, and
genome-wide analysis. Genome wide analysis studies among Turkish and
Japanese BD patients confirm the marked association with HLA-B5101. Other
significant associations include interleukin (IL)-10 and IL-23R/IL-12Rβ2 genes.
Other possible susceptibility loci in a Turkish cohort demonstrate associations
with STAT4 (a transcription factor in a signaling pathway related to cytokines
such as IL-12, type I interferons, and IL-23) and ERAP1 (an endoplasmic
reticulum–expressed aminopeptidase that functions in processing of peptides
onto major histocompatibility complex class I).
The autoinflammatory nature of BD is suggested by its episodic nature, the
prominent innate immune system activation, the absence of identifiable
autoantibodies, and the co-association with the MEFV (Mediterranean fever)
gene. An infectious agent may be responsible for inducing the aberrant innate
immune system attacks in the genetically predisposed host. A number of
infectious agents have been implicated and include streptococci, herpes simplex
virus type 1, and parvovirus B19.

Clinical Manifestations and Diagnosis

The course of BD is characterized by exacerbations and remissions. There is also
marked heterogeneity in disease manifestation (Table 186.1 ).

Table 186.1

Consensus Classification of Pediatric Behçet Disease

ITEM DESCRIPTION
Recurrent oral aphthosis At least three attacks/year
Genital ulceration or aphthosis Typically with scar
Skin involvement Necrotic folliculitis, acneiform lesions, erythema nodosum
Ocular involvement Anterior uveitis, posterior uveitis, retinal vasculitis
Neurologic signs With the exception of isolated headaches
Vascular signs Venous thrombosis, arterial thrombosis, arterial aneurysm
From Koné-Paut I, Shahram F, Darce-Bello M, et al, for PEDBD group: Consensus classification
criteria for paediatric Behçet's disease from a prospective observational cohort: PEDBD, Ann
Rheum Dis 75:958–964, 2016.

The mean age of the first symptom is between 8 and 12 yr. The most frequent
initial symptom is a painful oral ulcer (Fig. 186.1 ). The oral ulcers are often
recurrent, may be single or multiple, range from 2-10 mm, and may be in any
Clinical Manifestations
International classification criteria have been developed for the diagnosis of
Sjögren syndrome in adult patients, but these criteria apply poorly to children.
Although diagnostic criteria in children have been proposed, they have not been
validated (Table 187.1 ). Recurrent parotid gland enlargement and parotitis are
the most common manifestations in children (>70%), whereas sicca syndrome
(dry mouth, painful mucosa, sensitivity to spicy foods, halitosis, widespread
dental caries) predominates in adults. In a cross-sectional study of children with
Sjögren syndrome, manifestations included recurrent parotitis (72%), sicca
symptoms (38%), polyarthritis (18%), vulvovaginitis (12%), hepatitis (10%),
Raynaud phenomenon (10%), fever (8%), renal tubular acidosis (9%),
lymphadenopathy (8%), and central nervous system (CNS) involvement (5%).
Table 187.1
Proposed Criteria for Pediatric Sjögren
Syndrome*

I. CLINICAL SYMPTOMS
1. Oral: recurrent parotitis or enlargement of parotid gland, dry
mouth (xerostomia)
2. Ocular: dry eyes (xerophthalmia) recurrent conjunctivitis without
obvious allergic or infectious etiology, keratoconjunctivitis sicca
3. Other mucosal: recurrent vaginitis
4. Systemic: fever, noninflammatory arthralgias, hypokalemic
paralysis, abdominal pain
II. IMMUNOLOGIC ABNORMALITIES
Presence of at least 1 of the following antibodies: anti-SSA, anti-
SSB, high-titer antinuclear antibody, rheumatoid factor
III. OTHER ABNORMALITIES OR INVESTIGATIONS
1. Biochemical: elevated serum amylase
2. Hematologic: leukopenia, high erythrocyte sedimentation rate
3. Immunologic: polyclonal hyperimmunoglobulinemia
4. Renal: renal tubular acidosis
5. Histologic proof of lymphocytic infiltration of salivary glands or
other organs (i.e., liver)
 6. Objective documentation of ocular dryness (rose bengal staining
or Schirmer test)
7. Positive findings of parotid gland scintigraphy
IV. Exclusion of all other autoimmune diseases

* Diagnosis requires ≥4 criteria.

From Bartunkova J. Primary Sjögren syndrome in children and adolescents:

proposal for diagnostic criteria, Clin Exp Rheumatol 17:381–386, 1999.

Subjective symptoms of xerostomia complaints are relatively rare in juvenile

cases, perhaps indicating that Sjögren syndrome is a slowly progressive disease;
however, increased dental caries is seen clinically in children. Serologic markers
(antinuclear antibodies [ANAs], antibodies to Ro [SSA] and La [SSB]) and
articular manifestations are significantly more common in adults. Reported
frequencies of ANAs and SSA and SSB antibodies in children are 78%, 75%,
and 65%, respectively, with rheumatoid factor present in 67%. Additional
clinical manifestations from a variety of organ involvement patterns include a
decreased sense of smell, hoarseness, chronic otitis media, leukocytoclastic
vasculitis (purpura), and internal organ exocrine disease involving the lungs
(diffuse interstitial lymphocytosis), pancreas, hepatobiliary system,
gastrointestinal tract, kidneys (renal tubular acidosis), musculoskeletal (arthritis
and arthralgia), hematologic (cytopenias), peripheral nervous system (sensory
and autonomic neuropathy), and CNS (optic neuritis, transverse myelitis,
meningoencephalitis).
Nonexocrine disease manifestations of Sjögren syndrome may be related to
inflammatory vascular disease (skin, muscle and joints, serosal surfaces, CNS,
peripheral nervous system), noninflammatory vascular disease (Raynaud
phenomenon), mediator-induced disease (hematologic cytopenias, fatigue,
fever), and autoimmune endocrinopathy (thyroiditis).

Diagnosis
Clinical presentation of recurrent parotitis and or recurrent parotid gland
swelling in a child or adolescent is characteristic and should raise the suspicion
considered and evaluated. If the workup is reassuring, the inflammatory episodes
resolve, and the child is otherwise well without unusual physical findings,
observance is often warranted because these episodes are likely to resolve as the
child's immune system matures.
Table 188.1
Differential Diagnosis of Periodic Fever
Hereditary
See Table 188.2 .
Nonhereditary

A. Infectious
1. Hidden infectious focus (e.g., aortoenteric fistula, lung
sequestration)
2. Recurrent infection/reinfection (e.g., chronic meningococcemia,
immune deficiency)
3. Specific infection (e.g., Whipple disease, malaria)
B. Noninfectious inflammatory disorder:
1. Adult-onset Still disease
2. Systemic-onset juvenile idiopathic arthritis
3. Periodic fever, aphthous stomatitis, pharyngitis, and adenitis
4. Schnitzler syndrome
5. Behçet syndrome
6. Crohn disease
7. Sarcoidosis
C. Neoplastic
1. Lymphoma (e.g., Hodgkin disease, angioimmunoblastic
lymphoma)
2. Solid tumor (e.g., pheochromocytoma, myxoma, colon
carcinoma)
3. Histiocytic disorders
D. Vascular (e.g., recurrent pulmonary embolism)
E. Hypothalamic
F. Psychogenic periodic fever
 G. Factitious or fraudulent

Adapted from Simon A, van der Meer JWM, Drenth JPH: Familial
autoinflammatory syndromes. In Firestein GS, Budd RC, Gabriel SE, et al,
editors: Kelley's textbook of rheumatology, ed 9, Philadelphia, 2012, Saunders
(Table 97-2).

Classification of Autoinflammatory
Disorders
Because of the rapidly expanding number of autoinflammatory disorders and
their varied clinical presentation, it can be difficult to group these disorders in a
meaningful manner. Some autoinflammatory disorders present with prominent
fevers and are known as hereditary periodic fever syndromes . These include 2
disorders with an autosomal recessive mode of inheritance, familial
Mediterranean fever (FMF ; MIM249100) and the hyperimmunoglobulinemia D
(hyper-IgD) with periodic fever syndrome (HIDS ; MIM260920). Hereditary
periodic fever syndromes with an autosomal dominant mode of inheritance
include the tumor necrosis factor (TNF) receptor–associated periodic syndrome
(TRAPS ; MIM191190) and a spectrum of disorders known as the cryopyrin-
associated periodic syndromes (CAPS ), or cryopyrinopathies. From mildest to
most severe, CAPS include the familial cold autoinflammatory syndrome
(FCAS1 ; MIM120100), Muckle-Wells syndrome (MWS ; MIM191100), and
neonatal-onset multisystem inflammatory disease (NOMID ; MIM607115) (also
known as chronic infantile neurologic cutaneous and articular syndrome,
CINCA ) (Table 188.2 ).

Table 188.2
Autoinflammatory Disorders

GENETIC
FUNCTIONAL ASSOCIATED
DISEASE DEFECT/PRESUMED INHERITANCE AFFECTED CELLS
DEFECTS FEATURES
PATHOGENESIS
Familial Mutations of MEFV AR Mature granulocytes, Decreased Recurrent
Mediterranean (lead to gain of pyrin cytokine-activated production of pyrin fever, serositis,
fever function, resulting in monocytes permits ASC- and
inappropriate IL-1β induced IL-1 inflammation
release) processing and responsive to
 inflammation colchicine.
following Predisposes to
subclinical serosal vasculitis and
injury; macrophage inflammatory
apoptosis decreased bowel disease
Mevalonate Mutations of MVK (lead AR Affecting Periodic fever
kinase deficiencyto a block in the cholesterol and
(hyper IgD mevalonate pathway). synthesis; leukocytosis
syndrome) Interleukin-1β mediates pathogenesis of with high IgD
the inflammatory disease is unclear levels
phenotype
Muckle–Wells Mutations of NLRP3 AD PMNs, monocytes Defect in Urticaria,
syndrome (also called PYPAF1 or cryopyrin, involved SNHL,
NALP3 ) lead to in leukocyte amyloidosis
constitutive activation of apoptosis and NF-
the NLRP3 κB signaling and
inflammasome IL-1 processing
Familial cold Mutations of AD PMNs, monocytes Same as above Nonpruritic
autoinflammatory NLRP3 (see above) urticaria,
syndrome Mutations of arthritis, chills,
NLRP12 fever, and
leukocytosis
after cold
exposure
Neonatal-onset Mutations of NLRP3 PMNs, chondrocytes Same as above Neonatal-onset
multisystem (see above) rash, chronic
inflammatory meningitis, and
disease (NOMID) arthropathy
or chronic with fever and
infantile inflammation
neurologic
cutaneous and
articular
syndrome
(CINCA)
TNF receptor– Mutations of AD PMNs, monocytes Mutations of 55- Recurrent
associated TNFRSF1A (resulting in kDa TNF receptor fever, serositis,
periodic increased TNF leading to rash, and ocular
syndrome inflammatory signaling) intracellular or joint
(TRAPS) receptor retention inflammation
or diminished
soluble cytokine
receptor available
to bind TNF
Pyogenic sterile Mutations of PSTPIP1 AD Hematopoietic tissues, Disordered actin Destructive
arthritis, (also called C2BP1 ) upregulated in reorganization arthritis,
pyoderma (affects both pyrin and activated T cells leading to inflammatory
gangrenosum, protein tyrosine compromised skin rash,
acne (PAPA) phosphatase to regulate physiologic myositis
syndrome innate and adaptive signaling during
immune responses) inflammatory
response
Blau syndrome Mutations of NOD2 AD Monocytes Mutations in Uveitis,
(also called CARD15 ) nucleotide binding granulomatous
(involved in various site of CARD15, synovitis,
 inflammatory processes) possibly disrupting campodactyly,
interactions with rash, and
lipopolysaccharides cranial
and NF-κB neuropathies,
signaling 30% develop
Crohn disease
Chronic recurrent Mutations of LPIN2 AR Neutrophils, bone Undefined Chronic
multifocal (increased expression of marrow cells recurrent
osteomyelitis and the proinflammatory multifocal
congenital genes) osteomyelitis,
dyserythropoietic transfusion-
anemia (Majeed dependent
syndrome) anemia,
cutaneous
inflammatory
disorders
Early-onset Mutations in IL-10 AR Monocyte/macrophage, IL-10 deficiency Enterocolitis,
inflammatory (results in increase of activated T cells leads to increase of enteric fistulas,
bowel disease many proinflammatory TNFγ and other perianal
cytokines) proinflammatory abscesses,
cytokines chronic
folliculitis
Early-onset Mutations in IL-10RA AR Monocyte/macrophage, Mutation in IL-10 Enterocolitis,
inflammatory (see above) activated T cells receptor alpha leads enteric fistulas,
bowel disease to increase of TNFγ perianal
and other abscesses,
proinflammatory chronic
cytokines folliculitis
Early-onset Mutations in IL-10RB AR Monocyte/macrophage, Mutation in IL-10 Enterocolitis,
inflammatory (see above) activated T cells receptor beta leads enteric fistulas,
bowel disease to increase of TNFγ perianal
and other abscesses,
proinflammatory chronic
cytokines folliculitis
AD, autosomal dominant; AR, autosomal recessive; Ig, immunoglobulin; IL, interleukin; NF-κB,
nuclear factor-κB; PMN, polymorphonuclear neutrophil; SNHL, sensorineural hearing loss; TNF,
tumor necrosis factor.
From Verbsky JW, Routes JR: Recurrent fever, infections, immune disorders, and
autoinflammatory diseases. In Kliegman RM, Lyse PS, Bordini BJ, et al, editors: Nelson pediatric
symptom-based diagnosis. Philadelphia, 2018, Elsevier, Table 41-5.

A variety of mendelian autoinflammatory disorders may or may not exhibit

prominent fevers and are not considered periodic fever syndromes, but do have
continuous or repeated episodes of spontaneous inflammation with unique
clinical characteristics. These include the syndrome of pyogenic arthritis with
pyoderma gangrenosum and acne (PAPA ; MIM604416), deficiency of the
interleukin-1 (IL-1) receptor antagonist (DIRA ; MIM612852), Blau syndrome
caused by mutations in NOD2 (also known as early-onset sarcoidosis ;
MIM186580), autoinflammation with phospholipase Cγ2 -associated antibody
 FIG. 188.1 Characteristic patterns of body temperature during inflammatory attacks in
the familial autoinflammatory syndromes. Interindividual variability for each syndrome
is considerable, and even for the individual patient, the fever pattern may vary greatly
from episode to episode. Note the different time scales on the x axes. CINCA/NOMID,
Chronic infantile neurologic cutaneous and articular syndrome/neonatal-onset
multisystemic inflammatory disease; FCAS, familial cold autoinflammatory syndrome;
HIDS, hyper-IgD syndrome; MWS, Muckle-Wells syndrome; TRAPS, tumor necrosis
factor receptor–associated periodic syndrome. (From Simon A, van der Meer JWM,
Drenth JPH: Familial autoinflammatory syndromes. In Firestein GS, Budd RC, Gabriel
SE, et al, editors: Kelley's textbook of rheumatology, ed 9, Philadelphia, 2012,
Saunders, Fig 97-1.)

Table 188.3
Clinical Grouping of Autoinflammatory
Diseases by Skin Manifestations

1. Neutrophilic urticaria (the cryopyrinopathies)

Recurrent fever attacks of short duration (typically <24 hr)
• CAPS/FCAS: familial cold autoinflammatory syndrome
• CAPS/MWS: Muckle-Wells syndrome
• FCAS2/NLRP12
Continuous low-grade fever
• CAPS/NOMID: neonatal-onset multisystem inflammatory disease
(NOMID)/chronic infantile neurologic cutaneous and articular
syndrome (CINCA)
 2. Granulomatous skin lesions and minimal or low-grade fever attacks
• Blau syndrome/early-onset sarcoidosis (pediatric granulomatous
arthritis)
3. Pustular skin rashes and fever
With inflammatory bone disease
• DIRA: deficiency of interleukin-1 receptor agonist
• Majeed syndrome
With pyogenic arthritis
• PAPA: pyogenic arthritis, pyoderma gangrenosum, and acne
syndrome
Without other organ involvement
• DITRA: deficiency of interleukin-36 receptor antagonist
• CAMPS: CARD14-mediated psoriasis
4. Atypical neutrophilic dermatosis with histiocytic-like infiltrate
• CANDLE: proteasome associated autoinflammatory syndromes
5. Livedo reticularis, vasculopathy with ulcerations
• SAVI; STING associated vasculopathy, infantile onset
6. Livedo racemosa, vasculitis with ulcerations
• ADA2; adenosine deaminase-2 deficiency

CAPS, Cryopyrin-associated periodic syndromes.

Modified from Almeida de Jesus A, Goldbach-Mansky R: Monogenic

autoinflammatory diseases: concept and clinical manifestations, Clin Immunol
147:155–174, 2013 (Table 1).

Table 188.4
Autoinflammatory Bone Disorders

MAJEED CMO AND LUPO

CRMO SYNDROME DIRA CHERUBISM MICE

Ethnicity Worldwide, Arabic European, Puerto Worldwide Occurs in various

but mostly Rican, Arabic backgrounds
European
Fever Uncommon Common Uncommon No Not assessed
Sites of Metaphyses of Similar to CRMO Anterior rib ends, Mandible > Vertebrae hind >
osseous long bones > metaphyses of long maxilla forefeet
involvement vertebrae, bones, vertebrae, Rarely ribs
clavicle, others
 sternum,
pelvis, others
Extraosseous PPP, psoriasis, Dyserythropoietic Generalized Cervical Dermatitis,
manifestations IBD, others anemia, Sweet pustulosis, nail lymphadenopathy extramedullary
syndrome, HSM, changes, lung hematopoiesis,
growth failure disease, vasculitis splenomegaly
Family history Psoriasis, PPP, Psoriasis in some No known No known Heterozygotes
of arthritis, IBD, obligate carriers associations associations normal
inflammatory others
disorders
Inheritance Not clear Autosomal Autosomal Autosomal Autosomal recessive
recessive recessive dominant;
incomplete
penetrance
Gene defect Unknown LPIN2 IL1RN SH3BP2 >> Pstpip2
PTPN11
Protein name ? Lipin2 IL-1Ra SH3BP2 PSTPIP2 (MAYP)
Protein ? Fat metabolism: Antagonist of IL-1 ↑ Myeloid cell Macrophage
function (PAP enzyme receptor response to M- proliferation,
activity), ↑ CSF and macrophage
message to RANKL, ↑ TNF- recruitment to sites
oxidative stress, ? α expression in of inflammation,
role in mitosis macrophages cytoskeletal function
Cytokine ↑ serum TNF- Not tested ↑ IL-1α, IL-1β, ↑ serum TNF-α in cmo: ↑ serum
abnormalities α MIP-1α, TNF-α, IL- mouse model IL-6, MIP-1α,
8, IL-6 ex vivo TNF-α, CSF-1,
monocyte assay; IP-10
skin reveals ↑ IL-17 Lupo: ↑ serum
staining MIP-1α, IL-4,
RANTES, TGF-
β
CRMO, Chronic recurrent multifocal osteomyelitis; CSF, colony-stimulating factor; DIRA,
deficiency of interleukin-1 receptor antagonist; HSM, hepatosplenomegaly; IBD, inflammatory
bowel disease; IL, interleukin; IL-1Ra, interleukin-1 receptor antagonist; IP-10, interferon-inducible
protein-10; M-CSF, macrophage colony-stimulating factor; MIP-1α, macrophage inflammatory
protein-1α; PAP, phosphatidate phosphatase; PPP, palmar-plantar pustulosis; PSTPIP2, proline-
serine-threonine phosphatase interacting protein; RANKL, receptor activator of nuclear factor-κB
ligand; RANTES, regulated on activation, normal T cell expressed and secreted; SH3BP2, SH3
binding protein 2; TGF, transforming growth factor; TNF-α, tumor necrosis factor alpha.
From Ferguson PJ, Laxer RM: Autoinflammatory bone disorders. In Cassidy JT, Petty RE, Laxer
RM, et al, editors: Textbook of pediatric rheumatology, ed 6, Philadelphia, 2010, Saunders (Table
44-2).

Table 188.5
Clues That May Assist in Diagnosis of Autoinflammatory
Syndromes
AGE OF ONSET
At birth NOMID, DIRA, MWS
 Infancy and 1st yr of life HIDS, FCAS, NLRP12
Toddler PFAPA
Late childhood PAPA
Most common of autoinflammatory syndromes to have onset in TRAPS, DITRA
adulthood
Variable (mostly in childhood) All others
ETHNICITY AND GEOGRAPHY
Armenians, Turks, Italian, Sephardic Jews FMF
Arabs FMF, DITRA (Arab Tunisian)
Dutch, French, German, Western Europe HIDS, MWS, NLRP12
United States FCAS
Can occur in blacks (West Africa origin) TRAPS
Eastern Canada, Puerto Rico DIRA
Worldwide All others
TRIGGERS
Vaccines HIDS
Cold exposure FCAS, NLRP12
Stress, menses FMF, TRAPS, MWS, PAPA, DITRA
Minor trauma PAPA, MWS, TRAPS, HIDS
Exercise FMF, TRAPS
Pregnancy DITRA
Infections All, especially DITRA
ATTACK DURATION
<24 hr FCAS, FMF
1-3 days FMF, MWS, DITRA (fever)
3-7 days HIDS, PFAPA
>7 days TRAPS, PAPA
Almost always “in attack” NOMID, DIRA
INTERVAL BETWEEN ATTACKS
3-6 wk PFAPA, HIDS
>6 wk TRAPS
Mostly unpredictable All others
Truly periodic PFAPA, cyclic neutropenia
USEFUL LABORATORY TESTS
Acute-phase reactants must be normal between attacks PFAPA
Urine mevalonic acid in attack HIDS
IgD > 100 mg/dL HIDS
Proteinuria (amyloidosis) FMF, TRAPS, MWS, NOMID
RESPONSE TO THERAPY
Corticosteroid dramatic PFAPA
Corticosteroid partial TRAPS, FCAS, MWS, NOMID, PAPA*
Colchicine FMF, PFAPA (30% effective)
Cimetidine PFAPA (30% effective)
Etanercept TRAPS, FMF arthritis
Anti–IL-1 dramatic DIRA (anakinra), FCAS, MWS, NOMID,
PFAPA
Anti–IL-1 mostly TRAPS, FMF
Anti–IL-1 partial HIDS, PAPA
* For intraarticular corticosteroids.

DIRA, Deficiency of IL-1 receptor antagonist; DITRA, deficiency of IL-36 receptor antagonist
(generalized pustular psoriasis); FCAS, familial cold autoinflammatory syndrome; FMF, familial
weekly to 1-2 flares per year. Table 188.6 lists diagnostic criteria for FMF.

FIG. 188.2 Characteristic erysipeloid erythema associated with familial Mediterranean
fever. This rash appears during a flare and overlies the ankle or dorsum of the foot.

Table 188.6
Diagnostic Criteria for Familial
Mediterranean Fever (FMF)*
Major Criteria

1. Typical attacks † with peritonitis (generalized)

2. Typical attacks with pleuritis (unilateral) or pericarditis
3. Typical attacks with monoarthritis (hip, knee, ankle)
4. Typical attacks with fever alone
5. Incomplete abdominal attack

Minor Criteria

1. Incomplete attacks ‡ involving chest pain

2. Incomplete attacks involving monoarthritis
3. Exertional leg pain
4. Favorable response to colchicine
* Requirements for diagnosis of FMF are ≥1 major criteria or ≥2 minor criteria.

† Typical attacks are defined as recurrent (≥3 of the same type), febrile (≥38°C),

and short (lasting between 12 hr and 3 days).

‡ Incomplete attacks are defined as painful and recurrent attacks not fulfilling the

criteria for a typical attack.

From Livneh A, Langevitz P, Zemer D, et al: Criteria for the diagnosis of

familial Mediterranean fever, Arthritis Rheum 40:1879–1885, 1997.

FMF is caused by autosomal recessive mutations in MEFV , a gene encoding a

781 amino acid protein denoted pyrin (Greek for “fever”). Pyrin is expressed in
granulocytes, monocytes, and dendritic cells (DCs) and in peritoneal, synovial,
and dermal fibroblasts. The N-terminal approximately 90 amino acids of pyrin
are the prototype for a motif (the PYRIN domain) that mediates protein-protein
interactions and is found in >20 different human proteins that regulate
inflammation and apoptosis. Many of the FMF-associated mutations in pyrin are
found at the C-terminal B30.2 domain of pyrin, encoded by exon 10 of MEFV.
More than 50 such FMF mutations are listed in an online database
(http://fmf.igh.cnrs.fr/ISSAID/infevers/ ), almost all of which are missense
substitutions. Homozygosity for the M694V mutation may be associated with an
earlier age of onset, arthritis, and an increased risk of amyloidosis. The
substitution of glutamine for glutamic acid at residue 148 (E148Q) is considered
either a mild mutation or a functional polymorphism in the pyrin protein. The
carrier frequency of FMF mutations among several Mediterranean populations is
very high, suggesting the possibility of a heterozygote advantage.
FMF occurs primarily among ethnic groups of Mediterranean ancestry, most
frequently Jews, Turks, Armenians, Arabs, and Italians. Because of a higher
frequency of the M694V mutation, FMF is more severe and more readily
recognized in the Sephardic (North African) than the Ashkenazi (East European)
Jewish population. With the advent of genetic testing, mutation-positive FMF
has been documented worldwide, although at lower frequency than in the
Mediterranean basin and Middle East.
Through PYRIN-domain interactions, pyrin can activate caspase-1 , the
enzyme that converts the 31 kDa pro–IL-1β molecule into the biologically active
17 kDa IL-1β, which is a major mediator of fever and inflammation. FMF
mutations lead to a gain-of-function activation of caspase-1 and IL-1β–
Table 188.7
Diagnostic Indicators of Hyper-IgD Syndrome
At Time of Attacks

1. Elevated erythrocyte sedimentation rate and leukocytosis

2. Abrupt onset of fever (≥38.5°C)
3. Recurrent attacks
4. Lymphadenopathy (especially cervical)
5. Abdominal distress (e.g., vomiting, diarrhea, pain)
6. Skin manifestations (e.g., erythematous macules and papules)
7. Arthralgias and arthritis
8. Splenomegaly

Constantly Present

1. Elevated IgD (above upper limit of normal) measured on 2 occasions at

least 1 mo apart*
2. Elevated IgA (≥2.6 g/L)

Specific Features

1. Mutations in mevalonate kinase gene

2. Decreased mevalonate kinase enzyme activity

* Extremely high serum concentrations of IgD are characteristic but not

obligatory.

From Firestein GS, Budd RC, Gabriel SE, et al, editors: Kelly & Firestein's
textbook of rheumatology, ed 10, Philadelphia, 2016, Elsevier (Table 97-4, p
1674).

Standards for the treatment of HIDS are evolving. Very few patients respond
to colchicine, and milder disease courses may respond to nonsteroidal
 FIG. 188.6 Cutaneous manifestations of tumor necrosis factor receptor–associated
periodic syndrome. A, Right flank of a patient with the T50M mutation. B, Serpiginous
rash involving the face, neck, torso, and upper extremities of a child with the C30S
mutation. C, Erythematous, macular patches with crusting on the flexor surface of the
right arm of a patient with the T50M mutation. (From Hull KM, Drewe, Aksentijevich I, et
al: The TNF receptor-associated periodic syndrome [TRAPS]: emerging concepts of an
autoinflammatory syndrome, Medicine (Baltimore) 81:349–368, 2002.)

Table 188.8
Diagnostic Indicators of Tumor Necrosis
Factor Receptor–Associated Periodic
Syndrome (TRAPS)
1. Recurrent episodes of inflammatory symptoms spanning >6 mo duration
(several symptoms generally occur simultaneously)
a. Fever
b. Abdominal pain
c. Myalgia (migratory)
d. Rash (erythematous macular rash occurs with myalgia)
e. Conjunctivitis or periorbital edema
f. Chest pain
g. Arthralgia or monoarticular synovitis
2. Episodes last >5 days on average (although variable)
3. Responsive to glucocorticosteroids but not colchicine
4. Affects family members in autosomal dominant pattern (although may not
 always be present)
5. Any ethnicity may be affected

From Hull KM, Drewe E, Aksentijevich I, et al: The TNF receptor-associated

periodic syndrome (TRAPS): emerging concepts of an autoinflammatory
disorder, Medicine (Baltimore) 81:349–368, 2002.

Almost all the TRAPS-associated mutations are in the extracellular domain of

the TNFR1 protein, with about one-third involving the substitution of another
amino acid for a highly conserved cysteine residue, thus disrupting disulfide
bonds and leading to protein misfolding. A number of other missense mutations
not involving cysteine residues have been shown to have a similar effect on
TNFR1 protein folding. Misfolded TNFR1 aggregates intracellularly and leads
to constitutive signaling through mitogen-activated protein kinases or nuclear
factor (NF)-κB, resulting in the release of proinflammatory cytokines such as IL-
6, IL-1β and TNF-α. The substitution of glutamine for arginine at residue 92
(R92Q) and the substitution of leucine for proline at residue 46 (P46L) are seen
in >1% of the white and black population, respectively. These variants do not
lead to the same biochemical or signaling abnormalities seen with more-severe
TRAPS mutations, and as with E148Q in FMF, debate surrounds whether they
are mild mutations or functional polymorphisms.
Colchicine is generally not effective in TRAPS. For relatively mild disease,
NSAIDs may suffice. For more severe disease with infrequent attacks,
corticosteroids at the time of an attack may be effective, but it is not unusual for
steroid requirements to increase over time. Etanercept is often effective in
reducing the severity and frequency of flares, but longitudinal follow-up of
TRAPS patients treated with etanercept indicates waning efficacy with time. Of
note, treatment of TRAPS with anti-TNF-α monoclonal antibodies has
sometimes led to a paradoxical worsening of disease. Clinical responses to
anakinra, canakinumab, a monoclonal anti–IL-1β antibody, and tocilizumab, a
monoclonal anti-IL6 antibody, has been favorable in TRAPS patients.

Cryopyrin-Associated Periodic Fever

Syndromes
CAPS represent a spectrum of clinical disorders, including familial cold

FIG. 188.7 Urticarial-like rash. Inflammatory clinical manifestations and organ damage
in the IL-1–mediated diseases; in neonatal-onset multisystem inflammatory disease
(NOMID), which is the severe form of cryopyrin-associated periodic syndromes (CAPS);
and deficiency of IL-1 receptor antagonist (DIRA). This rash is not truly urticarial and
occurs due to neutrophil infiltrates into the skin. (From Jesus AA, Goldbach-Mansky R:
IL-1 blockade in autoinflammatory syndromes. Annu Rev Med 65:223–244, 2014, Fig.
2.)

Table 188.9
Diagnostic Criteria for Familial Cold
Autoinflammatory Syndrome (FCAS)

1. Recurrent intermittent episodes of fever and rash that primarily follow

generalized cold exposures
2. Autosomal dominant pattern of disease inheritance
3. Age of onset <6 mo
4. Duration of most attacks <24 hr
5. Presence of conjunctivitis associated with attacks
6. Absence of deafness, periorbital edema, lymphadenopathy, and serositis

From Hoffman HM, Wanderer AA, Broide DH: Familial cold autoinflammatory
syndrome: phenotype and genotype of an autosomal dominant periodic fever, J
Allergy Clin Immunol 108:615–620, 2001.

In contrast to FCAS, the febrile episodes of MWS are not cold induced but
are characterized by the same urticarial-like rash seen in FCAS (Fig. 188.8 ).
Many MWS patients also develop progressive sensorineural hearing loss, and
untreated, approximately 30% of MWS patients develop AA amyloidosis.
NOMID patients present in the neonatal period with a diffuse, urticarial rash,
daily fevers, and dysmorphic features (Fig. 188.9 ). Significant joint deformities,
particularly of the knees, may develop because of bony overgrowth of the
epiphyses of the long bones (Fig. 188.10 ). NOMID patients also develop
chronic aseptic meningitis, leading to increased intracranial pressure, optic disc
edema, visual impairment, progressive sensorineural hearing loss, and
intellectual disability (Fig. 188.11 ).

FIG. 188.8 Urticarial-like skin rash in a patient with Muckle-Wells syndrome. (Courtesy
Dr. D. L. Kastner, National Institutes of Health, Bethesda, Maryland; from Simon A, van
der Meer JWM, Drenth JPH: Familial autoinflammatory syndromes. In Firestein GS,
Budd RC, Gabriel SE, et al, editors: Kelley's textbook of rheumatology, ed 9,
Philadelphia, 2012, Saunders, Fig 97-14.)
disease occurs infrequently in children but typically manifests as renal
insufficiency, proteinuria, transient pyuria, or microscopic hematuria caused by
early monocellular infiltration or granuloma formation in kidney tissue. Only a
small fraction of children have hypercalcemia or hypercalciuria, which is
therefore an infrequent cause of kidney disease. Sarcoid granulomas can also
infiltrate the heart and lead to cardiac arrhythmias and, rarely, sudden death.
Other rare sites of disease involvement include blood vessels of any size, the
gastrointestinal tract, parotid gland, muscles, bones, and testes.

Table 190.1

Sarcoidosis: Extrapulmonary Localizations

SYMPTOMS
Skin Papules, nodules, plaques, scar sarcoidosis, lupus pernio, subcutaneous sarcoidosis
Peripheral Mostly cervical or supraclavicular; inguinal, axillary, epitrochlear, or submandibular lymph
lymphadenopathy node sites also possible; painless and mobile
Eye Anterior, intermediate, or posterior uveitis; retinal vascular change; conjunctival nodules;
lacrimal gland enlargement
Liver Often symptom free; abnormal liver function tests in 20–30% of patients; hepatomegaly;
rarely hepatic insufficiency, chronic intrahepatic cholestasis, or portal hypertension
Spleen Splenomegaly; rarely, pain or pancytopenia; very rarely, splenic rupture
Heart Atrioventricular or bundle branch block; ventricular tachycardia or fibrillation; congestive
heart failure; pericarditis; impairment of sympathetic nerve activity; sudden death
Nervous system Facial nerve palsy, optic neuritis, leptomeningitis, diabetes insipidus, hypopituitarism,
seizures, cognitive dysfunction, deficits, hydrocephalus, psychiatric manifestations, spinal
cord disease, polyneuropathy, small-fiber neuropathy
Kidney Rare symptoms; increased creatininemia sometimes associated with hypercalcemia;
nephrocalcinosis; kidney stones
Parotitis Symmetric parotid swelling; Heerfordt syndrome when associated with uveitis, fever, and
facial palsy
Nose Nasal stuffiness, nasal bleeding, crusting, anosmia
Larynx Hoarseness, breathlessness, stridor, dysphagia
Bones Often asymptomatic; hands and feet classically most involved, also large bones and axial
skeleton
Skeletal muscles Proximal muscle weakness, amyotrophy, myalgia, intramuscular nodules
Genitourinary All organs can be involved, including breast, uterus, epididymis, and testicle
tract
Gastrointestinal Most often symptom free, but the esophagus, stomach, small intestine, and colon can be
tract involved
Adapted from Valerye D, Prasse A, Nunes H, et al: Sarcoidosis, Lancet 383:1155–1167, 2014
(Table 1, p 1159).
). Perineal desquamation is common in the acute phase. Periungual
desquamation of the fingers and toes begins 2-3 wk after the onset of illness and
may progress to involve the entire hand and foot (Fig. 191.6 ).
Table 191.1
Clinical and Laboratory Features of Kawasaki
Disease
Epidemiologic Case Definition (Classic Clinical Criteria)*

Fever persisting at least 5 days †

Presence of at least 4 principal features:
Changes in extremities
• Acute: erythema of palms, soles; edema of hands, feet
• Subacute: periungual peeling of fingers, toes in wk 2 and
3
Polymorphous exanthem
Bilateral bulbar conjunctival injection without exudate
Erythema and cracking of lips, strawberry tongue, and/or
erythema of oral and pharyngeal mucosa
Cervical lymphadenopathy (>1.5 cm diameter), usually unilateral
Exclusion of other diseases with similar findings ‡

These features do not have to occur concurrently.

Other Clinical and Laboratory Findings
Cardiovascular System

Myocarditis, pericarditis, valvular regurgitation, shock

Coronary artery abnormalities
Aneurysms of medium-sized noncoronary arteries
Peripheral gangrene
Aortic root enlargement

Respiratory System
 Peribronchial and interstitial infiltrates on chest radiograph
Pulmonary nodules

Musculoskeletal System

Arthritis, arthralgias (pleocytosis of synovial fluid)

Gastrointestinal Tract

Diarrhea, vomiting, abdominal pain

Hepatitis, jaundice
Hydrops of gallbladder
Pancreatitis

Central Nervous System

Extreme irritability
Aseptic meningitis (pleocytosis of cerebrospinal fluid)
Facial nerve palsy
Sensorineural hearing loss

Genitourinary System

Urethritis/meatitis, hydrocele

Other Findings

Desquamating rash in groin

Retropharyngeal phlegmon
Anterior uveitis by slit-lamp examination
Erythema, induration at bacille Calmette-Guérin inoculation site

Laboratory Findings in Acute Kawasaki Disease

Leukocytosis with neutrophilia and immature forms

 Elevated erythrocyte sedimentation rate
Elevated C-reactive protein
Anemia
Abnormal plasma lipids
Hypoalbuminemia
Hyponatremia
Thrombocytosis after wk 1 §
Sterile pyuria
Elevated serum transaminases
Elevated serum γ-glutamyl transpeptidase
Pleocytosis of cerebrospinal fluid
Leukocytosis in synovial fluid

* Patients with fever at least 5 days and <4 principal criteria can be diagnosed

with Kawasaki disease when coronary artery abnormalities are detected by 2-

dimensional echocardiography or angiography.
† In the presence of ≥4 principal criteria, particularly when redness and swelling

of the hands and feet are present, Kawasaki disease diagnosis can be made on
day 4 of illness. Experienced clinicians who have treated many patients with
Kawasaki disease may establish diagnosis before day 4 in rare cases.
‡ See differential diagnosis (Table 191.2 ).

§ Some infants present with thrombocytopenia and disseminated intravascular

coagulation.

From McCrindle BW, Rowley A, Newburger JW et al: Diagnosis, treatment, and

long-term management of Kawasaki disease: a scientific statement for health
professionals from the American Heart Association, Circulation 135(17):e927–
e999, 2017.)
Adenovirus, measles, and scarlet fever lead the list of common childhood
infections that mimic KD (Table 191.2 ). Children with adenovirus typically
have exudative pharyngitis and exudative conjunctivitis, allowing differentiation
from KD. A common clinical problem is the differentiation of scarlet fever from
KD in a child who is a group A streptococcal carrier. Patients with scarlet fever
typically have a rapid clinical response to appropriate antibiotic therapy. Such
treatment for 24-48 hr with clinical reassessment generally clarifies the
diagnosis. Furthermore, ocular findings are quite rare in group A streptococcal
pharyngitis and may assist in the diagnosis of KD.
Table 191.2
Differential Diagnosis of Kawasaki Disease
Viral Infections*

Adenovirus
Enterovirus
Measles
Epstein-Barr virus
Cytomegalovirus

Bacterial Infections

Scarlet fever
Rocky Mountain spotted fever
Leptospirosis
Bacterial cervical lymphadenitis ± retropharyngeal phlegmon
Meningococcemia
Urinary tract infection

Rheumatologic Disease

Systemic-onset juvenile idiopathic arthritis

Behçet disease
Rheumatic fever
Other

Toxic shock syndromes

Serum sickness
Staphylococcal scalded skin syndrome
Macrophage activation syndrome
Drug hypersensitivity reactions
Stevens-Johnson syndrome
Aseptic meningitis

* Detection of a virus does not exclude Kawasaki disease in the presence of the

principal clinical features (see Table 191.1 ).

Features of measles that distinguish it from KD include exudative

conjunctivitis, Koplik spots, rash that begins on the face and hairline and behind
the ears, and leukopenia. Cervical lymphadenitis can be the initial diagnosis in
children who are ultimately recognized to have KD. Less common infections
such as Rocky Mountain spotted fever and leptospirosis are occasionally
confused with KD. Rocky Mountain spotted fever is a potentially lethal
bacterial infection, and appropriate antibiotics should not be withheld if the
diagnosis is under consideration. Its distinguishing features include pronounced
myalgias and headache at onset, centripedal rash, and petechiae on the palms and
soles. Leptospirosis can also be an illness of considerable severity. Risk factors
include exposure to water contaminated with urine from infected animals. The
classic description of leptospirosis is of a biphasic illness with a few
asymptomatic days between an initial period of fever and headache and a late
phase with renal and hepatic failure. In contrast, patients with KD have
consecutive days of fever at diagnosis and rarely have renal or hepatic failure.
Children with KD and pronounced myocarditis may demonstrate hypotension
with a clinical picture similar to that of toxic shock syndrome. Features of toxic
shock syndrome that are not usually seen in KD include renal insufficiency,
coagulopathy, pancytopenia, and myositis. Drug hypersensitivity reactions,
including Stevens-Johnson syndrome, share some characteristics with KD. Drug
reaction features such as the presence of periorbital edema, oral ulcerations, and
a normal or minimally elevated ESR are not seen in KD. Systemic-onset
juvenile idiopathic arthritis (sJIA) is also characterized by fever and rash, but
physical findings include diffuse lymphadenopathy and hepatosplenomegaly.
Arthritis is required to develop at some point in the disease course to make the
diagnosis, but may not be present in the 1st few wk of illness. Laboratory
findings may include coagulopathy, elevated fibrin degradation product values,
and hyperferritinemia. Interestingly, there are reports of children with sJIA who
have echocardiographic evidence of CAA. Coronary aneurysms have also been
reported in Behçet disease, primary cytomegalovirus infection, and
meningococcemia.

Treatment
Patients with acute KD should be treated with 2 g/kg of IVIG as a single
infusion, usually administered over 10-12 hr within 10 days of disease onset, and
ideally as soon as possible after diagnosis (Table 191.3 ). In addition, moderate
(30-50 mg/kg/day divided every 6 hr) to high-dose aspirin (80-100 mg/kg/day
divided every 6 hr) should be administered until the patient is afebrile, then
lowered to antiplatelet doses. Other NSAIDs should not be given during therapy
with aspirin because they may block the action of aspirin. The mechanism of
action of IVIG in KD is unknown, but treatment results in defervescence and
resolution of clinical signs of illness in approximately 85% of patients. The
prevalence of coronary disease, in 20–25% in children treated with aspirin alone,
is <5% in those treated with IVIG and aspirin within the 1st 10 days of illness.
Strong consideration should be given to treating patients with persistent fever,
abnormal dimensions of the coronary arteries, or signs of systemic inflammation
who are diagnosed after the 10th day of fever. The dose of aspirin is usually
decreased from antiinflammatory to antithrombotic doses (3-5 mg/kg/day as a
single dose) after the patient has been afebrile for 48 hr. Aspirin is continued for
its antithrombotic effect until 6-8 wk after illness onset and is then discontinued
in patients who have had normal echocardiography findings throughout the
course of their illness. Patients with CAA continue with aspirin therapy and may
require anticoagulation, depending on the degree of coronary dilation (see later).
Table 191.3
Treatment of Kawasaki Disease
Acute Stage
 Intravenous immune globulin 2 g/kg over 10-12 hr
and
Aspirin 30-50 mg/kg/day or 80-100 mg/kg/day divided every 6 hr orally
until patient is afebrile for at least 48 hr

Convalescent Stage

Aspirin 3-5 mg/kg once daily orally until 6-8 wk after illness onset if
normal coronary findings throughout course

Long-Term Therapy for Patients With Coronary Abnormalities

Aspirin 3-5 mg/kg once daily orally

Clopidogrel 1 mg/kg/day (maximum 75 mg/day)
Most experts add warfarin or low-molecular-weight heparin for those
patients at particularly high risk of thrombosis

Acute Coronary Thrombosis

Prompt fibrinolytic therapy with tissue plasminogen activator or other

thrombolytic agent under supervision of a pediatric cardiologist

Corticosteroids have been used as primary therapy with the 1st dose of IVIG
in hopes of improving coronary outcomes. A North American trial using a single
pulse dose of intravenous methylprednisolone (30 mg/kg) with IVIG as primary
therapy did not improve coronary outcomes. However, a trial in Japan utilizing
the Kobayashi score to identify high-risk children demonstrated improved
coronary outcomes with a regimen of prednisolone (2 mg/kg) plus IVIG as
primary therapy. Furthermore, a systematic review and meta-analysis of 16
comparative studies demonstrated that early treatment with corticosteroids
improved coronary artery outcomes in children with KD. Despite these
promising results, administration of corticosteroids as primary therapy to all
children with KD awaits the development of a risk score that identifies high-risk
children in a multiracial population.
IVIG-resistant KD occurs in approximately 15% of patients and is defined
by persistent or recrudescent fever 36 hr after completion of the initial IVIG
infusion. Patients with IVIG resistance are at increased risk for CAA.
Therapeutic options for the child with IVIG resistance include a 2nd dose of
IVIG (2 g/kg), a tapering course of corticosteroids, and/or infliximab (Table
191.4 ). For the most severely affected patients with enlarging coronary
aneurysms, additional therapies such as cyclosporine or cyclophosphamide may
be administered, with consultation from specialists in pediatric rheumatology
and cardiology.

Table 191.4
Treatment Options for IVIG-Resistant Patients With
Kawasaki Disease*
AGENT DESCRIPTION DOSE
MOST FREQUENTLY ADMINISTERED
IVIG: 2nd infusion Pooled polyclonal 2 g/kg IV
IG
IVIG + IVIG + IVIG: 2 g/kg IV + prednisolone 2 mg⋅kg−1 ⋅d−1 IV divided every 8 hr
prednisolone corticosteroid until afebrile, then prednisone orally until CRP normalized, then taper
over 2-3 wk
Infliximab Monoclonal Single infusion: 5 mg/kg IV given over 2 hr
antibody against
TNF-α
ALTERNATIVE TREATMENTS
Cyclosporine Inhibitor of IV: 3 mg⋅kg−1 ⋅d−1 divided every 12 hr
calcineurin-NFAT PO: 4-8 mg⋅kg−1 ⋅d−1 divided every 12 hr
pathway Adjust dose to achieve trough 50-150 ng/mL; 2 hr peak level 300-
600 ng/mL
Anakinra Recombinant IL- 2-6 mg⋅kg−1 ⋅d−1 given by subcutaneous injection
1β receptor
antagonist
Cyclophosphamide Alkylating agent 2 mg⋅kg−1 ⋅d−1 IV
blocks DNA
replication
Plasma exchange Replaces plasma Not applicable
with albumin
* IVIG resistance is defined as persistent or recrudescent fever at least 36 hours and <7 days after
completion of 1st IVIG infusion. The top 3 treatments have been most frequently used, although
no comparative effectiveness trial has been performed. Pulsed high-dose corticosteroid treatment
is not recommended. The alternative treatments have been used in a limited number of patients
with KD.
CRP, C-reactive protein; IG, immunoglobulin; IL, interleukin; IV, intravenous(ly); IVIG, intravenous
immune globulin; NFAT, nuclear factor of activated T cells; PO, oral; TNF, tumor necrosis factor.

FIG. 192.1 Distribution of vessel involvement in large, medium, and small vessel
vasculitis. There is substantial overlap with respect to arterial involvement, and all 3
major categories of vasculitis can affect any-size artery. Large vessel vasculitis affects
large arteries more often than other vasculitides. Medium vessel vasculitis
predominantly affects medium arteries. Small vessel vasculitis predominantly affects
small vessels, but medium arteries and veins may be affected, although immune
complex small vessel vasculitis rarely affects arteries. Not shown is variable vessel
vasculitis , which can affect any type of vessel, from aorta to veins. The diagram
depicts (from left to right ) aorta, large artery, medium artery, small artery/arteriole,
capillary, venule, and vein. ANCA, Antineutrophil cytoplasmic antibody; GBM,
glomerular basement membrane. (From Jennette JC, Falk RJ, Bacon PA, et al: 2012
Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides,
Arthritis Rheum 65(1):1–11, 2013, Fig 2, p 4.)

Table 192.1
Classification of Childhood Vasculitis
2012 Chapel Hill Consensus EUROPEAN LEAGUE AGAINST RHEUMATISM/PEDIATRIC
Conference Nomenclature of RHEUMATOLOGY EUROPEAN SOCIETY Classification of
Vasculitides Childhood Vasculitis
I. Large vessel vasculitis Predominantly large vessel vasculitis
Takayasu arteritis Takayasu arteritis
Giant cell arteritis Predominantly medium vessel vasculitis
II. Medium vessel vasculitis Childhood polyarteritis nodosa
Polyarteritis nodosa Cutaneous polyarteritis nodosa
Kawasaki disease Kawasaki disease
III. Small vessel vasculitis Predominantly small vessel vasculitis
Antineutrophil cytoplasmic Granulomatous:
antibody (ANCA)–associated • Granulomatosis with polyangiitis (Wegener granulomatosis)*
 vasculitis • Eosinophilic granulomatosis with polyangiitis (Churg-Strauss
• Microscopic polyangiitis syndrome)*
• Granulomatosis with Nongranulomatous:
polyangiitis • Microscopic polyangiitis*
• Eosinophilic • Henoch-Schönlein purpura (IgA vasculitis)
granulomatosis with • Isolated cutaneous leukocytoclastic vasculitis
polyangiitis • Hypocomplementemic urticarial vasculitis
Immune complex small vessel Other vasculitides
vasculitis Behçet disease
• Anti–glomerular basement Vasculitis secondary to infection (including hepatitis B–associated
membrane (anti-GBM) polyarteritis nodosa), malignancies, and drugs (including
disease hypersensitivity vasculitis)
• IgA vasculitis (Henoch- Vasculitis associated with connective tissue disease
Schönlein purpura) Isolated vasculitis of central nervous system
• Hypocomplementemic Cogan syndrome
urticarial vasculitis Unclassified
IV. Variable vessel vasculitis
Behçet disease
Cogan syndrome
V. Single-organ vasculitis
Cutaneous leukocytoclastic
vasculitis
Cutaneous arteritis
Primary central nervous system
vasculitis
Isolated aortitis
Others
VI. Vasculitis associated with
systemic disease
Lupus vasculitis
Rheumatoid vasculitis
Sarcoid vasculitis
Others
VII. Vasculitis associated with
probable etiology
Hepatitis C virus–associated
cryoglobulinemic vasculitis
Hepatitis B virus–associated
vasculitis
Syphilis-associated aortitis
Drug-associated immune
complex vasculitis
Drug-associated ANCA-
associated vasculitis
Cancer-associated vasculitis
Others

* Associated with antineutrophil cytoplasmic antibody.

Adapted from Jennette JC, Falk RJ, Bacon PA, et al: 2012 Revised International
Chapel Hill Consensus Conference nomenclature of vasculitides, Arthritis
Rheum 65:1–11; 2013; and Ozen S, Pistorio A, Iusan SM, et al:
EULAR/PRINTO/PRES criteria for Henoch-Schönlein purpura, childhood
polyarteritis nodosa, childhood Wegener granulomatosis and childhood Takayasu
arteritis: Ankara 2008. Part II. Final classification criteria, Ann Rheum Dis
69:798–806; 2010.
Table 192.2
Features That Suggest a Vasculitic Syndrome
Clinical Features

Fever, weight loss, fatigue of unknown origin

Skin lesions (palpable purpura, fixed urticaria, livedo reticularis, nodules,
ulcers)
Neurologic lesions (headache, mononeuritis multiplex, focal central
nervous system lesions)
Arthralgia or arthritis, myalgia, or myositis, serositis
Hypertension, hematuria, renal failure
Pulmonary infiltrates or hemorrhage
Myocardial ischemia, arrhythmias

Laboratory Features

Increased erythrocytes sedimentation rate or C-reactive protein level

Leukocytosis, anemia, thrombocytosis
Eosinophilia
Antineutrophil cytoplasmic antibodies
Elevated factor VIII–related antigen (von Willebrand factor)
Cryoglobulinemia
Circulating immune complexes
Hematuria

From Petty RE, Laxer RM, Lindsley CB, Wedderburn LR: Textbook of pediatric
rheumatology, ed 7, Philadelphia, 2016, Elsevier Saunders.
Table 192.3
Clinicopathologic Characteristics of Vasculitides in
Childhood

VESSELS
SYNDROME FREQUENCY CHARACTERISTIC PATHOLOGY
AFFECTED
Polyarteritis
Polyarteritis nodosa Rare Medium-size and Focal segmental (often near bifurcations);
small muscular fibrinoid necrosis; gastrointestinal, renal
arteries and microaneurysms; lesions at various stages of
sometimes arterioles evolution
Kawasaki disease Common Coronary and other Thrombosis, fibrosis, aneurysms, especially
muscular arteries of coronary vessels
Leukocytoclastic Vasculitis
Henoch-Schönlein purpura Common Arterioles and Leukocytoclasis; mixed cells, eosinophils,
(IgA vasculitis) venules, often small IgA deposits in affected vessels
arteries and veins
Hypersensitivity angitis Rare Arterioles and Leukocytoclastic or lymphocytic, varying
venules eosinophils, occasionally granulomatous;
widespread lesions at same stage of
evolution
Granulomatous Vasculitis
Granulomatosis with Rare Small arteries and Upper and lower respiratory tract,
polyangiitis (Wegener veins, occasionally necrotizing granulomata glomerulonephritis
granulomatosis) larger vessels
Eosinophilic Rare Small arteries and Necrotizing extravascular granulomata; lung
granulomatosis with veins, often involvement; eosinophilia
polyangiitis (Churg- arterioles and
Strauss syndrome) venules
Giant Cell Arteritis
Takayasu arteries Uncommon Large arteries Granulomatous inflammation, giant cells;
aneurysms, dissection
Temporal arteritis Rare Medium-size and Granulomatous inflammation, giant cell
large arteries arteries
Adapted from Cassidy JT, Petty RE: Textbook of pediatric rheumatology, ed 6, Philadelphia, 2011,
Elsevier Saunders.

Childhood vasculitis varies from a relatively benign and self-limited disease

such as Henoch-Schönlein purpura to catastrophic disease with end-organ
damage, as seen in granulomatosis with polyangiitis (formerly Wegener
granulomatosis). Vasculitis generally manifests as a heterogeneous multisystem
disease. Although some features, such as purpura, are easily identifiable, others,
such as hypertension secondary to renal artery occlusion or glomerulonephritis,
can be subtler. Ultimately, the key to recognizing vasculitis relies heavily on
pattern recognition. Demonstration of vessel injury and inflammation on biopsy
or vascular imaging is required to confirm a diagnosis of vasculitis.
resolves within 2 wk but can recur.
Gastrointestinal (GI) manifestations occur in up to 80% of children with HSP
and include abdominal pain, vomiting, diarrhea, paralytic ileus, and melena.
Intussusception, mesenteric ischemia, and intestinal perforation are rare but
serious complications. Endoscopic evaluation is usually not needed but may
identify vasculitis of the intestinal tract.
Renal involvement occurs in up to 30% of children with HSP, manifesting as
microscopic hematuria, proteinuria, hypertension, frank nephritis, nephrotic
syndrome, and acute or chronic renal failure. However, progression to end-stage
renal disease (ESRD) is uncommon in children (1–2%) (see Chapter 538.3 ).
Renal manifestations can be delayed for several months after the initial illness,
so close follow-up with serial urinalyses and blood pressure monitoring is
necessary.
Neurologic manifestations of HSP, caused by hypertension (posterior
reversible encephalopathy syndrome) or central nervous system (CNS)
vasculitis, may also occur, including intracerebral hemorrhage, seizures,
headaches, depressed level of consciousness, cranial or peripheral neuropathies,
and behavior changes. Other, less common potential manifestations of HSP are
inflammatory eye disease, carditis, pulmonary hemorrhage, orchitis, and
testicular torsion.

Diagnosis
The diagnosis of HSP is clinical and often straightforward when the typical rash
is present. However, in at least 25% of cases, the rash appears after other
manifestations, making early diagnosis challenging. Table 192.4 summarizes the
EULAR/PRES classification criteria for HSP. Most patients are afebrile.
Table 192.4
Classification Criteria for Henoch-Schönlein
Purpura*
European League Against Rheumatism/Pediatric Rheumatology
European Society Criteria †

Palpable purpura (in absence of coagulopathy or thrombocytopenia) and 1

 or more of the following criteria must be present:
• Abdominal pain (acute, diffuse, colicky pain)
• Arthritis or arthralgia
• Biopsy of affected tissue demonstrating predominant IgA
deposition
• Renal involvement (proteinuria >3 g/24 hr), hematuria or red
cell casts

* Classification criteria are developed for use in research and not validated for

clinical diagnosis.
† Developed for use in pediatric populations only.

Adapted from Ozen S, Pistorio A, Iusan SM, et al: EULAR/PRINTO/PRES

criteria for Henoch-Schönlein purpura, childhood polyarteritis nodosa, childhood
Wegener granulomatosis and childhood Takayasu arteritis: Ankara 2008. Part II.
Final classification criteria, Ann Rheum Dis 69:798–806; 2010.

The differential diagnosis for HSP depends on specific organ involvement

but usually includes other small vessel vasculitides, infections, acute
poststreptococcal glomerulonephritis, hemolytic-uremic syndrome,
coagulopathies, and other acute intraabdominal processes. Additional disorders
in the differential include papular-purpuric glove and sock syndrome, systemic
lupus erythematosus (SLE), other vasculitides (urticarial, hypersensitivity), and
thrombocytopenia.
Infantile acute hemorrhagic edema (AHE) , an isolated cutaneous
leukocytoclastic vasculitis that affects infants <2 yr of age, resembles HSP
clinically. AHE manifests as fever; tender edema of the face, scrotum, hands,
and feet; and ecchymosis (usually larger than the purpura of HSP) on the face
and extremities (Fig. 192.4 ). The trunk is spared, but petechiae may be seen in
mucous membranes. The patient usually appears well except for the rash. The
platelet count is normal or elevated, and the urinalysis results are normal. The
younger age, the nature of the lesions, absence of other organ involvement, and a
biopsy may help distinguish infantile AHE from HSP.
Infradiaphragmatic (mid-aortic syndrome) disease may produce hypertension,
abdominal bruits, and pain. Most patients have involvement in both areas.

Diagnosis
Specific pediatric criteria for TA have been proposed (Table 192.5 ).
Radiographic demonstration of large vessel vasculitis is necessary . A thorough
physical examination is required to detect an aortic murmur, diminished or
asymmetric pulses, and vascular bruits. Four extremity blood pressures should
be measured; >10 mm Hg asymmetry in systolic pressure is indicative of
disease.
Table 192.5
Proposed Classification Criteria for Pediatric-
Onset Takayasu Arteritis
Angiographic abnormalities (conventional, CT, or magnetic resonance
angiography) of the aorta or its main branches and at least 1 of the
following criteria:
• Decreased peripheral artery pulse(s) and/or claudication of
extremities
• Blood pressure difference between arms or legs of >10 mm Hg
• Bruits over the aorta and/or its major branches
• Hypertension (defined by childhood normative data)
• Elevated acute-phase reactant (erythrocyte sedimentation rate or
C-reactive protein)

Adapted from Ozen S, Pistorio A, Iusan SM, et al: EULAR/PRINTO/PRES

criteria for Henoch-Schönlein purpura, childhood polyarteritis nodosa, childhood
Wegener granulomatosis and childhood Takayasu arteritis: Ankara 2008. Part II.
Final classification criteria, Ann Rheum Dis 69:798–806; 2010.

Differential Diagnosis
In the early phase of TA, when nonspecific symptoms predominate, the
differential diagnosis includes a wide array of systemic infections, autoimmune
Clinical Manifestations
The clinical presentation of PAN is variable but generally reflects the
distribution of inflamed vessels. Constitutional symptoms are present in most
children at disease onset. Weight loss and severe abdominal pain suggest
mesenteric arterial inflammation and ischemia. Renovascular arteritis can cause
hypertension, hematuria, or proteinuria, although glomerulonephritis is not
typical. Cutaneous manifestations include purpura, livedo reticularis, ulcerations,
digital ischemia, and painful nodules. Arteritis affecting the nervous system can
result in cerebrovascular accidents, transient ischemic attacks, psychosis, and
ischemic motor or sensory peripheral neuropathy (mononeuritis multiplex ).
Myocarditis or coronary arteritis can lead to heart failure and myocardial
ischemia; pericarditis and arrhythmias have also been reported. Arthralgias,
arthritis, or myalgias are frequently present. Less common symptoms include
testicular pain that mimics testicular torsion, bone pain, and vision loss as a
result of retinal arteritis. The pulmonary vasculature is usually spared in PAN.

Diagnosis
The diagnosis of PAN requires demonstration of vessel involvement on biopsy
or angiography (Table 192.6 ). Biopsy of cutaneous lesions shows small or
medium vessel vasculitis (see Fig. 192.6 ). Kidney biopsy in patients with renal
manifestations may show necrotizing arteritis. Electromyography in children
with peripheral neuropathy identifies affected nerves, and sural nerve biopsy
may reveal vasculitis. Conventional arteriography is the gold standard diagnostic
imaging study for PAN and reveals areas of aneurysmal dilation and segmental
stenosis, the classic “beads on a string” appearance (Fig. 192.7 ). MRA and
CTA, less invasive imaging alternatives, are gaining acceptance, but may not be
as effective in identifying small vessel disease or in younger children.

Table 192.6

Proposed Classification Criteria for Pediatric-Onset Polyarteritis Nodosa*

CRITERION FINDINGS
Histopathology Necrotizing vasculitis in medium or small arteries
Angiographic Angiography showing aneurysm, stenosis, or occlusion of medium or small artery not from
abnormalities noninflammatory cause
Cutaneous Livedo reticularis, tender subcutaneous nodules, superficial skin ulcers, deep skin ulcers,
 findings digital necrosis, nail bed infarctions, or splinter hemorrhages
Muscle Myalgia or muscle tenderness
involvement
Hypertension Systolic or diastolic blood pressure >95th percentile for height
Peripheral Sensory peripheral neuropathy, motor mononeuritis multiplex
neuropathy
Renal Proteinuria (>300 mg/24 hr equivalent), hematuria or red blood cell casts, impaired renal
involvement function (glomerular filtration rate <50% normal)
* The presence of 5 criteria provides 89.6% sensitivity and 99.6% specificity for the diagnosis of

childhood-onset polyarteritis nodosa.

Adapted from Ozen S, Pistorio A, Iusan SM, et al: EULAR/PRINTO/PRES criteria for Henoch-
Schönlein purpura, childhood polyarteritis nodosa, childhood Wegener granulomatosis and
childhood Takayasu arteritis: Ankara 2008. Part II. Final classification criteria, Ann Rheum Dis
69:798–806; 2010.

FIG. 192.7 Child with polyarteritis nodosa. Abdominal aortogram shows bilateral renal
artery aneurysms (arrows) , superior mesenteric artery aneurysm (asterisk) , and left
common iliac artery occlusion (arrowhead) . (Courtesy of Dr. M. Hogan.)

Differential Diagnosis
Early skin lesions may resemble those of HSP, although the finding of nodular
affected tissues, thus the term pauci-immune vasculitis . ANCA-associated
vasculitis is categorized into 3 distinct forms: granulomatosis with polyangiitis
(GPA) , formerly Wegener granulomatosis; microscopic polyangiitis (MPA) ;
and eosinophilic granulomatosis with polyangiitis , formerly Churg-Strauss
syndrome (CSS ) (see Table 192.1 ).

Epidemiology
GPA is a necrotizing granulomatous small and medium vessel vasculitis that
occurs at all ages and targets the upper and lower respiratory tracts and the
kidneys. Although most cases of GPA occur in adults, the disease also occurs in
children with a mean age at diagnosis of 14 yr. There is a female predominance
of 3-4 : 1, and pediatric GPA is most prevalent in Caucasians.
MPA is a small vessel necrotizing vasculitis with clinical features similar to
those of GPA, but without granulomas and upper airway involvement. CSS is a
small vessel necrotizing granulomatous (allergic granulomatosis) vasculitis
associated with a history of refractory asthma and peripheral eosinophilia. MPA
and CSS are rare in children, and there does not appear to be a gender
predilection in either disease.

Pathology
Necrotizing vasculitis is the cardinal histologic feature in both GPA and MPA.
Kidney biopsies typically demonstrate crescentic glomerulonephritis with little
or no immune complex deposition (“pauci-immune”), in contrast to biopsies
from patients with SLE. Although granulomatous inflammation is common in
GPA and CSS, it is typically not present in MPA. Biopsies showing perivascular
eosinophilic infiltrates distinguish CSS syndrome from both MPA and GPA
(Table 192.7 ).

Table 192.7
Differential Diagnostic Features of Small Vessel Vasculitis

HENOCH- CHURG-
GRANULOMATOSIS MICROSCOPIC
FEATURE SCHÖNLEIN STRAUSS
WITH POLYANGIITIS POLYANGIITIS
PURPURA SYNDROME*
Signs and symptoms of + + + +
 small vessel vasculitis †
IgA-dominant immune + − − −
deposits
Circulating − + (PR3) + (MPO > PR3) + (MPO)
antineutrophil
cytoplasmic antibodies
Necrotizing vasculitis − + + +
Granulomatous − + + −
inflammation
Asthma and eosinophilia − − + −
*
Eosinophilic granulomatosis with polyangiitis.
† Signs and symptoms of small vessel vasculitis include purpura, other rash, arthralgias, arthritis,

and constitutional symptoms.

MPO, Myeloperoxidase-reactive antibodies; PR3, proteinase-3–reactive antibodies; +, present; −,
absent.
Adapted from Jeannett JC, Falk RJ: Small-vessel vasculitis, N Engl J Med 337:1512–1523, 1997.

Pathogenesis
The etiology of ANCA-associated vasculitis remains unknown, although
neutrophils, monocytes, and endothelial cells are involved in disease
pathogenesis. Neutrophils and monocytes are activated by ANCAs, specifically
by the ANCA-associated antigens proteinase-3 (PR3) and myeloperoxidase
(MPO), and release proinflammatory cytokines such as TNF-α and IL-8.
Localization of these inflammatory cells to the endothelium results in vascular
damage characteristic of the ANCA vasculitides. Why the respiratory tract and
kidneys are preferential targets in GPA and MPA is unknown.

Clinical Manifestations
Early disease course is characterized by nonspecific constitutional symptoms,
including fever, malaise, weight loss, myalgias, and arthralgias. In GPA, upper
airway involvement can manifest as sinusitis, nasal ulceration, epistaxis, otitis
media, and hearing loss. Lower respiratory tract symptoms in GPA include
cough, wheezing, dyspnea, and hemoptysis. Pulmonary hemorrhage can cause
rapid respiratory failure. Compared with adults, childhood GPA is more
frequently complicated by subglottic stenosis (Fig. 192.8 ). Inflammation-
induced damage to the nasal cartilage can produce a saddle nose deformity (Fig.
192.8 ). Ophthalmic involvement includes conjunctivitis, scleritis, uveitis, optic
neuritis, and invasive orbital pseudotumor (causing proptosis). Perineural
vasculitis or direct compression on nerves by granulomatous lesions can cause
cranial and peripheral neuropathies. Hematuria, proteinuria, and hypertension in
GPA signal renal disease. Cutaneous lesions include palpable purpura and ulcers.
Venous thromboembolism is a rare but potentially fatal complication of GPA.
The frequencies of organ system involvement throughout the disease course in
GPA follow: respiratory tract, 74%; kidneys, 83%; joints, 65%; eyes, 43%; skin,
47%; sinuses, 70%; and nervous system, 20%. Table 192.8 lists the classification
criteria for pediatric-onset GPA.

FIG. 192.8 Adolescent girl with granulomatosis with polyangiitis. A and B, Anterior and
lateral views of saddle nose deformity. C, Segment of subglottic posterior tracheal
irregularity (between arrows ) on lateral neck radiograph.

Table 192.8
EULAR/PReS Classification Criteria for
Pediatric-Onset Granulomatosis with
Polyangiitis*

Histopathology showing granulomatous inflammation

Upper airway involvement
Laryngeal, tracheal or bronchial involvement
Antineutrophil cytoplasmic antibody (ANCA) positivity
Renal involvement
 Proteinuria, hematuria, red blood cell casts, necrotizing pauci-immune
glomerulonephritis

* Diagnosis requires 3 of 6 criteria.

Adapted from: Ozen S, Pistorio A, Iusan SM, et al: EULAR/PRINTO/PRES

criteria for Henoch-Schönlein purpura, childhood polyarteritis nodosa, childhood
Wegener granulomatosis and childhood Takayasu arteritis: Ankara 2008. Part II.
Final classification criteria, Ann Rheum Dis 69:798–806; 2010.

The clinical presentation of MPA closely resembles that of GPA, although

sinus disease is less common; systemic features of fever, malaise, weight loss,
myalgias, and arthralgias may be dominant. MPA predominantly affects the
kidney and lungs; other organ systems include skin, CNS, muscle, heart, and
eyes.
CSS frequently causes inflammation of the upper and lower respiratory tracts,
but cartilage destruction is rare. CSS may initially demonstrate chronic or
recurrent rhinitis/sinusitis, nasal polyposis, nonfixed pulmonary lesions, and
difficult-to-treat asthma. Eosinophilia (>10% of leukocytes) with pulmonary
infiltrates may precede a vasculitic phase. Other organ involvement includes
skin, cardiac, peripheral neuropathy, GI tract, and muscle. Renal involvement in
CSS is uncommon.

Diagnosis
GPA should be considered in children who have recalcitrant sinusitis, pulmonary
infiltrates, and evidence of nephritis. Chest radiography often fails to detect
pulmonary lesions, and chest CT may show nodules, ground-glass opacities,
mediastinal lymphadenopathy, and cavitary lesions (Fig. 192.9 ). The diagnosis
is confirmed by the presence of c-ANCA with anti-PR3 specificity (PR3-
ANCAs) and the finding of necrotizing granulomatous vasculitis on pulmonary,
sinus, or renal biopsy. The ANCA test result is positive in approximately 90% of
children with GPA, and the presence of anti-PR3 increases the specificity of the
test.
(small vessels with neutrophilic perivascular or extravascular neutrophilic
infiltration) (Table 192.9 ). Hypocomplementemic urticarial vasculitis
involves small vessels and manifests as recurrent urticaria that resolves over
several days but leaves residual hyperpigmentation. This condition is associated
with low levels of complement component C1q and systemic findings that
include fever, GI symptoms, arthritis, and glomerulonephritis. Some patients
with urticarial vasculitis have normal complement levels. Cryoglobulinemic
vasculitis can complicate mixed essential cryoglobulinemia and is a small vessel
vasculitis affecting skin, joints, kidneys, and lungs.

Table 192.9

Criteria for Diagnosis of Hypersensitivity Vasculitis*

CRITERION DEFINITION
Age at onset >16 yr Development of symptoms after 16 yr of age
Medication at disease Medication that may have been a precipitating factor was taken at the onset of
onset symptoms
Palpable purpura Slightly elevated purpuric rash over 1 or more areas; does not blanch with pressure
and is not related to thrombocytopenia
Maculopapular rash Flat and raised lesions of various sizes over 1 or more areas of the skin
Biopsy, including arteriole Histologic changes showing granulocytes in a perivascular or extravascular location
and venule
* For purposes of classification, a patient is said to have hypersensitivity vasculitis if at least 3 of

these criteria are present. The presence of ≥3 criteria has a diagnostic sensitivity of 71.0% and
specificity of 83.9%. The age criterion is not applicable for children.
Adapted from Calabrese LH, Michel BA, Bloch DA, et al: The American College of Rheumatology
1990 criteria for the classification of hypersensitivity vasculitis, Arthritis Rheum 33:1108–1113,
1990 (Table 2, p 1110); and Textbook of pediatric rheumatology, ed 7, Philadelphia, 2016, Elsevier
(Table 38.2, p 511).

Primary angiitis of the central nervous system represents vasculitis

confined to the CNS and requires exclusion of other systemic vasculitides.
Large vessel disease (angiography positive) may be progressive or
nonprogressive and may manifest with focal deficits similar to an occlusive
stroke, with hemiparesis, focal gross or fine motor deficits, language disorders,
or cranial nerve deficits. Diffuse cognitive, memory, and concentration deficits
as well as behavioral disorders are seen in 30–40% of patients. Small vessel
disease (angiography negative, biopsy positive) more often results in language
problems and diffuse deficits, such as cognitive, memory, behavior, and
concentration problems, as well as focal seizures. In both types of cerebral
angiitis, patients may have an elevated ESR or CRP and abnormal CSF findings
(increased protein, pleocytosis), although these are not consistent findings in all
patients. Diagnosis remains a challenge, and brain biopsy is often indicated to
confirm the diagnosis and exclude vasculitis mimics such as infections that
could worsen with immunosuppressive therapy (Table 192.10 ).
Table 192.10
Differential Diagnosis of Small Vessel Primary
Central Nervous System (CNS) Vasculitis in
Children
CNS Vasculitis Complicating Other Diseases
Infections

• Bacterial: Mycobacterium tuberculosis, Mycoplasma pneumoniae,

Streptococcus pneumoniae
• Viral: Epstein-Barr virus, cytomegalovirus, enterovirus, varicella-zoster
virus, hepatitis C virus, parvovirus B19, West Nile virus
• Fungal: Candida albicans, Actinomyces, Aspergillus
• Spirochetal: Borrelia burgdorferi, Treponema pallidum

Rheumatic and Inflammatory Diseases

• Systemic vasculitis such as granulomatosis with polyangiitis, microscopic

polyangiitis, Henoch-Schönlein purpura, Kawasaki disease, polyarteritis
nodosa, Behçet disease
• Systemic lupus erythematosus, juvenile dermatomyositis, morphea
• Inflammatory bowel disease
• Autoinflammatory syndromes
• Hemophagocytic lymphohistiocytosis
• Neurosarcoidosis
• Adenosine deaminase-2 deficiency

Other
 • Drug-induced vasculitis
• Malignancy-associated vasculitis

Nonvasculitis Inflammatory Brain Diseases

Demyelinating Diseases

• Multiple sclerosis, acute demyelinating encephalomyelitis (ADEM), optic

neuritis, transverse myelitis

Antibody-Mediated Inflammatory Brain Disease

• Anti–NMDA receptor encephalitis, neuromyelitis optica (NMO), antibody-

associated limbic encephalitis (antibodies against LGI, AMP, AMP-binding
protein), Hashimoto encephalopathy, celiac disease, pediatric autoimmune
neuropsychiatric disorders associated with streptococcal infections
(PANDAS)

T-Cell–Associated Inflammatory Brain Disease

• Rasmussen encephalitis

Other

• Febrile infection-related epilepsy syndrome (FIRES)

Noninflammatory Vasculopathies

• Hemoglobinopathies (sickle cell disease), thromboembolic disease

• Radiation vasculopathy, graft-versus-host disease
• Metabolic and genetic diseases such as cerebral autosomal dominant
arteriopathy with subcortical infarcts and leukoencephalopathy
(CADASIL), mitochondrial encephalopathy lactic acidosis and stroke-like
episodes (MELAS), CARASIL (cerebral autosomal recessive arteriopathy
with subcortical infarcts and leukoencephalopathy), moyamoya disease,
 Fabray disease
• Malignancy (lymphoma)

Modified from Gowdie P, Twilt M, Benseler SM: Primary and secondary central
nervous system vasculitis. J Child Neurol 27:1448–1459, 2012.

Nonprogressive angiography-positive CNS vasculitis, also known as

transient CNS angiopathy, represents a more benign variant and can be seen
after varicella infection. Cogan syndrome is rare in children; its potential
clinical manifestations include constitutional symptoms; inflammatory eye
disease such as uveitis, episcleritis, or interstitial keratitis; vestibuloauditory
dysfunction (vertigo, hearing loss, tinnitus); arthritis; and large vessel vasculitis
or aortitis. Cerebral autosomal dominant arteriopathy with subcortical infarcts
and leukoencephalopathy (CADASIL ) is caused by mutations in the NOTCH3
gene and manifests with stroke, mood changes, cognitive decline, and migraines;
it is a vasculitis mimic and demonstrates osmophilic granules in cerebral arteries.
CARASIL (cerebral autosomal recessive arteriopathy with subcortical infarcts
and leukoencephalopathy) is another mimic of angiitis caused by mutations in
the HTRA1 gene. It manifests with early-onset hair loss, spasticity, stroke,
memory loss, and personality changes.
Identification of these vasculitis syndromes requires a comprehensive history
and physical examination. Table 192.11 outlines other diagnostic considerations.
Although tailored to disease severity, treatment generally includes prednisone
(up to 2 mg/kg/day). Potent immunosuppressive medications, such as
cyclophosphamide, are often indicated, particularly in primary angiitis of the
CNS to prevent rapid neurologic decline. For hypersensitivity vasculitis,
withdrawal of the triggering medication or toxin is indicated if possible.

Table 192.11

Diagnostic Considerations for Other Vasculitis Syndromes

VASCULITIS SYNDROME APPROACH TO DIAGNOSIS
Hypersensitivity vasculitis Skin biopsy demonstrating leukocytoclastic vasculitis
Hypocomplementemic urticarial vasculitis Biopsy of affected tissue demonstrating small vessel
vasculitis
Low levels of circulating C1q
Cryoglobulinemic vasculitis Biopsy of affected tissue demonstrating small vessel
vasculitis
Measurement of serum cryoglobulins
 Exclusion of hepatitides B and C infections
Primary angiitis of CNS Conventional, CT, or MRA evidence of CNS vasculitis
Consideration of dura or brain biopsy
Nonprogressive angiography-positive CNS Conventional, CT, or MRA evidence of CNS vasculitis
vasculitis
Cogan syndrome Ophthalmology and audiology evaluations
Conventional, CT, or MRA evidence of CNS or aortic
vasculitis
CNS, Central nervous system; CT, computed tomography; MRA, magnetic resonance
angiography.

Bibliography
Abril A. Churg-Strauss syndrome: an update. Curr Rheumatol
Rep . 2011;13:489–495.
Benseler SM. Central nervous system vasculitis in children.
Curr Rheumatol Rep . 2006;8:442–449.
Cassidy JT, Petty RE. Systemic vasculitis. Textbook of pediatric
rheumatology . ed 5. Elsevier Saunders: Philadelphia; 2005.
Dedeoglu F, Sundel RP. Vasculitis in children. Rheum Dis Clin
North Am . 2007;33:555–583.
Gray PEA, Bock A, Ziegler DS, et al. Neonatal Sweet
syndrome: a potential marker of serious systemic illness.
Pediatrics . 2012;129(5):e1333–e1359.
Gowdie P, Twitt M, Benseler SM. Primary and secondary
central nervous system vasculitis. J Child Neurol .
2012;27(11):1448–1459.
Van Mater H. Pediatric inflammatory brain diseases: a
diagnostic approach. Curr Opin Rheumatol . 2014;26(5):553–
561.

Bibliography
Barut K, Sahin S, Kasapcopur O. Pediatric vasculitis. Curr Opin
Rheumatol . 2016;28(1):29–38.
Eleftheriou D, Brogan PA. Therapeutic advances in the
 Subsequent, repeated physical examinations of children with musculoskeletal
pain complaints may reveal eventual development and manifestations of
rheumatic or other diseases. The need for additional testing should be
individualized, depending on the specific symptoms and physical findings.
Laboratory screening and radiography should be pursued if there is suspicion of
certain underlying disease processes. Possible indicators of a serious, vs a
benign, cause of musculoskeletal pain include pain present at rest, pain that may
be relieved by activity, objective joint swelling on physical examination,
stiffness or limited range of motion in joints, bony tenderness, muscle weakness,
poor growth and/or weight loss, and constitutional symptoms (e.g., fever,
malaise) (Table 193.1 ). In the case of laboratory screenings, a complete blood
count (CBC) and erythrocyte sedimentation rate (ESR) are likely to be abnormal
in children whose pain is secondary to a bone or joint infection, SLE, or a
malignancy. Bone tumors, fractures, and other focal pathology resulting from
infection, malignancy, or trauma can often be identified through imaging studies,
including plain radiographs, MRI, and less often technetium-99m bone scans.

Table 193.1

Potential Indicators of Benign vs Serious Causes of Musculoskeletal Pain

CLINICAL FINDING BENIGN CAUSE SERIOUS CAUSE
Effects of rest vs activity on Relieved by rest and Present at rest and may be relieved by activity
pain worsened by activity
Time of day pain occurs End of the day and nights Morning*
Objective joint swelling No Yes
Joint characteristics Hypermobile/normal Stiffness, limited range of motion
Bony tenderness No Yes
Muscle strength Normal Muscle weakness
Gait Normal Limp or refusal to walk
Growth Normal growth pattern or Poor growth and/or weight loss
weight gain
Constitutional symptoms Fatigue without other Yes
(e.g., fever, malaise) constitutional symptoms
Lab findings Normal CBC, ESR, CRP Abnormal CBC, raised ESR and CRP
Imaging findings Normal Effusion, osteopenia, radiolucent metaphyseal lines,
joint space loss, bony destruction
* Cancer pain is often severe and worst at night.

CBC, Complete blood count; CRP, C-reactive protein level; ESR, erythrocyte sedimentation rate.
Adapted from Malleson PN, Beauchamp RD: Diagnosing musculoskeletal pain in children, CMAJ
165:183–188, 2001.

The presence of persistent pain, accompanied by psychological distress, sleep

disturbance, and/or functional impairment, in the absence of objective laboratory
or physical examination abnormalities, suggests the diagnosis of an idiopathic
musculoskeletal pain syndrome. All pediatric musculoskeletal pain syndromes
share this general constellation of symptoms at presentation. Several more
specific pain syndromes routinely seen by pediatric practitioners can be
differentiated by anatomic region and associated symptoms. Table 193.2 outlines
pediatric musculoskeletal pain syndromes, including growing pains (see Chapter
193.1 ), fibromyalgia (Chapter 193.3 ), complex regional pain syndrome
(Chapter 193.4 ), localized pain syndromes, low back pain, and chronic sports-
related pain syndromes (e.g., Osgood-Schlatter disease).

Table 193.2
Common Musculoskeletal Pain Syndromes in Children by
Anatomic Region

ANATOMIC REGION PAIN SYNDROMES

Shoulder Impingement syndrome
Elbow “Little League elbow” Tennis elbow
Avulsion fractures Panner disease
Osteochondritis dissecans
Arm Localized hypermobility syndrome
Complex regional pain syndrome
Pelvis and hip Avulsion injuries Slipped capital femoral epiphysis
Legg-Calvé-Perthes syndrome Congenital hip dysplasia
Knee Osteochondritis dissecans Patellofemoral syndrome
Osgood-Schlatter disease Malalignment syndromes
Sinding-Larsen syndrome
Leg Growing pains Shin splints
Complex regional pain syndrome Stress fractures
Localized hypermobility syndrome Compartment syndromes
Foot Plantar fasciitis Achilles tendonitis
Tarsal coalition Juvenile bunion
Stress fractures
Spine Musculoskeletal strain Scoliosis
Spondylolisthesis Scheuermann disease (kyphosis)
Spondylolysis Low back pain
Generalized Hypermobility syndrome
Juvenile fibromyalgia
Generalized pain syndrome
Adapted from Anthony KK, Schanberg LE: Assessment and management of pain syndromes and
arthritis pain in children and adolescents, Rheum Dis Clin North Am 33:625–660, 2007 (Box 1).

Treatment
following morning (Table 193.3 ). Pain often follows a day with exercise or
other physical activities. Physical findings are normal, and gait is not impaired.

Table 193.3
Inclusion and Exclusion Criteria for Growing Pains
Including Features of Restless Leg Syndromes (RLS)

INCLUSIONS EXCLUSIONS RLS FEATURES

Nature of Intermittent; some Persistent; increasing intensity, pain during the Urge to move legs often
pain pain-free days and day accompanied by unpleasant
nights, deep aching, sensations in legs, but may
cramping not be painful
Unilateral Bilateral Unilateral
or bilateral
Location Anterior thigh, calf, Articular, back, or groin pain Urge to move and
of pain posterior knee—in discomfort throughout leg
muscles not the
joints
Onset of Late afternoon or Pain still present next morning Worse later in day or night
pain evening but also present at periods
of rest or inactivity
throughout the day
Physical Normal Swelling, erythema, tenderness; local trauma or
findings infection; reduced joint range of motion; limping,
fever, weight loss, mass
Laboratory Normal Objective evidence of abnormalities; increased
findings erythrocyte sedimentation rate or C-reactive
protein; abnormal complete blood count,
radiography, bone scan, or MRI
Adapted from Evans AM, Scutter SD: Prevalence of “growing pains” in young children, J Pediatr
145:255–258, 2004; and Walters AS, Gabelia D, Frauscher B: Restless legs syndrome (Willis-
Ekbom disease) and growing pains: are they the same thing? A side-by-side comparison of the
diagnostic criteria for both and recommendations for future research, Sleep Med 14:1247–1252,
2013.

Although growing pains are generally considered a benign, time-limited

condition, evidence suggests they represent a pain amplification syndrome .
Indeed, growing pains persist in a significant percentage of children, with some
children developing other pain syndromes such as abdominal pain and
headaches. Growing pains are more likely to persist in children with a parent
who has a history of a pain syndrome and in children who have lower pain
thresholds not just at the site of pain, but throughout their body. Disordered
somatosensory testing, lower bone strength, and lower calcium intake have also
been shown to be present in children with growing pains.
Treatment should also focus on reassurance, education, and healthy sleep
disease, migraines, temporomandibular joint disorder, premenstrual syndrome,
mood and anxiety disorders, chronic fatigue syndrome), suggesting that these
disorders may be part of a larger spectrum of related syndromes.

FIG. 193.1 Fibromyalgia questionnaire. American College of Rheumatology criteria.
IBS, Irritable bowel syndrome. (Adapted from Wolfe F, Clauw DJ, Fitzcharles MA, et al.
The American College of Rheumatology preliminary diagnostic criteria for fibromyalgia
and measurement of symptom severity. Arthritis Care Res 62:600–610, 2010.)

Table 193.4
American College of Rheumatology
Fibromyalgia Diagnostic Criteria
 The following 3 conditions must be met:
1. Widespread pain index (WPI) ≥7 and symptom severity (SS) scale score
≥5 or WPI 3-6 and SS scale score ≥9.
2. Symptoms have been present at a similar level for at least 3 mo.
3. The patient does not have a disorder that would otherwise explain the
pain.

Ascertainment of WPI
The WPI is the number of areas in which a patient has had pain over the last
week. The score will be between 0 and 19: left shoulder girdle left, right
shoulder girdle, left upper arm, right upper arm, left lower arm, right lower arm,
left hip (buttock, trochanter), right hip (buttock, trochanter), left upper leg, right
upper leg, left lower leg, right lower leg, left jaw, right jaw, chest, abdomen,
upper back, lower back, and neck.
Ascertainment of Ss Scale Score
The SS scale score is the sum of the severity of 3 symptoms (fatigue, waking
unrefreshed, and cognitive symptoms) plus the severity of somatic symptoms in
general. The final score is between 0 and 12.

• For each of the 3 symptoms, the level of severity over the past week is rated
using the following scale:
0 = No problem
1 = Slight or mild problems, generally mild or intermittent
2 = Moderate, considerable problems, often present and/or at a
moderate level
3 = Severe: pervasive, continuous, life-disturbing problems
• Considering somatic symptoms in general, the following scale is used to
indicated the number of symptoms:
0 = No symptoms
1 = Few symptoms
2 = Moderate number of symptoms
3 = Great deal of symptoms
• Somatic symptoms that can be considered include muscle pain, irritable
bowel syndrome, fatigue, thinking problems, muscle weakness, headache,
abdominal pain, numbness/tingling, dizziness, insomnia, depression,
 constipation, pain in the upper abdomen, nausea, nervousness, chest pain,
blurred vision, fever, diarrhea, dry mouth, itching, wheezing, Raynaud
phenomenon, hives/welts, ringing in ears, vomiting, heartburn, oral ulcers,
loss of/change in taste, seizures, dry eyes, shortness of breath, loss of
appetite, rash, sun sensitivity, hearing difficulties, easy bruising, hair loss,
frequent urination, painful urination, and bladder spasms.

Adapted from Wolfe F, Clauw DJ, Fitzcharles MA, et al: The American College
of Rheumatology preliminary diagnostic criteria for fibromyalgia and
measurement of symptom severity, Arthritis Care Res 62: 600–610, 2010.

FIG. 193.2 Fibromyalgia tender points.

Although the precise cause of JPFS is unknown, there is an emerging

understanding that the development and maintenance of JPFS are related both to
biologic and psychological factors. JPFS is an abnormality of central pain
processing characterized by disordered sleep physiology, enhanced pain
perception with abnormal levels of substance P in cerebrospinal fluid, disordered
mood, and dysregulation of hypothalamic-pituitary-adrenal and other
neuroendocrine axes, resulting in lower tender-point pain thresholds and
increased pain sensitivity. Evolving evidence also suggests that up to 50% of
patients with fibromyalgia may have a small fiber polyneuropathy (see Chapter
although in adults, the Budapest criteria have been shown to be more sensitive
and specific than previous diagnostic guidelines (Table 193.5 ). The diagnosis
requires an initiating noxious event or immobilization; continued pain, allodynia,
and hyperalgesia out of proportion to the inciting event; evidence of edema, skin
blood flow abnormalities, or sudomotor activity; and exclusion of other
disorders. Associated features include atrophy of hair or nails; altered hair
growth; loss of joint mobility; weakness, tremor, dystonia; and sympathetically
maintained pain.
Table 193.5
Budapest Clinical Diagnostic Criteria for
Complex Regional Pain Syndrome
All the following criteria must be met:
1. Continuing pain, which is disproportionate to any inciting event
2. Must report at least 1 symptom in each of the following 4 categories:
• Sensory : Hyperesthesia and/or allodynia
• Vasomotor : Temperature asymmetry, skin color changes, and/or
skin color asymmetry
• Sudomotor/edema : Edema, sweating changes, and/or sweating
asymmetry
• Motor/trophic : Decreased range of motion, motor dysfunction
(tremor, weakness, dystonia) and/or trophic changes (hair, nail,
skin)
3. Must display at least 1 sign at time of evaluation in ≥2 of the following 4
categories:
• Sensory : Evidence of hyperesthesia (to pin prick) and/or allodynia
(to light touch, temperature sensation, deep somatic pressure,
and/or joint movement)
• Vasomotor : Evidence of temperature asymmetry (>1°C), skin color
changes, and/or skin color asymmetry
• Sudomotor/edema : Edema, sweating changes, and/or sweating
asymmetry
• Motor/trophic : Decreased range of motion, motor dysfunction
(tremor, weakness, dystonia) and/or trophic changes (hair, nail,
skin)
4. There is no other diagnosis that better explains the signs and symptoms.
Adapted from Harden RN, Bruel S, Stanton-Hicks, et al: Proposed new
diagnostic criteria for complex regional pain syndrome, Pain Med 8:326–331,
2007.

Although the majority of pediatric patients with CRPS present with a history
of minor trauma or repeated stress injury (e.g., caused by competitive sports), a
sizable proportion are unable to identify a precipitating event. Usual age of onset
is between 8 and 16 yr, and girls outnumber boys with the disease by as much as
6 : 1. Childhood CRPS differs from the adult form in that lower extremities,
rather than upper extremities, are most often affected. The incidence of CRPS in
children is unknown, largely because it is often undiagnosed or diagnosed late,
with the diagnosis frequently delayed by almost 1 yr. Left untreated, CRPS can
have severe consequences for children, including bone demineralization, muscle
wasting, and joint contractures.
An evidence-based approach to the treatment of CRPS continues to suggest a
multistage approach. Aggressive physical therapy (PT) should be initiated as
soon as the diagnosis is made and CBT added as needed. PT is recommended 3-
4 times/wk, and children may need analgesic premedication at the onset,
particularly before PT sessions. PT is initially limited to desensitization and then
moves to weight-bearing, range-of-motion, and other functional activities. CBT
used as an adjunctive therapy targets psychosocial obstacles to fully participating
in PT and provides pain-coping skills training. Sympathetic and epidural nerve
blocks should be attempted only under the auspices of a pediatric pain specialist.
The goal of both pharmacologic and adjunctive treatments for CRPS is to
provide sufficient pain relief to allow the child to participate in aggressive
physical rehabilitation. If CRPS is identified and treated early, the majority of
children and adolescents can be treated successfully with low-dose amitriptyline
(10-50 mg orally 30 min before bedtime), aggressive PT, and CBT interventions.
Opioids and anticonvulsants such as gabapentin can also be helpful. Notably,
multiple studies have shown that noninvasive treatments, particularly PT and
CBT, are at least as efficacious as nerve blocks in helping children with CRPS
achieve resolution of their symptoms.
There is growing evidence that some patients with CRPS I have a small fiber
polyneuropathy (see Chapter 193.2 ).

Bibliography
hydroxychloroquine, colchicine, cyclophosphamide, cyclosporine, and anti–
tumor necrosis factor [TNF] agents), as reported in small series and case reports.

Table 194.1

Suggested Criteria for Relapsing Polychondritis*

MAJOR
Typical inflammatory episodes of ear cartilage
Typical inflammatory episodes of nose cartilage
Typical inflammatory episodes of laryngotracheal cartilage
MINOR
Eye inflammation (conjunctivitis, keratitis, episcleritis, uveitis)
Hearing loss
Vestibular dysfunction
Seronegative inflammatory arthritis
*
The diagnosis is established by the presence of 2 major or 1 major and 2 minor
criteria. Histologic examination of affected cartilage is required when the
presentation is atypical.

Data from Michet CJ Jr, McKenna CH, Luthra HS, et al: Relapsing
polychondritis: survival and predictive role of early disease manifestations, Ann
Intern Med 104:74-78, 1986.

Mucha-Habermann Disease/Pityriasis
Lichenoides Et Varioliformis Acuta
Pityriasis lichenoides et varioliformis acuta (PLEVA ) is a benign, self-limited
cutaneous vasculitis characterized by episodes of macules, papules, and
papulovesicular lesions that can develop central ulceration, necrosis, and
crusting (Fig. 194.1 ). Different stages of development are usually seen at once.
PLEVA fulminans or febrile ulceronecrotic Mucha-Habermann disease
(FUMHD ) is the severe, life threatening form of PLEVA. Large, coalescing,
ulceronecrotic lesions are seen, accompanied by high fever and elevated
erythrocyte sedimentation rate (ESR). Systemic manifestations can include
interstitial pneumonitis, abdominal pain, malabsorption, arthritis, and neurologic
manifestations. PLEVA has a male predominance and occurs more frequently in
childhood. The diagnosis is confirmed by biopsy of skin lesions, which reveals
perivascular and intramural lymphocytic inflammation affecting capillaries and
venules in the upper dermis that may lead to keratinocyte necrosis. When disease
is severe, corticosteroids have been used with questionable effect, and
methotrexate has been reported to induce rapid remission in resistant cases.
Cyclosporine and anti-TNF agents have also been efficacious in case reports.

FIG. 194.1 Pityriasis lichenoides et varioliformis acuta (PLEVA). Symmetric, oval and
round, reddish brown macular, popular, necrotic, and crusted lesions on chest of 9 yr
old boy. (From Paller AS, Mancini AJ, editors: Hurwitz clinical pediatric dermatology, ed
5, Philadelphia, 2016, Elsevier, Fig 4-33, p 87.)

Sweet Syndrome
Sweet syndrome, or acute febrile neutrophilic dermatosis , is a rare entity in
children. It is characterized by fever, elevated neutrophil count, and raised,
tender erythematous plaques and nodules over the face, extremities, and trunk.
Skin biopsy reveals neutrophilic perivascular infiltration in the upper dermis.
Female predominance is seen in the adult population, whereas gender
distribution is equal in children. Established criteria are useful for diagnosis
(Table 194.2 ). Children can also have arthritis, sterile osteomyelitis, myositis,
and other extracutaneous manifestations. Sweet syndrome may be idiopathic or
secondary to malignancy (particularly acute myelogenous leukemia), drugs
(granulocyte colony-stimulating factor, tretinoin or trimethoprim-
sulfamethoxazole), or rheumatic diseases (Behçet disease, antiphospholipid
antibody syndrome, systemic lupus erythematosus). The condition usually
responds to treatment with corticosteroids, treatment of underlying disease, or
removal of associated medication.
Table 194.2
Diagnostic Criteria for Classic Sweet
Syndrome*
Major Criteria

Abrupt onset of painful erythematous plaques or nodules

Histopathologic evidence of dense neutrophilic infiltrate without evidence
of leukocytoclastic vasculitis

Minor Criteria

Pyrexia >38°C
Association with underlying hematologic or visceral malignancy,
inflammatory disease or pregnancy, or preceded by an upper respiratory
or gastrointestinal infection or vaccination
Excellent response to systemic corticosteroids or potassium iodide
Abnormal laboratory values at presentation (3 of 4):
Erythrocyte sedimentation rate >20 mm/hr
Positive C-reactive protein test result
>8,000 leukocytes/mm3
>70% neutrophils/mm3

* The diagnosis is established by the presence of 2 major criteria plus 2 of the 4

minor criteria.

Adapted from Walker DC, Cohen PR: Trimethoprim-sulfamethoxazole-

associated acute febrile neutrophilic dermatosis: case report and review of drug
induced Sweet's syndrome. J Am Acad Dermatol 34:918–923, 1996.
to the collection of blood cultures are addressed in the blood culture section.

Laboratory Diagnosis of Bacterial and

Fungal Infections
Although the scope and availability of molecular methods for detection of
bacterial and fungal pathogens have increased rapidly, the diagnosis of many of
these infections depends on microscopic detection of organisms or cultivation of
organisms on culture media .

Microscopy
The Gram stain is an extremely valuable diagnostic technique to provide rapid
and inexpensive information regarding the absence or presence of inflammatory
cells and organisms in clinical specimens. For some specimen types, the
presence of inflammatory and epithelial cells is used to judge the suitability of a
specimen for culture. For example, the presence of >10 epithelial cells per low-
power field in a sputum specimen is highly suggestive of a specimen
contaminated with oral secretions. In addition, a preliminary assessment of the
etiologic agent can be made based on the morphology (e.g., cocci vs rods) and
stain reaction (e.g., gram-positive isolates are purple; gram-negative isolates are
red) of the microorganisms. However, a negative Gram stain does not rule out
infection, since 104 to 105 microorganisms per milliliter (mL) in the specimen
are required for detection by this method.
In addition to the Gram stain, many other stains are used in microbiology, both
to detect organisms and to help infer their identity (Table 195.1 ).

Table 195.1
Stains Used for Microscopic Examination

TYPE OF
CLINICAL USE
STAIN
Gram stain Stains bacteria (with differentiation of gram-positive and gram-negative organisms), fungi,
leukocytes, and epithelial cells.
Potassium A 10% solution dissolves cellular and organic debris and facilitates detection of fungal elements
hydroxide in clinical specimens.
(KOH)
Calcofluor Nonspecific fluorochrome that binds to cellulose and chitin in fungal cell walls, can be combined
white stain with 10% KOH to dissolve cellular material.
Ziehl-Neelsen Acid-fast stains, using basic carbolfuchsin, followed by acid-alcohol decolorization and
and Kinyoun methylene blue counterstaining.
stains Acid-fast organisms (e.g., Mycobacterium ) resist decolorization and stain pink.
A weaker decolorizing agent is used for partially acid-fast organisms (e.g., Nocardia,
Cryptosporidium, Cyclospora, Isospora ).
Auramine- Acid-fast stain using fluorochromes that bind to mycolic acid in mycobacterial cell walls and
rhodamine resist acid-alcohol decolorization; usually performed directly on clinical specimens.
stain Acid-fast organisms stain orange-yellow against a black background.
Acridine Fluorescent dye that intercalates into DNA, used to aid in differentiation of organisms from
orange stain debris during direct specimen examination, and also for detection of organisms that are not
visible with Gram stain.
Bacteria and fungi stain orange, and background cellular material stains green.
Lugol iodine Added to wet preparations of fecal specimens for ova and parasites to enhance contrast of the
stain internal structures (nuclei, glycogen vacuoles).
Wright and Primarily for detecting blood parasites (Plasmodium, Babesia, and Leishmania ), detection of
Giemsa stains amoeba in preparations of cerebrospinal fluid, and fungi in tissues (yeasts, Histoplasma )
Trichrome Stains stool specimens for identification of protozoa.
stain
Direct Used for direct detection of a variety of organisms in clinical specimens by using specific
fluorescent- fluorescein-labeled antibodies (e.g., Pneumocystis jiroveci, many viruses).
antibody stain

Isolation and Identification

The approach to isolation of microorganisms in a clinical specimen will vary
depending on the body site and pathogen suspected. For body sites that are
usually sterile, such as cerebrospinal fluid, nutrient-rich media such as sheep
blood agar and chocolate agar are used to aid in the recovery of fastidious
pathogens. In contrast, stool specimens contain abundant amounts of commensal
bacteria, and thus to isolate pathogens, selective and differential media must be
used. Selective media will inhibit the growth of some organisms to aid in
isolation of suspect pathogens; differential media rely on growth characteristics
or carbohydrate assimilation characteristics to impart a growth pattern that
differentiates organisms. MacConkey agar supports growth of gram-negative
rods while suppressing gram-positive organisms, and a color change in the
media from clear to pink distinguishes lactose-fermenting organisms from other
gram-negative rods. Special media, such as Sabouraud dextrose agar and
inhibitory mold agar, are used to recover fungi in clinical specimens. Many
pathogens, including Bartonella , Bordetella pertussis , Legionella , Mycoplasma
, some Vibrio spp., and certain fungal pathogens such as Malassezia furfur ,
require specialized growth media or incubation conditions. Consultation with the
laboratory is advised when these pathogens are suspected.
Once an organism is recovered in culture, additional testing is performed to
Molecular tests to detect viruses use the polymerase chain reaction (PCR) and
other comparable nucleic acid amplification methods. FDA-cleared multiplex
tests have become available for the diagnosis of respiratory, gastrointestinal, and
central nervous system (CNS) infections. Some of these tests detect 20 or more
different agents at the same time and may require only about 65 min to perform.
The infectious agents detected by multiplex panels may include bacteria, fungi,
and parasites as well as viruses (Table 195.2 ).

Table 195.2
Multiplex Molecular Assays for Viral Diagnosis

TEST MANUFACTURER PATHOGENS DETECTED*

RESPIRATORY
NxTag Luminex, Austin, TX Flu A, AH1, AH3, Flu B, RSV A/B, PIV 1-4, HMPV, RV/EV, † HCoV
OC43/229E/NL63/HKU1, AdV, human bocavirus, Mycoplasma pneumoniae,
Chlamydophila pneumoniae
Verigene Luminex, Austin, TX Flu A, AH1, AH3, Flu B, RSV A/B, PIV 1-4, HMPV, RV, AdV, Bordetella
pertussis , B. parapertussis/bronchiseptica , B. holmesii
FilmArray BioFire, Salt Lake Flu A, AH1, AH1(2009), AH3, Flu B, RSV, PIV 1-4, HMPV, RV/EV, † CoV
City, UT OC43/229E/ NL63/HKU1, AdV, Mycoplasma pneumoniae, Chlamydophila
pneumoniae, Bordetella pertussis
ePlex GenMark Flu A, AH1, AH1(2009), AH3, Flu B, RSV, PIV 1-4, HMPV, RV, AdV B/C/E
GASTROINTESTINAL
NxTag Luminex, Austin, TX Rotavirus A, norovirus GI/GII, AdV 40/41, Campylobacter , Clostridium
difficile toxin A/B, Escherichia coli O157, enterotoxigenic E. coli , LT/ST,
Shiga-like toxin–producing E. coli (stx1/2), Salmonella , Shigella , Vibrio
cholerae , Yersinia enterocolitica, Cryptosporidium, Entamoeba histolytica,
Giardia
Verigene Luminex, Austin, TX Rotavirus, norovirus, Campylobacter , Salmonella , Shigella, Vibrio , Yersinia ,
stx1/2
FilmArray BioFire, Salt Lake Rotavirus A, norovirus GI/GII, AdV 40/41, astrovirus, sapovirus I, II, IV, V,
City, UT Campylobacter , C. difficile toxin A/B, Plesiomonas shigelloides , Salmonella ,
Y. enterocolitica , Vibrio , enteroaggregative E. coli , enteropathogenic E. coli ,
enterotoxigenic E. coli , Shiga-like toxin–producing E. coli (stx1/2)/E. coli
O157, Shigella /enteroinvasive E. coli , Cryptosporidium , Cyclospora
cayetanensis , E. histolytica , Giardia lamblia
CENTRAL NERVOUS SYSTEM
FilmArray BioFire, Salt Lake HSV-1, HSV-2, VZV, CMV, HHV-6, enterovirus, parechovirus, E. coli K1,
City, UT Haemophilus influenzae , Listeria monocytogenes , Neisseria meningitidis ,
Streptococcus agalactiae, Streptococcus pneumoniae, Cryptococcus
neoformans/gattii
* Cleared by the U.S. Food and Drug Administration (FDA) as of March 2017. Other versions that
detect additional viruses are available outside the United States.
† Detects rhinoviruses and enteroviruses but does not distinguish between them.

AdV, Adenovirus; AH1, influenza A, hemagglutinin type 1; AH3, influenza A, hemagglutinin type 3;
CMV, cytomegalovirus; CoV, coronavirus; EV, enterovirus; flu A, influenza A; flu B, influenza B;
CHAPTER 197

Immunization Practices
Henry H. Bernstein, Alexandra Kilinsky, Walter A. Orenstein

Immunization is one of the most beneficial and cost-effective disease-prevention

measures available. As a result of effective and safe vaccines, smallpox has been
eradicated, polio is close to worldwide eradication, and measles and rubella are
no longer endemic in the United States. However, cases of vaccine-preventable
diseases, including measles, mumps, and pertussis, continue to occur in the
United States. Incidence of most vaccine-preventable diseases of childhood has
been reduced by ≥99% from representative 20th century annual morbidity,
usually before development of the corresponding vaccines (Table 197.1a ), with
most of the newer vaccines not achieving quite the same percentage decrease
(Table 197.1b ). An analysis of effective prevention measures recommended for
widespread use by the U.S. Preventive Services Task Force (USPSTF) reported
that childhood immunization received a perfect score based on clinically
preventable disease burden and cost-effectiveness.

Table 197.1a
Comparison of 20th Century Annual Morbidity and Current
Morbidity: Vaccine-Preventable Diseases

20TH CENTURY ANNUAL 2016 REPORTED PERCENT

DISEASE
MORBIDITY* CASES † DECREASE
Smallpox 29,005 0 100%
Diphtheria 21,053 0 100%
Measles 530,217 122 >99%
Mumps 162,344 5,629 96%
Pertussis 200,752 15,808 92%
Polio (paralytic) 16,316 0 100%
Rubella 47,745 9 >99%
Congenital rubella syndrome 152 2 99%
Tetanus 580 31 95%
 Haemophilus influenzae 20,000 22 ‡ >99%
type b (Hib)
* Data from Roush SW, Murphy TV, Vaccine-Preventable Disease Table Working Group: Historical

comparisons of morbidity and mortality for vaccine-preventable diseases in the United States,
JAMA 298(18):2155–2163, 2007.
†
Data from Centers for Disease Control and Prevention: Notifiable diseases and mortality tables,
MMWR 66(52):ND-924–ND-941, 2018.
‡
Hib <5 yr of age. An additional 237 cases of Haemophilus influenzae (<5 yr of age) have been
reported with unknown serotype.

Table 197.1b
Comparison of Pre–Vaccine Era Estimated Annual
Morbidity With Current Estimate: Vaccine-Preventable
Diseases

PRE–VACCINE ERA 2016 ESTIMATE (UNLESS PERCENT

DISEASE
ANNUAL ESTIMATE* OTHERWISE SPECIFIED) DECREASE
Hepatitis A 117,333* 4,000 † 97%
Hepatitis B (acute) 66,232* 20,900 † 68%
Pneumococcus
(invasive)
All ages 63,067* 30,400 § 52%
<5 yr of age 16,069* 1,700 § 89%
Rotavirus 62,500 ‡ 30,625 ǁ 51%
(hospitalizations, <3 yr
of age)
Varicella 4,085,120* 102,128 ¶ 98%
* Data from Roush SW, Murphy TV; Vaccine-Preventable Disease Table Working Group: Historical

comparisons of morbidity and mortality for vaccine-preventable diseases in the United States,
JAMA 298(18):2155–2163, 2007.
† Data from Centers for Disease Control and Prevention: Viral hepatitis surveillance—United
States, 2016.
‡ Data from Centers for Disease Control and Prevention: Prevention of rotavirus gastroenteritis
among infants and children: recommendations of the Advisory Committee on Immunization
Practices, MMWR Recomm Rep 58(RR-2):1–25, 2009.
§ Data from Centers for Disease Controls and Prevention: Active bacterial core surveillance, 2016

(unpublished).
ǁ
Data from New Vaccine Surveillance Network 2017 data: U.S. rotavirus disease now has biennial
pattern (unpublished).
¶ Data from Centers for Disease Control and Prevention: Varicella Program, 2017 (unpublished).
 The major indications for inducing passive immunity are immunodeficiencies
in children with B-lymphocyte defects who have difficulty making antibodies
(e.g., hypogammaglobulinemia, secondary immunodeficiencies), who have
exposure to infectious diseases or to imminent risk of exposure when there is
inadequate time for them to develop an active immune response to a vaccine
(e.g., newborn exposed to maternal hepatitis B), and who have infectious
diseases that require antibody administration as part of the specific therapy
(Table 197.2 ).

Table 197.2
Immunoglobulin and Animal Antisera Preparations

PRODUCT MAJOR INDICATIONS

Immune globulin intramuscular (IGIM) Replacement therapy in antibody-deficiency disorders
Hepatitis A prophylaxis
Measles prophylaxis
Rubella prophylaxis (pregnant women)
Immune globulin intravenous (IGIV) Replacement therapy in antibody-deficiency disorders
Kawasaki disease
Pediatric HIV infection
Hypogammaglobulinemia in chronic B-lymphocyte
lymphocytic leukemia
Varicella postexposure prophylaxis
Guillain-Barré syndrome and chronic inflammatory
demyelinating polyneuropathy and multifocal motor
neuropathy
Toxic shock syndrome
May be useful in a variety of other conditions
Immune globulin subcutaneous (IGSC) Treatment of patients with primary immunodeficiencies
Hepatitis B immunoglobulin (IM) Postexposure prophylaxis
Prevention of perinatal infection in infants born to hepatitis B
surface antigen–positive mothers
Rabies immunoglobulin (IM) Postexposure prophylaxis
Tetanus immunoglobulin (IM) Wound prophylaxis
Treatment of tetanus
Varicella-zoster immunoglobulin (VariZIG, Postexposure prophylaxis of susceptible people at high risk for
IM) complications from varicella
Cytomegalovirus (IV) Prophylaxis of disease in seronegative transplant recipients
Vaccinia immunoglobulin (IV) Reserved for certain complications of smallpox immunization and
has no role in treatment of smallpox
Human botulism (IV), BabyBIG Treatment of infant botulism
Diphtheria antitoxin, equine Treatment of diphtheria
Heptavalent botulinum antitoxin against all 7 Treatment of noninfant food and wound botulism
(A-G) botulinum toxin types (BAT)
Palivizumab (monoclonal antibody), Prophylaxis for infants against respiratory syncytial virus (see
humanized mouse (IM) Chapter 287 )
Data from American Academy of Pediatrics: Passive immunization. In Kimberlin DW, Brady MT,
recommendations for use of palivizumab (see Chapter 287 ). Monoclonal
antibodies also are used to prevent transplant rejection and to treat some types of
cancer, autoimmune diseases, and asthma. Use of mAbs against interleukin
(IL)-2 and tumor necrosis factor (TNF)-α are being used as part of the
therapeutic approach to patients with a variety of malignant and autoimmune
diseases.
Serious adverse events associated with palivizumab are rare, primarily
including cases of anaphylaxis and hypersensitivity reactions. Adverse reactions
to mAbs directed at modifying the immune response, such as antibodies against
IL-2 or TNF-α, can be more serious and include cytokine release syndrome,
fever, chills, tremors, chest pain, immunosuppression, and infection with various
organisms, including mycobacteria.

Active Immunization
Vaccines are defined as whole or parts of microorganisms administered to
prevent an infectious disease. Vaccines can consist of whole inactivated
microorganisms (e.g., polio, hepatitis A), parts of the organism (e.g., acellular
pertussis, HPV, hepatitis B), polysaccharide capsules (e.g., pneumococcal and
meningococcal polysaccharide vaccines), polysaccharide capsules conjugated to
protein carriers (e.g., Hib, pneumococcal, and meningococcal conjugate
vaccines), live-attenuated microorganisms (e.g., measles, mumps, rubella,
varicella, rotavirus, and live-attenuated influenza vaccines), and toxoids (e.g.,
tetanus, diphtheria) (Table 197.3 ). A toxoid is a bacterial toxin modified to be
nontoxic but still capable of inducing an active immune response against the
toxin.

Table 197.3

Currently Available* Vaccines in the United States by Type

PRODUCT TYPE
Adenovirus Live, oral vaccine indicated for active immunization for the prevention of febrile acute
respiratory disease caused by adenovirus types 4 and 7, for use in military populations
17-50 yr of age
Anthrax vaccine Cell-free filtrate of components including protective antigen
adsorbed
Bacille Calmette- Live-attenuated mycobacterial strain used to prevent tuberculosis in very limited
Guérin (BCG) vaccine circumstances
Cholera vaccine Oral vaccine containing live-attenuated Vibrio cholerae CVD 103-HgR strain for
 protection against serogroup O1 in adults age 18-64 traveling to cholera-affected areas
Diphtheria and tetanus Toxoids of diphtheria and tetanus
toxoids adsorbed
Diphtheria and tetanus Toxoids of diphtheria and tetanus and purified and detoxified components from
toxoids and acellular Bordetella pertussis
pertussis (DTaP)
vaccine
DTaP–hepatitis B– DTaP with hepatitis B surface antigen (HBsAg) produced through recombinant
inactivated polio techniques in yeast with inactivated whole polioviruses
vaccine (DTaP-HepB-
IPV)
DTaP with IPV and DTaP with inactivated whole polioviruses and Hib polysaccharide conjugated to tetanus
Haemophilus toxoid
influenzae type b (Hib)
(DTaP-IPV/Hib)
DTaP and inactivated DTaP with inactivated whole polioviruses
polio vaccine (DTaP-
IPV)
Hib conjugate vaccine Polysaccharide conjugated to either tetanus toxoid or meningococcal group B outer
(Hib) membrane protein
Hepatitis A vaccine Inactivated whole virus
(HepA)
Hepatitis A–hepatitis Combined hepatitis A and B vaccine
B vaccine (HepA-
HepB)
Hepatitis B vaccine HBsAg produced through recombinant techniques in yeast
(HepB)
Human papillomavirus The L1 capsid proteins of HPV types 6 and 11 to prevent genital warts and types 16 18,
vaccine 9-valent 31, 33, 45, 52, and 58 to prevent cervical cancer (9vHPV).
(9vHPV)
Influenza virus Available either as trivalent (A/H3 N2 , A/H1 N1 , and B) split and purified inactivated
vaccine inactivated vaccines containing the hemagglutinin (H) and neuraminidase (N) of each type or as
(IIV † ) quadrivalent preparations (which include representative strains from 2 B strains in
addition to the 2 influenza A strains in trivalent inactivated influenza vaccine)
Influenza virus Live-attenuated, temperature-sensitive, cold-adapted quadrivalent vaccine containing the
vaccine live- H and N genes from the wild strains reassorted to have the 6 other genes from the cold-
attenuated, intranasal adapted parent
(LAIV)
Japanese encephalitis Purified, inactivated whole virus
vaccine
Measles, mumps, Live-attenuated viruses
rubella (MMR)
vaccine
Measles, mumps, Live-attenuated viruses
rubella, varicella
(MMRV) vaccine
Meningococcal Polysaccharide from each serogroup conjugated to diphtheria toxoid CRM197 protein
conjugate vaccine
against serogroups A,
C, W135, and Y
(MCV4)
Meningococcal Polysaccharides from each of the serogroups conjugated to diphtheria toxoid protein
polysaccharide
vaccine against
serogroups A, C,
 W135, and Y
(MPSV4)
Meningococcal B Recombinant proteins from serogroup B developed in Escherichia coli
(MenB)
Pneumococcal Pneumococcal polysaccharides conjugated to diphtheria toxin CRM197 , contains 13
conjugate vaccine (13 serotypes that accounted for >80% of invasive disease in young children prior to vaccine
valent) (PCV13) licensure
Pneumococcal Pneumococcal polysaccharides of 23 serotypes responsible for 85–90% of bacteremic
polysaccharide disease in the United States
vaccine (23 valent)
(PPSV23)
Poliomyelitis Inactivated whole virus highly purified from monkey kidney cells, trivalent types 1, 2,
(inactivated, enhanced and 3
potency) (IPV)
Rabies vaccines Inactivated whole virus
(human diploid and
purified chicken
fibroblasts)
Rotavirus vaccines Bovine rotavirus pentavalent vaccine (RV5) live reassortment attenuated virus, and
(RV5 and RV1) human live-attenuated virus (RV1)
Smallpox vaccine Vaccinia virus, an attenuated poxvirus that provides cross-protection against smallpox
(variola)
Tetanus and diphtheria Tetanus toxoid plus a reduced quantity of diphtheria toxoid compared to diphtheria
toxoids, adsorbed (Td, toxoid used for children <7 yr of age
adult use)
Tetanus and diphtheria Tetanus toxoid plus a reduced quantity of diphtheria toxoid plus acellular pertussis
toxoids adsorbed plus vaccine to be used in adolescents and adults and in children 7 through 10 yr of age who
acellular pertussis have not been appropriately immunized with DTaP
(Tdap) vaccine
Typhoid vaccine Vi capsular polysaccharide of Salmonella typhi Ty2 strain
(polysaccharide)
Typhoid vaccine (oral) Live-attenuated Ty21a strain of S. typhi
Varicella vaccine Live-attenuated Oka/Merck strain
Yellow fever vaccine Live-attenuated 17D-204 strain
Herpes zoster Live-attenuated Oka/Merck strain for use in adults ≥60 yr old (Zostavax)
(shingles) vaccine Recombinant zoster vaccine, adjuvanted (Shingrix) for use in adults ≥50 years
* As of November 2018.

† There are various types of inactivated flu vaccines—IIV3, IIV4, RIV4, ccIIV4, aIIV3.

Data from US Food and Drug Administration: Vaccines licensed for use in the United States.
http://www.fda.gov/BiologicsBloodVaccines/Vaccines/ApprovedProducts/ucm093833.htm .

Vaccines can contain a variety of other constituents besides the immunizing

antigen. Suspending fluids may be sterile water or saline but can be a complex
fluid containing small amounts of proteins or other constituents used to grow the
immunobiologic culture. Preservatives, stabilizers, and antimicrobial agents are
used to inhibit bacterial growth and prevent degradation of the antigen. Such
components can include gelatin, 2-phenoxyethanol, and specific antimicrobial
agents. Preservatives are added to multidose vials of vaccines, primarily to
lymphocyte help. These T-lymphocyte–independent vaccines are associated
with poor immune responses in children <2 yr old and with short-term immunity
and absence of an enhanced or booster response on repeat exposure to the
antigen. With some polysaccharide vaccines, repeat doses actually are associated
with reduced responses, as measured by antibody concentrations, compared to
1st doses (i.e., hyporesponsive ). To overcome problems with plain
polysaccharide vaccines, polysaccharides have been conjugated , or covalently
linked, to protein carriers, converting the vaccine to a T-lymphocyte–dependent
vaccine. In contrast to plain polysaccharide vaccines, conjugate vaccines induce
higher-avidity antibody, immunologic memory leading to booster responses on
repeat exposure to the antigen, long-term immunity, and community protection
by decreasing carriage of the organism (Table 197.4 ). As of 2018 in the United
States, licensed conjugate vaccines are available to prevent Hib, pneumococcal,
and meningococcal diseases.

Table 197.4

Characteristics of Polysaccharide and Conjugate Vaccines

CHARACTERISTIC CONJUGATE POLYSACCHARIDE
T-lymphocyte–dependent immune response Yes No
Immune memory Yes No
Persistence of protection Yes No
Booster effect Yes No
Reduction of carriage Yes No
Community protection Yes No
Lack of hyporesponsiveness Yes No

Serum antibodies may be detected as soon as 7-10 days after initial injection
of antigen. Early antibodies are usually of the IgM class that can fix
complement. IgM antibodies tend to decline as IgG antibodies increase. The IgG
antibodies tend to peak approximately 1 mo after vaccination and with most
vaccines persist for some time after a primary vaccine course. Secondary or
booster responses occur more rapidly and result from rapid proliferation of
memory B and T lymphocytes.
Assessment of the immune response to most vaccines is performed by
measuring serum antibodies. Although detection of serum antibody at levels
considered protective after vaccination can indicate immunity, loss of detectable
antibody over time does not necessarily mean susceptibility to disease. Some
vaccines induce immunologic memory, leading to a booster or anamnestic
Vaccine Delivery
To ensure potency, vaccines should be stored at recommended temperatures
before and after reconstitution. A comprehensive resource for providers on
vaccine storage and handling recommendations and best practice strategies is
available (https://www.cdc.gov/vaccines/hcp/admin/storage/index.html ).
Expiration dates should be noted and expired vaccines discarded. Lyophilized
vaccines often have long shelf lives. However, the shelf life of reconstituted
vaccines generally is short, ranging from 30 min for varicella vaccine to 8 hr for
MMR vaccine.
All vaccines have a preferred route of administration, which is specified in
package inserts and in AAP and ACIP recommendations. Most inactivated
vaccines, including DTaP, hepatitis A, hepatitis B, Hib, inactivated influenza
vaccine (IIV ), HPV, PCV13, MCV4, and Tdap, are administered IM. In
contrast, MPSV4 and the more commonly used live-attenuated vaccines (MMR,
MMRV, and varicella) should be dispensed by the SC route. Rotavirus vaccine is
administered orally. IPV and PPS23 (pneumococcal polysaccharide vaccine) can
be given IM or SC. One influenza vaccine, LAIV, when recommended, is
administered intranasally, and another influenza vaccine is administered by the
intradermal route. For IM injections, the anterolateral thigh muscle is the
preferred site for infants and young children. The recommended needle length
varies depending on age and size: inch for newborn infants, 1 inch for infants
2-12 mo old, and inches for older children. For adolescents and adults, the
deltoid muscle of the arm is the preferred site for IM administration with needle
lengths of inches depending on patient size. Most IM injections can be
made with 23-25 gauge needles. For SC injections, needle lengths generally
range from inch with 23-25 gauge needles.
Additional aspects of immunization important for pediatricians and other
healthcare providers are detailed on the websites listed in Table 197.5 .

Table 197.5
Vaccine Websites and Resources

ORGANIZATION WEBSITE
HEALTH PROFESSIONAL ASSOCIATIONS
American Academy of Family Physicians (AAFP) http://www.familydoctor.org/online/famdocen/home.html
American Academy of Pediatrics (AAP) http://www.aap.org/
AAP Childhood Immunization Support Program http://www.aap.org/immunization/
American Association of Occupational Health http://www.aaohn.org/
Nurses (AAOHN)

American College Health Association (ACHA) http://www.acha.org/

American College of Obstetricians and http://www.immunizationforwomen.org/
Gynecologists (ACOG)–Immunization for Women
American Medical Association (AMA) http://www.ama-assn.org/
American Nurses Association (ANA) http://www.nursingworld.org/
American Pharmacists Association (APhA) http://www.pharmacist.com/
American School Health Association (ASHA) http://www.ashaweb.org/
American Travel Health Nurses Association http://www.athna.org/
(ATHNA)
Association for Professionals in Infection Control http://www.apic.org/
and Epidemiology (APIC)
Association of State and Territorial Health http://www.astho.org/
Officials (ASTHO)
Association of Teachers of Preventive Medicine http://www.atpm.org/
(ATPM)
National Medical Association (NMA) http://www.nmanet.org/
Society of Teachers of Family Medicine—Group http://www.immunizationed.org/
on Immunization Education
NONPROFIT GROUPS AND UNIVERSITIES
Albert B. Sabin Vaccine Institute http://www.sabin.org/
Brighton Collaboration https://brightoncollaboration.org/public
Center for Vaccine Awareness and Research— http://www.texaschildrens.org/departments/immunization-
Texas Children's Center project
Children's Vaccine Program http://www.path.org/vaccineresources/
Every Child by Two (ECBT) http://www.ecbt.org/
Families Fighting Flu http://www.familiesfightingflu.org/
GAVI, the Vaccine Alliance http://www.gavialliance.org/
Health on the Net Foundation (HON) http://www.hon.ch/
Immunization Action Coalition (IAC) http://www.immunize.org/
Infectious Diseases Society of America (IDSA) http://www.idsociety.org/Index.aspx
Institute for Vaccine Safety (IVS), Johns Hopkins http://www.vaccinesafety.edu/
Bloomberg School of Public Health
National Academies: Health and Medicine http://www.nationalacademies.org/hmd/
Division
National Alliance for Hispanic Health http://www.hispanichealth.org/
National Foundation for Infectious Diseases http://www.nfid.org
(NFID)
National Foundation for Infectious Diseases http://www.preventchildhoodinfluenza.com/
(NFID)—Childhood Influenza Immunization
Coalition (CIIC)
National Network for Immunization Information http://www.immunizationinfo.net/
(NNii)
Parents of Kids with Infectious Diseases (PKIDS) http://www.pkids.org/
PATH Vaccine Resource Library http://www.path.org/vaccineresources/
Vaccine Education Center at the Children's http://www.chop.edu/service/vaccine-education-
Hospital of Philadelphia center/home.html
Vaccinate Your Baby http://www.vaccinateyourbaby.org/
GOVERNMENT ORGANIZATIONS
Centers for Disease Control and Prevention (CDC)
Advisory Committee on Immunization Practices http://www.cdc.gov/vaccines/acip/index.html
 (ACIP)
ACIP Vaccine Recommendations http://www.cdc.gov/vaccines/hcp/acip-recs/index.html
Current Vaccine Delays and Shortages http://www.cdc.gov/vaccines/vac-gen/shortages/
Epidemiology and Prevention of Vaccine- https://www.cdc.gov/vaccines/pubs/pinkbook/index.html
Preventable Diseases (also known as the Pink
Book )
Manual for the Surveillance of Vaccine- www.cdc.gov/vaccines/pubs/surv-manual/index.html
Preventable Diseases
Public Health Image Library https://phil.cdc.gov/phil/home.asp
Travelers' Health http://www.cdc.gov/travel/
CDC Health Information for International Travel https://wwwnc.cdc.gov/travel/yellowbook/2016/table-of-
(also known as the Yellow Book ) contents
Vaccine Adverse Events Reporting System http://www.cdc.gov/vaccinesafety/Activities/vaers.html
(VAERS)
Vaccine Administration: Recommendations and http://www.cdc.gov/vaccines/recs/vac-admin/default.htm
Guidelines
Vaccines and Immunizations http://www.cdc.gov/vaccines/
Vaccines for Children Program http://www.cdc.gov/vaccines/programs/vfc/index.html
Vaccines for Children—Vaccine Price List http://www.cdc.gov/vaccines/programs/vfc/awardees/vaccine-
management/price-list/index.html
Vaccine Information Statements www.cdc.gov/vaccines/hcp/vis/index.html
Vaccine Safety http://www.cdc.gov/vaccinesafety/index.html
Vaccine Storage and Handling http://www.cdc.gov/vaccines/recs/storage/default.htm
Department of Health and Human Services (HHS)
National Vaccine Program Office (NVPO) http://www.hhs.gov/nvpo/
Health Resources and Services Administration
National Vaccine Injury Compensation Program http://www.hrsa.gov/vaccinecompensation/
National Institute of Allergy and Infectious Diseases (NIAID)
Vaccines https://www.niaid.nih.gov/about/vrc
World Health Organization (WHO)
Immunization, Vaccines, and Biologicals http://www.who.int/immunization/en/

Recommended Immunization Schedule

All children in the United States should be vaccinated against 16 diseases (Figs.
197.1 and 197.2 ) (annually updated schedule available at
http://www.cdc.gov/vaccines/schedules/index.html ).
The 5th (booster) dose of DTaP vaccine is not necessary if the 4th dose was
administered at 4 yr or older. One dose of an adult preparation of Tdap is
recommended for all adolescents 11 through 12 yr of age, even if a dose of Tdap
or DTaP was administered inadvertently or as part of the catch-up series at 7-10
yr of age. Adolescents 13 through 18 yr who missed the 11 through 12 yr Tdap
booster dose should receive a single dose of Tdap if they have completed the
diphtheria, tetanus, and pertussis (DTP)/DTaP series. Tdap may be given at any
interval following the last Td. Table 197.6 lists preparations in which DTaP is
combined with other vaccines. One dose of Tdap vaccine is recommended for
pregnant adolescents with each pregnancy, preferably between 27 and 36 wk
gestation, regardless of time since last Tdap or Td. Currently available data
suggest that vaccinating earlier in the 27 through 36 wk period will maximize
passive antibody transfer to the infant. This recommendation was made in
response to data predicting lack of infant protection when maternal Tdap had
been received before pregnancy.

Table 197.6
Combination Vaccines Licensed and Available in the
United States

VACCINE PRODUCT TRADE NAME RECOMMENDED AGES

COMPONENTS
(MANUFACTURER)* (YEAR LICENSED) Primary Series Booster Dose
DTaP-IPV/Hib (Sanofi Pentacel (2008) DTaP-IPV + 2, 4, and 6 mo 15 through 18
Pasteur) PRP-T mo
DTaP-HepB-IPV Pediarix (2002) DTaP + HepB + 2, 4, and 6 mo
(GlaxoSmithKline) IPV
DTaP-IPV Kinrix (2008), DTaP + IPV 4 through 6
(GlaxoSmithKline) Quadracel (2015) yr
Booster for
5th dose of
DTaP
Booster for
4th dose of
IPV
HepA-HepB Twinrix (2001) HepA + HepB >18 yr of age; 0, 1,
(GlaxoSmithKline) and 6 mo schedule
MMRV (Merck & Co) ProQuad (2005) MMR + varicella † 4 through 6 yr
* Dash (-) indicates that products are supplied in their final form by the manufacturer and do not
require mixing or reconstitution by user; slash (/) indicates that products are mixed or
reconstituted by user.
† Although ProQuad is available for the 1st dose (at 12 through 15 mo of age), the CDC
recommends that MMR vaccine and varicella vaccine should be administered for the 1st dose in
this age-group, unless the parent or caregiver expresses a preference for MMRV vaccine.
DTaP, Diphtheria and tetanus toxoids and acellular pertussis vaccine; HepA, hepatitis A vaccine;
HepB, hepatitis B vaccine; IPV/Hib, trivalent inactivated polio vaccine and Haemophilus
influenzae type b vaccine; MMRV, measles-mumps-rubella and varicella vaccine, PRP-T, H.
influenzae type b capsular polysaccharide (polyribosyl-ribitol279 phosphate [PRP]) covalently
bound to tetanus toxoid (PRP-T).
Adapted from Cohn AC, MacNeil JR, Clark TA, et al: Prevention and control of meningococcal
disease: recommendations of the Advisory Committee on Immunization Practices, MMWR
62(2):1–28, 2013.

There are 3 licensed preparations of single-antigen Hib vaccines. The vaccine

conjugated to tetanus toxoid (PRP-T) is given in a 4-dose series at 2, 4, 6, and 12
through 15 mo of age, and the Hib vaccine conjugated to meningococcal outer
membrane protein (PRP-OMP) is recommended in a 3-dose series at 2, 4, and 12
through 15 mo of age. The 3rd Hib vaccine is licensed as a booster for children
15 mo through 4 yr of age. There are several vaccines in which Hib is a
component, in addition to single-antigen Hib conjugate vaccines (see Tables
197.6 and 197.7 ).

Table 197.7

Vaccines Recommended for Children and Adolescents With Underlying Conditions

or at High Risk
VACCINES SPECIAL SITUATIONS
PCV13 (and Chronic heart disease (particularly cyanotic congenital heart disease and cardiac failure),
PPSV23 in chronic lung disease (including asthma if treated with high-dose oral corticosteroid therapy),
certain chronic liver disease, chronic renal failure
conditions) Diabetes mellitus
Cerebrospinal fluid leak
Cochlear implant
Sickle cell disease and other hemoglobinopathies
Anatomic or functional asplenia
HIV infection
Nephrotic syndrome
Diseases associated with treatment with immunosuppressive drugs or radiation therapy,
including malignant neoplasms, leukemias, lymphomas, and Hodgkin disease
Generalized malignancy
Solid organ transplantation
Congenital or acquired immunodeficiencies
Multiple myeloma
Hep A Chronic liver disease
Clotting factor disorders
Men who have sex with men
Injection or non-injection drug use
Homelessness
Work with hepatitis A virus
Travel in countries with high or intermediate endemic hepatitis A
 Close, personal contact with international adoptee (e.g.,household or regular babysitting)
Flu Egg allergy more severe than hives
MCV4 Anatomic or functional asplenia (including sickle cell disease)
Persistent complement component deficiency
Residents of or travelers to countries in African meningitis belt or pilgrims on the Hajj
During outbreaks caused by a vaccine serogroup
HIV infection
MenB Anatomic or functional asplenia (including sickle cell disease)
Children with persistent complement component deficiency
During serogroup B outbreaks
Hib Persons at increased risk for Hib disease, including chemotherapy recipients and those with
anatomic or functional asplenia (including sickle cell disease), human immunodeficiency
virus (HIV) infection, immunoglobulin deficiency, or early component complement
deficiency
Recipients of hematopoietic stem cell transplant (HSCT)
Elective splenectomy
Hep B Infants born to HBsAg-positive mothers or mothers whose HBsAg status is unknown (administer
vaccine within 12 hr of birth)
HPV Immunocompromising conditions, including HIV infection
History of sexual abuse or assault
From Centers for Disease Control and Prevention: Child and adolescent schedule.
https://www.cdc.gov/vaccines/schedules/hcp/imz/child-adolescent.html

Influenza vaccine is recommended for all children beginning at 6 mo old,

with a minimum age of 6 mo for IIVs and 24 mo for LAIV. Various influenza
vaccine preparations are FDA-licensed for different age-groups.* Children 6 mo
through 8 yr of age being vaccinated for the first time should receive 2 doses at
least 4 wk apart. If such children only received a single dose of IIV the prior
season, they need 2 doses the following season. For additional guidelines, follow
dosing instructions in the influenza statement, which is updated annually by both
the CDC (https://www.cdc.gov/flu/professionals/acip/index.htm ) and AAP
(aapredbook.org ). Influenza vaccine usually is given in October or November,
although there are benefits even when administered as late as February or March
because influenza seasons most frequently peak in February. People ≥9 yr old
should receive 1 dose of influenza vaccine annually. For the 2016–2017 flu
season, the ACIP voted that LAIV should not be used at all because of low
vaccine effectiveness during the previous 3 influenza seasons.
IPV should be administered at 2, 4, and 6 through 18 mo of age with a booster
dose at 4 through 6 yr. The final dose in the series should be administered on or
after 4 yr of age and at least 6 mo after the previous dose. The final dose in the
IPV series should be administered at 4 yr or older regardless of the number of
previous doses, and the minimal interval from dose 3 to dose 4 is 6 mo. For
series that contain oral polio vaccine (OPV), the total number of doses needed to
complete the series is the same as that recommended for the U.S. IPV schedule.
increased risk of meningococcal disease. This includes people with complement
deficiencies or anatomic or functional asplenia, people at increased risk due to
serogroup B meningococcal disease outbreaks, and microbiologists who
routinely are exposed to isolates of Neisseria meningitidis . Young adults age 16-
23 (preferred range: 16-18 yr) who are not at increased risk for meningococcal
disease may be vaccinated with either of the 2 MenB vaccines, which are not
interchangeable, to provide short-term protection against most strains of
serogroup B meningococcal disease.
Hib vaccine and HepA vaccine are recommended for children with certain
high-risk conditions. HepB is recommended for infants born to HBsAg-positive
mothers or mothers whose HBsAg status is unknown (administer vaccine within
12 hr of birth) (see Table 197.7 ).
In addition to vaccines in the recommended childhood and adolescent
schedule, a variety of vaccines are available for children who will be traveling
to areas of the world where certain infectious diseases are common (Table 197.8
). Vaccines for travelers include typhoid fever, hepatitis A, hepatitis B, Japanese
encephalitis, MCV4 or MPS4, cholera, rabies, and yellow fever, depending on
the location and circumstances of travel. Measles is endemic in many parts of
the world. Children 6-11 mo old should receive a dose of MMR and hepatitis A
vaccines before international travel. However, doses of MMR and hepatitis A
vaccines received before 12 mo should not be counted in determining
compliance with the recommended 2-dose MMR schedule. For unvaccinated
children ≥12 mo old, administer 2 doses before international travel following the
recommended schedule. (Additional information on vaccines for international
travel can be found at http://wwwnc.cdc.gov/travel/ .)

Table 197.8
Recommended Immunizations for International Travel*

LENGTH OF STAY
IMMUNIZATIONS Brief, Long-
<1 Term/Residential,
mo >1 mo
Review and complete age-appropriate childhood and adolescent schedule (see + +
text for details)
• DTaP, poliovirus, pneumococcal, and Haemophilus influenzae type b (Hib) vaccines
may be given at 4 wk intervals if necessary to complete recommended schedule
before departure.
• Influenza
• MMR: 2 additional doses given if <12 mo old at 1st dose
 • Meningococcal disease (MenACWY) †
• Rotavirus
• Varicella
• Human papillomavirus (HPV)
• Hepatitis A: 2 additional doses given if <12 mo old at 1st dose ‡ §
• Hepatitis B §
• Tdap
Yellow fever ǁ + +
Typhoid fever ¶ ± +
Rabies** ± ±
Japanese encephalitis †† ± +
Cholera ‡‡ ± ±
* See disease-specific chapters in the Centers for Disease Control and Prevention's Yellow Book

for details. For further sources of information, see text.

† Recommended for regions of Africa with endemic infection and during local epidemics, and
required for travel to Saudi Arabia for the Hajj.
‡ For infants age 6-11 mo, 1st dose is recommended before departure for all international travel.
For unvaccinated children 12 mo and older, this vaccine is indicated for travelers to areas with
intermediate or high endemic rates of hepatitis A virus infection.
§ If there is insufficient time to complete 6 mo primary series, accelerated series can be given.
ǁ
For regions with endemic infection, see Health Information for International Travel
(http://www.cdc.gov/travel ). Because of the risk of serious adverse events after yellow fever
vaccination, clinicians should only vaccinate people who (1) are at risk of exposure to yellow fever
virus (YFV) or (2) require proof of vaccination to enter a country.
¶ Indicated for travelers who will consume food and liquids in areas of poor sanitation.

** Indicated for people with high risk for animal exposure (especially to dogs) and for travelers to
countries with endemic infection.
†† For regions with endemic infection (see Health Information for International Travel). For high-

risk activities in areas experiencing outbreaks, vaccine is recommended, even for brief travel.
‡‡ Cholera vaccine (CVD 103-HgR, Vaxchora) is recommended for adult (18-64 yr old) travelers to
an area of active toxigenic V. cholerae O1 transmission.
+, Recommended; ±, consider; DTaP, diphtheria and tetanus toxoids and acellular pertussis.
Data from Centers for Disease Control and Prevention: Travelers' health.
https://wwwnc.cdc.gov/travel .

Vaccine recommendations for children with immunocompromising

conditions , either primary (inherited) or secondary (acquired), vary according
to the underlying condition, the degree of immune deficit, the risk for exposure
to disease, and the vaccine (Table 197.9 and Fig. 197.3 ). Immunization of
children who are immunocompromised poses the following potential concerns:
the incidence or severity of some vaccine-preventable diseases is higher, and
therefore certain vaccines are recommended specifically for certain conditions;
vaccines may be less effective during the period of altered immunocompetence
and may need to be repeated when immune competence is restored; and because
of altered immunocompetence, some children and adolescents may be at
increased risk for an adverse event following receipt of a live-virus vaccine.
Live-attenuated vaccines generally are contraindicated in immunocompromised
persons. The exceptions include MMR , which may be given to a child with
HIV infection provided the child is asymptomatic or symptomatic without
evidence of severe immunosuppression, and varicella vaccine, which may be
given to HIV-infected children if the CD4+ lymphocyte count is at least 15%.
MMRV is not recommended in these situations.

Table 197.9
Vaccination of Persons With Primary and Secondary
Immune Deficiencies
PRIMARY
CATEGORY SPECIFIC CONTRAINDICATED RISK-SPECIFIC EFFECTIVENESS AN
IMMUNODEFICIENCY VACCINES * RECOMMENDED COMMENTS
VACCINES *
B lymphocyte (humoral) Severe antibody OPV a Annual IIV is the only The effectiveness of
deficiencies (e.g., X-linked Smallpox b vaccine given to any vaccine will be
agammaglobulinemia and LAIV patients receiving IG uncertain if it depend
common variable BCG therapy; routine only on the humoral
immunodeficiency) Yellow fever virus inactivated vaccines response (e.g.,
(YFV) and live- can be given if not PPSV23).
receiving IGIV. IG therapy interferes
bacteria vaccines e with the immune
No data for
response to live
rotavirus vaccines
vaccines MMR and
VAR.
Less severe antibody OPV a Vaccines should All vaccines are
deficiencies (e.g., selective BCG be given as on the probably effective.
IgA deficiency and IgG YFV vaccine annual Immune response
subclass deficiency) Other live vaccines immunization may be attenuated.
d appear to be safe. schedule for
immunocompetent
people. e
PPSV23 should be
given beginning at
2 yr of age. f

T lymphocyte (cell- Complete defects (e.g., All live vaccines c , d , g The only vaccine that All inactivated vaccines
mediated and humoral) SCID, complete DiGeorge should be given if the are probably ineffective.
syndrome) patient is receiving IG
is annual IIV if there is
 some residual antibody
protection.

Partial defects (e.g., most All live vaccines c , d , gRoutine Effectiveness of any
patients with DiGeorge inactivated vaccine depends on degr
syndrome, hyper-IgM vaccines should of immune suppression.
syndrome, Wiskott- be given. e
Aldrich syndrome, ataxia- PPSV23 should be
telangiectasia) given beginning at
2 yr of age. f
Interferon (IFN)-γ– All live vaccines for IL- None None
interleukin (IL)-12 axis 12/IL-12R deficiencies,
deficiencies IFN-γ, IFN-α, or STAT1
deficiencies
Complement Persistent complement, None PPSV23 should be All routine vaccines are
properdin, MBL, or factor given beginning at probably effective.
B deficiency; secondary 2 yr of age. f
deficiency because taking MCV series
eculizumab (Solaris) beginning in
infancy. h
MenB series
beginning at 10 yr
of age
Phagocytic function Chronic granulomatous Live-bacteria vaccines c None All inactivated
disease vaccines are safe and
probably effective.
Live-virus vaccines
are probably safe and
effective.
Phagocytic deficiencies MMR, MMRV, OPV, a PPSV23 should be All inactivated vaccines
that are undefined or smallpox, LAIV, YF, all given beginning at are safe and probably
accompanied by defect in bacteria vaccines 2 yr of age. f effective.
T-cell and NK-cell MCV series
dysfunction (e.g., beginning in
Chédiak-Higashi infancy. h
syndrome, leukocyte
adhesion defects,
myeloperoxidase
deficiency)
SECONDARY
SPECIFIC CONTRAINDICATED RISK-SPECIFIC EFFECTIVENESS AND
IMMUNODEFICIENCY VACCINES * RECOMMENDED VACCINES * COMMENTS
HIV/AIDS OPV a PPSV23 should be given Rotavirus vaccine is
Smallpox beginning at 2 yr of age. f recommended on standard
BCG MCV series beginning in schedule.
Combined MMRV infancy. h MMR and VAR are recommende
LAIV Consider Hib (if not for HIV-infected children who ar
Withhold MMR, asymptomatic or only low-level
administered in infancy). l
varicella, and zoster in immunocompromised.
severely All inactivated vaccines may be
immunocompromised effective.
persons.
YF vaccine may have
a contraindication or
 precaution depending
on the indicators of
immune function. j
Generalized malignant Live-virus and live- PPSV23 should be given Effectiveness of any vaccine depends
neoplasm, transplantation, bacteria vaccines, beginning at 2 yr of age. f on degree of immune suppression;
autoimmune disease, depending on immune Annual IIV (unless receiving inactivated standard vaccines are
immunosuppressive or status. c , d , m intensive chemotherapy or anti- indicated if not highly
radiation therapy B cell antibodies). immunosuppressed, but doses should
Hib vaccine may be indicated. n be repeated after chemotherapy ends.
Asplenia (functional, LAIV PPSV23 should be given All routine vaccines are probably
congenital anatomic, beginning at 2 yr of age. f effective.
surgical) MCV series beginning in
infancy. h
MenB series beginning at 10 yr
of age.
Hib (if not administered in
infancy) o
Chronic renal disease LAIV PPSV23 should given beginning All routine vaccines are probably
at 2 yr of age. f effective.
HepB is indicated if not
previously immunized.
CNS anatomic barrier None PPSV23 should be given beginning All standard vaccines are indicated.
defect (cochlear implant, at 2 yr of age. f
congenital dysplasia of the
inner ear, persistent CSF
communication with naso-
/oropharynx)
* Other vaccines that are universally or routinely recommended should be given if not
contraindicated.
a
OPV is no longer available in the United States.
b This table refers to contraindications for nonemergency vaccination (i.e., ACIP

recommendations)
c Live-bacteria vaccines: BCG and oral Ty21a Salmonella typhi vaccine.

d Live-virus vaccines: MMR, MMRV, VAR, OPV, LAIV, YF, zoster, rotavirus, and vaccinia
(smallpox). Smallpox vaccine is not recommended for children or the general public.
e Children who are delayed or underimmunized should be immunized with routinely
recommended vaccines, according to age and catch-up schedule.
f PPSV23 is begun at 2 yr or older. If PCV13 is required, PCV13 doses should be administered
first, followed by PPSV23 at least 8 wk later; a 2nd dose of PPSV23 is given 5 yr after the 1st.
g Regarding T-lymphocyte immunodeficiency as a contraindication for rotavirus vaccine, data exist
only for SCID.
h Age and schedule of doses depend on the product; repeated doses are required.

j YF vaccine is contraindicated in HIV-infected children <6 yr old who are highly

immunosuppressed. There is precaution for use of YF vaccine in asymptomatic HIV-infected
children <6 yr with total lymphocyte percentage of 15–24%, and >6 yr old with CD4+ T-lymphocyte
protected by vaccination to vaccine-preventable diseases, such as children too
young for vaccination and those with medical contraindications. (For more
information, see:
http://pediatrics.aappublications.org/content/early/2016/08/25/peds.2016-2145 .)

Improving Immunization Coverage

Standards for child and adolescent immunization practices have been developed
to support achievement of high levels of immunization coverage while providing
vaccines in a safe and effective manner and educating parents about risks and
benefits of vaccines (Table 197.10 ).

Table 197.10
Standards for Child and Adolescent Immunization
Practices
AVAILABILITY OF VACCINES
Vaccination services are readily available.
Vaccinations are coordinated with other healthcare services and provided in a medical home when possible.
Barriers to vaccination are identified and minimized.
Patient costs are minimized.
ASSESSMENT OF VACCINATION STATUS
Healthcare professionals review the vaccination and health status of patients at every encounter to determine
which vaccines are indicated.
Healthcare professionals assess for and follow only medically accepted contraindications.
EFFECTIVE COMMUNICATION ABOUT VACCINE BENEFITS AND RISKS
Parents or guardians and patients are educated about the benefits and risks of vaccination in a culturally
appropriate manner and in easy-to-understand language.*
Healthcare professionals offer strong and consistent recommendations for all universally recommended vaccines
according to the current immunization schedule. They use presumptive language (e.g., these vaccines are
routine) and deliver this recommendation in the same manner for all vaccines.
Healthcare professionals answer parents' or guardians' and patients' questions thoroughly and emphasize an
unwavering commitment to the recommendation. If parents or guardians and patients are hesitant or refuse,
healthcare professionals persevere and offer the vaccine again at the next most appropriate time.
PROPER STORAGE AND ADMINISTRATION OF VACCINES AND DOCUMENTATION OF
VACCINATIONS
Healthcare professionals follow appropriate procedures for vaccine storage and handling.
Up-to-date, written vaccination protocols are accessible at all locations where vaccines are administered.
Persons who administer vaccines and staff who manage or support vaccine administration are knowledgeable and
receive ongoing education.
Healthcare professionals simultaneously administer as many indicated vaccine doses as possible.
Vaccination records for patients are accurate, complete, and easily accessible.
Healthcare professionals report adverse events following vaccination promptly and accurately to the Vaccine
Adverse Event Reporting System (VAERS) and are aware of a separate program, the National Vaccine Injury
Compensation Program (VICP).
Healthcare professionals and personnel review the immunization timeline with parents or guardians and patients
 and schedule follow-up immunization visits before the family leaves the care setting.
All personnel who have contact with patients are appropriately vaccinated and communicate consistent messages
about vaccines.
IMPLEMENTATION OF STRATEGIES TO IMPROVE VACCINATION COVERAGE
Systems are used to remind parents or guardians, patients, and healthcare professionals when vaccinations are due
and to recall those who are overdue.
Office- or clinic-based patient record reviews and vaccination coverage assessments are performed annually.
Healthcare professionals practice community-based approaches.
Healthcare professionals understand cultural needs and disparities of different populations and use the most
effective strategies for these populations.
Most healthcare visits (including acute care or sick visits) are viewed as opportunities to review immunization
records, provide vaccines that are due, and catch up on missed vaccinations.
* Additional resources to help improve immunization rates include the following:

• Provider Resources for Vaccine Conversations with

Parents from CDC, AAP, and American Academy of
Family Physicians
(www.cdc.gov/vaccines/hcp/conversations/index.html )
• American Academy of Pediatrics (AAP) Training Guide
(https://shar.es/1JRNmJ )
• Centers for Disease Control and Prevention (CDC):
Pink Book, Chapter 6 : Vaccine administration
(https://www.cdc.gov/vaccines/pubs/pinkbook/vac-
admin.html ); and quality improvement projects and
educational materials
(https://www.cdc.gov/vaccines/ed/index.html )
• Immunization Action Coalition: Suggestions to improve
your immunization services
(http://www.immunize.org/catg.d/p2045.pdf )
Adapted from National Vaccine Advisory Committee: Standards for child and adolescent
immunization practices, Pediatrics 112:958–963, 2003; and Bernstein HH, Bocchini JA; AAP
Committee on Infectious Diseases: The need to optimize adolescent immunization, Pediatrics
139(3):e20164186, 2017, and Practical approaches to optimize adolescent immunization,
Pediatrics 139(3):e20164187, 2017.

Despite benefits that vaccines have to offer, many children are

underimmunized as a result of not receiving recommended vaccines or not
administered. Following evidence that a 3-dose series of Hib vaccine at these
ages was insufficient to ensure long-term, high-grade protection, a booster dose
was added at 12 mo of age. MMR is recommended in a 2-dose schedule at 12
mo and 40 mo of age. During the 2nd MMR visit, a booster of DTaP and IPV is
provided. A Td/IPV booster is recommended at age 14 yr. PCV13 is
recommended at 2, 4, and 12 mon of age. The UK was the first country to use
conjugate meningococcal C vaccine (MCV-C ) during a massive catch-up
campaign for children, adolescents, and young adults. The effectiveness of the
vaccine in the 1st year was ≥88%, and herd immunity was induced with an
approximate two-thirds reduction in the incidence among unvaccinated children.
Given the success of this strategy, MenC vaccination at age 3 wk was
discontinued as of July 2016. Now MenC is given in combination with the 4th
dose of Hib at 12 mo. MenB is given at 2, 4, and 12 mo of age. In September
2008, HPV vaccine was recommended for girls 12-13 yr old. As of April 2013,
the UK schedule did not include hepatitis B vaccine, varicella vaccine, or
influenza vaccine for universal childhood immunization, although annual
influenza vaccination is recommended for persons ≥65 yr old (see
http://www.nhs.uk/conditions/vaccinations/pages/vaccination-schedule-age-
checklist.aspx ).
The Japanese immunization schedule in 2016 is substantially different from
the Y.S. schedule. ‡ The Japanese do not use MMR, instead offering the choice
of MR (preferred in principle) or single-antigen measles and rubella vaccination.
Mumps vaccine is available on a voluntary basis. Japanese children are
vaccinated routinely; against diphtheria, tetanus, pertussis, and polio with DTaP
in combination with IPV; against Japanese encephalitis; and against tuberculosis
with BCG. Hib, PCV, HepB, varicella, and HPV vaccines are also included in
the routine vaccination schedule and made available free of charge under the
Preventive Vaccinations Act . Adults ≥65 yr old receive annual influenza
vaccinations. Rotavirus, HepA (from age 1 yr and above), meningococcus
(ACWY) (from age 2 yr and above), and yellow fever vaccines are available on
a voluntary basis.
Some children come to the United States having started or completed
international immunization schedules with vaccines produced outside the United
States. In general, doses administered in other countries should be considered
valid if administered at the same ages as recommended in the United States. For
missing doses, age-inappropriate doses, lost immunization records, or other
concerns, pediatricians have 2 options: administer or repeat missing or
 Cohn AC, Broder KR, Pickering LK. Immunizations in the US:
a rite of passage. Pediatr Clin North Am . 2005;52:669–693.
Diekema DS. American Academy of Pediatrics Committee on
Bioethics: responding to refusals of immunization of
children. Pediatrics . 2005;115:1428–1431.
O'Brien KL, Levine OS. Effectiveness of pneumococcal
conjugate vaccine. Lancet . 2006;368:1469–1470.
Omer SB, Pan WKY, Halsey NA, et al. Nonmedical exemptions
to school immunization requirements: secular trends and
association of state policies with pertussis incidence. JAMA .
2006;296:1757–1763.
Orenstein WA, Douglas RG, Rodewald LE, et al.
Immunizations in the US: success, structure and stress.
Health Aff (Millwood) . 2005;24:559–610.
O'Ryan M, Matson DO. New rotavirus vaccines: renewed
optimism. J Pediatr . 2006;149:448–451.
Pickering LK, Baker CJ, Kimberlin DW, et al. Red book: 2015
report of the Committee on Infectious Diseases . ed 30.
American Academy of Pediatrics: Elk Grove Village, IL;
2015:1–107.
Plotkin SA, Orenstein WA. Vaccines . ed 5. Elsevier:
Philadelphia; 2007.
Varricchio F, Iskander J, Destefano F, et al. Understanding
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Bibliography
Ahmed F, Temte JL, Campos-Outcalt D, et al. Methods for
developing evidence-based recommendations by the
Standard Precautions
Standard precautions, formerly known as universal precautions , are intended to
protect healthcare workers from pathogens and should be used whenever there is
direct contact with patients. Infected patients are often contagious before
symptoms of disease develop. Asymptomatic infected patients are quite capable
of transmitting infectious agents. Standard precautions involve the use of
barriers—gloves, gowns, masks, goggles, and face shields—as needed, to
prevent transmission of microbes associated with contact with blood and body
fluids (Table 198.1 ).

Table 198.1
Recommendations for Application of Standard Precautions
for Care of All Patients in All Healthcare Settings

COMPONENT RECOMMENDATIONS
Hand hygiene Before and after each patient contact, regardless of whether
gloves are used.
After contact with blood, body fluids, secretions,
excretions, or contaminated items; immediately after
removing gloves; before and after entering patient rooms.
Alcohol-containing antiseptic hand rubs preferred except
when hands are visibly soiled with blood or other
proteinaceous material or if exposure to spores (e.g.,
Clostridium difficile , Bacillus anthracis ) or nonenveloped
viruses (norovirus) is likely to have occurred; in these
cases, soap and water is required.
PERSONAL PROTECTIVE EQUIPMENT (PPE)
Gloves For touching blood, body fluids, secretions, excretions, or
contaminated items; for touching mucous membranes and
nonintact skin.
Employ hand hygiene before and after glove use.
Gown During procedures and patient-care activities when contact of
clothing or exposed skin with blood, body fluids, secretions, or
excretions is anticipated.
Mask, eye protection (goggles), face shield During procedures and patient-care activities likely to
generate splashes or sprays of blood, body fluids, or
secretions, such as suctioning and endotracheal intubation,
to protect healthcare personnel.
For patient protection, use of a mask by the person inserting
an epidural anesthesia needle or performing myelograms
when prolonged exposure of the puncture site is likely to
occur.
Soiled patient-care equipment Handle in a manner that prevents transfer of
microorganisms to others and to the environment.
Wear gloves if equipment is visibly contaminated.
Perform hand hygiene.
 ENVIRONMENT
Environmental control Develop procedures for routine care, cleaning, and disinfection
of environmental surfaces, especially frequently touched
surfaces in patient-care areas.
Textiles (linens) and laundry Handle in a manner that prevents transfer of microorganisms to
others and the environment.
PATIENT CARE
Injection practices (use of needles and other Do not recap, bend, break, or manipulate used needles; if
sharps) recapping is required, use a one-handed scoop technique
only.
Use needle-free safety devices when available, placing used
sharps in puncture-resistant container.
Use a sterile, single-use, disposable needle and syringe for
each injection.
Single-dose medication vials preferred when medications
may be administered to more than one patient.
Patient resuscitation Use mouthpiece, resuscitation bag, or other ventilation devices
to prevent contact with mouth and oral secretions.
Patient placement Prioritize for single-patient room if patient is at increased risk
for transmission, is likely to contaminate the environment, is
unable to maintain appropriate hygiene, or is at increased risk
for acquiring infection or developing adverse outcome following
infection.
Respiratory hygiene/cough etiquette (source Instruct symptomatic persons to cover nose/mouth when
containment of infectious respiratory secretions sneezing or coughing; use tissues with disposal in no-touch
in symptomatic patients) beginning at initial receptacles.
point of encounter, such as triage or reception Employ hand hygiene after soiling of hands with respiratory
areas in emergency department or physician secretions.
office Wear surgical mask if tolerated or maintain spatial
separation (>3 ft if possible).
Adapted from Kimberlin DW, Brady MT, Jackson MA, et al, editors: Red Book 2018–2021: Report
of the Committee on Infectious Diseases, ed 31, Elk Grove Village, IL, 2018, American Academy
of Pediatrics, pp 148–150.

Isolation
Isolation of patients infected with transmissible pathogens decreases the risk of
nosocomial transmission of organisms to staff and other patients. The specific
type of isolation depends on the infecting agent and potential route of
transmission. Transmission by contact is the most common mode of pathogen
transmission and involves direct contact with the patient or contact with a
contaminated intermediate object. Contact isolation requires the use of gown
and gloves when in contact with the patient or immediate surroundings.
Transmission by droplets involves the propulsion of infectious large particles
over a short distance (<3 ft), with deposition on another's mucous membranes or
skin. Droplet isolation requires the use of gloves and gowns, as well as masks
and eye guards when closer than 3 ft to the patient. Airborne transmission
occurs by dissemination of evaporated droplet nuclei (≤5 µm) or dust particles
carrying an infectious agent. Airborne infection isolation (AII ) requires the
use of masks and negative pressure air-handling systems to prevent spread of the
infectious agent. In the case of active pulmonary tuberculosis in older children
and adults, severe acute respiratory syndrome (SARS), or avian influenza, the
use of special high-density masks (N-95) or self-contained breathing systems
such as powered air-purifying respirators (PAPRs ) or controlled air-purifying
respirators (CAPRs ) are recommended. Positive pressure HEPA-filtered air-
handling systems are used in some institutions for housing seriously
immunocompromised patients and negative pressure systems for the care of
patients with highly contagious respiratory infections such as Ebola virus.
Standard precautions are indicated for all patients and are appropriate for use
in the clinic as well as the hospital. Additionally, for hospitalized patients,
further transmission-based precautions are indicated for certain infections
(Table 198.2 ). For contact and droplet isolation, single rooms are preferred but
not required. Cohorting children infected with the same pathogen is acceptable,
but the etiologic diagnosis should be confirmed by laboratory methods before
exposing infected children to one another. Transmission-based isolation
precautions should be continued for as long as a patient is considered
contagious.

Table 198.2
Clinical Syndromes and Conditions Warranting Empirical
Transmission-Based Precautions in Addition to Standard
Precautions Pending Confirmation of Diagnosis*

CLINICAL SYNDROME OR POTENTIAL EMPIRICAL PRECAUTIONS

(ALWAYS INCLUDES STANDARD
CONDITION † PATHOGENS ‡ PRECAUTIONS)
DIARRHEA
Acute diarrhea with a likely infectious Enteric pathogens § Contact precautions (pediatrics and
cause in an incontinent or diapered patient adult)
Meningitis Neisseria meningitidis Droplet precautions for 1st 24 hr of
antimicrobial therapy; mask and face
protection for intubation
Enteroviruses Contact precautions for infants and
children
Mycobacterium Airborne precautions if pulmonary
tuberculosis infiltrate
Airborne precautions plus contact
 precautions if potentially infectious
draining body fluid present
RASH OR EXANTHEMS, GENERALIZED, ETIOLOGY UNKNOWN
Petechial/ecchymotic with fever (general) N. meningitidis Droplet precautions for 1st 24 hr of
antimicrobial therapy
If positive history of travel to an area with Ebola, Lassa, and Marburg Droplet precautions plus contact
an ongoing outbreak of VHF in the 10 viruses precautions, with face/eye
days before onset of fever protection, emphasizing safety
sharps and barrier precautions
when blood exposure likely
Use N95 or higher respiratory
protection when aerosol-generating
procedure performed.
Vesicular Varicella-zoster, herpes Airborne precautions plus contact
simplex, variola precautions
(smallpox), and vaccinia
viruses
Vaccinia virus Contact precautions only if herpes
simplex, localized zoster in an
immunocompetent host, or vaccinia
viruses likely
Maculopapular with cough, coryza, and Rubeola (measles) virus Airborne precautions
fever
RESPIRATORY INFECTIONS
Cough/fever/upper lobe pulmonary M. tuberculosis , Airborne precautions plus contact
infiltrate in HIV-negative patient or patient respiratory viruses, precautions
at low risk for HIV infection Streptococcus pneumoniae,
Staphylococcus aureus
(MSSA or MRSA)
Cough/fever/pulmonary infiltrate in any M. tuberculosis , Airborne precautions plus contact
lung location in HIV-infected patient or respiratory viruses, S. precautions
patient at high risk for HIV infection pneumoniae, S. aureus Use eye/face protection if aerosol-
(MSSA or MRSA) generating procedure performed or
contact with respiratory secretions
anticipated.
If tuberculosis is unlikely and there
are no AIIRs or respirators
available, use droplet precautions
instead of airborne precautions.
Tuberculosis is more likely in HIV-
infected than in HIV-negative
patients.
Cough/fever/pulmonary infiltrate in any M. tuberculosis , severe Airborne precautions plus contact
lung location in patient with history of acute respiratory syndrome precautions plus eye protection
recent travel (10-21 days) to countries with virus (SARS-CoV), avian If SARS and tuberculosis unlikely,
active outbreaks of SARS, avian influenza influenza use droplet precautions instead of
airborne precautions.
Respiratory infections, particularly Respiratory syncytial virus, Contact plus droplet precautions
bronchiolitis and pneumonia, in infants parainfluenza virus, Droplet precautions may be
and young children adenovirus, influenza discontinued when adenovirus and
virus, human influenza have been ruled out.
metapneumovirus
SKIN OR WOUND INFECTION
Abscess or draining wound that cannot be S. aureus (MSSA or Contact precautions
covered MRSA), group A Add droplet precautions for 1st 24
 streptococcus hr of appropriate antimicrobial
therapy if invasive group A
streptococcal disease is suspected.
*
Infection control professionals should modify or adapt this table according to local conditions. To
ensure that appropriate empirical precautions are always implemented, hospitals must have
systems in place to evaluate patients routinely according to these criteria as part of their
preadmission and admission care.
† Patients with the syndromes or conditions listed may present with atypical signs or symptoms

(e.g., neonates and adults with pertussis may not have paroxysmal or severe cough). The
clinician's index of suspicion should be guided by the prevalence of specific conditions in the
community as well as clinical judgment.
‡
The organisms listed are not intended to represent the complete, or even most likely, diagnoses,
but rather possible etiologic agents that require additional precautions beyond standard
precautions, until they can be ruled out.
§ These pathogens include enterohemorrhagic Escherichia coli O157:H7, Shigella spp., hepatitis
A virus, norovirus, rotavirus, Clostridium difficile .
AIIRs, Airborne infection isolation rooms; HIV, human immunodeficiency virus; MRSA, methicillin-
resistant S. aureus ; MSSA, methicillin-susceptible S. aureus ; VHF, viral hemorrhagic fever.
Adapted from Centers for Disease Control and
Preventionwebsite,http://www.cdc.gov/hicpac/2007ip/2007ip_table2.html .

The use of isolation techniques in outpatient settings has not been well
studied. Professional offices should establish procedures to ensure that proper
cleaning, disinfection, and sterilization methods are employed. Many practices
and clinics provide separate waiting areas for sick and well children. Triage of
patients is essential to ensure that contagious children or adults are not present in
waiting areas. Outbreaks of measles and varicella in patients within the waiting
area have been reported where the air exhaust from examination rooms enters
the waiting area. Cleaning the clinic environment is important, especially in
high-touch areas. Toys and items that are shared among patients should be
cleaned between uses; if feasible, disposable toys should be used. Toys
contaminated with blood or body fluids should be autoclaved or discarded.

Additional Measures
Other preventive measures include aseptic technique, catheter care, prudent use
of antibiotics through use of an effective antibiotic stewardship program ,
isolation of contagious patients, periodic cleansing of the environment,
disinfection and sterilization of medical equipment, reporting of infections, safe
handling of needles and other sharp instruments, and establishment of employee
health services. Sterile technique must be used for all invasive procedures,
including catheter placement and manipulation. The use of barrier techniques at
the time of IV catheter placement has reduced the rate of catheter-related
bloodstream infections by half. Appropriate catheter use also includes limiting
the duration and number of catheters employed, scrubbing catheter hubs with
every access, and removing catheters as soon as they become unnecessary.

Surgical Prophylaxis
Surgical antibiotic prophylaxis should be employed when there is a high risk of
postoperative infection or when the consequences of such infection would be
catastrophic. The choice of prophylactic antibiotic depends on the surgical site
and type of surgery. A useful classification of surgical procedures based on
infectious risk recognizes 4 preoperative wound categories: clean wounds, clean-
contaminated wounds, contaminated wounds, and dirty and infected wounds
(Table 198.3 ). The American College of Surgeons, Surgical Infection Society,
and American Academy of Pediatrics have made clinical recommendations
regarding antibiotic prophylaxis.

Table 198.3
Common Surgical Procedures for Which Perioperative
Prophylactic Antibiotics Are Recommended

NON β-
SURGICAL
LIKELY PATHOGENS RECOMMENDED DRUGS LACTAM
PROCEDURE
ALTERNATIVE
CLEAN WOUNDS
Cardiac surgery (e.g., Skin flora, enteric gram- Cefazolin or cefuroxime Clindamycin or
open heart surgery) negative bacilli vancomycin
Vascular surgery
Neurosurgery
Orthopedic surgery
(e.g., joint
replacement)
CLEAN-CONTAMINATED WOUNDS
Head and neck surgery Skin flora, oral Cefazolin + metronidazole, ampicillin- Clindamycin
involving oral cavity or anaerobes, oral sulbactam
pharynx streptococci
Gastrointestinal and Enteric gram-negative Cefazolin + metronidazole, Clindamycin
genitourinary surgery bacilli, anaerobes, gram- cefotetan or piperacillin-
positive cocci sulbactam
If colon is involved, consider
 bacterial reduction with oral
neomycin and erythromycin.
CONTAMINATED WOUNDS
Traumatic wounds (e.g., Skin flora Cefazolin Clindamycin or
compound fracture) vancomycin
DIRTY WOUNDS
Appendectomy, penetrating Enteric gram-negative Cefazolin + metronidazole, cefoxitin, Clindamycin +
abdominal wounds, bacilli, anaerobes, gram- cefotetan or ampicillin-sulbactam aminoglycoside
colorectal surgery positive cocci
Adapted from Bratzler DW, Dellinger PD, Olsen KM, et al: Clinical practice guidelines from
antimicrobial prophylaxis in surgery, Am J Health Syst Pharm 70:195–283, 2013.

Clean wounds are uninfected operative wounds where no inflammation is

noted at the operative site and respiratory, alimentary, and genitourinary tracts
and the oropharynx are not entered. Such wounds are often the result of
nonemergent procedures with primary closure or drained by a closed system.
Operative incisional wounds after nonpenetrating trauma are included in this
category. For clean wounds, prophylactic antimicrobial therapy is not
recommended except in patients at high risk for infection and in circumstances
where the consequences of infection would be potentially life threatening, as
with implantation of a foreign body such as a prosthetic heart valve or
cerebrospinal fluid shunt, open heart surgery for repair of structural defects, and
surgery in immunocompromised patients or small infants.
Clean-contaminated wounds are operative wounds in which the respiratory,
alimentary, or genitourinary tract is entered under controlled conditions and that
do not have unusual bacterial contamination preoperatively. These wounds occur
in operations that involve the biliary tract, appendix, vagina, and oropharynx
where no evidence of infection or major break in technique is encountered, as
well as in urgent or emergency surgery in an otherwise clean procedure. In
procedures involving clean-contaminated wounds, the risk for bacterial
contamination and infection is variable. Recommendations for pediatric patients
derived from adult data suggest that antibiotic prophylaxis be provided for
procedures in children with obstructive jaundice, certain alimentary tract
procedures, and urinary tract surgery or instrumentation in the presence of
bacteriuria or obstructive uropathy.
Contaminated wounds include open, fresh, and accidental wounds; major
breaks in otherwise sterile operative technique; gross spillage from the GI tract;
penetrating trauma occurring <4 hr earlier; and incisions where acute
nonpurulent inflammation is encountered.
Dirty and infected wounds include penetrating traumatic wounds >4 hr
before surgery, wounds with retained devitalized tissue, and those in which
depends on the age and immune status of the children, season, hygiene practices,
crowding, and environmental characteristics of the facilities. The pathogen
characteristics, including infectivity, survivability in the environment, and
virulence, also influence transmission in childcare settings. Rates of infection,
duration of illness, and risk for hospitalization tend to decrease among children
in childcare facilities after the 1st 6 mo of attendance and decline to levels
observed among homebound children after 3 yr of age. Adult caregivers are also
at increased risk for acquiring and transmitting infectious diseases, particularly
in the 1st yr of working in these settings.

Table 199.1
Infectious Diseases in the Childcare Setting

INCREASED
DISEASE INCIDENCE WITH
CHILDCARE
Respiratory Tract Infections
Otitis media Yes
Sinusitis Probably
Pharyngitis Probably
Pneumonia Yes
Gastrointestinal Tract Infections
Diarrhea (rotavirus, calicivirus, astrovirus, enteric adenovirus, Giardia lamblia, Yes
Cryptosporidium, Shigella, Escherichia coli O157:H7, and Clostridium difficile )
Hepatitis A Yes
Skin Diseases
Impetigo Probably
Scabies Probably
Pediculosis Probably
Tinea (ringworm) Probably
Invasive Bacteria Infections
Haemophilus influenzae type b No*
Neisseria meningitidis Probably
Streptococcus pneumoniae Yes
Aseptic Meningitis
Enteroviruses Probably
Herpesvirus Infections
Cytomegalovirus Yes
Varicella-zoster virus Yes
Herpes simplex virus Probably
Bloodborne Infections
Hepatitis B Few case reports
HIV No cases reported
Hepatitis C No cases reported
Vaccine-Preventable Diseases
Measles, mumps, rubella, diphtheria, pertussis, tetanus Not established
 Polio No
H. influenzae type b No*
Varicella Yes
Rotavirus Yes
* Not in the post–vaccine era; yes in the pre–vaccine era.

Epidemiology
Respiratory tract infections and gastroenteritis are the most common diseases
associated with childcare. These infections occur in children and their household
contacts, as well as childcare workers, and can spread into the community. The
severity of illness caused by a given respiratory and enteric pathogen depends on
the person's underlying health status, the inoculum, and prior exposures to the
pathogen, either by infection or immunization. Hepatitis B virus (HBV)
transmission has been reported rarely in a childcare setting. Transmission of
hepatitis C virus (HCV), hepatitis D virus (HDV), and HIV has not been
reported in a childcare setting. Some organisms, such as hepatitis A virus (HAV),
can cause subclinical disease in young children and produce overt and
sometimes serious disease in older children and adults. Other diseases, such as
otitis media and varicella, usually affect children rather than adults. Several
agents, such as cytomegalovirus and parvovirus B19, can have serious
consequences for the fetuses of pregnant women or for immunocompromised
persons. Because many childcare workers are women of childbearing age, they
should be encouraged to discuss possible risks with their physician if they
become pregnant. Both infections and infestations of the skin and hair may be
acquired through contact with contaminated linens or through close personal
contact, which is inevitable in childcare settings.

Respiratory Tract Infections

Respiratory tract infections account for the majority of childcare-related
illnesses. Children <2 yr old who attend childcare centers have more upper and
lower respiratory tract infections than do age-matched children not in childcare.
The organisms responsible for these illnesses are similar to those that circulate in
the community and include respiratory syncytial virus (RSV), parainfluenza
viruses, influenza viruses, human metapneumoviruses, adenoviruses,
rhinoviruses, coronaviruses, parvovirus B19, and Streptococcus pneumoniae.
Table 199.2

Disease- or Condition-Specific Recommendations for Exclusion of Children in Out-

of-Home Childcare
MANAGEMENT OF
CONDITION MANAGEMENT OF CONTACTS
CASE
Clostridium Exclusion until stools are Symptomatic contacts should be excluded until stools are
difficile contained in the diaper or contained in the diaper or child is continent and stool frequency is
child is continent and stool no more than 2 stools above that child's normal frequency for the
frequency is no more than 2 time the child is in the program. Testing is not required for
stools above that child's asymptomatic contacts.
normal frequency for the
time the child is in the
program. Stool consistency
does not need to return to
normal to be able to return to
childcare. Neither test of
cure nor repeat testing
should be performed for
asymptomatic children in
whom C. difficile was
diagnosed previously.
Hepatitis A Serologic testing to confirm In facilities with diapered children, if 1 or more cases confirmed
virus (HAV) HAV infection in suspected in child or staff attendees or 2 or more cases in households of staff
infection cases. Exclusion until 1 wk or attendees, hepatitis A vaccine (HepA) or immune globulin
after onset of illness. intramuscular (IGIM) should be administered within 14 days of
exposure to all unimmunized staff and attendees. In centers
without diapered children, HepA or IGIM should be administered
to unimmunized classroom contacts of index case. Asymptomatic
IGIM recipients may return after receipt of IGIM.
Impetigo No exclusion if treatment has No intervention unless additional lesions develop.
been initiated and as long as
lesions on exposed skin are
covered.
Measles Exclusion until 4 days after Immunize exposed children without evidence of immunity within
beginning of rash and when 72 hr of exposure. Children who do not receive vaccine within 72
the child is able to hr or who remain unimmunized after exposure should be excluded
participate. until at least 2 wk after onset of rash in the last case of measles.
Mumps Exclusion until 5 days after In outbreak setting, people without documentation of immunity
onset of parotid gland should be immunized or excluded. Immediate readmission may
swelling. occur following immunization. Unimmunized people should be
excluded for 26 or more days following onset of parotitis in last
case. A 2nd dose of MMR vaccine (or MMRV, if age appropriate)
should be offered to all students (including those in postsecondary
school) and to all healthcare personnel born in or after 1957 who
have only received 1 dose of MMR vaccine. A 2nd dose of MMR
also may be considered during outbreaks for preschool-age
children who have received 1 MMR dose. People previously
vaccinated with 2 doses of a mumps-containing vaccine who are
identified by public health as at increased risk for mumps because
of an outbreak should receive a 3rd dose of a mumps-containing
vaccine to improve protection against mumps disease and related
complications.
Pediculosis Treatment at end of program Household and close contacts should be examined and treated if
capitis (head day and readmission on infested. No exclusion necessary.
lice) completion of 1st treatment.
infestation Children should not be
excluded or sent home early
from school because of head
lice, because this infestation
has low contagion within
classrooms.
Pertussis Exclusion until completion Immunization and chemoprophylaxis should be administered as
of 5 days of the recommended for household contacts. Symptomatic children and
recommended course of staff should be excluded until completion of 5 days of
antimicrobial therapy if antimicrobial therapy. Untreated adults should be excluded until
pertussis is suspected. 21 days after onset of cough.
Children and providers who
refuse treatment should be
excluded until 21 days have
elapsed from cough onset.
Rubella Exclusion for 7 days after During an outbreak, children without evidence of immunity
onset of rash for postnatal should be immunized or excluded for 21 days after onset of rash
infection. of the last case in the outbreak. Pregnant contacts should be
evaluated.
Infection with Exclusion until 3 When Salmonella serotype Typhi infection is identified in a child
Salmonella consecutive stool cultures care staff member, local or state health departments may be
serotypes obtained at least 48 hr after consulted regarding regulations for length of exclusion and
Typhi or cessation of antimicrobial testing, which may vary by jurisdiction.
Paratyphi therapy are negative, stools
are contained in the diaper or
child is continent, and stool
frequency is no more than 2
stools above that child's
normal frequency for the
time the child is in the
program.
Infection with Exclusion until stools are Symptomatic contacts should be excluded until stools are
nontyphoidal contained in the diaper or contained in the diaper or child is continent and stool frequency is
Salmonella child is continent and stool no more than 2 stools above that child's normal frequency for the
spp., frequency is no more than 2 time the child is in the program. Stool cultures are not required for
Salmonella of stools above that child's asymptomatic contacts.
unknown normal frequency for the
serotype time the child is in the
program. Stool consistency
does not need to return to
normal to be able to return to
childcare. Negative stool
culture results not required
for nonserotype Typhi or
Paratyphi Salmonella spp.
Scabies Exclusion until after Close contacts with prolonged skin-to-skin contact should receive
treatment given. prophylactic therapy. Bedding and clothing in contact with skin of
infected people should be laundered.
Infection with Exclusion until 2 stool Meticulous hand hygiene; stool cultures should be performed for
Shiga toxin– cultures (obtained at least 48 any symptomatic contacts. In outbreak situations involving
producing hr after any antimicrobial virulent STEC strains, stool cultures of asymptomatic contacts
Escherichia therapy, if administered, has may aid controlling spread. Center(s) with cases should be closed
 coli (STEC), been discontinued) are to new admissions during STEC outbreak.
including E. negative, and stools are
coli O157:H7 contained in the diaper or
child is continent, and stool
frequency is no more than 2
stools above that child's
normal frequency. Some
state health departments have
less stringent exclusion
policies for children who
have recovered from less
virulent STEC infection.
Shigellosis Exclusion until treatment Meticulous hand hygiene; stool cultures should be performed for
complete and one or more any symptomatic contacts.
posttreatment stool cultures
are negative for Shigella
spp., and stools are contained
in the diaper or child is
continent, and stool
frequency is no more than 2
stools above that child's
normal frequency for the
time the child is in the
program. Some states may
require more than 1 negative
stool culture.
Staphylococcus Exclusion only if skin Meticulous hand hygiene; cultures of contacts are not
aureus skin lesions are draining and recommended.
infections cannot be covered with a
watertight dressing.
Streptococcal Exclusion until at least 12 hr Symptomatic contacts of documented cases of group A
pharyngitis after treatment has been streptococcal infection should be tested and treated if test results
initiated. are positive.
Tuberculosis Most children younger than Local health department personnel should be informed for contact
10 yr are not considered investigation.
contagious. For those with
active disease, exclusion
until determined to be
noninfectious by physician
or health department
authority. No exclusion for
latent tuberculosis infection
(LTBI).
Varicella Exclusion until all lesions For people without evidence of immunity, varicella vaccine
have crusted or, in should be administered, ideally within 3 days, but up to 5 days
immunized people without after exposure, or when indicated, varicella-zoster immune
crusts, until no new lesions globulin (VariZIG) should be administered up to 10 days after
appear within 24 hr period. exposure; if VariZIG is not available, immune globulin
intravenous (IGIV) should be considered as an alternative. If
vaccine cannot be administered and VariZIG/IGIV is not
indicated, preemptive oral acyclovir or valacyclovir can be
considered.
From Kimberlin DW, Brady MT, Jackson MA, Long SS, editors: Red Book 2018–2021: Report of
the Committee on Infectious Diseases, ed 31, Elk Grove Village, IL, 2018, American Academy of
Pediatrics (Table 2.3 , pp 130–135).
Table 199.3

General Recommendations for Exclusion of Children in Out-of-Home Childcare

SYMPTOM(S) MANAGEMENT
Illness preventing participation in activities, as Exclusion until illness resolves and able to participate in
determined by childcare staff. activities.
Illness that requires more care than staff can Exclusion or placement in care environment where appropriate
provide without compromising health and care can be provided without compromising care of others.
safety of others.
Severe illness suggested by fever with Medical evaluation and exclusion until symptoms have resolved.
behavior changes, lethargy, irritability,
persistent crying, difficulty breathing, or
progressive rash.
Persistent abdominal pain (≥2 hr) or Medical evaluation and exclusion until symptoms have resolved.
intermittent abdominal pain associated with
fever, dehydration, or other systemic signs and
symptoms.
Vomiting ≥2 times in preceding 24 hr. Exclusion until symptoms have resolved, unless vomiting is
determined to be caused by a noncommunicable condition and
child is able to remain hydrated and participate in activities.
Diarrhea if stool not contained in diaper or if Medical evaluation for stools with blood or mucus; exclusion
fecal accidents occur in a child who is until stools are contained in the diaper or when toilet-trained
normally continent; if stool frequency ≥2 children no longer have accidents using the toilet and when stool
above normal for child or stools contain blood frequency becomes <2 stools above child's normal frequency/24
or mucus. hr.
Oral lesions Exclusion if unable to contain drool, or if unable to participate
because of other symptoms, or until child or staff member is
considered to be noninfectious (lesions smaller or resolved).
Skin lesions Exclusion if lesions are weeping and cannot be covered with a
waterproof dressing.
From Kimberlin DW, Brady MT, Jackson MA, Long SS, editors: Red Book 2018–2021: Report of
the Committee on Infectious Diseases , ed 31, Elk Grove Village, IL, 2018, American Academy of
Pediatrics (Table 2.2, p 129).

Routine vaccination has had a proven significant beneficial effect on the

health of children in childcare settings. In the United States, there are 16 diseases
and organisms for which all children should be immunized unless there are
contraindications: diphtheria, pertussis, tetanus, measles, mumps, rubella, polio,
hepatitides A and B, varicella, H. influenzae type b, S. pneumoniae, rotavirus, N.
meningitidis, influenza, and human papillomavirus (see Chapter 197 ). Rates of
immunization among children in licensed childcare facilities are high, in part
because of laws in almost all states that require age-appropriate immunizations
of children who attend licensed childcare programs. Vaccines against influenza,
H. influenzae type b, hepatitis B, rotavirus, varicella, S. pneumoniae, and
hepatitis A are of particular benefit to children in childcare centers.
wk.

Specialized Pediatric Travel Vaccinations

Table 200.1 summarizes the dosages and age restrictions of vaccines specifically
given to children traveling internationally.

Table 200.1
Travel Vaccinations for Children

ROUTE
VACCINE FORMULATION AND SCHEDULE INDICATIONS COMMENTS
DOSE
Hepatitis A Pediatric: Havrix IM; 0.5 Primary series: 2 Children >6 Inactivated vaccine
(GlaxoSmithKline); mL doses, 6-18 mo apart months of age Lifelong protection is
720 EU Booster: currently not likely.
VAQTA (Merck); recommended
25 U
Adult: Havrix IM; 1.0 Primary series: 2 Adults ≥19 yr Inactivated vaccine
(GlaxoSmithKline); mL doses, 6-18 mo apart old Lifelong protection is
1440 EU Booster: currently not likely.
VAQTA (Merck); recommended
50 U
Hepatitis A and Twinrix IM; 1.0 Primary series: 3 Adults ≥18 yr Inactivated vaccine
B (GlaxoSmithKline) mL doses at 0, 1, and 6 old Lifelong protection is
mo likely.
Accelerated schedule: Accelerated schedule
0, 7, and 21 days; 4th is as effective.
dose 12 mo later
Boosters: not needed
Immunoglobulin, Injectable IM Travel up to 1 mo Infants <1 yr old Passive
human duration: 0.1 mL/kg immunizations
Travel up to 2 mo against hepatitis A.
duration: 0.2 mL/kg Its use would require
Travel 2 mo or more: delay of measles and
0.2 mL/kg (repeat varicella vaccinations
every 2 mo) (at least 3 mo).
Japanese Inactivated: Ixiaro IM Primary series: 2 Travel to high- Booster recommendation
encephalitis (Intercell USA) 2 doses at days 0 and 28 risk areas; is extrapolated from
virus (JEV) mo Booster: 1 dose 1 yr prolonged stays recommendation for
to later if exposure to individuals ≥17 yr old.
<3 JEV expected
yr
old:
0.25
mL
≥3
yr
old:
 0.5
mL
Meningococcal, Quadrivalent: A, C, Y, SC; 0.5 Primary series: single ≥2 yr old Required for entry to
polysaccharide W135 mL dose Saudi Arabia during
Booster: 5 yr in the Hajj.
persons ≥4 yr old; 2–3 Recommended for
yr in children 2–4 yr travelers visiting
old “meningitis belt” in
sub-Saharan Africa
during dry months.
This vaccine is rarely
used in U.S. since
conjugate vaccines
are more
immunogenic.
Meningococcal, Quadrivalent: ACWY- IM: 0.5 Children 9-23 mo old: Routine Required for entry to
conjugate D: Menactra (Sanofi mL 2 doses, 3 mo apart vaccination in Saudi Arabia during
Pasteur) 2-55 yr old: 1 dose U.S. at ≥11-12 the Hajj.
yr old with Recommended for
recommended travelers visiting
booster 5 yr “meningitis belt” in
later sub-Saharan Africa
during dry months.
This vaccine should
not be used in infants
<9 mo old since it
may interfere with
antibody production
by pneumococcal
conjugate vaccine.
Quadrivalent: ACWY- IM; 0.5 Children initiating Routine Required for entry to
CRM: Menveo mL vaccination at 2 mo: vaccination in Saudi Arabia during
(Novartis) doses at 2, 4, 6, and U.S. at ≥11-12 the Hajj.
12 mo old yr old with Recommended for
Children starting recommended travelers visiting
vaccination at 7-23 booster 5 yr “meningitis belt” in
mo old: 2 doses, with later sub-Saharan Africa
2nd dose after 2 yr old during dry months.
and at least 3 mo after
1st dose
Rabies Inactivated IM; 1.0 Preexposure series: 3 Consider for young
mL doses at days 0, 7, and travelers planning
21 or 28 prolonged stays;
Booster: depends on especially away from
risk category and large urban centers with
serologic testing. adequate medical care
Postexposure: rabies systems and airport.
immune globulin; day
0; vaccines at days 0,
3, 7, and 14; 5th dose
at day 28 is
recommended if host
is
immunocompromised.
Typhoid fever Live-attenuated Ty21a1 Oral 1 capsule every other Persons ≥6 yr If series sequence not
 day for 4 doses old completed, all 4
Boosters: every 5 yr doses need to be
repeated.
Contraindicated in
immunocompromised
hosts. Cannot be
taken with hot
beverage. Person
must not be taking
antibiotics.
Injectable IM; 0.5 Primary series: 1 dose Persons ≥2 yr
Polysaccharide Vi mL Booster: every 2 yr old
antigen
Yellow fever Live injectable SC; 0.5 Primary series: 1 dose ≥9 mo old Contraindicated in
mL Dose must be given at immunocompromised
least 10 days before hosts. Avoid in
arrival to risk area. pregnancy and in
Booster: no longer breastfeeding
required by WHO. mothers, unless high-
U.S. travelers: risk travel cannot be
recommended every avoided.
10 yr for high-risk Contraindicated in
travelers. infants <4 mo old.
Avoid in persons with
thymus disorders.
Infants 6-8 mo old:
consider vaccination
with caution if risk or
travel cannot be
avoided; consult
travel medicine
specialist.
Caution in persons
≥60 yr old (high risk
for vaccine-related
infection).
Requires official
certificate of
vaccination.
IM, Intramuscular; SC, subcutaneous; WHO, World Health Organization.

Cholera
Cholera is present in many low- and middle-income countries, but the risk for
infection among travelers to these countries is extremely low. At present, no
cholera vaccine is available for travelers in the United States, although an
effective vaccine is available in other countries. Travelers entering countries
reporting cholera outbreaks are at minimal risk of acquiring cholera if they take
adequate safe food and water precautions and practice frequent handwashing. No
country or territory currently requires cholera vaccination as a condition for
chloroquine , is widespread, and in most areas of the world other agents must be
used (Table 200.2 ). Factors that must be considered in choosing appropriate
chemoprophylaxis medications and dosing schedules include age of the child,
travel itinerary (including whether the child will be traveling to areas of risk
within a particular country and whether chloroquine-resistant P. falciparum is
present in the country), vaccinations being given, allergies or other known
adverse reactions to antimalarial agents, and the availability of medical care
during travel.

Table 200.2
Antimalarial Chemoprophylaxis for Children

ADULT PEDIATRIC
AREA DRUG ADVANTAGES DISADVANTAGES COMMENTS
DOSE DOSE
Chloroquine- Mefloquine* 250 mg Weight <10 Once-weekly Bitter taste Children
resistant area † salt kg: 5 mg salt dosing No pediatric going to
(228 (4.6 mg formulation malaria-
mg base)/kg/wk Side effects of endemic
base) sleep area for ≥4
tablets disturbance, wk
One vivid dreams Children
tablet unlikely to
weekly take daily
Weight 10-19 medication
kg:
tablet/wk
Weight
20-30 kg:

tablet/wk
Weight
31-45 kg:

tablet/wk
Weight >45
kg: 1
tablet/wk
Doxycycline 100 mg 2 mg/kg daily Known Cannot give to Children ≥8 yr
‡ tablet (max: 100 safety children <8 yr old going to
One mg) profile old area for <4 wk
tablet Readily Daily dosing who cannot
daily available in Must take with take or cannot
most food or causes obtain
pharmacies stomach upset atovaquone-
Photosensitivity proguanil
Yeast
superinfections
 Atovaquone- 250/100 Pediatric Pediatric Daily dosing Children going
proguanil § adult tablet: 62.5 tablet Expensive to malaria-
(Malarone) tablet mg formulation Can cause endemic area
One atovaquone/25 available stomach upset for <4 wk
tablet mg proguanil Generally
daily well
Weight 5-8 tolerated
kg:
pediatric
tablet once
daily
Weight >8-10
kg:
pediatric
tablet once
daily
Weight >10-
20 kg: 1
pediatric
tablet once
daily
Weight >20-
30 kg: 2
pediatric
tablets once
daily
Weight >30-
40 kg: 3
pediatric
tablets once
daily
Weight >40
kg: 1 adult
tablet once
daily
Chloroquine- Chloroquine 500 mg 8.3 mg/kg salt Once- Bitter taste Best
susceptible phosphate salt (5 mg/kg weekly No pediatric medication for
area (300 base) weekly dosing formulation children
mg Generally traveling to
base) well areas with
One tolerated Plasmodium
tablet Safe in falciparum or
weekly pregnancy P. vivax that is
chloroquine
susceptible
* Chloroquine and mefloquine should be started 1-2 wk before departure and continued for 4 wk
after last exposure.
† Mefloquine resistance exists in western Cambodia and along the Thailand–Cambodia and
Thailand–Myanmar borders. Travelers to these areas should take doxycycline or atovaquone-
proguanil. See text for precautions about mefloquine use.
‡ Doxycycline should be started 1-2 days before departure and continued for 4 wk after last
should never be substituted for seeking appropriate medical care, but it can be
considered in special circumstances such as travel to remote areas, intolerance of
prophylaxis, or refusal of chemoprophylaxis by the traveler. Self-treatment
medication should be different than the prescribed chemoprophylaxis. The CDC
or a travel medicine specialist should be consulted if self-treatment medication is
being considered for a traveler.

The Returning Traveler

Posttravel evaluations are part of travel medicine and continuing care.
Physicians unfamiliar with diseases that occur in low- and middle-income
countries often misdiagnose the cause of illness in a child returning from travel
abroad. Among returning patients identified from the GeoSentinel Surveillance
Network sites who were ill, the common disorders included, in descending order
of frequency, malaria, giardiasis, dengue fever, campylobacteriosis, cutaneous
larva migrans, enteric fever, spotted fever (rickettsiosis), chikungunya fever,
hepatitis A, and influenza. Returning pediatric travelers who are severely ill or
with continued fevers should be seen in consultation with a pediatric travel
medicine or infectious diseases specialist. The cause of fever may be suggested
by the geographic area (Table 200.3 ) and incubation period (Table 200.4 ).

Table 200.3

Common Causes of Fever by Geographic Area

OTHER INFECTIONS CAUSING
GEOGRAPHIC COMMON TROPICAL DISEASE-CAUSING
OUTBREAKS OR CLUSTERS IN
AREA FEVER
TRAVELERS
Caribbean Chikungunya, dengue, malaria (Haiti), Zika Acute histoplasmosis, leptospirosis
Central America Chikungunya, dengue, malaria (primarily Plasmodium Leptospirosis, histoplasmosis,
vivax ), Zika coccidioidomycosis
South America Chikungunya, dengue, malaria (primarily P. vivax ), Bartonellosis, leptospirosis, enteric
Zika fever, histoplasmosis
South-Central Dengue, enteric fever, malaria (primarily non- Chikungunya
Asia falciparum)
Southeast Asia Dengue, malaria (primarily non-falciparum) Chikungunya, leptospirosis
Sub-Saharan Malaria (primarily P. falciparum ), tick-borne
Africa rickettsiae (main cause of fever in southern Africa),
acute schistosomiasis, dengue
From Wilson ME: Post-travel evaluation. In CDC Yellow Book , Chapter 5 (Table 5.2 ).
https://wwwnc.cdc.gov/travel/yellowbook/2018/post-travel-evaluation/fever-in-returned-travelers .
Table 200.4
Common Infections by Incubation Period

USUAL INCUBATION
DISEASE DISTRIBUTION
PERIOD (RANGE)
INCUBATION <14 DAYS
Chikungunya 2-4 days (1-14 days) Tropics, subtropics
Dengue 4-8 days (3-14 days) Topics, subtropics
Encephalitis, arboviral (Japanese 3-14 days (1-20 days) Specific agents vary by region
encephalitis, tick-borne encephalitis,
West Nile virus, other)
Enteric fever 7-18 days (3-60 days) Especially in Indian subcontinent
Acute HIV 10-28 days (10 days to 6 wk) Worldwide
Influenza 1-3 days Worldwide, can also be acquired while
traveling
Legionellosis 5-6 days (2-10 days) Widespread
Leptospirosis 7-12 days (2-26 days) Widespread, most common in tropical
areas
Malaria, Plasmodium falciparum 6-30 days (98% onset within 3 Tropics, subtropics
mo of travel)
Malaria, Plasmodium vivax 8 days to 12 mo (almost half Widespread in tropics and subtropics
have onset >30 days after
completion of travel)
Spotted-fever rickettsiae Few days to 2-3 wk Causative species vary by region
Zika virus infection 3-14 days Widespread in Latin America, endemic
through much of Africa, Southeast Asia,
and Pacific Islands
INCUBATION 14 DAYS TO 6 WK
Encephalitis, arboviral; enteric fever; See above incubation periods See above distribution for relevant
acute HIV; leptospirosis; malaria for relevant diseases. diseases.
Amebic liver abscess Weeks to months Most common in resource-poor countries
Hepatitis A 28-30 days (15-50 days) Most common in resource-poor countries
Hepatitis E 26-42 days (2-9 wk) Widespread
Acute schistosomiasis (Katayama 4-8 wk Most common in sub-Saharan Africa
syndrome)
INCUBATION >6 WK
Amebic liver abscess, hepatitis E, See above incubation periods See above distribution for relevant
malaria, acute schistosomiasis for relevant diseases. diseases.
Hepatitis B 90 days (60-150 days) Widespread
Leishmaniasis, visceral 2-10 mo (10 days to years) Asia, Africa, Latin America, southern
Europe, and the Middle East
Tuberculosis Primary, weeks; reactivation, Global distribution, rates, and levels of
years resistance vary widely.
From Wilson ME: Post-travel evaluation. In CDC Yellow Book , Chapter 5 (Table 5.3 ).
https://wwwnc.cdc.gov/travel/yellowbook/2018/post-travel-evaluation/fever-in-returned-travelers .

Among all persons returning from travel (children and adults), 3 major
patterns of illness have been noted (Table 200.5 ). The etiology of each of these
disease presentations in part depends on the country or geographic region visited
(see Table 200.3 ). Table 200.6 provides suggestive clues to a diagnosis.

Table 200.5
Patterns of Illness in Returning International Travelers
SYSTEMIC FEBRILE ILLNESS
Malaria
Dengue
Zika
Enteric fever (typhoid/paratyphoid)
Chikungunya virus
Spotted-fever rickettsiae
Hepatitis A
Acute HIV
Leptospirosis
Measles
Infectious mononucleosis
Respiratory causes (pneumonia, influenza)
Undetermined fever source
ACUTE DIARRHEA
Campylobacter
Shigella spp.
Salmonella spp.
Diarrheagenic Escherichia coli (enterotoxigenic E. coli , enteroadherent E. coli —not tested for by routine stool
culture methods)
Giardiasis (acute, persistent, or recurrent)
Entamoeba histolytica
Cryptosporidium spp.
Cyclospora cayetanensis
Presumed viral enteritis
DERMATOLOGIC MANIFESTATIONS
Rash with fever (dengue)
Arthropod-related dermatitis (insect bites)
Cutaneous larva migrans (Ancylostoma braziliense )
Bacterial skin infections—pyoderma, impetigo, ecthyma, erysipelas
Myiasis (tumbu and botfly)
Scabies
Tungiasis
Superficial mycosis
Animal bites
Leishmaniasis
Rickettsial diseases
Marine envenomation/dermatitis
Photoallergic dermatitis and phytophotodermatitis

Table 200.6

Common Clinical Findings and Associated Infections

COMMON CLINICAL INFECTIONS TO CONSIDER AFTER TROPICAL TRAVEL
 FINDINGS
Fever and rash Dengue, chikungunya, Zika, rickettsial infections, enteric fever (skin lesions may
be sparse or absent), acute HIV infection, measles
Fever and abdominal pain Enteric fever, amebic liver abscess
Undifferentiated fever and Dengue, malaria, rickettsial infection, enteric fever, chikungunya, Zika
normal or low white blood
cell count
Fever and hemorrhage Viral hemorrhagic fevers (dengue and others), meningococcemia, leptospirosis,
rickettsial infections
Fever and arthralgia or Chikungunya, dengue, Zika
myalgia, sometimes
persistent
Fever and eosinophilia Acute schistosomiasis, drug hypersensitivity reaction, fascioliasis and other
parasitic infections (rare)
Fever and pulmonary Common bacterial and viral pathogens, legionellosis, acute schistosomiasis, Q
infiltrates fever, leptospirosis
Fever and altered mental Cerebral malaria, viral or bacterial meningoencephalitis, African trypanosomiasis,
status scrub typhus
Mononucleosis syndrome Epstein-Barr virus (EBV) infection, cytomegalovirus (CMV) infection,
toxoplasmosis, acute HIV infection
Fever persisting >2 wk Malaria, enteric fever, EBV infection, CMV infection, toxoplasmosis, acute HIV
infection, acute schistosomiasis, brucellosis, tuberculosis, Q fever, visceral
leishmaniasis (rare)
Fever with onset >6 wk after Plasmodium vivax or P. ovale malaria, acute hepatitis (B, C, or E), tuberculosis,
travel amebic liver abscess
From Wilson ME: Post-travel evaluation. In CDC Yellow Book, Chapter 5 (Table 5.6).
https://wwwnc.cdc.gov/travel/yellowbook/2018/post-travel-evaluation/fever-in-returned-travelers .

Fever is a particularly worrisome symptom. Children with a febrile/systemic

illness following recent travel to a malarial destination should be promptly
evaluated for malaria, especially if having traveled to sub-Saharan Africa and
Papua New Guinea. P. falciparum malaria will generally present within 1-2 mo
after return from travel to a malaria-endemic area, but can occur within the 1st yr
after return. In contrast, symptoms of P. vivax or P. ovale malaria are typically
later in onset following travel (i.e., several months), are milder in disease
severity, and may occur in a relapsing pattern if undiagnosed or improperly
untreated. Other symptoms of malaria can be nonspecific and include chills,
malaise, headache, myalgias, vomiting, diarrhea, cough, and possible seizures.
Children are more likely than adults to have higher fevers and also
gastrointestinal symptoms, hepatomegaly, splenomegaly, and severe anemia.
Thrombocytopenia (without increased bleeding) and fever in a child returning
from an endemic area are highly suggestive of malaria.
Thick and thin blood smears need to be performed for diagnosis if malaria is
clinically suspected. If results are negative initially, 2 or more additional smears
should be done 12-24 hr after the initial smears. Rapid malaria antigen tests
(BinaxNOW Malaria) are FDA-approved and sensitive for diagnosing
 Intermittent fever is an exaggerated circadian rhythm that includes a period
of normal temperatures on most days; extremely wide fluctuations may be
termed septic or hectic fever . Sustained fever is persistent and does not vary
by >0.5°C (0.9°F)/day. Remittent fever is persistent and varies by >0.5°C/day.
Relapsing fever is characterized by febrile periods separated by intervals of
normal temperature; tertian fever occurs on the 1st and 3rd days (malaria
caused by Plasmodium vivax ), and quartan fever occurs on the 1st and 4th
days (malaria caused by Plasmodium malariae ). Diseases characterized by
relapsing fevers should be distinguished from infectious diseases that have a
tendency to relapse (Table 201.1 ). Biphasic fever indicates a single illness with
2 distinct periods (camelback fever pattern); poliomyelitis is the classic
example. A biphasic course is also characteristic of other enteroviral infections,
leptospirosis, dengue fever, yellow fever, Colorado tick fever, spirillary rat-bite
fever (Spirillum minus), and the African hemorrhagic fevers (Marburg, Ebola,
and Lassa fevers). The term periodic fever is used narrowly to describe fever
syndromes with a regular periodicity (cyclic neutropenia and periodic fever,
aphthous stomatitis, pharyngitis, adenopathy) or more broadly to include
disorders characterized by recurrent episodes of fever that do not follow a
strictly periodic pattern (familial Mediterranean fever, TNF receptor–associated
periodic syndrome [Hibernian fever], hyper-IgD syndrome, Muckle-Wells
syndrome) (see Chapter 188 ). Factitious fever , or self-induced fever, may be
caused by intentional manipulation of the thermometer or injection of pyrogenic
material.

Table 201.1
Fevers Prone to Relapse
INFECTIOUS CAUSES
Relapsing fever (Borrelia recurrentis )
Q fever (Coxiella burnetii )
Typhoid fever (Salmonella typhi )
Syphilis (Treponema pallidum )
Tuberculosis
Histoplasmosis
Coccidioidomycosis
Blastomycosis
Melioidosis (Pseudomonas pseudomallei )
Lymphocytic choriomeningitis (LCM) infection
Dengue fever
Yellow fever
Chronic meningococcemia
 Colorado tick fever
Leptospirosis
Brucellosis
Oroya fever (Bartonella bacilliformis )
Acute rheumatic fever
Rat-bite fever (Spirillum minus )
Visceral leishmaniasis
Lyme disease (Borrelia burgdorferi )
Malaria
Babesiosis
Noninfluenza respiratory viral infection
Epstein-Barr virus infection
NONINFECTIOUS CAUSES
Behçet disease
Crohn disease
Weber-Christian disease (panniculitis)
Leukoclastic angiitis syndromes
Sweet syndrome
Systemic lupus erythematosus and other autoimmune disorders
PERIODIC FEVER SYNDROMES (see Chapter 188 )
Familial Mediterranean fever
Cyclic neutropenia
Periodic fever, aphthous stomatitis, pharyngitis, and adenopathy (PFAPA)
Hyper–immunoglobulin D syndrome
Hibernian fever (tumor necrosis factor superfamily immunoglobulin A–associated syndrome [TRAPS])
Muckle-Wells syndrome
Others

The double quotidian fever (or fever that peaks twice in 24 hr) is classically
associated with inflammatory arthritis. In general, a single isolated fever spike is
not associated with an infectious disease. Such a spike can be attributed to the
infusion of blood products and some drugs, as well as some procedures, or to
manipulation of a catheter on a colonized or infected body surface. Similarly,
temperatures in excess of 41°C (105.8°F) are most often associated with a
noninfectious cause. Causes for very high temperatures (>41°C [105.8°F])
include central fever (resulting from central nervous system dysfunction
involving the hypothalamus or spinal cord injury), malignant hyperthermia,
malignant neuroleptic syndrome, drug fever, or heat stroke. Temperatures that
are lower than normal (<36°C [96.8°F]) can be associated with overwhelming
sepsis but are more often related to cold exposure, hypothyroidism, or overuse of
antipyretics.

Clinical Features
The clinical features of fever can range from no symptoms to extreme malaise.
Children might complain of feeling hot or cold, display facial flushing, and
experience shivering. Fatigue and irritability may be evident. Parents often
report that the child looks ill or pale and has a decreased appetite. The
underlying etiology also produces accompanying symptoms. Although the
underlying etiologies can manifest in varied ways clinically, there are some
predictable features. For example, fever with petechiae in an ill-appearing
patient indicates the high possibility of life-threatening conditions such as
meningococcemia, Rocky Mountain spotted fever, or acute bacterial
endocarditis.
Changes in heart rate, most frequently tachycardia, accompany fever.
Normally heart rate rises by 10 beats/min per 1°C (1.8°F) rise in temperature for
children >2 mo old. Relative tachycardia, when the pulse rate is elevated
disproportionately to the temperature, is usually caused by noninfectious
diseases or infectious diseases in which a toxin is responsible for the clinical
manifestations. Relative bradycardia (temperature-pulse dissociation), when
the pulse rate remains low in the presence of fever, can accompany typhoid
fever, brucellosis, leptospirosis, or drug fever. Bradycardia in the presence of
fever also may be a result of a conduction defect resulting from cardiac
involvement with acute rheumatic fever, Lyme disease, viral myocarditis, or
infective endocarditis.

Evaluation
Most acute febrile episodes in a normal host can be diagnosed by a careful
history and physical examination and require few, if any, laboratory tests.
Because infection is the most likely etiology of the acute fever, the evaluation
should initially be geared to discovering an underlying infectious cause (Table
201.2 ). The details of the history should include the onset and pattern of fever
and any accompanying signs and symptoms. The patient often displays signs or
symptoms that provide clues to the cause of the fever. Exposures to other ill
persons at home, daycare, and school should be noted, along with any recent
travel or medications. The past medical history should include information about
underlying immune deficiencies or other major illnesses and receipt of childhood
vaccines.

Table 201.2
Evaluation of Acute Fever
 Thorough history: onset, other symptoms, exposures (daycare, school, family, pets, playmates), travel,
medications, other underlying disorders, immunizations
Physical examination: complete, with focus on localizing symptoms
Laboratory studies on a case-by-case basis:
• Rapid antigen testing
• Nasopharyngeal: respiratory viruses by polymerase chain reaction
• Throat: group A streptococcus
• Stool: NAAT for enteric pathogens, calprotectin
• Blood: complete blood count, blood culture, C-reactive protein, sedimentation rate, procalcitonin
• Urine: urinalysis, culture
• Cerebrospinal fluid: cell count, glucose, protein, Gram stain, culture
• Chest radiograph or other imaging studies on a case-by-case basis
NAAT, Nucleic acid amplification test.

Physical examination should begin with a complete evaluation of vital signs,

which should include pulse oximetry because hypoxia may indicate lower
respiratory infection. In the acutely febrile child, the physical examination
should focus on any localized complaints, but a complete head-to-toe screen is
recommended, because clues to the underlying diagnosis may be found. For
example, palm and sole lesions may be discovered during a thorough skin
examination and provide a clue for infection with coxsackievirus .
If a fever has an obvious cause, then laboratory evaluation may not be
required, and management is tailored to the underlying cause with as-needed
reevaluation. If the cause of the fever is not apparent, further diagnostic
evaluation should be considered on a case-by-case basis. The history of
presentation and abnormal physical examination findings guide the evaluation.
The child with respiratory symptoms and hypoxia may require a chest
radiograph or rapid antigen testing for respiratory syncytial virus or influenza
. The child with pharyngitis can benefit from rapid antigen detection testing for
group A streptococcus and a throat culture. Dysuria, back pain, or a history of
vesicoureteral reflux should prompt a urinalysis and urine culture, and bloody
diarrhea should prompt a stool culture. A complete blood count and blood
culture should be considered in the ill-appearing child, along with cerebrospinal
fluid studies if the child has neck stiffness or if the possibility of meningitis is
considered. Well-defined high-risk groups require a more extensive evaluation
on the basis of age, associated disease, or immunodeficiency status and might
warrant prompt antimicrobial therapy before a pathogen is identified. Fever in
neonates and young infants (0-3 mo old), fever in older children, and fever of
unknown origin are discussed in Chapters 202 , 203 , and 204 , respectively.
Streptococcus pneumoniae (Chapter 209 ), Neisseria meningitidis (Chapter 218
), Staphylococcus aureus (Chapter 208.1 ), and Listeria monocytogenes (Chapter
215 ). Specific bacterial infections that can present with fever in this age-group,
although often with symptoms other than isolated fever, include pneumonia
(Chapter 428 ), gastroenteritis (Chapter 366 ), osteomyelitis (Chapter 704 ),
septic arthritis (Chapter 705 ), omphalitis (Chapter 125 ), cellulitis, and other
skin and soft tissue infections (Chapter 685 ).

Table 202.1
Bacterial Pathogens in Neonates and Young Infants With
Urinary Tract Infection, Bacteremia, or Meningitis

FREQUENCY URINARY TRACT INFECTION BACTEREMIA AND MENINGITIS

Common Escherichia coli Escherichia coli
Group B streptococcus
Less common Klebsiella spp. Streptococcus pneumoniae
Enterococcus spp. Staphylococcus aureus
Klebsiella spp.
Rare Group B streptococcus
Staphylococcus aureus Listeria monocytogenes
Pseudomonas aeruginosa Neisseria meningitidis
Enterobacter spp. Salmonella spp.
Citrobacter spp. Enterobacter spp.
Proteus mirabilis Enterococcus spp.
Cronobacter sakazakii

Herpes simplex virus (HSV ) infections (Chapter 279 ) should also be

considered in febrile neonates <28 days old, particularly given the high rate of
mortality and significant morbidity among survivors. Neonatal HSV is rare, with
a prevalence of 0.2–0.3% among febrile neonates. Most of these infections are
caused by HSV type 2, though HSV type 1 can also cause neonatal infection.
Neonates with disseminated disease and skin, eye, and mouth (SEM) disease
typically present at 5-12 days of life. Neonates with central nervous system
(CNS) disease generally present at 16-19 days. Perinatally acquired HSV may
occasionally manifests beyond 28 days of age, although some of these later-
onset cases may represent postnatal acquisition.
In febrile infants who appear well, viral illnesses are much more common than
bacterial or serious viral infections. The most common viruses include
respiratory syncytial virus (RSV ; Chapter 287 ), enteroviruses (Chapter 277 ),
influenza viruses (Chapter 285 ), parainfluenza viruses (Chapter 286 ), human
metapneumovirus (Chapter 288 ), adenovirus (Chapter 289 ), parechoviruses
Table 202.2
Protocols to Identify Febrile Infants at Low Risk of Serious
Bacterial Infection (SBI)
BOSTON CRITERIA
Febrile infants 0-27 days
1. Empirical antimicrobials
2. Admit to hospital
Febrile infants 28-89 days: Non–low risk
1. Empirical antimicrobials
2. Admit to hospital
Febrile infants 28-89 days: Low risk
1. One dose of IV Ceftriaxone
2. Discharge to home with follow-up in 24 hr
3. Risk of SBI 5.4%
Low Risk Criteria
1. Normal examination and well-appearing
2. Caregiver available by telephone
3. No antimicrobials, no DTaP vaccine in previous 48 hours
4. Meets all laboratory/radiographic criteria
a. Peripheral blood: WBC count <20,000 per mm3
b. Urine
i. Urinalysis with <10 WBCs per hpf
ii. Dipstick negative for leukocyte esterase
c. CSF: WBC count <10 per mm3
d. Chest radiograph: No infiltrate on chest radiograph (only obtained if signs of respiratory illness)
PHILADELPHIA CRITERIA
Febrile infants 0-28 days
1. Empirical antimicrobials
2. Admit to hospital
Febrile infants 29-56 days: Non–low risk
1. Empirical antimicrobials
2. Admit to hospital
Febrile infants 29-56 days: Low risk
1. No antibiotics
2. Discharge to home with follow-up in 24 hr
3. Risk of SBI <1%
Low Risk Criteria
1. Normal examination and well-appearing
2. Caregiver available to be contacted
3. Meets all laboratory/ radiographic criteria
a. Peripheral blood
i. WBC count <15,000 per mm3
ii. Band-neutrophil ratio <0.2
b. Urine
i. <10 WBCs per hpf
ii. No bacteria on Gram stain
c. CSF
i. WBC count <8 per mm3
ii. Negative Gram stain
iii. Non-bloody specimen
 d. Chest radiograph: No infiltrate
e. Stool: (only obtained if loose, watery stool)
i. No blood
ii. Few or no WBC on smear
ROCHESTER CRITERIA
Febrile infants 0-60 days: Non–low risk
1. Empirical antimicrobials
2. Admit to hospital
Febrile infants 0-60 days: Low risk
1. No antimicrobials
2. Discharge to home with follow-up in 24 hr
3. Risk of SBI 1%
Low Risk Criteria
1. Normal examination and well-appearing
2. Previously healthy, term gestation, no perinatal/recent antimicrobial therapy, no unexplained
hyperbilirubinemia
3. Meets all laboratory/ radiographic criteria
a. Peripheral blood
i. WBC count 5-15,000 per mm3
ii. Absolute band count ≤1500 per mm3
b. Urine
i. ≤10 WBCs per hpf
ii. No bacteria on Gram stain
c. CSF: Not included
d. Chest radiograph: No infiltrate (only obtained if signs of respiratory illness)
e. Stool (only obtained if loose, watery stool)
i. ≤5 WBC per hpf
DTaP, Diphtheria-tetanus-pertussis; WBC, white blood cell; CSF, cerebrospinal fluid; IV,
intravenous; SBI, serious bacterial infection; hpf, high-power field

Many experts advocate that all neonates ≤28 days old undergo a complete
evaluation for serious infection, receive empirical antimicrobials, and be
hospitalized. Of the 3 widely used criteria, only the Rochester criteria allow
neonates ≤28 days to be designated as “low risk” and managed outside the
hospital without antimicrobials. In one study, <1% of low-risk infants ≤28 days
old had SBI; however, in another study applying the Boston and Philadelphia
criteria to neonates, 3–4% of those classified as low risk had SBI.
Young febrile infants ≥29 days old who appear ill (with signs of systemic
illness) require complete evaluation for SBI, including antimicrobials and
hospitalization; however, well-appearing infants can be managed safely as
outpatients using low-risk criteria as indicated in Table 202.2 . In each of these
approaches, infants must have a normal physical examination, must be able to
reliably obtain close follow-up, and must meet certain laboratory and/or
radiographic criteria. Based on these protocols, all infants following the Boston
or Philadelphia criteria would undergo lumbar puncture (LP), whereas low-risk
infants following the Rochester criteria would not. There is substantial variation
dipstick alone (99.2% vs 98.7%), but that dipstick alone had a higher positive
predictive value (PPV, 66.8% for dipstick alone vs 51.2% for traditional UA).
Enhanced UA includes hemocytometer cell count (to decrease variability of
urine cell counts) and Gram stain on uncentrifuged urine. The enhanced UA has
a higher sensitivity but comparable specificity to traditional UA. However, the
enhanced UA has not been studied in the most common protocols for evaluation
of the febrile infant, and many institutions/office practices do not perform this
test.

Cerebrospinal Fluid
CSF evaluation consists of culture and Gram stain, cell count, glucose and
protein. Polymerase chain reaction (PCR) testing may also be sent based on the
clinical scenario, usually for enterovirus or HSV. Normal CSF parameters vary
by age of the infant and should be interpreted in combination with other clinical
and historical risk factors, given that some infants with normal CSF parameters
may have CNS infections (Table 202.3 ). The CSF Gram stain can be a useful
adjunct to other CSF parameters given the high specificity of the test (99.3–
99.9%; i.e., relatively few false-positive results), although the range of reported
sensitivity is much broader (67–94.1%).

Table 202.3

Values of Cerebrospinal Fluid (CSF) Studies in Neonates and Infants by Age

CSF WHITE BLOOD CELL COUNTS CELLS/mm3
Upper limit of normal by age*
1-28 days 18
29-60 days 8.5
61-90 days 8.5
90th percentile by age †
0-7 days 26
8-28 days 8–9
29-56 days 6–8
95th percentile by age ‡
0-28 days 19
29-56 days 9
CSF Protein mg/dL
Upper limit of normal by age*
1-28 days 131
29-60 days 105.5
61-90 days 71
 90th percentile by age †
0-7 days 153
8-28 days 84–106
29-56 days 84–105
95th percentile by age §
0-14 days 132
15-28 days 100
29-42 days 89
43-56 days 83
CSF Glucose mg/dL
Lower limit of normal by age*
1-28 days 30
29-60 days 30.5
61-90 days 33.5
10th percentile for infants 0-56 days † 38–43
* Data from Byington CL, Kendrick J, Sheng X: Normative cerebrospinal fluid profiles in febrile
infants, J Pediatr 158(1):130–134, 2011. All infants had nontraumatic lumbar puncture (LP) and no
evidence of bacterial or viral infection.
† Data from Chadwick SL, Wilson JW, Levin JE, Martin JM: Cerebrospinal fluid characteristics of

infants who present to the emergency department with fever: establishing normal values by week
of age, Pediatr Infect Dis J 30(4):e63–e67, 2011. All infants were excluded if they had identified
viral or bacterial meningitis, positive blood or urine cultures, a ventriculoperitoneal shunt, recent
neurosurgery/antibiotics/seizure, or a traumatic LP.
‡ Data from Kestenbaum LA, Ebberson J, Zorc JJ, et al: Defining cerebrospinal fluid white blood
cell count reference values in neonates and young infants, Pediatrics 125(2):257–264, 2010.
Infants were excluded for traumatic LP, serious bacterial infection, congenital infection, seizure,
presence of ventricular shunt, or positive CSF testing for enterovirus.
§ Data from Shah SS, Ebberson J, Kestenbaum LA, et al: Age-specific reference values for
cerebrospinal fluid protein concentration in neonates and young infants, J Hosp Med 6(1):22–27,
2011. Infants were excluded for traumatic LP, serious bacterial infection, congenital infection,
seizure, presence of a ventricular shunt, positive CSF testing for enterovirus, or elevated serum
bilirubin.

The interpretation of CSF can be challenging in the setting of a traumatic LP,

where the CSF is contaminated with peripheral blood. Some clinicians assume a
ratio of WBCs to red blood cells (RBCs) of 1 : 500 in the CSF. Others advocate
calculating the expected CSF WBCs based on the peripheral blood WBCs and
RBCs and then using the observed-to-predicted ratio of CSF WBCs to aid in the
identification of bacterial meningitis. This calculation assumes that the ratio of
WBCs to RBCs in the peripheral blood remains constant after introduction into
the CSF. The formula is:
CHAPTER 203

Fever in the Older Child

Paul L. Aronson, Mark I. Neuman

Fever is the most common reason for a child to seek medical care. While most
infants and children have benign viral causes of fever, a small percentage will
have more serious infections. Unlike the situation in infants <2 mo of age, in
older children with fever, pediatricians can rely more readily on symptoms and
physical examination findings to establish a diagnosis. Diagnostic testing,
including laboratory testing and radiographic studies, is not routinely indicated
unless diagnostic uncertainty exists after examination or the patient appears
critically ill. Occult infections, such as urinary tract infection, may be present,
and screening for such infections should be guided by patient age, patient
gender, and degree of fever.

Diagnosis
The many potential causes of fever in older infants and children can be broadly
categorized into viral and bacterial infections, further organized by body region,
as well as the less common inflammatory, oncologic, endocrine, and medication-
induced causes (Table 203.1 ).

Table 203.1
Etiologies of Fever in Children >2 Mo of Age
INFECTIOUS
Central Nervous System
Bacterial meningitis
Viral meningitis
Viral encephalitis
Epidural abscess
Brain abscess
Ear, Nose, and Throat
Acute otitis media
Mastoiditis
Viral upper respiratory infection (i.e., common cold)
Acute bacterial sinusitis
Acute streptococcal pharyngitis
Acute viral pharyngitis
Retropharyngeal abscess
Ludwig angina
Peritonsillar abscess
Herpangina
Herpes simplex virus gingivostomatitis
Acute bacterial lymphadenitis
Viral laryngotracheobronchitis (i.e., croup)
Bacterial tracheitis
Epiglottitis
Lemierre syndrome
Face and Ocular
Parotitis (viral and bacterial)
Erysipelas
Preseptal cellulitis
Orbital cellulitis
Lower Respiratory Tract
Acute viral bronchiolitis
Pneumonia (viral and bacterial)
Complicated pneumonia (e.g., empyema, pleural effusion)
Tuberculosis
Cardiac
Pericarditis
Myocarditis
Endocarditis
Gastrointestinal
Gastroenteritis (viral and bacterial)
Mesenteric adenitis
Acute appendicitis
Hepatitis
Pancreatitis
Gallbladder disease (e.g., cholecystitis, cholangitis)
Intraabdominal abscess
Genitourinary
Urinary tract infection/pyelonephritis
Renal abscess
Epididymitis
Pelvic inflammatory disease
Tuboovarian abscess
Skin, Soft Tissue, and Muscle
Viral exanthemas (e.g., varicella, coxsackievirus, roseola, measles)
Scarlet fever
Syphilis
Cellulitis
Abscess
Necrotizing fasciitis
Myositis (viral and bacterial)
Bone and Joint
Osteomyelitis
 Septic arthritis
Transient synovitis
Discitis
Toxin Mediated
Toxic shock syndrome
Staphylococcal scalded skin syndrome
Invasive Bacterial Infections
Occult bacteremia
Bacterial sepsis
Bacterial meningitis
Disseminated gonococcal infection
Vector-Borne (Tick, Mosquito)
Lyme disease
Rickettsiae (e.g., Rocky Mountain spotted fever, ehrlichiosis)
Arboviruses (e.g., West Nile virus)
Dengue fever
Inflammatory
Kawasaki disease
Acute rheumatic fever
Systemic lupus erythematosus
Inflammatory bowel disease
Juvenile idiopathic arthritis
Henoch-Schönlein purpura
Other rheumatologic diseases (e.g., dermatomyositis)
Periodic fever syndromes
Serum-like sickness syndrome
Oncologic
Leukemia
Lymphoma
Solid tumors (e.g., neuroblastoma)
Endocrine
Thyrotoxicosis/thyroid storm
Medication Induced
Serotonin syndrome
Anticholinergic toxidrome (e.g., antihistamines)
Sympathomimetic toxidrome (e.g., cocaine)
Salicylate toxicity
Other
Hemophagocytic lymphohistiocytosis
Macrophage activation syndrome
Ectodermal dysplasia
Dysautonomia

Viral Infections
Viral infections are the most common cause of fever, and the prevalence of
specific viral infections varies by season. In the summer and early fall,
enteroviruses (e.g., coxsackieviruses) predominate, usually presenting as hand-
foot-and-mouth disease, herpangina, aseptic meningitis, or a variety of other
manifestations. In the late fall and winter, viral upper and lower respiratory tract
 groups together, as well as separately for B, previously healthy children ≥28 days old,
and C, neonates and children with comorbidities ≥28 days old. *Pseudomonas
aeruginosa, Klebsiella spp., Neisseria meningitidis, Haemophilus influenzae, other
gram-negative pathogens. † Enterococcus spp., viridans group streptococci, other
gram-positive pathogens. (From Agyeman PKA, Schlapbach LJ, Giannoni E, et al:
Epidemiology of blood culture-proven bacterial sepsis in children in Switzerland: a
population-based cohort study, Lancet Child Adolesc 1:124–133, 2017, Fig 4.)

Infants and children age 2-24 mo merit special consideration because they
have limited verbal skills, are at risk for occult bacterial infections, and may be
otherwise asymptomatic except for fever (see Chapter 202 ).

Occult Urinary Tract Infection

Among children 2-24 mo old without symptoms or physical examination
findings that identify another focal source of infection, the prevalence of urinary
tract infection (UTI) may be as high as 5–10%. The highest risk of UTI occurs in
females and uncircumcised males, with a very low rate of infection (<0.5%) in
circumcised males. Table 203.2 lists risk factors for UTI.

Table 203.2
Risk Factors for Urinary Tract Infection in Children 2-24 Mo
of Age
FEMALE
White race
Age <1 yr
Temperature ≥39°C (102.2°F)
Fever duration ≥2 days
No obvious source of infection
MALE
Uncircumcised boys at higher risk
Nonblack race
Temperature ≥39°C (102.2°F)
Fever duration >1 day
No obvious source of infection
Adapted from Subcommittee on Urinary Tract Infection et al. Urinary tract infection: clinical
practice guideline for the diagnosis and management of the initial UTI in febrile infants and
children 2 to 24 months, Pediatrics 128(3):595–610, 2011.

Occult Bacteremia
Occult bacteremia is defined as a positive blood culture for a pathogen in a well-
CHAPTER 204

Fever of Unknown Origin

Andrew P. Steenhoff

Fever of unknown origin (FUO ) is a diagnostic dilemma for pediatricians

because it is often difficult to distinguish clinically between benign and
potentially life-threatening causes. Pediatricians face the important challenge of
not missing the diagnosis of a serious illness or an easily treatable condition that
can result in increased morbidity. Fortunately, FUO is usually an uncommon
presentation of a common disease, with most of these common diseases being
easily treatable.
The classification of FUO is best reserved for children with a temperature
>38°C (100.4°F) documented by a healthcare provider and for which the cause
could not be identified after at least 8 days of evaluation (Table 204.1 ). It is
important to differentiate FUO from fever without a source ; FWS is fever
where the source has not yet been identified and is differentiated from FUO by
the duration of the fever. FWS can progress to FUO if no cause is elicited after 7
days of evaluation.

Table 204.1
Summary of Definitions and Major Features of 4 Subtypes
of Fever of Unknown Origin (FUO)

HEALTHCARE-
IMMUNE-
FEATURE CLASSIC FUO ASSOCIATED HIV-RELATED FUO
DEFICIENT FUO
FUO
Definition >38°C (100.4°F), >3 wk, >2 ≥38°C (100.4°F), ≥38°C (100.4°F), ≥38°C (100.4°F), >3 wk for
visits or 1 wk in hospital >1 wk, not >1 wk, negative outpatients, >1 wk for
present or cultures after 48 hr inpatients, HIV infection
incubating on confirmed
admission
Patient Community, clinic, or Acute care Hospital or clinic Community, clinic, or
location hospital hospital hospital
 Leading Cancer, infections, Healthcare- Majority caused by HIV itself, typical and
causes inflammatory conditions, associated infections, but atypical mycobacteria,
undiagnosed, habitual infections, cause documented CMV, lymphomas,
hyperthermia postoperative in only 40–60% toxoplasmosis,
complications, cryptococcosis, immune
drug fever reconstitution inflammatory
syndrome (IRIS)
History Travel, contacts, animal and Operations and Stage of Drugs, exposures, risk
emphasis insect exposure, procedures, chemotherapy, factors, travel, contacts,
medications, immunizations, devices, anatomic drugs administered, stage of HIV infection
family history, cardiac valve considerations, underlying
disorder drug treatment immunosuppressive
disorder
Examination Fundi, oropharynx, temporal Wounds, drains, Skin folds, IV sites, Mouth, sinuses, skin, lymph
emphasis artery, abdomen, lymph devices, sinuses, lungs, perianal area nodes, eyes, lungs, perianal
nodes, spleen, joints, skin, urine area
nails, genitalia, rectum or
prostate, lower-limb deep
veins
Investigation Imaging, biopsies, Imaging, bacterial CXR, bacterial Blood and lymphocyte
emphasis sedimentation rate, skin tests cultures cultures count; serologic tests; CXR;
stool examination; biopsies
of lung, bone marrow, and
liver for cultures and
cytologic tests; brain
imaging
Management Observation, outpatient Depends on Antimicrobial Antiviral and antimicrobial
temperature chart, situation treatment protocols protocols, vaccines,
investigations, avoidance of revision of treatment
empirical drug treatments regimens, good nutrition
Time course Months Weeks Days Weeks to months
of disease
Tempo of Weeks Days Hours Days to weeks
investigation
CMV, Cytomegalovirus; CXR, chest radiograph; HIV, human immunodeficiency virus; IV,
intravenous line.
Adapted from Mackowak PA, Durack DT: Fever of unknown origin. In Mandell GL, Bennett, JE,
Dolin R, editors: Mandell, Douglas, and Bennett's principles and practice of infectious diseases ,
ed 7, Philadelphia, 2010, Elsevier (Table 51-1).

Etiology
The many causes of FUO in children are infectious, rheumatologic (connective
tissue or autoimmune), autoinflammatory, oncologic, neurologic, genetic,
factitious, and iatrogenic processes (Table 204.2 ). Although oncologic disorders
should be seriously considered, most children with malignancies do not have
fever alone. The possibility of drug fever should be considered if the patient is
receiving any drug. Drug fever is usually sustained and not associated with other
symptoms. Discontinuation of the drug is associated with resolution of the fever,
generally within 72 hr, although certain drugs, such as iodides, are excreted for a
prolonged period, with fever that can persist for as long as 1 mo after drug
withdrawal.

Table 204.2
Diagnostic Considerations for Fever of Unknown Origin in
Children
ABSCESSES
Abdominal
Brain
Dental
Hepatic
Paraspinal
Pelvic
Perinephric
Rectal
Subphrenic
Psoas
BACTERIAL DISEASES
Actinomycosis
Bartonella henselae (cat-scratch disease)
Brucellosis
Campylobacter
Chlamydia
Francisella tularensis (tularemia)
Listeria monocytogenes (listeriosis)
Meningococcemia (chronic)
Mycoplasma pneumoniae
Rat-bite fever (Streptobacillus moniliformis ; streptobacillary form of rat-bite fever)
Salmonella
Tuberculosis
Whipple disease
Yersiniosis
LOCALIZED INFECTIONS
Cholangitis
Infective endocarditis
Lymphogranuloma venereum
Mastoiditis
Osteomyelitis
Pneumonia
Pyelonephritis
Psittacosis
Sinusitis
SPIROCHETES
Borrelia burgdorferi (Lyme disease)
Relapsing fever (Borrelia recurrentis)
Leptospirosis
Rat-bite fever (Spirillum minus ; spirillary form of rat-bite fever)
Syphilis
FUNGAL DISEASES
Blastomycosis (extrapulmonary)
Coccidioidomycosis (disseminated)
Histoplasmosis (disseminated)
RICKETTSIAE
African tick-bite fever
Ehrlichia canis
Q fever
Rocky Mountain spotted fever
Tick-borne typhus
VIRUSES
Cytomegalovirus
Hepatitis viruses
HIV
Epstein-Barr virus
PARASITIC DISEASES
Amebiasis
Babesiosis
Giardiasis
Malaria
Toxoplasmosis
Trichinosis
Trypanosomiasis
Visceral larva migrans (Toxocara )
RHEUMATOLOGIC DISEASES
Behçet disease
Juvenile dermatomyositis
Juvenile idiopathic arthritis
Rheumatic fever
Systemic lupus erythematosus
HYPERSENSITIVITY DISEASES
Drug fever
Hypersensitivity pneumonitis
Serum sickness
Weber-Christian disease
NEOPLASMS
Atrial myxoma
Cholesterol granuloma
Hodgkin disease
Inflammatory pseudotumor
Leukemia
Lymphoma
Pheochromocytoma
Neuroblastoma
Wilms tumor
GRANULOMATOUS DISEASES
Granulomatosis with polyangiitis
Crohn disease
Granulomatous hepatitis
Sarcoidosis
FAMILIAL AND HEREDITARY DISEASES
Anhidrotic ectodermal dysplasia
Autonomic neuropathies
Fabry disease
Familial dysautonomia
Familial Hibernian fever
Familial Mediterranean fever, many other autoinflammatory diseases (Chapter 188 )
Hypertriglyceridemia
Ichthyosis
Sickle cell crisis
Spinal cord/brain injury
MISCELLANEOUS
Addison disease
Castleman disease
Chronic active hepatitis
Cyclic neutropenia
Diabetes insipidus (central and nephrogenic)
Drug fever
Factitious fever
Hemophagocytic syndromes
Hypothalamic-central fever
Infantile cortical hyperostosis
Inflammatory bowel disease
Kawasaki disease
Kikuchi-Fujimoto disease
Metal fume fever
Pancreatitis
Periodic fever syndromes
Poisoning
Pulmonary embolism
Thrombophlebitis
Thyrotoxicosis, thyroiditis

Most fevers of unknown origin result from atypical presentations of common

diseases. In some cases, the presentation as an FUO is characteristic of the
disease (e.g., JIA), but the definitive diagnosis can be established only after
prolonged observation, because initially there are no associated or specific
findings on physical examination, and all laboratory results are negative or
normal.
In the United States the systemic infectious diseases most commonly
implicated in children with FUO are salmonellosis, tuberculosis, rickettsial
diseases, syphilis, Lyme disease, cat-scratch disease, atypical prolonged
presentations of common viral diseases, Epstein-Barr virus (EBV) infection,
cytomegalovirus (CMV) infection, viral hepatitis, coccidioidomycosis,
histoplasmosis, malaria, and toxoplasmosis. Less common infectious causes of
FUO include tularemia, brucellosis, leptospirosis, and rat-bite fever. Acquired
immunodeficiency syndrome alone is not usually responsible for FUO, although
febrile illnesses often occur in patients with AIDS as a result of opportunistic
infections (see Table 204.1 ).
Juvenile idiopathic arthritis (JIA) and systemic lupus erythematosus
(SLE) are the connective tissue diseases most often associated with FUO.
elevated or changing body temperature suggests dehydration caused by
vomiting, diarrhea, or central or nephrogenic diabetes insipidus. It also should
suggest anhidrotic ectodermal dysplasia, familial dysautonomia, or exposure to
atropine. The general activity of the patient and the presence or absence of
rashes should also be noted.

Table 204.3
Subtle Physical Findings with Special Significance in
Patients with Fever of Unknown Origin

BODY SITE PHYSICAL FINDING DIAGNOSIS

Head Sinus tenderness Sinusitis
Temporal artery Nodules, reduced pulsations Temporal arteritis
Oropharynx Ulceration Disseminated histoplasmosis, SLE, IBD, Behçet
syndrome, periodic fever syndromes
Tender tooth Periapical abscess, sinus referred pain
Fundi or Choroid tubercle Disseminated granulomatosis*
conjunctivae Petechiae, Roth spots Endocarditis
Thyroid Enlargement, tenderness Thyroiditis
Heart Murmur Infective or marantic endocarditis
Relative bradycardia Typhoid fever, malaria, leptospirosis, psittacosis,
central fever, drug fever
Abdomen Enlarged iliac crest lymph nodes, Lymphoma, endocarditis, disseminated
splenomegaly granulomatosis*
Audible abdominal aortic or renal artery Large vessel vasculitis such as Takayasu arteritis
bruit
Costovertebral tenderness Chronic pyelonephritis, perinephric abscess
Rectum Perirectal fluctuance, tenderness Abscess
Prostatic tenderness, fluctuance Abscess
Genitalia Testicular nodule Periarteritis nodosa, cancer
Epididymal nodule Disseminated granulomatosis
Spine Spinal tenderness Vertebral osteomyelitis
Paraspinal tenderness Paraspinal collection
Lower Deep venous tenderness Thrombosis or thrombophlebitis
extremities
Upper or lower Pseudoparesis Syphilitic bone disease
extremities
Skin and nails Petechiae, splinter hemorrhages, Vasculitis, endocarditis
subcutaneous nodules, clubbing
* Includes tuberculosis, histoplasmosis, coccidioidomycosis, sarcoidosis, granulomatosis with
polyangiitis, and syphilis.
Adapted from Mackowak PA, Durack DT: Fever of unknown origin. In Mandell GL, Bennett, JE,
Dolin R, editors: Mandell, Douglas, and Bennett's principles and practice of infectious diseases,
ed 7, Philadelphia, 2010, Elsevier (Table 51-8).
Table 204.4

Examples of Potential Diagnostic Clues to Infections Presenting as Fever of

Unknown Origin
ETIOLOGY HISTORICAL CLUES PHYSICAL CLUES
Anaplasmosis Transmitted by bite of Ixodes tick in association Fever, headache, arthralgia, myalgia,
with outdoor activity in northern-central and pneumonitis, thrombocytopenia,
eastern United States lymphopenia, elevated liver enzymes
Babesiosis Transmitted by bite of Ixodes tick in association Arthralgias, myalgias, relative
with outdoor activity in northeastern United States bradycardia, hepatosplenomegaly,
anemia, thrombocytopenia, elevated
liver enzymes
Bartonellosis Recent travel to Andes Mountains (Oroya fever; Conjunctivitis, retroorbital pain,
Bartonella bacilliformis ), association with anterior tibial bone pain, macular rash,
homelessness in urban settings (Bartonella nodular plaque lesions, regional
quintana ) or scratch of infected kitten or feral cat lymphadenopathy
(Bartonella henselae )
Blastomycosis Contact with soil adjacent to Mississippi and Ohio Arthritis, atypical pneumonia,
River valleys, Saint Lawrence River in New York pulmonary nodules, and/or fulminant
and Canada, and North American Great Lakes or adult respiratory distress syndrome;
exposure to infected dogs verrucous, nodular, or ulcerative skin
lesions; prostatitis
Brucellosis Associated with contact or consumption of Arthralgias, hepatosplenomegaly,
products from infected goats, pigs, camels, yaks, suppurative musculoskeletal lesions,
buffalo, or cows and with abattoir work sacroiliitis, spondylitis, uveitis,
hepatitis, pancytopenia
Coccidioidomycosis Exposure to soil or dust in southwestern United Arthralgias, pneumonia, pulmonary
States cavities, pulmonary nodules, erythema
multiforme, erythema nodosum
Ehrlichiosis Transmitted by bite of Amblyomma, Dermacentor, Pneumonitis, hepatitis,
or Ixodes tick in association with outdoor activity thrombocytopenia, lymphopenia
in midwestern and southeastern United States
Enteric fever Recent travel to a low- or middle-income country Headache, arthritis, abdominal pain,
(Salmonella (LMIC) with consumption of potentially relative bradycardia,
enterica serovar contaminated food or water hepatosplenomegaly, leukopenia
typhi )
Histoplasmosis Exposure to bat or blackbird excreta in roosts, Headache, pneumonia, pulmonary
chicken houses, or caves in region surrounding cavities, mucosal ulcers, adenopathy,
Ohio and Mississippi River valleys erythema nodosum, erythema
multiforme, hepatitis, anemia,
leukopenia, thrombocytopenia
Leptospirosis Occupational exposure among workers in sewers, Bitemporal and frontal headache, calf
rice and sugarcane fields, and abattoirs; and lumbar muscle tenderness,
recreational water sports and exposure to conjunctival suffusion, hepatic and
contaminated waters or infected dogs renal failure, hemorrhagic pneumonitis
Leishmaniasis Associated with recent travel to areas endemic for Hepatosplenomegaly,
(visceral disease) sand flies lymphadenopathy, and
hyperpigmentation of face, hand, foot,
and abdominal skin (kala-azar)

Malaria Recent travel to endemic areas in Asia, Africa, and Fever, headaches, nausea, emesis,
Central/South America diarrhea, hepatomegaly, splenomegaly,
anemia
 Psittacosis Associated with contact with birds, especially Fever, pharyngitis,
(Chlamydia psittaci psittacine birds hepatosplenomegaly, pneumonia,
) blanching maculopapular eruptions;
erythema multiforme, marginatum, and
nodosum
Q fever (Coxiella Associated with farm, veterinary, or abattoir work; Atypical pneumonia, hepatitis,
burnetii ) consumption of unpasteurized milk; contact with hepatomegaly, relative bradycardia,
infected sheep, goats, or cattle splenomegaly
Rat-bite fever Recent bite or scratch by rat, mouse, or squirrel; Headaches, myalgias, polyarthritis, and
(Streptobacillus ingestion of food or water contaminated by rat maculopapular, morbilliform, petechial,
moniliformis ) excrement vesicular, or pustular rash over the
palms, soles, and extremities
Relapsing fever Associated with poverty, crowding, and poor High fever with rigors, headache,
(Borrelia sanitation (louse-borne), or with camping (tick- delirium, arthralgias, myalgias, and
recurrentis ) borne), particularly in the Grand Canyon hepatosplenomegaly
Rocky Mountain Associated with outdoor activity in the South Headache, petechial rash involving the
spotted fever Atlantic or southeastern United States and extremities, palms, and soles
exposure to Dermacentor tick bites
Tuberculosis Recent contact with tuberculosis; recent Night sweats, weight loss, atypical
immigration from endemic country; work or pneumonia, cavitary pulmonary lesions
residence in homeless shelters, correctional
facilities, or healthcare facilities
Tularemia Associated with bites by Amblyomma or Ulcerated skin lesions at a bite site,
Dermacentor ticks, deer flies, and mosquitoes or pneumonia, relative bradycardia,
direct contact with tissues of infected animals such lymphadenopathy, conjunctivitis
as rabbits, squirrels, deer, raccoons, cattle, sheep,
and swine
Whipple disease Potential association with exposure to sewage Chronic diarrhea, arthralgia, weight
(Tropheryma loss, malabsorption, malnutrition
whipplei )
Adapted from Wright WF, Mackowiak PA: Fever of unknown origin. In Bennett JF, Dolin R, Blaser
MJ, editors: Mandell, Douglas, and Bennett's principles and practice of infectious diseases, ed 8,
Philadelphia, 2015, Elsevier (Table 56-9).

A careful ophthalmic examination is important. Red, weeping eyes may be a

sign of connective tissue disease, particularly polyarteritis nodosa. Palpebral
conjunctivitis in a febrile patient may be a clue to measles, coxsackievirus
infection, tuberculosis, infectious mononucleosis, lymphogranuloma venereum,
or cat-scratch disease. In contrast, bulbar conjunctivitis in a child with FUO
suggests Kawasaki disease or leptospirosis. Petechial conjunctival hemorrhages
suggest infective endocarditis. Uveitis suggests sarcoidosis, JIA, SLE, Kawasaki
disease, Behçet disease, and vasculitis. Chorioretinitis suggests CMV,
toxoplasmosis, and syphilis. Proptosis suggests an orbital tumor, thyrotoxicosis,
metastasis (neuroblastoma), orbital infection, Wegener granulomatosis
(granulomatosis with polyangiitis), or pseudotumor.
The ophthalmoscope should also be used to examine nail-fold capillary
abnormalities that are associated with connective tissue diseases such as juvenile
dermatomyositis and systemic scleroderma. Immersion oil or lubricating jelly is
Perturbations of the mucosal and skin barriers or the normal microbial flora can
also be characterized as secondary immunodeficiencies, predisposing the host to
infections, if only temporarily.
The major pathogens causing infections among immunocompetent hosts are
also the main pathogens responsible for infections among children with
immunodeficiencies. In addition, less virulent organisms, including normal skin
flora, commensal bacteria of the oropharynx or gastrointestinal (GI) tract,
environmental fungi, and common community viruses of low-level
pathogenicity, can cause severe, life-threatening illnesses in
immunocompromised patients (Table 205.1 ). For this reason, close
communication with the diagnostic laboratory is critical to ensure that the
laboratory does not disregard normal flora and organisms normally considered
contaminants as being unimportant.

Table 205.1
Most Common Causes of Infections in
Immunocompromised Children
BACTERIA, AEROBIC
Acinetobacter
Bacillus
Burkholderia cepacia
Citrobacter
Corynebacterium
Enterobacter spp.
Enterococcus faecalis
Enterococcus faecium
Escherichia coli
Klebsiella spp.
Listeria monocytogenes
Mycobacterium spp.
Neisseria meningitidis
Nocardia spp.
Pseudomonas aeruginosa
Staphylococcus aureus
Staphylococcus, coagulase-negative
Streptococcus pneumoniae
Streptococcus, viridans group
BACTERIA, ANAEROBIC
Bacillus
Clostridium
Fusobacterium
Peptococcus
Peptostreptococcus
Propionibacterium
Veillonella
 FUNGI
Aspergillus
Candida albicans
Other Candida spp.
Cryptococcus neoformans
Fusarium spp.
Pneumocystis jiroveci
Zygomycoses (Mucor, Rhizopus, Rhizomucor)
VIRUSES
Adenoviruses
Cytomegalovirus
Epstein-Barr virus
Herpes simplex virus
Human herpesvirus 6
Polyomavirus (BK)
Respiratory and enteric community-acquired viruses
Varicella-zoster virus
PROTOZOA
Cryptosporidium parvum
Giardia lamblia
Toxoplasma gondii

205.1
Infections Occurring With Primary
Immunodeficiencies
Marian G. Michaels, Hey Jin Chong, Michael Green

Currently, more than 300 genes involving inborn errors of immunity have been
identified, accounting for a wide array of diseases presenting with susceptibility
to infection, allergy, autoimmunity, and autoinflammation, as well as
malignancy.

Abnormalities of the Phagocytic System

Children with abnormalities of the phagocytic and neutrophil system have
problems with bacteria as well as environmental fungi. Disease manifests as

FIG. 205.1 Algorithm for the initial management of the febrile neutropenic patient.
Monotherapy can be considered with cefepime, imipenem/cilastatin,
meropenem,piperacillin-tazobactam, or ticarcillin–clavulanic acid. *Aminoglycoside
antibiotics should be avoided if the patient is also receiving nephrotoxic, ototoxic, or
neuromuscular blocking agents; has renal or severe electrolyte dysfunction; or is
suspected of having meningitis (because of poor blood-brain perfusion). (Adapted from
Freifeld AG, Bow EJ, Sepkowitz KA, et al: Clinical practice guideline for the use of
antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious
Diseases Society of America, Clin Infect Dis 52:e56–e93, 2011.)

Table 205.2
Host Defense Defects and Common Pathogens by Time
After Bone Marrow or Hematopoietic Stem Cell
Transplantation

TIME COMMON
HOST DEFENSE DEFECTS CAUSES
PERIOD PATHOGENS
Pretransplant Neutropenia Underlying disease Aerobic gram-negative
Abnormal anatomic barriers Prior chemotherapy bacilli
Preengraftment Neutropenia Chemotherapy Aerobic gram-
Abnormal anatomic barriers Radiation positive cocci
Indwelling catheters Aerobic gram-
negative bacilli
Candida
Aspergillus
Herpes simplex
virus (in previously
infected patients)
Community-
acquired viral
pathogens
Postengraftment Abnormal cell-mediated immunity Chemotherapy Gram-positive cocci
 Abnormal anatomic barriers Immunosuppressive Aerobic gram-
medications negative bacilli
Radiation Cytomegalovirus
Indwelling catheters Adenoviruses
Unrelated cord blood Community-
donor acquired viral
pathogens
Pneumocystis
jiroveci
Late Delayed recovery of immune function Time required to Varicella-zoster
posttransplant (cell-mediated, humoral, and abnormal develop donor-related virus
anatomic barriers) immune function Streptococcus
Graft-versus-host pneumoniae
disease

A comprehensive laboratory evaluation, including a complete blood cell

count, serum creatinine, blood urea nitrogen, and serum transaminases, should
be obtained. Blood cultures should be taken from each port of any central
venous catheter (CVC) and from a peripheral vein. Although the latter sampling
is often omitted with continued fevers and neutropenia, it should be obtained
before the initial antibiotic administration and reconsidered in children with 1 or
more positive cultures from a CVC, facilitating localization of the source of the
infection. Other microbiologic studies should be done if there are associated
clinical symptoms, including a nasal aspirate for viruses in patients with upper
respiratory findings; stool for viruses such as rotavirus or norovirus and for
Clostridium difficile toxin in patients with diarrhea; urinalysis and culture in
young children or in older patients with symptoms of urgency, frequency,
dysuria, or hematuria; and biopsy and culture of cutaneous lesions. Chest
radiographs should be obtained in any patient with lower respiratory tract
symptoms, although pulmonary infiltrates may be absent in children with severe
neutropenia. Sinus films should be obtained for children >2 yr of age if
rhinorrhea is prolonged. Abdominal CT scans should also be considered in
children with profound neutropenia and abdominal pain to evaluate for the
presence of typhlitis. Chest CT scan and fungal biomarkers (e.g., galactomannan,
β-D -glucan) testing should be considered for children not responding to broad-
spectrum antibiotics who have continued fever and neutropenia for >96 hr.
Biopsies for cytology, Gram stain, and culture should be considered if
abnormalities are found during endoscopic procedures or if lung nodules are
identified radiographically.
Classic studies by Pizzo and colleagues demonstrated that before the routine
institution of empirical antimicrobial therapy for fever and neutropenia, 75% of
children with fever and neutropenia were ultimately found to have a documented
the presence of chronic GVHD significantly affects anatomic barriers and is
associated with defects in humoral, splenic, and cell-mediated immune function.
Viral infections, including primary infection with or reactivation of varicella-
zoster virus (VZV), are responsible for >40% of infections during this period.
This may decrease over time as the Oka varicella vaccine strain has a lower rate
of reactivation than wild-type varicella. Bacterial infections, particularly of the
upper and lower respiratory tract, account for approximately 30% of infections.
These may be associated with deficiencies in immunoglobulin production,
especially IgG2. Fungal infections account for <20% of confirmed infections
during the late posttransplantation period.

Solid-Organ Transplantation
Factors predisposing to infection after organ transplantation include those that
either existed before transplantation or are secondary to intraoperative events or
posttransplantation therapies (Table 205.3 ). Some of these additional risks
cannot be prevented, and some risks acquired during or after the operation
depend on decisions or actions of members of the transplant team. Organ
recipients are at risk for infection from potential exposure to pathogens in the
donor organ. Although some donor-derived infections can be anticipated through
donor screening, many pathogens are not routinely screened for, and strategies
defining when and how to screen for all but a small subset of potential pathogens
have not been identified or implemented. Similar to other children who have
undergone surgical procedures; surgical site infections are a frequent cause of
infection early after transplantation. Beyond this, the need for
immunosuppressive agents to prevent rejection is the major factor predisposing
to infection following transplantation. Despite efforts to optimize
immunosuppressive regimens to prevent or treat rejection with minimal
impairment of immunity, all current regimens interfere with the ability of the
immune system to prevent infection. The primary target of the majority of these
immunosuppressive agents in organ recipients is the cell-mediated immune
system, but regimens can and do impair many other aspects of the transplant
recipient's immune system as well.

Table 205.3
Risk Factors for Infections After Solid-Organ
Transplantation in Children
 PRETRANSPLANTATION FACTORS
Age of patient
Underlying disease, malnutrition
Specific organ transplanted
Previous exposures to infectious agents
Previous immunizations
Presence of infection in the donor
INTRAOPERATIVE FACTORS
Duration of transplant surgery
Exposure to blood products
Technical problems
Organisms transmitted with donor organ
POSTTRANSPLANTATION FACTORS
Immunosuppression
Induction immunosuppression type
Maintenance immunosuppression
Augmented treatment for rejection
Indwelling catheters
Nosocomial exposures
Community exposures

Timing
The timing of specific types of infections is generally predictable, regardless of
which organ is transplanted. Infectious complications typically develop in 1 of 3
intervals: early (0-30 days after transplantation), intermediate (30-180 days), or
late (>180 days); most infections present in the 1st 180 days after
transplantation. Table 205.4 should be used as a general guideline to the types of
infections encountered but may be modified with the introduction of newer
immunosuppressive therapies and by the use of prophylaxis.

Table 205.4
Timing of Infectious Complications After Solid-Organ
Transplantation
EARLY PERIOD (0-30 DAYS)
Bacterial Infections
Gram-negative enteric bacilli
• Small bowel, liver, neonatal heart
Pseudomonas, Burkholderia, Stenotrophomonas, Alcaligenes
• Cystic fibrosis lung
Gram-positive organisms
• All transplant types
Fungal Infections
• All transplant types
Viral Infections
 Herpes simplex virus
• All transplant types
Nosocomial respiratory viruses
• All transplant types
MIDDLE PERIOD (1-6 MO)
Viral Infections
Cytomegalovirus
• All transplant types
• Seronegative recipient of seropositive donor
Epstein-Barr virus
• All transplant types (small bowel the highest-risk group)
• Seronegative recipient
Varicella-zoster virus
• All transplant types
• Opportunistic infections
Pneumocystis jiroveci
• All transplant types
Toxoplasma gondii
• Seronegative recipient of cardiac transplant from a seropositive donor
Bacterial Infections
Pseudomonas, Burkholderia, Stenotrophomonas, Alcaligenes
• Cystic fibrosis lung
Gram-negative enteric bacilli
• Small bowel
LATE PERIOD (>6 MO)
Viral Infections
Epstein-Barr virus
• All transplant types, but less risk than middle period
Varicella-zoster virus
• All transplant types
Community-acquired viral infections
• All transplant types
Bacterial Infections
Pseudomonas, Burkholderia, Stenotrophomonas, Alcaligenes
• Cystic fibrosis lung
• Lung transplants with chronic rejection
Gram-negative bacillary bacteremia
• Small bowel
Fungal Infections
Aspergillus
• Lung transplants with chronic rejection
Adapted from Green M, Michaels MG: Infections in solid organ transplant recipients. In Long SS,
Prober C, Fisher M, editors: Principles and practice of pediatric infectious disease , ed 5,
Philadelphia, 2018, Elsevier (Table 95-1).

Early infections are usually the result of a complication of the transplant

surgery itself, the unexpected acquisition of a bacterial or fungal pathogen from
the donor, or the presence of an indwelling catheter. In contrast, infections
during the intermediate period typically result from a complication of the
immunosuppression, which tends to be at its greatest intensity during the 1st 6
mo after transplantation. This is the period of greatest risk for infections caused
by opportunistic pathogens such as CMV, EBV, and P. jiroveci. Anatomic
Table 207.1
Mechanisms of Resistance to β-Lactam Antibiotics
I. Alter target site (PBP)
A. Decrease affinity of PBP for β-lactam antibiotic
1. Modify existing PBP
a. Create mosaic PBP
(1) Insert nucleotides obtained from neighboring bacteria (e.g., penicillin-resistant Streptococcus
pneumoniae )
(2) Mutate structural gene of PBP(s) (e.g., ampicillin-resistant β-lactamase–negative Haemophilus
influenzae )
2. Import new PBP (e.g., mecA in methicillin-resistant Staphylococcus aureus )
II. Destroy β-lactam antibiotic
A. Increase production of β-lactamases, carbapenemases
1. Acquire more efficient promoter
a. Mutate existing promoter
b. Import new promoter
2. Deregulate control of β-lactamase production
a. Mutate regulator genes (e.g., ampD in “stably derepressed” Enterobacter cloacae )
B. Modify structure of resident β-lactamase
1. Mutate structural gene (e.g., ESBLs in Klebsiella pneumoniae )
C. Import new β-lactamase(s) with different spectrum of activity
III. Decrease concentration of β-lactam antibiotic inside cell
A. Restrict its entry (loss of porins)
B. Pump it out (efflux mechanisms)
ESBLs, Extended-spectrum β-lactamases; PBP, Penicillin-binding protein.
Adapted from Opal SM, Pop-Vicas A: Molecular mechanisms of antibiotic resistance in bacteria.
In Bennett JF, Dolin R, Blaser MJ, editors: Mandell, Douglas, and Bennett's principles and practice
of infectious diseases, ed 8, Philadelphia, 2015, Elsevier (Table 18-4).

Table 207.2
Aminoglycoside-Modifying Enzymes*

ENZYMES USUAL ANTIBIOTICS MODIFIED COMMON GENERA

PHOSPHORYLATION
APH(2″) K, T, G SA, SR
APH(3′)-I K E, PS, SA, SR
APH(3′)-III K ± A E, PS, SA, SR
ACETYLATION
AAC(2′) G PR
AAC(3)-I ±T, G E, PS
AAC(3)-III, -IV, or -V K, T, G E, PS
AAC(6′) K, T, A E, PS, SA
ADENYLATION
ANT(2″) K, T, G E, PS
ANT(4′) K, T, A SA
BIFUNCTIONAL ENZYMES
 AAC(6′)-APH(2″) G, Ar SA, Ent
AAC(6′)-lbcr G, K, T, FQ* E
* Aminoglycoside-modifying enzymes confer antibiotic resistance through 3 general reactions: N-

acetylation, O-nucleotidylation, and O-phosphorylation. For each of these general reactions, there
are several different enzymes that attack a specific amino or hydroxyl group.
A, Amikacin; AAC, aminoglycoside acetyltransferase; ANT, aminoglycoside
nucleotidyltransferase; APH, aminoglycoside phosphotransferase; cr, ciprofloxacin resistance; Ar,
arbekacin, E, Enterobacteriaceae; Ent, enterococci, FQ, fluoroquinolone (acetylates the
piperazine ring in some fluoroquinolones), G, gentamicin; K, kanamycin; PR, Providencia-Proteus
; PS, pseudomonads; SA, staphylococci; SR, streptococci; T, tobramycin.
Adapted from Opal SM, Pop-Vicas A: Molecular mechanisms of antibiotic resistance in bacteria.
In Bennett JF, Dolin R, Blaser MJ, editors: Mandell, Douglas, and Bennett's principles and practice
of infectious diseases, ed 8, Philadelphia, 2015, Elsevier (Table 18-5).

Antimicrobial resistance has reached crisis proportions , driven by the

emergence of new resistance mechanisms (e.g., carbapenemases, including
Klebsiella pneumoniae –associated carbapenemases, or KPCs ) and by overuse
of antibiotics, both in healthcare and in other venues, such as agribusiness and
animal husbandry. This increase in antibiotic resistance has rendered some
bacterial infections encountered in clinical practice virtually untreatable.
Accordingly, there is an urgent need to develop new antimicrobials, as well as
rediscover some older antibiotics that have been out of use in recent decades but
still retain activity against resistant organisms. It is vital that practitioners use
antibiotics only as necessary, with the narrowest feasible antimicrobial spectrum,
to help thwart emergence of resistance. In addition, advocacy for vaccines ,
particularly conjugate pneumococcal vaccine, can also decrease the selective
pressure that excessive antimicrobial use exerts on resistance.
Effective antibiotic action requires achieving therapeutic levels of the drug at
the site of infection. Although measuring the level of antibiotic at the site of
infection is not always possible, one may measure the serum level and use this
level as a surrogate marker for achievement of the desired effect at the tissue
level. Various target serum levels are appropriate for different antibiotic agents
and are assessed by the peak and trough serum levels and the area under the
therapeutic drug level curve (Fig. 207.1 ). These levels in turn are a reflection of
the route of administration, drug absorption (IM, PO), volume of distribution,
and drug elimination half-life, as well as of drug-drug interactions that might
enhance or impede enzymatic inactivation of an antibiotic or result in
antimicrobial synergism or antagonism (Fig. 207.2 ).
colonized prosthetic material is usually required for cure.

Antibiotics Commonly Used in Pediatric

Practice
Table 207.3 lists antibiotic medications and pediatric indications.

Table 207.3

Selected Antibacterial Medications (Antibiotics)*

DRUG (TRADE NAMES, INDICATIONS (MECHANISM OF ACTION)
COMMENTS
FORMULATIONS) AND DOSING
Amikacin sulfate Aminoglycoside antibiotic active against Cautions: Anaerobes,
Amikin gram-negative bacilli, especially Streptococcus (including
Injection: 50 mg/mL, 250 Escherichia coli, Klebsiella, Proteus, S. pneumoniae ) are
mg/mL Enterobacter, Serratia, and Pseudomonas resistant. May cause
Neonates: Postnatal age ≤7 days, weight ototoxicity and
1,200-2,000 g: 7.5 mg/kg q12-18h IV or IM; nephrotoxicity. Monitor
weight >2,000 g: 10 mg/kg q12h IV or IM; renal function. Drug
postnatal age >7 days, weight 1,200-2,000 g: eliminated renally.
7.5 mg/kg q8-12h IV or IM; weight >2,000 g: Administered IV over
10 mg/kg q8h IV or IM 30-60 min
Children: 15-25 mg/kg/24 hr divided q8-12h Drug interactions: May
IV or IM potentiate other ototoxic
Adults: 15 mg/kg/24 hr divided q8-12h IV or and nephrotoxic drugs
IM Target serum
concentrations: Peak
25-40 mg/L; trough <10
mg/L
Amoxicillin Penicillinase-susceptible β-lactam: gram- Cautions: Rash,
Amoxil, Polymox positive pathogens except Staphylococcus; diarrhea, abdominal
Capsule: 250, 500 mg Salmonella, Shigella, Neisseria, E. coli , and cramping. Drug
Tablet: chewable: 125, 250 Proteus mirabilis eliminated renally
mg Children: 20-50 mg/kg/24 hr divided q8-12h Drug interaction:
Suspension: 125 mg/5 mL, PO. Higher dose of 80-90 mg/kg 24 hr PO for Probenecid
250 mg/5 mL otitis media
Drops: 50 mg/mL Adults: 250-500 mg q8-12h PO
Uncomplicated gonorrhea: 3 g with 1 g
probenecid PO
Amoxicillin-clavulanate β-Lactam (amoxicillin) combined with β- Cautions: Drug dosed
Augmentin lactamase inhibitor (clavulanate) enhances on amoxicillin
Tablet: 250, 500, 875 mg amoxicillin activity against penicillinase- component. May cause
Tablet, chewable: 125, producing bacteria. S. aureus (not diarrhea, rash. Drug
200, 250, 400 mg methicillin-resistant organism), eliminated renally
Suspension: 125 mg/5 mL, Streptococcus, Haemophilus influenzae, Drug interaction:
200 mg/5 mL, 250 mg/5 Moraxella catarrhalis, E. coli, Klebsiella, Probenecid
mL, 400 mg/5 mL Bacteroides fragilis Comment: Higher dose
Neonates: 30 mg/kg/24 hr divided q12h PO may be active against
 Children: 20-45 mg/kg 24 hr divided q8-12h penicillin-
PO. Higher dose 80-90 mg/kg/24 hr PO for tolerant/resistant S.
otitis media pneumoniae
Ampicillin β-Lactam with same spectrum of Cautions: Less
Polycillin, Omnipen antibacterial activity as amoxicillin bioavailable than
Capsule: 250, 500 mg Neonates: Postnatal age ≤7 days weight amoxicillin, causing
Suspension: 125 mg/5 mL, ≤2,000 g: 50 mg/kg/24 hr IV or IM q12h greater diarrhea
250 mg/5 mL, 500 mg/5 (meningitis: 100 mg/kg/24 hr divided q12h Drug interaction:
mL IV or IM); weight >2,000 g: 75 mg/kg/24 hr Probenecid
Injection divided q8h IV or IM (meningitis: 150
mg/kg/24 hr divided q8h IV or IM). Postnatal
age >7 days weight <1,200 g: 50 mg/kg/24 hr
IV or IM q12h (meningitis: 100 mg/kg/24 hr
divided q12h IV or IM); weight 1,200-2,000
g: 75 mg/kg/24 hr divided q8h IV or IM
(meningitis: 150 mg/kg/24 hr divided q8hr IV
or IM); weight >2,000 g: 100 mg/kg/24 hr
divided q6h IV or IM (meningitis: 200
mg/kg/24 hr divided q6h IV or IM)
Children: 100-200 mg/kg/24 hr divided q6h
IV or IM (meningitis: 200-400 mg/kg/24 hr
divided q4-6h IV or IM)
Adults: 250-500 mg q4-8h IV or IM
Ampicillin-sulbactam β-Lactam (ampicillin) and β-lactamase Cautions: Drug dosed
Unasyn inhibitor (sulbactam) enhances ampicillin on ampicillin
Injection activity against penicillinase-producing component. May cause
bacteria: S. aureus, H. influenzae, M. diarrhea, rash. Drug
catarrhalis, E. coli, Klebsiella, B. fragilis eliminated renally
Children: 100-200 mg/kg/24 hr divided q4-8h Note: Higher dose may
IV or IM be active against
Adults: 1-2 g q6-8h IV or IM (max daily penicillin-
dose: 8 g) tolerant/resistant S.
pneumoniae
Drug interaction:
Probenecid
Azithromycin Azalide antibiotic with activity against S. Note: Very long half-life
Zithromax aureus, Streptococcus, H. influenzae, permitting once-daily
Tablet: 250 mg Mycoplasma, Legionella, Chlamydia dosing. No metabolic-based
Suspension: 100 mg/5 mL, trachomatis, Babesia microti drug interactions (unlike
200 mg/5 mL Children: 10 mg/kg PO on day 1 (max dose: erythromycin and
500 mg) followed by 5 mg/kg PO q24h for 4 clarithromycin), limited GI
days distress. Shorter-course
Group A streptococcus pharyngitis: 12 regimens (e.g., 1-3 days)
mg/kg/24 hr PO (max dose: 500 mg) for 5 under investigation. 3 day,
days therapy (10 mg/kg/24 hr × 3
Adults: 500 mg PO day 1 followed by 250 days) and single-dose
mg for 4 days therapy (30 mg/kg): use with
Uncomplicated C. trachomatis infection: increasing frequency (not for
single 1 g dose PO streptococcus pharyngitis)

Aztreonam β-Lactam (monobactam) antibiotic with Cautions: Rash,

Azactam activity against gram-negative aerobic thrombophlebitis,
Injection bacteria, Enterobacteriaceae, and eosinophilia. Renally
Pseudomonas aeruginosa eliminated
Neonates: Postnatal age ≤7 days weight Drug interaction:
≤2,000 g: 60 mg/kg/24 hr divided q12h IV or Probenecid
 IM; weight >2,000 g: 90 mg/kg/24 hr divided
q8h IV or IM; postnatal age >7 days weight
<1,200 g: 60 mg/kg/24 hr divided q12h IV or
IM; weight 1,200-2,000 g: 90 mg/kg/24 hr
divided q8h IV or IM; weight >2,000 g: 120
mg/kg/24 hr divided q6-8h IV or IM
Children: 90-120 mg/kg/24 hr divided q6-8h
IV or IM. For cystic fibrosis, up to 200
mg/kg/24 hr IV
Adults: 1-2 g IV or IM q8-12h (max dose: 8
g/24 hr)
Cefadroxil First-generation cephalosporin active Cautions: β-Lactam
Generic against S. aureus, Streptococcus, E. coli, safety profile (rash,
Capsule: 500 mg Klebsiella , and Proteus eosinophilia). Renally
Tablet: 1,000 mg Children: 30 mg/kg/24 hr divided q12h PO eliminated. Long half-
Suspension: 125 mg/5 mL, (max dose: 2 g) life permits q12-24h
250 mg/5 mL, 500 mg/5 Adults: 250-500 mg q8-12h PO dosing
mL Drug interaction:
Probenecid
Cefazolin First-generation cephalosporin active Caution: β-Lactam
Ancef, Kefzol against S. aureus, Streptococcus, E. coli, safety profile (rash,
Injection Klebsiella , and Proteus eosinophilia). Renally
Neonates: Postnatal age ≤7 days 40 mg/kg/24 eliminated. Does not
hr divided q12h IV or IM; >7 days 40-60 adequately penetrate
mg/kg/24 hr divided q8h IV or IM CNS
Children: 50-100 mg/kg/24 hr divided q8h IV Drug interaction:
or IM Probenecid
Adults: 0.5-2g q8h IV or IM (max dose: 12
g/24 hr)
Cefdinir Extended-spectrum, semisynthetic Cautions: Reduce
Omnicef cephalosporin dosage in renal
Capsule: 300 mg Children 6 mo-12 yr: 14 mg/kg/24 hr in 1 or insufficiency (creatinine
Oral suspension: 125 mg/5 2 doses PO (max dose: 600 mg/24 hr) clearance <60 mL/min).
mL Adults: 600 mg q24h PO Avoid taking
concurrently with iron-
containing products and
antacids because
absorption is markedly
decreased; take at least 2
hr apart
Drug interaction:
Probenecid
Cefepime Expanded-spectrum, fourth-generation Adverse events:
Maxipime cephalosporin active against many gram- Diarrhea, nausea,
Injection positive and gram-negative pathogens, vaginal candidiasis
including P. aeruginosa and many Cautions: β-lactam
multidrug-resistant pathogens safety profile (rash,
Children: 100-150 mg/kg/24 hr q8-12h IV or eosinophilia). Renally
IM eliminated
Adults: 2-4 g/24 hr q12h IV or IM Drug interaction:
Probenecid
Cefixime Third-generation cephalosporin active Cautions: β-Lactam
Suprax against streptococci, H. influenzae, M. safety profile (rash,
Tablet: 200, 400 mg catarrhalis, Neisseria gonorrhoeae, Serratia eosinophilia). Renally
Suspension: 100 mg/5 mL marcescens , and Proteus vulgaris . No eliminated. Does not
 antistaphylococcal or antipseudomonal adequately penetrate
activity CNS
Children: 8 mg/kg/24 hr divided q12-24h PO Drug interaction:
Adults: 400 mg/24 hr divided q12-24h PO Probenecid
Cefoperazone sodium Third-generation cephalosporin active Cautions: Highly
Cefobid against many gram-positive and gram- protein-bound
Injection negative pathogens cephalosporin with
Neonates: 100 mg/kg/24 hr divided q12h IV limited potency
or IM reflected by weak
Children: 100-150 mg/kg/24 hr divided q8- antipseudomonal
12h IV or IM activity. Variable Gram-
Adults: 2-4 g/24 hr divided q8-12h IV or IM positive activity.
(max dose: 12 g/24 hr) Primarily hepatically
eliminated in bile
Drug interaction:
Disulfiram-like reaction
with alcohol
Cefotaxime sodium Third-generation cephalosporin active Cautions: β-Lactam
Claforan against Gram-positive and Gram-negative safety profile (rash,
Injection pathogens. No antipseudomonal activity eosinophilia). Renally
Neonates: ≤7 days: 100 mg/kg/24 hr divided eliminated. Each gram
q12h IV or IM; >7 days: weight <1,200 g 100 of drug contains 2.2
mg/kg/24 hr divided q12h IV or IM; weight mEq sodium. Active
>1,200 g: 150 mg/kg/24 hr divided q8h IV or metabolite
IM Drug interaction:
Children: 150 mg/kg/24 hr divided q6-8h IV Probenecid
or IM (meningitis: 200 mg/kg/24 hr divided
q6-8h IV)
Adults: 1-2 g q8-12h IV or IM (max dose: 12
g/24 hr)
Cefotetan disodium Second-generation cephalosporin active Cautions: Highly protein-
Cefotan against S. aureus, Streptococcus, H. bound cephalosporin, poor
Injection influenzae, E. coli, Klebsiella, Proteus , and CNS penetration; β-lactam
Bacteroides . Inactive against Enterobacter safety profile (rash,
Children: 40-80 mg/kg/24 hr divided q12h IV eosinophilia), disulfiram-like
or IM reaction with alcohol.
Adults: 2-4 g/24 hr divided q12h IV or IM Renally eliminated (~20% in
(max dose: 6 g/24 hr) bile)
Cefoxitin sodium Second-generation cephalosporin active Cautions: Poor CNS
Mefoxin against S. aureus, Streptococcus, H. penetration; β-lactam
Injection influenzae, E. coli, Klebsiella, Proteus , and safety profile (rash,
Bacteroides . Inactive against Enterobacter eosinophilia). Renally
Neonates: 70-100 mg/kg/24 hr divided q8- eliminated. Painful
12h IV or IM given intramuscularly
Children: 80-160 mg/kg/24 hr divided q6-8h Drug interaction:
IV or IM Probenecid
Adults: 1-2 g q6-8h IV or IM (max dose: 12
g/24 hr)
Cefpodoxime proxetil Third-generation cephalosporin active Cautions: β-Lactam
Vantin against S. aureus, Streptococcus, H. safety profile (rash,
Tablet: 100 mg, 200 mg influenzae, M. catarrhalis, N. gonorrhoeae, eosinophilia). Renally
Suspension: 50 mg/5 mL, E. coli, Klebsiella , and Proteus . No eliminated. Does not
100 mg/5 mL antipseudomonal activity adequately penetrate
Children: 10 mg/kg/24 hr divided q12h PO CNS. Increased
Adults: 200-800 mg/24 hr divided q12h PO bioavailability when
 (max dose: 800 mg/24 hr) taken with food
Uncomplicated gonorrhea: 200 mg PO as Drug interaction:
single-dose therapy Probenecid; antacids
and H2 receptor
antagonists may
decrease absorption
Ceftaroline fosamil Fifth-generation cephalosporin active Caution: β-Lactam
Teflaro against S. aureus (including MRSA when safety profile (rash,
Injection used for skin and soft tissue infection), eosinophilia)
Streptococcus pyogenes, Streptococcus Drug interaction:
agalactiae, Escherichia coli, Klebsiella Probenecid
pneumoniae, H. influenzae, and Klebsiella
oxytoca
Children: skin/skin structure infections or
community-acquired pneumonia, 24
mg/kg/24 hr divided q8h IV (2-23 mo old)
×5-14 days; 36 mg/kg/24 hr divided q8h IV
(weight ≤33 kg) ×5-14 days; 400 mg q8h IV
(weight >33 kg)
Adults: 600 mg q12h IV
Cefprozil Second-generation cephalosporin active Cautions: β-Lactam
Cefzil against S. aureus, Streptococcus, H. safety profile (rash,
Tablet: 250, 500 mg influenzae, E. coli, M. catarrhalis, eosinophilia). Renally
Suspension: 125 mg/5 mL, Klebsiella , and Proteus spp. eliminated. Good
250 mg/5 mL Children: 30 mg/kg/24 hr divided q8-12h PO bioavailability; food
Adults: 500-1,000 mg/24 hr divided q12h PO does not affect
(max dose: 1.5 g/24 hr) bioavailability
Drug interaction:
Probenecid
Ceftazidime Third-generation cephalosporin active Cautions: β-Lactam
Fortaz, Ceptaz, Tazicef, against gram-positive and gram-negative safety profile (rash,
Tazidime pathogens, including P. aeruginosa eosinophilia). Renally
Injection Neonates: Postnatal age ≤7 days: 100 eliminated. Increasing
mg/kg/24 hr divided q12h IV or IM; >7 days pathogen resistance
weight ≤1,200 g: 100 mg/kg/24 hr divided developing with long-
q12h IV or IM; weight >1,200 g: 150 term, widespread use
mg/kg/24 hr divided q8h IV or IM Drug interaction:
Children: 150 mg/kg/24 hr divided q8h IV or Probenecid
IM (meningitis: 150 mg/kg/24 hr IV divided
q8h)
Adults: 1-2 g q8-12h IV or IM (max dose: 8-
12 g/24 hr)

Ceftizoxime Third-generation cephalosporin active Cautions: β-Lactam

Cefizox against gram-positive and gram-negative safety profile (rash,
Injection pathogens. No antipseudomonal activity eosinophilia). Renally
Children: 150 mg/kg/24 hr divided q6-8h IV eliminated
or IM Drug interaction:
Adults: 1-2 g q6-8h IV or IM (max dose: 12 Probenecid
g/24 hr)
Ceftriaxone sodium Third-generation cephalosporin widely Cautions: β-Lactam
Rocephin active against gram-positive and gram- safety profile (rash,
Injection negative pathogens. No antipseudomonal eosinophilia).
activity Eliminated via kidney
Neonates: 50-75 mg/kg q24h IV or IM (33–65%) and bile; can
 Children: 50-75 mg/kg q24h IV or IM cause sludging. Long
(meningitis: 75 mg/kg dose once then 80-100 half-life and dose-
mg/kg/24 hr divided q12-24h IV or IM) dependent protein
Adults: 1-2 g q24h IV or IM (max dose: 4 binding favors q24h
g/24 hr) rather than q12h dosing.
Can add 1% lidocaine
for IM injection
Drug interaction:
Probenecid. In neonates,
co-administration with
calcium-containing
products can result in
severe precipitation and
attendant embolic
complications
Cefuroxime (cefuroxime Second-generation cephalosporin active Cautions: β-Lactam
axetil for oral against S. aureus, Streptococcus, H. safety profile (rash,
administration) influenzae, E. coli, M. catarrhalis, eosinophilia). Renally
Ceftin, Kefurox, Zinacef Klebsiella , and Proteus eliminated. Food
Injection Neonates: 40-100 mg/kg/24 hr divided q12h increases PO
Suspension: 125 mg/5 mL IV or IM bioavailability
Tablet: 125, 250, 500 mg Children: 200-240 mg/kg/24 hr divided q8h Drug interaction:
IV or IM; PO administration: 20-30 mg/kg/24 Probenecid
hr divided q8-12h PO
Adults: 750-1,500 mg q8h IV or IM (max
dose: 6 g/24 hr)
Cephalexin First-generation cephalosporin active Cautions: β-Lactam
Keflex, Keftab against S. aureus, Streptococcus, E. coli, safety profile (rash,
Capsule: 250, 500 mg Klebsiella , and Proteus eosinophilia). Renally
Tablet: 500 mg, 1 g Children: 25-100 mg/kg/24 hr divided q6-8h eliminated
Suspension: 125 mg/5 mL, PO Drug interaction:
250 mg/5 mL, 100 mg/mL Adults: 250-500 mg q6h PO (max dose: 4 Probenecid
drops g/24 hr)

Cephradine First-generation cephalosporin active Cautions: β-Lactam

Velosef against S. aureus, Streptococcus, E. coli, safety profile (rash,
Capsule: 250, 500 mg Klebsiella , and Proteus eosinophilia). Renally
Suspension: 125 mg/5 mL, Children: 50-100 mg/kg/24 hr divided q6-12h eliminated
250 mg/5 mL PO Drug interaction:
Adults: 250-500 mg q6-12h PO (max dose: 4 Probenecid
g/24 hr)

Ciprofloxacin Quinolone antibiotic active against P. Cautions: Concerns of

Cipro aeruginosa, Serratia, Enterobacter, Shigella, joint destruction in
Tablet: 100, 250, 500, 750 Salmonella, Campylobacter, N. juvenile animals not
mg gonorrhoeae, H. influenzae, M. catarrhalis, seen in humans;
Injection some S. aureus , and some Streptococcus tendonitis,
Ophthalmic solution and Neonates: 10 mg/kg q 12 hr PO or IV superinfection,
ointment Children: 15-30 mg/kg/24 hr divided q12h dizziness, confusion,
Otic suspension PO or IV; cystic fibrosis: 20-40 mg/kg/24 hr crystalluria, some
Oral suspension: 250 and divided q8-12h PO or IV photosensitivity
500 mg/5 mL Adults: 250-750 mg q12h; 200-400 mg IV Drug interactions:
q12h PO (max dose: 1.5 g/24 hr) Theophylline;
magnesium-, aluminum-
, or calcium-containing
antacids; sucralfate;
 probenecid; warfarin;
cyclosporine
Clarithromycin Macrolide antibiotic with activity against Cautions: Adverse
Biaxin S. aureus, Streptococcus, H. influenzae, events less than
Tablet: 250, 500 mg Legionella, Mycoplasma, and C. erythromycin; GI upset,
Suspension: 125 mg/5 mL, trachomatis dyspepsia, nausea,
250 mg/5 mL Children: 15 mg/kg/24 hr divided q12h PO cramping
Adults: 250-500 mg q12h PO (max dose: 1 Drug interactions: Same
g/24 hr) as erythromycin:
astemizole
carbamazepine,
terfenadine,
cyclosporine,
theophylline, digoxin,
tacrolimus
Clindamycin Protein synthesis inhibitor active against Cautions: Diarrhea, nausea,
Cleocin most gram-positive aerobic and anaerobic Clostridium difficile –
Capsule: 75, 150, 300 mg cocci except Enterococcus associated colitis, rash.
Suspension: 75 mg/5 mL Neonates: Postnatal age ≤7 days weight Administer slow IV over 30-
Injection <2,000 g; 10 mg/kg/24 hr divided q12h IV or 60 min. Topically active as
Topical solution, lotion, IM; weight >2,000 g: 15 mg/kg/24 hr divided an acne treatment
and gel q8h IV or IM; >7 days weight <1,200 g: 10
Vaginal cream mg/kg/24 hr IV or IM divided q12h; weight
1,200-2,000 g: 15 mg/kg/24 hr divided q8h
IV or IM; weight >2,000 g: 20 mg/kg/24 hr
divided q8h IV or IM
Children: 10-40 mg/kg/24 hr divided q6-8h
IV, IM, or PO
Adults: 150-600 mg q6-8h IV, IM, or PO
(max dose: 5 g/24 hr IV or IM or 2 g/24 hr
PO)
Cloxacillin sodium Penicillinase-resistant penicillin active Cautions: β-Lactam
Tegopen against S. aureus and other gram-positive safety profile (rash,
Capsule: 250, 500 mg cocci except Enterococcus and coagulase- eosinophilia). Primarily
Suspension: 125 mg/5 mL negative staphylococci hepatically eliminated;
Children: 50-100 mg/kg/24 hr divided q6h requires dose reduction
PO in renal disease. Food
Adults: 250-500 mg q6h PO (max dose: 4 decreases bioavailability
g/24 hr) Drug interaction:
Probenecid

Colistin (Colistimethate Treatment of multidrug resistant gram- Cautions:

sodium; polymyxin E) negative organisms (Enterobacteriaceae Nephrotoxicity (~3% in
Injection including extended-spectrum beta young children; higher
Inhalation lactamase and carbapenemase-producing rates in adolescents and
strains) adults); adjust dose for
Children: 2.5-5 mg/kg/day divided in 2-4 renal insufficiency;
divided doses IV neurotoxicity
Adults: 300 mg/day in 2-4 divided doses IV (headaches, paresthesia,
ataxia)
Drug interactions:
Should not be
administered
concomitantly with
polymyxins or
aminoglycosides
Co-trimoxazole Antibiotic combination with sequential Cautions: Drug dosed
(trimethoprim- antagonism of bacterial folate synthesis on TMP (trimethoprim)
sulfamethoxazole; TMP- with broad antibacterial activity: Shigella, component.
SMX) Legionella, Nocardia, Chlamydia, Sulfonamide skin
Bactrim, Cotrim, Septra, Pneumocystis jiroveci. Dosage based on reactions: rash,
Sulfatrim TMP component erythema multiforme,
Tablet: SMX 400 mg and Children: 6-20 mg TMP/kg/24 hr or IV Stevens-Johnson
TMP 80 mg divided q12h PO syndrome, nausea,
Tablet DS: SMX 800 mg Pneumocystis carinii pneumonia: 15-20 mg leukopenia. Renal and
and TMP 160 mg TMP/kg/24 hr divided q12h PO or IV hepatic elimination;
Suspension: SMX 200 mg P. carinii prophylaxis: 5 mg TMP/kg/24 hr or reduce dose in renal
and TMP 40 mg/5 mL 3 times/wk PO failure
Injection Adults: 160 mg TMP q12h PO Drug interactions:
Protein displacement
with warfarin, possibly
phenytoin, cyclosporine
Daptomycin Disrupts bacterial cell membrane function, Cautions: Should not be
Cubicin causing depolarization leading to used for pneumonia
inhibition of protein, DNA and RNA because drug inactivated
synthesis, which results in bacterial cell by surfactants.
death. Active against enterococci Associated with rash,
(including glycopeptide-resistant strains), renal failure, anemia,
staphylococci (including MRSA), and headache. Is
streptococci, and corynebacteria. reported to cause
Approved for skin and soft tissue myopathy,
infections. Acceptable for bacteremia and rhabdomyolysis, and
right-sided endocarditis with susceptible eosinophilic pneumonia
strains Drug interactions:
Adults: In skin and soft tissue infections, 4 Should not be
mg/kg daptomycin IV once daily. For S. administered with
aureus bacteremia or right-sided endocarditis, statins
6 mg/kg IV once daily
Children: For skin/skin structure infections,
12-23 mo, 10 mg/kg IV q24h; 2-6 yr, 9
mg/kg IV q24h; 7-11 yr, 7 mg/kg q24h; 12-17
yr, 5 mg/kg q24h, all for up to 14 days. For
staphylococcal bacteremia, 1-6 yr, 12 mg/kg
q24h; 7-11 yr, 9 mg/kg q24h; 12-17 yr, 7
mg/kg q24h; all for up to 42 days. For
staphylococcal endocarditis, 1-5 yr, 10 mg/kg
IV q24h for at least 6 wk; ≥6 yr, 6 mg/kg IV
q24h for at least 6 wk

Demeclocycline Tetracycline active against most gram- Cautions: Teeth

Declomycin positive cocci except Enterococcus , many staining, possibly
Tablet: 150, 300 mg gram-negative bacilli, anaerobes, Borrelia permanent (if
Capsule: 150 mg burgdorferi (Lyme disease), Mycoplasma, administered <8 yr old)
and Chlamydia with prolonged use;
Children: 8-12 mg/kg/24 hr divided q6-12h photosensitivity,
PO diabetes insipidus,
Adults: 150 mg PO q6-8h nausea, vomiting,
Syndrome of inappropriate antidiuretic diarrhea, superinfections
hormone secretion: 900-1,200 mg/24 hr or Drug interactions:
13-15 mg/kg/24 hr divided q6-8h PO with Aluminum-, calcium-,
dose reduction based on response to 600-900 magnesium-, zinc- and
mg/24 hr iron-containing food,
 milk, dairy products
may decrease absorption
Dicloxacillin Penicillinase-resistant penicillin active Cautions: β-Lactam
Dynapen, Pathocil against S. aureus and other gram-positive safety profile (rash,
Capsule: 125, 250, 500 mg cocci except Enterococcus and coagulase- eosinophilia). Primarily
Suspension: 62.5 mg/5 mL negative staphylococci renally (65%) and bile
Children: 12.5-100 mg/kg/24 hr divided q6h (30%) elimination. Food
PO may decrease
Adults: 125-500 mg q6h PO bioavailability
Drug interaction:
Probenecid
Doripenem Carbapenem antibiotic with broad- Cautions: β-Lactam
Doribax spectrum activity against gram-positive safety profile; does not
Injection cocci and gram-negative bacilli, including undergo hepatic
P. aeruginosa and anaerobes metabolism. Renal
Children: dose unknown. Adults: 500 mg q8h elimination (70–75%);
IV dose adjustment for
renal failure
Drug interactions:
Valproic acid,
probenecid
Doxycycline Tetracycline antibiotic active against most Cautions: Teeth
Vibramycin, Doxy gram-positive cocci except Enterococcus , staining, possibly
Injection many gram-negative bacilli, anaerobes, B. permanent (<8 yr old)
Capsule: 50, 100 mg burgdorferi (Lyme disease), Mycoplasma , with prolonged use;
Tablet: 50, 100 mg and Chlamydia photosensitivity, nausea,
Suspension: 25 mg/5 mL Children: 2-5 mg/kg/24 hr divided q12-24h vomiting, diarrhea,
Syrup: 50 mg/5 mL PO or IV (max dose: 200 mg/24 hr) superinfections
Adults: 100-200 mg/24 hr divided q12-24h Drug interactions:
PO or IV Aluminum-, calcium-,
magnesium-, zinc-, iron-
, kaolin-, and pectin-
containing products,
food, milk, dairy
products may decrease
absorption.
Carbamazepine,
rifampin, and
barbiturates may
decrease half-life

Erythromycin Bacteriostatic macrolide antibiotic most Cautions: Motilin

E-Mycin, Ery-Tab, Eryc, active against gram-positive organisms, agonist leading to
Ilosone Corynebacterium diphtheriae , and marked abdominal
Estolate 125, 500 mg Mycoplasma pneumoniae cramping, nausea,
Tablet EES: 200 mg Neonates: Postnatal age ≤7 days: 20 vomiting, and diarrhea.
Tablet base: 250, 333, 500 mg/kg/24 hr divided q12h PO; >7 days Associated with
mg weight <1,200 g: 20 mg/kg/24 hr divided hypertrophic pyloric
Suspension: estolate 125 q12h PO; weight >1,200 g: 30 mg/kg/24 hr stenosis in young
mg/5 mL, 250 mg/5 mL, divided q8h PO (give as 5 mg/kg/dose q6h to infants. Many different
EES 200 mg/5 mL, 400 improve feeding intolerance) salts with questionable
mg/5 mL Children: Usual max dose: 2 g/24 hr tempering of GI adverse
Estolate drops: 100 Base: 30-50 mg/kg/24 hr divided q6-8h PO events. Rare cardiac
mg/mL. EES drops: 100 Estolate: 30-50 mg/kg/24 hr divided q8-12h toxicity with IV use.
mg/2.5 mL. Available in PO Dose of salts differ.
combination with Stearate: 20-40 mg/kg/24 hr divided q6h PO Topical formulation for
sulfisoxazole (Pediazole), Lactobionate: 20-40 mg/kg/24 hr divided q6- treatment of acne
dosed on erythromycin 8h IV Drug interactions:
content Gluceptate: 20-50 mg/kg/24 hr divided q6h Antagonizes hepatic
IV; usual max dose: 4 g/24 hr IV CYP 3A4 activity:
Adults: Base: 333 mg PO q8h; astemizole,
estolate/stearate/base: 250-500 mg q6h PO carbamazepine,
terfenadine,
cyclosporine,
theophylline, digoxin,
tacrolimus,
carbamazepine
Gentamicin Aminoglycoside antibiotic active against Cautions: Anaerobes, S.
Garamycin gram-negative bacilli, especially E. coli, pneumoniae, and other
Injection Klebsiella, Proteus, Enterobacter, Serratia, Streptococcus are
Ophthalmic solution, and Pseudomonas resistant. May cause
ointment, topical cream Neonates: Postnatal age ≤7 days weight ototoxicity and
1,200-2,000 g: 2.5 mg/kg q12-18h IV or IM; nephrotoxicity. Monitor
weight <2,000 g: 2.5 mg/kg q12h IV or IM; renal function. Drug
postnatal age >7 days weight 1,200-2,000 g: eliminated renally.
2.5 mg/kg q8-12h IV or IM; weight >2,000 g: Administered IV over
2.5 mg/kg q8h IV or IM 30-60 min
Children: 2.5 mg/kg/24 hr divided q8-12h IV Drug interactions: May
or IM. Alternatively, may administer 5-7.5 potentiate other ototoxic
mg/kg/24 hr IV once daily and nephrotoxic drugs
Intrathecal: Preservative-free preparation for Target serum
intraventricular or intrathecal use: neonate: 1 concentrations: Peak 6-
mg/24 hr; children: 1-2 mg/24 hr intrathecal; 12 mg/L; trough >2
adults: 4-8 mg/24 hr mg/L with intermittent
Adults: 3-6 mg/kg/24 hr divided q8h IV or daily dose regimens
IM only
Imipenem-cilastatin Carbapenem antibiotic with broad- Cautions: β-Lactam
Primaxin spectrum activity against gram-positive safety profile (rash,
Injection cocci and gram-negative bacilli, including eosinophilia), nausea,
P. aeruginosa and anaerobes. No activity seizures. Cilastatin
against Stenotrophomonas maltophilia possesses no
Neonates: Postnatal age ≤7 days weight antibacterial activity;
<1,200 g: 20 mg/kg q18-24h IV or IM; reduces renal imipenem
weight >1,200 g: 40 mg/kg divided q12h IV metabolism. Primarily
or IM; postnatal age >7 days weight 1,200- renally eliminated
2,000 g: 40 mg/kg q12h IV or IM; weight Drug interaction:
>2,000 g: 60 mg/kg q8h IV or IM Possibly ganciclovir
Children: 60-100 mg/kg/24 hr divided q6-8h
IV or IM
Adults: 2-4 g/24 hr divided q6-8h IV or IM
(max dose: 4 g/24 hr)

Linezolid Oxazolidinone antibiotic active against Adverse events:

Zyvox gram-positive cocci (especially drug- Myelosuppression,
Tablet: 400, 600 mg resistant organisms), including pseudomembranous
Oral suspension: 100 mg/5 Staphylococcus, Streptococcus, E. faecium, colitis, nausea, diarrhea,
mL and Enterococcus faecalis . Interferes with headache
Injection: 100 mg/5 mL protein synthesis by binding to 50S Drug interaction:
ribosome subunit Probenecid
Children: 10 mg/kg q12h IV or PO
Adults: Pneumonia: 600 mg q12h IV or PO;
 skin infections: 400 mg q12h IV or PO
Loracarbef Carbacephem very closely related to Cautions: β-Lactam
Generic cefaclor (second-generation cephalosporin) safety profile (rash,
Capsule: 200 mg active against S. aureus, Streptococcus, H. eosinophilia). Renally
Suspension: 100 mg/5 mL, influenzae, M. catarrhalis, E. coli, eliminated
200 mg/5 mL Klebsiella , and Proteus Drug interaction:
Children: 30 mg/kg/24 hr divided q12h PO Probenecid
(max dose: 2 g)
Adults: 200-400 mg q12h PO (max dose: 800
mg/24 hr)
Meropenem Carbapenem antibiotic with broad- Cautions: β-Lactam
Merrem spectrum activity against gram-positive safety profile; appears to
Injection cocci and gram-negative bacilli, including possess less CNS
P. aeruginosa and anaerobes. No activity excitation than
against S. maltophilia imipenem. 80% renal
Children: 60 mg/kg/24 hr divided q8h IV elimination
meningitis: 120 mg/kg/24 hr (max dose: 6 Drug interaction:
g/24 hr) q8h IV Probenecid
Adults: 1.5-3 g q8h IV
Metronidazole Highly effective in the treatment of Cautions: Dizziness,
Flagyl, Metro I.V., infections caused by anaerobes. Oral seizures, metallic taste,
Topical gel, vaginal gel therapy of C. difficile colitis nausea, disulfiram-like
Injection Neonates: weight <1,200 g: 7.5 mg/kg/48 hr reaction with alcohol.
Tablet: 250, 500 mg PO or IV; postnatal age ≤7 days weight Administer IV slow over
1,200-2,000 g: 7.5 mg/kg/24 hr q24h PO or 30-60 min. Adjust dose
IV; weight 2,000 g: 15 mg/kg/24 hr divided with hepatic impairment
q12h PO or IV; postnatal age <7 days weight Drug interactions:
1,200-2,000 g: 15 mg/kg/24 hr divided q12h Carbamazepine,
PO or IV; weight >2,000 g: 30 mg/kg/24 hr rifampin, phenobarbital
divided q12 h PO or IV may enhance
Children: 30 mg/kg/24 hr divided q6-8h PO metabolism; may
or IV increase levels of
Adults: 30 mg/kg/24 hr divided q6h PO or IV warfarin, phenytoin,
(max dose: 4 g/24 hr) lithium

Mezlocillin sodium Extended-spectrum penicillin active Cautions: β-Lactam

Mezlin against E. coli, Enterobacter, Serratia , and safety profile (rash,
Infection Bacteroides; limited antipseudomonal eosinophilia); painful
activity given intramuscularly;
Neonates: Postnatal age ≤7 days: 150 each gram contains 1.8
mg/kg/24 hr divided q12h IV; >7 days: 225 mEq sodium. Interferes
mg/kg divided q8h IV with platelet aggregation
Children: 200-300 mg/kg/24 hr divided q4-6h with high doses;
IV; cystic fibrosis 300-450 mg/kg/24 hr IV increases noted in liver
Adults: 2-4 g/dose q4-6h IV (max dose: 12 function test results.
g/24 hr) Renally eliminated.
Inactivated by β-
lactamase enzyme
Drug interaction:
Probenecid
Mupirocin Topical antibiotic active against Caution: Minimal systemic
Bactroban Staphylococcus and Streptococcus absorption because drug
Ointment Topical application: Nasal (eliminate nasal metabolized within the skin
carriage) and to the skin 2-4 times daily
Nafcillin sodium Penicillinase-resistant penicillin active Cautions: β-Lactam
Nafcil, Unipen against S. aureus and other gram-positive safety profile (rash,
Injection cocci, except Enterococcus and coagulase- eosinophilia), phlebitis;
Capsule: 250 mg negative staphylococci painful given
Tablet: 500 mg Neonates: Postnatal age ≤7 days weight intramuscularly; oral
1,200-2,000 g: 50 mg/kg/24 hr divided q12h absorption highly
IV or IM; weight >2,000 g: 75 mg/kg/24 hr variable and erratic (not
divided q8h IV or IM; postnatal age >7 days recommended)
weight 1,200-2,000 g: 75 mg/kg/24 hr Adverse effect:
divided q8h; weight >2,000 g: 100 mg/kg/24 Neutropenia
hr divided q6-8h IV (meningitis: 200
mg/kg/24 hr divided q6h IV)
Children: 100-200 mg/kg/24 hr divided q4-6h
IV
Adults: 4-12 g/24 hr divided q4-6h IV (max
dose: 12 g/24 hr)
Nalidixic acid First-generation quinolone effective for Cautions: Vertigo,
NegGram short-term treatment of lower UTIs caused dizziness, rash. Not for
Tablet: 250, 500, 1,000 mg by E. coli, Enterobacter, Klebsiella , and use in systemic
Suspension: 250 mg/5 mL Proteus infections
Children: 50-55 mg/kg/24 hr divided q6h PO; Drug interactions:
suppressive therapy: 25-33 mg/kg/24 hr Liquid antacids
divided q6-8h PO
Adults: 1 g q6h PO; suppressive therapy: 500
mg q6h PO
Neomycin sulfate Aminoglycoside antibiotic used for topical Cautions: In patients
Mycifradin application or orally before surgery to with renal dysfunction
Tablet: 500 mg decrease GI flora (nonabsorbable) and because small amount
Topical cream, ointment hyperammonemia absorbed may
Solution: 125 mg/5 mL Infants: 50 mg/kg/24 hr divided q6h PO accumulate
Children: 50-100 mg/kg/24 hr divided q6-8h Adverse events:
PO Primarily related to
Adults: 500-2,000 mg/dose q6-8h PO topical application,
abdominal cramps,
diarrhea, rash
Aminoglycoside
ototoxicity and
nephrotoxicity if
absorbed

Nitrofurantoin Effective in treatment of lower UTIs Cautions: Vertigo,

Furadantin, Furan, caused by gram-positive and gram- dizziness, rash, jaundice,
Macrodantin negative pathogens interstitial pneumonitis.
Capsule: 50, 100 mg Children: 5-7 mg/kg/24 hr divided q6h PO Do not use with
Extended-release capsule: (max dose: 400 mg/24 hr); suppressive moderate to severe renal
100 mg therapy 1-2.5 mg/kg/24 hr divided q12-24h dysfunction
Macrocrystal: 50, 100 mg PO (max dose: 100 mg/24 hr) Drug interactions:
Suspension: 25 mg/5 mL Adults: 50-100 mg/24 hr divided q6h PO Liquid antacids
Ofloxacin Quinolone antibiotic for treatment of Adverse events: Burning,
Ocuflox 0.3% ophthalmic conjunctivitis or corneal ulcers stinging, eye redness
solution: 1, 5, 10 mL (ophthalmic solution) and otitis externa or (ophthalmic solution),
Floxin 0.3% otic solution: chronic suppurative otitis media (otic dizziness with otic solution if
5, 10 mL solution) caused by susceptible gram- not warmed
positive, gram-negative, anaerobic
bacteria, or C. trachomatis
Child >1-12 yr:
Conjunctivitis: 1-2 drops in affected eye(s)
 q2-4h for 2 days, then 1-2 drops qid for 5
days
Corneal ulcers: 1-2 drops q 30 min while
awake and at 4 hr intervals at night for 2
days, then 1-2 drops hourly for 5 days while
awake, then 1-2 drops q6h for 2 days
Otitis externa (otic solution): 5 drops into
affected ear bid for 10 days
Chronic suppurative otitis media: treat for 14
days
Child >12 yr and adults: Ophthalmic
solution doses same as for younger children.
Otitis externa (otic solution): Use 10 drops
bid for 10 or 14 days as for younger children
Oxacillin sodium Penicillinase-resistant penicillin active Cautions: β-Lactam
Prostaphlin against S. aureus and other gram-positive safety profile (rash,
Injection cocci, except Enterococcus and coagulase- eosinophilia)
Capsule: 250, 500 mg negative staphylococci Moderate oral
Suspension: 250 mg/5 mL Neonates: Postnatal age ≤7 days weight bioavailability (35–
1,200-2,000 g: 50 mg/kg/24 hr divided q12h 65%) Primarily renally
IV; weight >2,000 g: 75 mg/kg/24 hr IV eliminated
divided q8h IV; postnatal age >7 days weight Drug interaction:
<1,200 g: 50 mg/kg/24 hr IV divided q12h Probenecid
IV; weight 1,200-2,000 g: 75 mg/kg/24 hr Adverse effect:
divided q8h IV; weight >2,000 g: 100 Neutropenia
mg/kg/24 hr IV divided q6h IV
Infants: 100-200 mg/kg/24 hr divided q4-6h
IV
Children: PO 50-100 mg/kg/24 hr divided q4-
6h IV
Adults: 2-12 g/24 hr divided q4-6h IV (max
dose: 12 g/24 hr)

Penicillin G Penicillin active against most gram- Cautions: β-Lactam

Injection positive cocci; S. pneumoniae (resistance is safety profile (rash,
Tablets increasing), group A streptococcus, and eosinophilia), allergy,
some gram-negative bacteria (e.g., N. seizures with excessive
gonorrhoeae, N. meningitidis ) doses particularly in
Neonates: Postnatal age ≤7 days weight patients with marked
1,200-2,000 g: 50,000 units/kg/24 hr divided renal disease.
q12h IV or IM (meningitis: 100,000 U/kg/24 Substantial pathogen
hr divided q12h IV or IM); weight >2,000 g: resistance. Primarily
75,000 U/kg/24 hr divided q8h IV or IM renally eliminated
(meningitis: 150,000 U/kg/24 hr divided q8h Drug interaction:
IV or IM); postnatal age >7 days weight Probenecid
≤1,200 g: 50,000 U/kg/24 hr divided q12h IV
(meningitis: 100,000 U/kg/24 hr divided
q12h IV); weight 1,200-2,000 g: 75,000
U/kg/24 hr q8h IV (meningitis: 225,000
U/kg/24 hr divided q8h IV); weight >2,000 g:
100,000 U/kg/24 hr divided q6h IV
(meningitis: 200,000 U/kg/24 hr divided q6h
IV)
Children: 100,000-250,000 units/kg/24 hr
divided q4-6h IV or IM (max dose: 400,000
U/kg/24 hr)
 Adults: 2-24 million units/24 hr divided q4-
6h IV or IM
Penicillin G, benzathine Long-acting repository form of penicillin Cautions: β-Lactam
Bicillin effective in treatment of infections safety profile (rash,
Injection responsive to persistent, low penicillin eosinophilia), allergy.
concentrations (1-4 wk), e.g., group A Administer by IM
streptococcus pharyngitis, rheumatic fever injection only.
prophylaxis Substantial pathogen
Neonates weight >1,200 g: 50,000 units/kg resistance. Primarily
IM once renally eliminated
Children: 300,000-1.2 million units/kg q 3-4 Drug interaction:
wk IM (max dose: 1.2-2.4 million units/dose) Probenecid
Adults: 1.2 million units IM q 3-4 wk
Penicillin G, procaine Repository form of penicillin providing Cautions: β-Lactam
Crysticillin low penicillin concentrations for 12 hr safety profile (rash,
Injection Neonates weight >1,200 g: 50,000 eosinophilia) allergy.
units/kg/24 hr IM Administer by IM
Children: 25,000-50,000 units/kg/24 hr IM injection only.
for 10 days (max dose: 4.8 million Substantial pathogen
units/dose) resistance. Primarily
Gonorrhea: 100,000 units/kg (max dose: 4.8 renally eliminated
million units/24 hr) IM once with probenecid Drug interaction:
25 mg/kg (max dose: 1 g) Probenecid
Adults: 0.6-4.8 million units q12-24h IM
Penicillin V Preferred oral dosing form of penicillin, Cautions: β-Lactam
Pen VK, V-Cillin K active against most gram-positive cocci; S. safety profile (rash,
Tablet: 125, 250, 500 mg pneumoniae (resistance is increasing), eosinophilia), allergy,
Suspension: 125 mg/5 mL, other streptococci, and some gram- seizures with excessive
250 mg/5 mL negative bacteria (e.g., N. gonorrhoeae, N. doses particularly in
meningitidis ) patients with renal
Children: 25-50 mg/kg/24 hr divided q4-8h disease. Substantial
PO pathogen resistance.
Adults: 125-500 mg q6-8h PO (max dose: 3 Primarily renally
g/24 hr) eliminated. Inactivated
by penicillinase
Drug interaction:
Probenecid

Piperacillin Extended-spectrum penicillin active Cautions: β-Lactam

Pipracil against E. coli, Enterobacter, Serratia, P. safety profile (rash,
Injection aeruginosa, and Bacteroides eosinophilia); painful
Neonates: Postnatal age ≤7 days 150 given intramuscularly;
mg/kg/24 hr divided q8-12h IV; >7 days; 200 each gram contains 1.9
mg/kg divided q6-8h IV mEq sodium. Interferes
Children: 200-300 mg/kg/24 hr divided q4-6h with platelet
IV; cystic fibrosis: 350-500 mg/kg/24 hr IV aggregation/serum
Adults: 2-4 g/dose q4-6h (max dose: 24 g/24 sickness–like reaction
hr) IV with high doses;
increases in liver
function test results.
Renally eliminated.
Inactivated by
penicillinase
Drug interaction:
Probenecid
Piperacillin-tazobactam Extended-spectrum penicillin (piperacillin) Cautions: β-Lactam
Zosyn combined with a β-lactamase inhibitor safety profile (rash,
Injection (tazobactam) active against S. aureus, H. eosinophilia); painful
influenzae, E. coli, Enterobacter, Serratia, given intramuscularly;
Acinetobacter, P. aeruginosa, and each gram contains 1.9
Bacteroides mEq sodium
Children: 300-400 mg/kg/24 hr divided q6-8h Interferes with platelet
IV or IM aggregation, serum
Adults: 3.375 g q6-8h IV or IM sickness–like reaction
with high doses,
increases in liver
function test results.
Renally eliminated
Drug interaction:
Probenecid
Quinupristin/dalfopristin Streptogramin antibiotic (quinupristin) Adverse events: Pain,
Synercid active against vancomycin-resistant E. edema, or phlebitis at
IV injection: powder for faecium (VRE) and methicillin-resistant S. injection site, nausea,
reconstitution, 10 mL aureus (MRSA). Not active against E. diarrhea
contains 150 mg faecalis Drug interactions :
quinupristin, 350 mg Children and adults: VRE: 7.5 mg/kg q8h IV Synercid is a potent
dalfopristin for VRE; skin infections: 7.5 mg/kg q12h IV inhibitor of CYP 3A4
Sulfadiazine Sulfonamide antibiotic primarily indicated Cautions: Rash,
Tablet: 500 mg for treatment of lower UTIs caused by E. Stevens-Johnson
coli, P. mirabilis, and Klebsiella syndrome, nausea,
Toxoplasmosis: leukopenia, crystalluria.
Neonates: 100 mg/kg/24 hr divided q12h PO Renal and hepatic
with pyrimethamine 1 mg/kg/24 hr PO (with elimination; avoid use
folinic acid) with renal disease. Half-
Children: 120-200 mg/kg/24 hr divided q6h life: ~10 hr
PO with pyrimethamine 2 mg/kg/24 hr Drug interactions:
divided q12h PO ≥3 days, then 1 mg/kg/24 hr Protein displacement
(max dose: 25 mg/24 hr) with folinic acid with warfarin,
Rheumatic fever prophylaxis: weight ≤30 kg: phenytoin, methotrexate
500 mg/24 hr q24h PO; weight >30 kg: 1
g/24 hr q24h PO

Sulfamethoxazole Sulfonamide antibiotic used for treatment Cautions: Rash,

Gantanol of otitis media, chronic bronchitis, and Stevens-Johnson
Tablet: 500 mg lower UTIs caused by susceptible bacteria syndrome, nausea,
Suspension: 500 mg/5 mL Children: 50-60 mg/kg/24 hr divided q12h leukopenia, crystalluria.
PO Renal and hepatic
Adults: 1 g/dose q12h PO (max dose: 3 g/24 elimination; avoid use
hr) with renal disease. Half-
life: ~12 hr. Initial dose
often a loading dose
(doubled)
Drug interactions:
Protein displacement
with warfarin,
phenytoin, methotrexate
Sulfisoxazole Sulfonamide antibiotic used for treatment Cautions: Rash,
Gantrisin of otitis media, chronic bronchitis, and Stevens-Johnson
Tablet: 500 mg lower UTIs caused by susceptible bacteria syndrome, nausea,
Suspension: 500 mg/5 mL Children: 120-150 mg/kg/24 hr divided q4-6h leukopenia, crystalluria.
Ophthalmic solution, PO (max dose: 6 g/24 hr) Renal and hepatic
ointment Adults: 4-8 g/24 hr divided q4-6h PO elimination; avoid use
with renal disease. Half-
life: ~7-12 hr. Initial
dose often a loading
dose (doubled)
Drug interactions:
Protein displacement
with warfarin,
phenytoin, methotrexate
Tigecycline Tetracycline-class antibiotic (glycylcycline) Cautions: Pregnancy;
Tygacil active against Enterobacteriaceae, children <8 yr old;
Injection including extended spectrum β-lactamase photosensitivity;
producers; streptococci (including VRE); hypersensitivity to
staphylococci (including MRSA); and tetracyclines; hepatic
anaerobes impairment (~60%
Children: unknown hepatic clearance)
Adults: 100 mg loading dose followed by 50 Drug interaction:
mg q12h IV Warfarin;
mycophenolate mofetil
Tobramycin Aminoglycoside antibiotic active against Cautions: S.
Nebcin, Tobrex gram-negative bacilli, especially E. coli, pneumoniae , other
Injection Klebsiella, Enterobacter, Serratia, Proteus, Streptococcus, and
Ophthalmic solution, and Pseudomonas anaerobes are resistant.
ointment Neonates: Postnatal age ≤7 days, weight May cause ototoxicity
1,200-2,000 g: 2.5 mg/kg q12-18h IV or IM; and nephrotoxicity.
weight >2,000 g: 2.5 mg/kg q12h IV or IM; Monitor renal function.
postnatal age >7 days, weight 1,200-2,000 g: Drug eliminated renally.
2.5 mg/kg q8-12h IV or IM; weight >2,000 g: Administered IV over
2.5 mg/kg q8h IV or IM 30-60 min
Children: 2.5 mg/kg/24 hr divided q8-12h IV Drug interactions: May
or IM. Alternatively, may administer 5-7.5 potentiate other ototoxic
mg/kg/24 hr IV. Preservative-free preparation and nephrotoxic drugs
for intraventricular or intrathecal use: Target serum
neonate, 1 mg/24 hr; children, 1-2 mg/24 hr; concentrations: Peak 6-
adults, 4-8 mg/24 hr 12 mg/L; trough <2
Adults: 3-6 mg/kg/24 hr divided q8h IV or mg/L
IM

Trimethoprim Folic acid antagonist effective in Cautions: Megaloblastic

Proloprim, Trimpex prophylaxis and treatment of E. coli, anemia, bone marrow
Tablet: 100, 200 mg Klebsiella, P. mirabilis, and Enterobacter suppression, nausea,
UTIs; P. carinii pneumonia epigastric distress, rash
Children: For UTI: 4-6 mg/kg/24 hr divided Drug interactions:
q12h PO Possible interactions
Children >12 yr and adults: 100-200 mg q12h with phenytoin,
PO. P. carinii pneumonia (with dapsone): 15- cyclosporine, rifampin,
20 mg/kg/24 hr divided q6h for 21 days PO warfarin
Vancomycin Glycopeptide antibiotic active against most Cautions: Ototoxicity
Vancocin, Lyphocin gram-positive pathogens including and nephrotoxicity
Injection staphylococci (including MRSA and particularly when co-
Capsule: 125 mg, 250 mg coagulase-negative staphylococci), S. administered with other
Suspension pneumoniae including penicillin-resistant ototoxic and
strains, Enterococcus (resistance is nephrotoxic drugs
increasing), and C. difficile –associated Infuse IV over 45-60
colitis min. Flushing (red man
Neonates: Postnatal age ≤7 days, weight syndrome) associated
 <1,200 g: 15 mg/kg/24 hr divided q24h IV; with rapid IV infusions,
weight 1,200-2,000 g: 15 mg/kg/24 hr fever, chills, phlebitis
divided q12-18h IV; weight >2,000 g: 30 (central line is
mg/kg/24 hr divided q12h IV; postnatal age preferred). Renally
>7 days, weight <1,200 g: 15 mg/kg/24 hr eliminated.
divided q24h IV; weight 1,200-2,000 g: 15 Target serum
mg/kg/24 hr divided q8-12h IV; weight concentrations: Peak (1
>2,000 g: 45 mg/kg/24 hr divided q8h IV hr after 1 hr infusion)
Children: 45-60 mg/kg/24 hr divided q8-12h 30-40 mg/L; trough 5-10
IV; C. difficile –associated colitis; 40-50 mg/L
mg/kg/24 hr divided q6-8h PO
* In the Drug column, the generic drug name is in bold . In the Indications column, bold indicates

major organisms targeted and mechanisms of action.

CNS, Central nervous system; GI, gastrointestinal; IM, intramuscular/ly; IV, intravenous/ly; PO,
oral/ly; q12-24h, every 12 to 24 hours; bid, twice daily; qid, 4 times daily; UTIs, urinary tract
infections.

Penicillins
Although there has been ever-increasing emergence of resistance to penicillins,
these agents remain valuable and are commonly used for management of many
pediatric infectious diseases.
Penicillins remain the drugs of choice for pediatric infections caused by group
A and group B streptococcus, Treponema pallidum (syphilis), L. monocytogenes,
and N. meningitidis. The semisynthetic penicillins (nafcillin, cloxacillin,
dicloxacillin) are useful for management of susceptible (non-MRSA)
staphylococcal infections. The aminopenicillins (ampicillin, amoxicillin) were
developed to provide broad-spectrum activity against gram-negative organisms,
including E. coli and H. influenzae, but the emergence of resistance (typically
mediated by a β-lactamase) has limited their utility in many clinical settings. The
carboxypenicillins (ticarcillin) and ureidopenicillins (piperacillin, mezlocillin,
azlocillin) also have bactericidal activity against most strains of P. aeruginosa.
Resistance to penicillin is mediated by a variety of mechanisms (see Table
207.1 ). The production of β-lactamase is a common mechanism exhibited by
many organisms that may be overcome, with variable success, by including a β-
lactamase inhibitor in the therapeutic formulation with the penicillin. Such
combination products (ampicillin-sulbactam, amoxicillin-clavulanate, ticarcillin–
clavulanic acid [no longer available in the U.S.], piperacillin-tazobactam) are
potentially very useful for management of resistant isolates, but only if the
resistance is β-lactamase mediated. Notably, MRSA and S. pneumoniae mediate
resistance to penicillins through mechanisms other than β-lactamase production,
rendering these combination agents of little value for the management of these
infections.
Table 207.4 lists adverse reactions to penicillins.

Table 207.4
Adverse Reactions to Penicillins

TYPE OF REACTION FREQUENCY (%) OCCURS MOST FREQUENTLY WITH

ALLERGIC
Immunoglobulin E antibody 0.04-0.015 Penicillin G
Anaphylaxis*
Early urticaria* (<72 hr)
Cytotoxic antibody Rare Penicillin G
Hemolytic anemia*
Antigen-antibody complex disease Rare Penicillin G
Serum sickness*
Delayed hypersensitivity 2-5 Ampicillin, amoxicillin
Contact dermatitis*
IDIOPATHIC 2-5 Ampicillin
Skin rash
Fever
Late-onset urticaria
GASTROINTESTINAL
Diarrhea 3-11 Ampicillin
C. difficile –associated colitis Rare Ampicillin
HEMATOLOGIC
Hemolytic anemia Rare Penicillin G
Neutropenia 10-17 Penicillin G, nafcillin, oxacillin †
Platelet dysfunction 43-73 Piperacillin
HEPATIC
Elevated serum aspartate transaminase 0.01-22 Flucloxacillin, oxacillin
ELECTROLYTE DISTURBANCE
Hypokalemia Rare Nafcillin, oxacillin
Hyperkalemia, acute Rare Penicillin G
NEUROLOGIC
Seizures Rare Penicillin G
Bizarre sensations Rare Procaine penicillin
RENAL

Interstitial nephritis* Variable Any penicillin

* Reaction can occur with any of the penicillins.

† With prolonged therapy.

Adapted from Doi Y, Chambers HF: Penicillins and β-lactamase inhibitors. In Bennett JF, Dolin R,
Blaser MJ, editors: Mandell, Douglas, and Bennett's principles and practice of infectious diseases,
ed 8, Philadelphia, 2015, Elsevier (Table 20-7).
pneumonia but is not indicated for MRSA pneumonia. Ceftaroline's activity is
attributed to its ability to bind to penicillin-binding protein 2a with higher
affinity than other β-lactams. Another fifth-generation cephalosporin with a
similar spectrum of activity, ceftobiprole , has been approved for use in Canada
and the European Union.

Table 207.5
Classification of Parenteral and Oral Cephalosporins

FIRST SECOND THIRD FOURTH

CEPHALOSPORINS CEPHAMYCINS
GENERATION GENERATION GENERATION GENERATION
Parenteral Cefazolin Cefamandole Cefmetazole Cefoperazone Cefepime
(Ancef, Kefzol) (Mandol)* (Zefazone)* (Cefobid)* (Maxipime)
Cephalothin Cefonicid Cefotetan Cefotaxime* Cefpirome
(Keflin, Seffin)* (Monocid)* (Cefotan) (Claforan) (Cefrom)*
Cephapirin Cefuroxime Cefoxitin Ceftazidime Ceftolozane
(Cefadyl)* (Kefurox, (Mefoxin) (Fortaz) (combined with
Cephradine Zinacef) Ceftizoxime tazobactam;
(Velosef)* (Cefizox)* CXA-101)
Ceftriaxone
(Rocephin)
Moxalactam*
Oral Cefadroxil Cefaclor Cefdinir
(Duricef, (Ceclor)* (Omnicef)
Ultracef) Cefprozil Cefditoren
Cephalexin (Cefzil) (Spectracef)
(Keflex, Cefuroxime Cefixime
Biocef, axetil (Suprax)
Keftab) (Ceftin) Cefpodoxime
Cephradine Loracarbef (Vantin)
(Velosef)* (Lorabid)* Ceftibuten
(Cedax)
* Not currently available in the United States.

Adapted from Craig WA, Andes DR: Cephalosporins.IN Bennett JF, Dolin R, Blaser MJ, editors:
Mandell, Douglas, and Bennett's principles and practice of infectious diseases, ed 8, Philadelphia,
2015, Elsevier (Table 21-1).

Another fifth-generation cephalosporin, ceftolozane , is a derivative of

ceftazidime with improved activity against Pseudomonas spp. It is not stable
against most ESBLs or carbapenemases. It is marketed in combination with the
β-lactam inhibitor tazobactam, to improve its activity against β-lactamase–
producing Enterobacteriaceae. Experience with children is limited.
Table 207.6 lists adverse reactions to cephalosporins.

Table 207.6
Potential Adverse Effects of Cephalosporins

TYPE SPECIFIC FREQUENCY

Hypersensitivity Rash 1–3%
Urticaria <1%
Serum sickness <1%
Anaphylaxis 0.01%
Gastrointestinal Diarrhea 1–19%
Nausea, vomiting 1–6%
Transient transaminase elevation 1–7%
Biliary sludge 20–46%*
Hematologic Eosinophilia 1–10%
Neutropenia <1%
Thrombocytopenia <1-3%
Hypoprothrombinemia <1%
Impaired platelet aggregation <1%
Hemolytic anemia <1%
Renal Interstitial nephritis <1%
Central nervous system Seizures <1%
Encephalopathy <1%
False-positive laboratory Coombs positive 3%
Glucosuria Rare
Serum creatinine Rare
Other Drug fever Rare
Disulfiram-like reaction † Rare
Superinfection Rare
Phlebitis Rare
Calcium-antibiotic precipitation* Unknown; can be associated with embolic events
* Ceftriaxone.

† Cephalosporins with thiomethyl tetrazole ring (MTT) side chain.

Adapted from Craig WA, Andes DR: Cephalosporins. In Bennett JF, Dolin R, Blaser MJ, editors:
Mandell, Douglas, and Bennett's principles and practice of infectious diseases, ed 8, Philadelphia,
2015, Elsevier (Table 21-6).

Carbapenems
The carbapenems include imipenem (formulated in combination with cilastatin),
meropenem, ertapenem, and doripenem. The basic structure of these agents is
similar to that of β-lactam antibiotics, and these drugs have a similar mechanism
of action. The carbapenems provide the broadest spectrum of antibacterial
activity of any licensed class of antibiotics and are active against gram-positive,
gram-negative, and anaerobic organisms. Among the carbapenems, meropenem
is the only agent licensed for treatment of pediatric meningitis. At this time,
ertapenem and doripenem are not approved for pediatric use. Importantly,
infection; however, not all strains of MSSA or MRSA are susceptible to
clindamycin. Inducible clindamycin resistance in isolates initially reported as
susceptible must be ruled out by D-test or molecular methods. Clindamycin is
bacteriostatic and should not be used to treat endocarditis, persistent bacteremia,
or CNS infections caused by S. aureus. Given that the mechanism of action of
clindamycin involves inhibition or protein synthesis, many experts use
clindamycin to treat S. aureus toxin–mediated illnesses (e.g., TSS) to inhibit
toxin production.
Although the very-broad- spectrum carbapenems (meropenem, ertapenem,
and imipenem) have activity against MSSA, they have no activity against
MRSA. As a result, carbapenems are rarely used for empirical therapy of
possible staphylococcal infection and are too broad in most cases for use in
identified MSSA infections. Quinolone antibiotics have unpredictable activity
against MSSA and no activity against MRSA. Linezolid and daptomycin are
useful for serious S. aureus infections, particularly those caused by MRSA,
when treatment with vancomycin is ineffective or not tolerated.(Table 208.1 ). A
number of novel antistaphylococcal antibiotics have emerged for use in resistant
or refractory MSSA and MRSA infection in adults that may be required for
pediatric therapy in select patients under the guidance of a pediatric infectious
disease specialist. These include ceftaroline , a broad-spectrum
antistaphylococcal cephalosporin, and oritavancin and dalbavancin ,
lipoglycopeptides structurally related to vancomycin with very long half-lives
and broad activity against gram-positive organisms. Rifampin or gentamicin
may be added to a β-lactam or vancomycin for synergy in serious infections such
as endocarditis, particularly when prosthetic valve material is involved.

Table 208.1
Parenteral Antimicrobial Agent(s) for Treatment of Serious
Staphylococcus aureus Infections

SUSCEPTIBILITY ANTIMICROBIALS COMMENTS

I. INITIAL EMPIRICAL THERAPY (ORGANISM OF UNKNOWN SUSCEPTIBILITY)
Drugs of choice: Vancomycin + For life-threatening infections (e.g., septicemia,
nafcillin or oxacillin endocarditis, CNS infection); linezolid could be substituted
if the patient has received several recent courses of
vancomycin
Vancomycin For non–life-threatening infection without signs of severe
sepsis (e.g., skin infection, cellulitis, osteomyelitis,
pyarthrosis) when rates of MRSA colonization and
 infection in the community are substantial
Cefazolin or nafcillin For non–life-threatening infection when low likelihood of
MRSA is suspected

Clindamycin For non–life-threatening infection without signs of severe

sepsis when rates of MRSA colonization and infection in
the community are substantial and prevalence of
clindamycin resistance is low
II. METHICILLIN-SUSCEPTIBLE, PENICILLIN-RESISTANT S. aureus
Drugs of choice: Nafcillin*
Alternatives (depending on Cefazolin
susceptibility results): Clindamycin Only for patients with a serious penicillin allergy and
clindamycin-susceptible strain
Vancomycin Only for penicillin- and cephalosporin-allergic patients
Ampicillin + When broader coverage, including gram-negative
sulbactam organisms is required
III. METHICILLIN-RESISTANT S. aureus (MRSA)
Drugs of choice: Vancomycin*
Alternatives: susceptibility Clindamycin (if
testing results available susceptible)
before alternative drugs are Daptomycin †
used Linezolid †
Trimethoprim-
sulfamethoxazole
* One of the adjunctive agents, gentamicin or rifampin, should be added to the therapeutic
regimen for life-threatening infections such as endocarditis or central nervous system (CNS)
infection. Consultation with an infectious diseases specialist should be considered to determine
which agent to use and duration of use.
† Linezolid and daptomycin are agents with activity in vitro and efficacy with multidrug-resistant,
gram-positive organisms, including S. aureus . Because experience with these agents in children
is limited, consultation with an infectious diseases specialist should be considered before use.
Daptomycin is ineffective for treatment of pneumonia.

In many infections, oral antimicrobials may be substituted to complete the

course of treatment, after an initial period of parenteral therapy and
determination of antimicrobial susceptibilities, or can be used as initial treatment
in less severe infections. Dicloxacillin (50-100 mg/kg/24 hr divided 4 times
daily PO) and cephalexin (25-100 mg/kg/24 hr divided 3-4 times daily PO) are
absorbed well orally (PO) and are effective against MSSA. Amoxicillin-
clavulanate (40-80 mg amoxicillin/kg/24 hr divided 3 times daily PO) is also
effective when a broader spectrum of coverage is required. Clindamycin (30-40
mg/kg/24 hr divided 3-4 times daily PO) is highly absorbed from the intestinal
tract and is frequently used for empirical coverage when both MRSA and MSSA
are possible, as well as for susceptible MRSA infections or for MSSA in
penicillin/cephalosporin-allergic patients. Compliance with oral clindamycin
may be limited in small children because of poor palatability of oral
alterations in the level of consciousness, oliguria, and hypotension, which in
severe cases may progress to shock and disseminated intravascular coagulation.
Complications, including acute respiratory distress syndrome (ARDS),
myocardial dysfunction, and renal failure, are commensurate with the degree of
shock. Recovery occurs within 7-10 days and is associated with desquamation,
particularly of palms and soles; hair and nail loss have also been observed after
1-2 mo. Immunity to the toxins is slow to develop, so recurrences can occur,
especially if there is inadequate antibiotic treatment and/or recurrent tampon use.
Many cases of apparent scarlet fever without shock may be caused by TSST-1–
producing S. aureus strains.

Table 208.2
Diagnostic Criteria of Staphylococcal Toxic Shock
Syndrome
MAJOR CRITERIA (ALL REQUIRED)
Acute fever; temperature >38.8°C (101.8°F)
Hypotension (orthostatic, shock; blood pressure below age-appropriate norms)
Rash (erythroderma with convalescent desquamation)
MINOR CRITERIA (ANY 3 OR MORE)
Mucous membrane inflammation (vaginal, oropharyngeal or conjunctival hyperemia, strawberry tongue)
Vomiting, diarrhea
Liver abnormalities (bilirubin or transaminase greater than twice the upper limit of normal)
Renal abnormalities (blood urea nitrogen or creatinine greater than twice the upper limit of normal, or greater than
5 white blood cells per high-power field)
Muscle abnormalities (myalgia or creatinine phosphokinase greater than twice the upper limit of normal)
Central nervous system abnormalities (alteration in consciousness without focal neurologic signs)
Thrombocytopenia (≤100,000/mm3 )
EXCLUSIONARY CRITERIA
Absence of another explanation
Negative blood cultures (except occasionally for Staphylococcus aureus )
Data from Kimberlin DW, Brady MT, Jackson MA, Long SS, editors: Red book: 2015 report of the
Committee on Infectious Diseases , ed 30, Elk Grove Village, IL, 2015, American Academy of
Pediatrics.

Diagnosis
There is no specific laboratory test, and diagnosis depends on meeting certain
clinical and laboratory criteria in the absence of an alternate diagnosis (see Fig.
208.2 ). Appropriate tests reveal involvement of multiple organ systems,
including the hepatic, renal, muscular, gastrointestinal, cardiopulmonary, and
infections (IPIs) in children. By 2005, however, IPIs began to increase slightly
because of an increase in non-PCV7 serotypes, particularly serotype 19A.
Serotype replacement can result from expansion of existing nonvaccine
serotypes, as well as from vaccine-type pneumococci acquiring the
polysaccharide capsule of a nonvaccine serotype (serotype switching ). Since
the introduction of PCV13 in 2010 in the United States, there has been a decline
in IPIs caused by new vaccine serotypes, including 19A. Nonetheless, 19A
remains an important cause of meningitis. Indirect protection of unvaccinated
persons has occurred since PCV introduction, and this herd protection is likely a
result of decreases in nasopharyngeal carriage of virulent pneumococcal vaccine
serotypes.
S. pneumoniae is the most frequent cause of bacteremia, bacterial pneumonia,
otitis media, and bacterial meningitis in children. The decreased ability in
children <2 yr old to produce antibody against the T-cell–independent
polysaccharide antigens and the high prevalence of colonization may explain an
increased susceptibility to pneumococcal infection and the decreased
effectiveness of polysaccharide vaccines. Children at increased risk of
pneumococcal infections include those with sickle cell disease, asplenia,
deficiencies in humoral (B-cell) and complement-mediated immunity, HIV
infection, certain malignancies (e.g., leukemia, lymphoma), chronic heart, lung,
or renal disease (particularly nephrotic syndrome), cerebrospinal fluid (CSF)
leak, and cochlear implants. Table 209.1 lists other high-risk groups. Some
American Indian, Alaska Native, and African American children may also be at
increased risk. Children <5 yr old in out-of-home daycare are at increased risk
(approximately 2-fold higher) of experiencing IPIs than other children. Males
are more frequently affected than females. Because immunocompetent
vaccinated children have had fever episodes of IPI, the proportion of infected
children with immunologic risk factors has increased (estimated at 20%).

Table 209.1
Children at Increased Risk of Invasive Pneumococcal
Infection

RISK GROUP CONDITION

Immunocompetent Chronic heart disease*
children Chronic lung disease †
Diabetes mellitus
Cerebrospinal fluid leaks
 Cochlear implant
Children with Sickle cell disease and other hemoglobinopathies
functional or anatomic Congenital or acquired asplenia, or splenic dysfunction
asplenia
Children with HIV infection
immunocompromising Chronic renal failure and nephrotic syndrome
conditions Diseases associated with treatment with immunosuppressive drugs or radiation therapy,
including malignant neoplasm, leukemia, lymphoma, and Hodgkin disease; or stem cell
and solid-organ transplantation
Congenital immunodeficiency ‡
Toll-like receptor signaling defects (IRAK-4, IKBKG, MyD88)
NEMO gene defects
* Particularly cyanotic congenital heart disease and cardiac failure.

† Including asthma if treated with high-dose oral corticosteroid therapy.

‡ Includes B-(humoral) or T-lymphocyte deficiency; complement deficiencies, particularly

C1,C2,C3, and C4 deficiency; and phagocytic disorders, excluding chronic granulomatous

disease.
Adapted from Centers for Disease Control and Prevention: Licensure of a 13-valent
pneumococcal conjugate vaccine (PCV13) and recommendations for use among children:
Advisory Committee on Immunization Practices, MMWR 59(RR-11):1–18, 2010 (Table 2).

Pneumococcal disease usually occurs sporadically but can be spread from

person to person by respiratory droplet transmission. S. pneumoniae is an
important cause of secondary bacterial pneumonia in patients with influenza.
During influenza epidemics and pandemics, most deaths result from bacterial
pneumonia, and pneumococcus is the predominant bacterial pathogen isolated in
this setting. Pneumococcal copathogenicity may be important in disease caused
by other respiratory viruses as well.

Pathogenesis
Invasion of the host is affected by a number of factors. Nonspecific defense
mechanisms, including the presence of other bacteria in the nasopharynx, may
limit multiplication of pneumococci. Aspiration of secretions containing
pneumococci is hindered by the epiglottic reflex and by respiratory epithelial
cell cilia, which move infected mucus toward the pharynx. Similarly, normal
ciliary flow of fluid from the middle ear through the eustachian tube and sinuses
to the nasopharynx usually prevents infection with nasopharyngeal flora,
including pneumococci. Interference with these normal clearance mechanisms
by allergy, viral infection, or irritants (e.g., smoke) may allow colonization and
subsequent infection with these organisms in otherwise normally sterile sites.
20% fewer tympanostomy tube placements than unvaccinated children.
Following PCV13, a 64% reduction in IPIs caused by vaccine serotypes has
been seen, particularly in children <5 yr old. The number of pneumococcal
isolates and percentage of isolates with high-level penicillin resistance from
cultures taken from children with otitis media or mastoiditis for clinical
indications have decreased, largely related to decreases in serotype 19A. Rates of
hospitalization for pneumococcal pneumonia among U.S. children decreased
after PCV13 introduction. The number of cases of pneumococcal meningitis in
children remain unchanged, but the proportion of PCV13 serotypes have
decreased significantly. In addition, pneumococcal conjugate vaccines
significantly reduce nasopharyngeal carriage of vaccine serotypes. PCVs have
significantly decreased rates of invasive pneumococcal disease in children with
sickle cell disease, and studies suggest substantial protection for HIV-infected
children and splenectomized adults. Adverse events after the administration of
PCV have included local swelling and redness and slightly increased rates of
fever, when used in conjunction with other childhood vaccines.

Table 209.2

Comparison of Pneumococcal Vaccines Licensed in United States*

CARRIER
PNEUMOCOCCAL CAPSULAR POLYSACCHARIDES MANUFACTURER
PROTEIN
Diphtheria 4, 6B, 9V, 14, 18C, 19F, 23F Wyeth Lederle (PCV7,
CRM197 protein Prevnar)
Diphtheria 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 23F Wyeth Lederle (PCV13,
CRM197 protein Prevnar 13)
None 1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, Sanofi Pasteur MSD
18C, 19A, 19F, 20, 22F, 23F, 33F (PPSV23, Pneumovax II)
* PCV7 serotypes in bold .

Immunologic responsiveness and efficacy after administration of

pneumococcal polysaccharide vaccines (PPSV23) is unpredictable in children <2
yr old. PPSV23 contains purified polysaccharide of 23 pneumococcal serotypes
responsible for >95% of invasive disease. The clinical efficacy of PPSV23 is
controversial, and studies have yielded conflicting results.
Immunization with PCV13 is recommended for all infants on a schedule for
primary immunization, in previously unvaccinated infants, and for transition for
those partially vaccinated with PCV7 (Table 209.3 ). High-risk children ≥2 yr
old, such as those with asplenia, sickle cell disease, some types of immune
deficiency (e.g., antibody deficiencies), HIV infection, cochlear implant, CSF
leak, diabetes mellitus, and chronic lung, heart, or kidney disease (including
nephrotic syndrome), may benefit also from PPSV23 administered after 2 yr of
age following priming with the scheduled doses of PCV13. Thus, it is
recommended that children 2 yr of age and older with these underlying
conditions receive supplemental vaccination with PPSV23. A 2nd dose of
PPSV23 is recommended 5 yr after the 1st dose of PPSV23 for persons ≥2 yr old
who are immunocompromised, have sickle cell disease, or functional or
anatomic asplenia. Additional recommendations have been made for at-risk
children 6-18 yr old (Table 209.4 ).

Table 209.3

Recommended Routine Vaccination Schedule for 13-Valent Pneumococcal Conjugate

Vaccine (PCV13) Among Infants and Children Who Have Not Received Previous
Doses of 7-Valent Vaccine (PCV7) or PCV13, by Age at 1st Dose—United States, 2010
PRIMARY PCV13 PCV13 BOOSTER
AGE AT 1ST DOSE (mo)
SERIES* DOSE †
2-6 3 doses 1 dose at age 12-15
mo
7-11 2 doses 1 dose at age 12-15
mo
12-23 2 doses —
24-59 (healthy children) 1 dose —
24-71 (children with certain chronic diseases or 2 doses —
immunocompromising conditions ‡ )
* Minimum interval between doses is 8 wk except for children vaccinated at age <12 mo, for whom

minimum interval between doses is 4 wk. Minimum age for administration of 1st dose is 6 wk.
† Given at least 8 wk after the previous dose.

‡ See Table 209.1 .

From Centers for Disease Control and Prevention. Licensure of a 13-valent pneumococcal
conjugate vaccine (PCV13) and recommendations for use among children: Advisory Committee
on Immunization Practices, MMWR 59(RR-11):1–18 (Table 8); 59:258–261, 2010 (Table 3).

Table 209.4
Medical Conditions or Other Indications for Administration
of PCV13,* and Indications for PPSV23 † Administration,
and Revaccination for Children Age 6–18 Yr ‡
 UNDERLYING PCV13 PPSV23 REVACCINATION
RISK GROUP MEDICAL
RECOMMENDED RECOMMENDED 5 YR AFTER 1ST
CONDITION DOSE
Immunocompetent Chronic heart disease § ✓
persons Chronic lung disease || ✓
Diabetes mellitus ✓
Cerebrospinal fluid ✓ ✓
leaks
Cochlear implants ✓ ✓
Alcoholism ✓
Chronic liver disease ✓
Cigarette smoking ✓
Persons with Sickle cell disease, ✓ ✓ ✓
functional or anatomic other
asplenia hemoglobinopathies
Congenital or acquired ✓ ✓ ✓
asplenia
Immunocompromised Congenital or acquired ✓ ✓ ✓
persons immunodeficiencies ¶
HIV infection ✓ ✓ ✓
Chronic renal failure ✓ ✓ ✓
Nephrotic syndrome ✓ ✓ ✓
Leukemia ✓ ✓ ✓
Lymphoma ✓ ✓ ✓
Hodgkin disease ✓ ✓ ✓
Generalized ✓ ✓ ✓
malignancy
Iatrogenic ✓ ✓ ✓
immunosuppression**
Solid-organ transplant ✓ ✓ ✓
Multiple myeloma ✓ ✓ ✓
* 13-valent pneumococcal conjugate vaccine.

† 23-valent pneumococcal polysaccharide vaccine.

‡ Children age 2-5 yr with chronic conditions (e.g., heart disease, diabetes),
immunocompromising conditions (e.g., HIV), functional or anatomic asplenia (including sickle cell
disease), cerebrospinal fluid leaks, or cochlear implants, and who have not previously received
PCV13, have been recommended to receive PCV13 since 2010.
§ Including congestive heart failure and cardiomyopathies.

|| Including chronic obstructive pulmonary disease, emphysema, and asthma.

¶ Includes B- (humoral) or T-lymphocyte deficiency, complement deficiencies (particularly C1, C2,

C3, and C4 deficiencies), and phagocytic disorders (excluding chronic granulomatous disease).
** Diseases requiring treatment with immunosuppressive drugs, including long-term systemic

corticosteroids and radiation therapy.

From Centers for Disease Control and Prevention: Use of 13-valent pneumococcal conjugate
vaccine and 23-valent pneumococcal polysaccharide vaccine among children aged 6-18 years
with immunocompromising conditions: recommendations of the Advisory Committee on
Immunization Practices, MMWR 62:521–524, 2013.
by the presence of shock and multiorgan system failure early in the course of the
infection (Table 210.1 ). The 2nd syndrome is GAS necrotizing fasciitis ,
characterized by extensive local necrosis of subcutaneous soft tissues and skin.
The 3rd syndrome is the group of focal and systemic infections that do not meet
the criteria for TSS or necrotizing fasciitis and includes bacteremia with no
identified focus, meningitis, pneumonia, peritonitis, puerperal sepsis,
osteomyelitis, suppurative arthritis, myositis, and surgical wound infections.
GAS TSS, necrotizing fasciitis, and focal and systemic infections can be present
in any combination.

Table 210.1
Definition of Streptococcal Toxic Shock Syndrome
CLINICAL CRITERIA
Hypotension plus 2 or more of the following:
Renal impairment
Coagulopathy
Hepatic involvement
Adult respiratory distress syndrome
Generalized erythematous macular rash
Soft tissue necrosis
DEFINITE CASE
Clinical criteria plus group A streptococcus from a normally sterile site
PROBABLE CASE
Clinical criteria plus group A streptococcus from a nonsterile site

The pathogenic mechanisms responsible for severe, invasive GAS infections,

including streptococcal TSS and necrotizing fasciitis, have yet to be defined
completely, but an association with streptococcal pyrogenic exotoxins is strongly
suspected. At least 2 of the 3 original streptococcal pyrogenic exotoxins (A and
C), the newly discovered streptococcal pyrogenic exotoxins, and potentially
other as yet unidentified toxins produced by GAS act as superantigens , which
stimulate intense activation and proliferation of T lymphocytes and
macrophages, resulting in the production of large quantities of proinflammatory
cytokines. These cytokines are capable of inducing shock and tissue injury and
appear to mediate many of the clinical manifestations of severe, invasive GAS
infections.

Diagnosis
adherence to the Jones Criteria in 3 circumstances: (1) when chorea occurs as the
only major manifestation of acute RF, (2) when indolent carditis is the only
manifestation in patients who first come to medical attention only months after
the apparent onset of acute RF, and (3) in a limited number of patients with
recurrence of acute RF in particularly high-risk populations.

Table 210.2
Guidelines for the Diagnosis of Initial or Recurrent Attack
of Rheumatic Fever (Jones Criteria, Updated 2015)1-5
MAJOR MINOR SUPPORTING EVIDENCE OF ANTECEDENT GROUP A
MANIFESTATIONS MANIFESTATIONS STREPTOCOCCAL INFECTION
Carditis Clinical Positive throat culture or rapid streptococcal antigen test
Polyarthritis features: Elevated or increasing streptococcal antibody titer
Erythema Arthralgia
marginatum Fever
Subcutaneous Laboratory
nodules features:
Chorea Elevated acute-
phase reactants:
Erythrocyte
sedimentation rate
C-reactive protein
Prolonged P-R
interval
1. Initial attack : 2 major manifestations, or 1 major and 2 minor manifestations, plus evidence of
recent GAS infection. Recurrent attack : 2 major, or 1 major and 2 minor, or 3 minor
manifestations (the latter only in the Moderate/High-Risk population), plus evidence of recent GAS
infection (see text).
2. Low-Risk population is defined as acute rheumatic fever (ARF) incidence <2 per 100,000
school-age children per year, or all-age rheumatic heart disease (RHD) prevalence of <1 per
1,000 population. Moderate/High-Risk population is defined as ARF incidence >2 per 100,000
school-age children per year, or all-age RHD prevalence of >1 per 1,000 population.
3. Carditis is now defined as clinical and/or subclinical (echocardiographic valvulitis). See Table
210.3 .
4. Arthritis (major) refers only to polyarthritis in Low-Risk populations, but also to monoarthritis or
polyarthralgia in Moderate/High-Risk populations.
5. Minor criteria for Moderate/High-Risk populations only include monoarthralgia (polyarthralgia
for Low-Risk populations), fever of >38°C (>38.5°C in Low-Risk populations), ESR >30 mm/hr
(>60 mm/hr in Low-Risk populations).
From Gewitz MH, Baltimore RS, Tani LY, et al: Revision of the Jones Criteria for the diagnosis of
acute rheumatic fever in the era of Doppler echocardiography: a scientific statement from the
American Heart Association, Circulation 131(20):1806–1818, 2015.
Systemic lupus erythematosus (SLE) can usually be distinguished from acute
RF by antinuclear antibodies in SLE. Other causes of arthritis such as pyogenic
arthritis, malignancies, serum sickness, Lyme disease, sickle cell disease, and
reactive arthritis related to gastrointestinal infections (e.g., Shigella, Salmonella,
Yersinia ) should also be considered. Poststreptococcal reactive arthritis is
discussed earlier (see Chapter 210).

Table 210.3

Differential Diagnosis of Acute Rheumatic Fever

ARTHRITIS CARDITIS CHOREA
Juvenile idiopathic arthritis Viral myocarditis Huntington chorea
Reactive arthritis (e.g., Shigella, Salmonella, Yersinia ) Viral pericarditis Wilson disease
Serum sickness Infective endocarditis Systemic lupus erythematosus
Sickle cell disease Kawasaki disease Tic disorder
Malignancy Congenital heart disease Hyperactivity
Systemic lupus erythematosus Mitral valve prolapse Encephalitis
Lyme disease (Borrelia burgdorferi) Innocent murmurs
Pyogenic arthritis
Poststreptococcal reactive arthritis

When carditis is the sole major manifestation of suspected acute RF, viral
myocarditis, viral pericarditis, Kawasaki disease, and infective endocarditis
should also be considered. Patients with infective endocarditis may present with
both joint and cardiac manifestations. These patients can usually be
distinguished from patients with acute RF by blood cultures and the presence of
extracardiac findings (e.g., hematuria, splenomegaly, splinter hemorrhages).
When chorea is the sole major manifestation of suspected acute RF, Huntington
chorea, Wilson disease, SLE, and various encephalitides should also be
considered.

Treatment
All patients with acute rheumatic fever should be placed on bed rest and
monitored closely for evidence of carditis. They can be allowed to ambulate
when the signs of acute inflammation have improved. However, patients with
carditis require longer periods of bed rest.

Antibiotic Therapy
Appropriate antibiotic therapy instituted before the 9th day of symptoms of acute
GAS pharyngitis is highly effective in preventing first attacks of acute RF.
However, approximately 30% of patients with acute RF do not recall a preceding
episode of pharyngitis and did not seek therapy.

Secondary Prevention
Secondary prevention is directed at preventing acute GAS pharyngitis in patients
at substantial risk of recurrent acute RF. Secondary prevention requires
continuous antibiotic prophylaxis, which should begin as soon as the diagnosis
of acute RF has been made and immediately after a full course of antibiotic
therapy has been completed. Because patients who have had carditis with their
initial episode of acute RF are at higher risk for having carditis with recurrences
and for sustaining additional cardiac damage, they should receive long-term
antibiotic prophylaxis well into adulthood and perhaps for life (Tables 210.4 and
210.5 ).

Table 210.4
Chemoprophylaxis for Recurrences of Acute Rheumatic
Fever (Secondary Prophylaxis)

DRUG DOSE ROUTE

Penicillin G 600,000 IU for children weighing ≤60 lb and 1.2 million IU for children Intramuscular
benzathine >60 lb, every 4 wk*
or
Penicillin V 250 mg, twice daily Oral
or
Sulfadiazine or 0.5 g, once daily for patients weighing ≤60 lb Oral
sulfisoxazole 1.0 g, once daily for patients weighing >60 lb
For People Who Are Allergic to Penicillin and Sulfonamide Drugs
Macrolide or azalide Variable Oral
* In high-risk situations, administration every 3 wk is recommended.

Adapted from Gerber MA, Baltimore RS, Eaton CB, et al: Prevention of rheumatic fever and
diagnosis and treatment of acute streptococcal pharyngitis: a scientific statement from the
American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee of
the Council on Cardiovascular Disease in the Young, Circulation 119:1541–1551, 2009.

Table 210.5

Duration of Prophylaxis for People Who Have Had Acute Rheumatic Fever: AHA
Recommendations
CATEGORY DURATION
Rheumatic fever without carditis 5 yr or until 21 yr of age, whichever is longer
Rheumatic fever with carditis but without residual heart 10 yr or until 21 yr of age, whichever is longer
disease (no valvular disease* )
Rheumatic fever with carditis and residual heart disease 10 yr or until 40 yr of age, whichever is longer;
(persistent valvular disease* ) sometimes lifelong prophylaxis
* Clinical or echocardiographic evidence.

Adapted from Gerber MA, Baltimore RS, Eaton CB, et al: Prevention of rheumatic fever and
diagnosis and treatment of acute streptococcal pharyngitis: a scientific statement from the
American Heart Association (AHA) Rheumatic Fever, Endocarditis, and Kawasaki Disease
Committee of the Council on Cardiovascular Disease in the Young, Circulation 119:1541–1551,
2009.

Patients who did not have carditis with their initial episode of acute RF have a
relatively low risk for carditis with recurrences. Antibiotic prophylaxis should
continue in these patients until the patient reaches 21 yr of age or until 5 yr have
elapsed since the last rheumatic fever attack, whichever is longer. The decision
to discontinue prophylactic antibiotics should be made only after careful
consideration of potential risks and benefits and of epidemiologic factors such as
the risk for exposure to GAS infections.
The regimen of choice for secondary prevention is a single intramuscular
injection of benzathine penicillin G (600,000 IU for children weighing ≤60 lb
and 1.2 million IU for those >60 lb) every 4 wk (Table 210.4 ). In certain high-
risk patients, and in certain areas of the world where the incidence of rheumatic
fever is particularly high, use of benzathine penicillin G every 3 wk may be
necessary because serum concentrations of penicillin may decrease to marginally
effective levels after 3 wk. In the United States, administration of benzathine
penicillin G every 3 wk is recommended only for those who have recurrent acute
RF despite adherence to a 4 wk regimen. In compliant patients, continuous oral
antimicrobial prophylaxis can be used. Penicillin V (250 mg twice daily) and
sulfadiazine or sulfisoxazole (500 mg for those weighing ≤60 lb or 1,000 mg for
those >60 lb, once daily) are equally effective when used in such patients. For
the exceptional patient who is allergic to both penicillin and sulfonamides, a
macrolide (erythromycin or clarithromycin) or azalide (azithromycin) may be
used. Table 210.5 notes the duration of secondary prophylaxis.

Bibliography
birth. In utero infection may result in septic abortion or immediate distress after
birth. More than 80% of early-onset GBS disease presents as sepsis; pneumonia
and meningitis are other common manifestations. Asymptomatic bacteremia is
uncommon but can occur. In symptomatic patients, nonspecific signs such as
hypothermia or fever, irritability, lethargy, apnea, and bradycardia may be
present. Respiratory signs are prominent regardless of the presence of
pneumonia and include cyanosis, apnea, tachypnea, grunting, flaring, and
retractions. A fulminant course with hemodynamic abnormalities, including
tachycardia, acidosis, and shock, may ensue. Persistent fetal circulation may
develop. Clinically and radiographically, pneumonia associated with early-onset
GBS disease is difficult to distinguish from respiratory distress syndrome .
Patients with meningitis often present with nonspecific findings, as described for
sepsis or pneumonia, with more specific signs of CNS involvement initially
absent.

Table 211.1

Characteristics of Early- and Late-Onset Group B Streptococcus Disease

EARLY-ONSET
LATE-ONSET DISEASE
DISEASE
Age at onset 0-6 days 7-90 days
Increased risk after obstetric Yes No
complications
Common clinical manifestations Sepsis, pneumonia, Bacteremia, meningitis, osteomyelitis, other focal
meningitis infections
Common serotypes Ia, Ib, II, III, V III predominates
Case fatality rate 4.7% 2.8%
Adapted from Schrag SJ, Zywicki S, Farley MM, et al: Group B streptococcal disease in the era of
intrapartum antibiotic prophylaxis, N Engl J Med 342:15–20, 2000.

Late-onset neonatal GBS disease presents at ≥7 days of life (may be seen in

1st 2-3 mo) and usually manifests as bacteremia (45–65%) and meningitis (25–
35%). Focal infections involving bone and joints, skin and soft tissue, the
urinary tract, or lungs may also be seen. Cellulitis and adenitis are often
localized to the submandibular or parotid regions. In contrast to early-onset
disease, maternal obstetric complications are not risk factors for the development
of late-onset GBS disease. Infants with late-onset disease are often less severely
ill on presentation than infants with early-onset disease, and the disease is often
less fulminant.
Invasive GBS disease in children beyond early infancy is uncommon.
Treatment
Penicillin G is the treatment of choice of confirmed GBS infection. Empirical
therapy of neonatal sepsis that could be caused by GBS generally includes
ampicillin and an aminoglycoside, both for the need for broad coverage pending
organism identification and for synergistic bactericidal activity. Once GBS has
been definitively identified and a good clinical response has occurred, therapy
may be completed with penicillin alone. Especially in patients with meningitis,
high doses of penicillin (450,000-500,000 units/kg/day) or ampicillin (300
mg/kg/day) are recommended because of the relatively high mean inhibitory
concentration (MIC) of penicillin for GBS as well as the potential for a high
initial CSF inoculum. The duration of therapy varies according to the site of
infection and should be guided by clinical circumstances (Table 211.2 ).
Extremely ill near-term patients with respiratory failure have been successfully
treated with extracorporeal membrane oxygenation.

Table 211.2

Recommended Duration of Therapy for Manifestations of Group B Streptococcus

Disease
TREATMENT DURATION
Bacteremia without a focus 10 days
Uncomplicated meningitis 14 days
Ventriculitis At least 4 wk
Septic arthritis or osteomyelitis 3-4 wk
Data from the American Academy of Pediatrics: Group B streptococcal infections. In Kimberlin
DW, Brady MT, Jackson MA, Long SS, editors: Red book: 2015 report of the Committee on
Infectious Diseases , ed 30. Elk Grove Village, IL, 2015, American Academy of Pediatrics, pp
746–747.

In patients with GBS meningitis, some experts recommend that additional

CSF be sampled at 24-48 hr to determine whether sterility has been achieved.
Persistent GBS growth may indicate an unsuspected intracranial focus or an
insufficient antibiotic dose.
For recurrent neonatal GBS disease , standard intravenous antibiotic therapy
followed by attempted eradication of GBS mucosal colonization has been
suggested. This suggestion is based on the findings in several studies that
invasive isolates from recurrent episodes are usually identical to each other and
to colonizing isolates from the affected infant. Rifampin has most frequently
been used for this purpose, but one report demonstrates that eradication of GBS
CHAPTER 212

Non–Group A or B Streptococci
David B. Haslam

The genus Streptococcus is exceptionally diverse and includes the major human
pathogens Streptococcus pyogenes (group A streptococcus), Streptococcus
agalactiae (group B streptococcus), and Streptococcus pneumoniae . Other
important pathogens include large-colony species–bearing Lancefield groups C
and G antigens and numerous small-colony variants that may or may not express
Lancefield carbohydrate antigen among the viridians streptococci (Table 212.1 ).
This chapter focuses on Streptococcus dysgalactiae subspecies equisimilis,
commonly known as “group C and G streptococci”; Chapter 209 discusses S.
pneumoniae, and Chapter 213 discusses enterococci.

Table 212.1
Relationship of Streptococci Identified by Hemolysis and
Lancefield Grouping to Sites of Colonization and Disease
Group A Streptococcus Group B Other β-HEMOLYTIC Viridans
(S. pyogenes ) Streptococcus STREPTOCOCCI Streptococci
(S. agalactiae
)
Hemolysis β β β α
Lancefield A B C-H, K-V
group Especially C and G
Species or M types (>180) Serotypes (Ia, Ib, Streptococcus
strains II, III, IV, V, VI, bovis
VII, and VIII) Streptococcus
mitis
Streptococcus
mutans
Streptococcus
sanguis
Many others
Normal Pharynx, skin, anus Gastrointestinal Pharynx, skin, Pharynx,
 flora and genitourinary gastrointestinal and nose, skin,
tract genitourinary tracts genitourinary
tract
Common Pharyngitis, tonsillitis, erysipelas, Puerperal sepsis Wound infections, Endocarditis,
human impetigo, septicemia, wound chorioamnionitis, puerperal sepsis, human bite
diseases infections, necrotizing fasciitis, endocarditis, cellulitis, sinusitis, infections
cellulitis, meningitis, pneumonia, neonatal sepsis, endocarditis, brain
scarlet fever, toxic shock–like meningitis, abscess, sepsis,
syndrome, rheumatic fever, acute osteomyelitis, nosocomial infections,
glomerulonephritis pneumonia opportunistic infections
α, Partial hemolysis; β, complete hemolysis; γ, no hemolysis (nonhemolytic).

All members of the genus Streptococcus are gram-positive, catalase-negative

organisms. Lancefield carbohydrate antigen, hemolytic activity, and colony
morphology have classically been used to further distinguish and classify
streptococci. These features provide a useful framework for the clinician and are
still the most commonly used classification schema. However, grouping based
on these phenotypic features does not precisely correlate with genetic
relatedness, and it is becoming clear that disease propensity is better correlated
with sequence homology than with Lancefield grouping or hemolytic activity.
In this chapter, groups C and G streptococci refer exclusively to the large
colony-forming organisms, often called “S. pyogenes– like,” because their
microbiologic and clinical features tend to mimic those of group A
streptococcus. Despite their different Lancefield antigens, the group C and G
streptococci are almost identical genetically and are placed within the S.
dysgalactiae subsp. equisimilis (SDSE ) group. Their genome sequences are
approximately equidistant between S. pyogenes and animal pathogens that bear
the group C antigen, which are classified as S. dysgalactiae subsp. dysgalactiae.
These 2 subspecies of S. dysgalactiae likely will be split into distinct species in
the future, when their sequence-based grouping will reflect their propensity to
cause human (represented by subsp. equisimilis ) and animal (represented by
subsp. dysgalactiae ) infections.
The groups C and G streptococci share a number of virulence factors with S.
pyogenes , including the production of streptolysin O, M protein, streptococcal
pyrogenic exotoxin B, and hyaluronidase. The M protein is similar to that of S.
pyogenes and may account for postinfectious glomerulonephritis that is
occasionally seen after infection with these organisms. A toxic shock–like
syndrome associated with groups C and G streptococcal infection has been
related to M protein type and production of a pyrogenic exotoxin by SDSE.
SDSE organisms are common habitants of the pharynx, detected in up to 5%
of asymptomatic children. Other potential sites of colonization include the skin
Enterococci are highly resistant to cephalosporins and semisynthetic penicillins
such as nafcillin, oxacillin, and methicillin. They are moderately resistant to
extended-spectrum penicillins such as ticarcillin and carbenicillin. Ampicillin,
imipenem, and penicillin are the most active β-lactams against these organisms.
Some strains of E. faecalis and E. faecium demonstrate decreased resistance to
β-lactam antibiotics because of mutations in penicillin-binding protein 5. In
addition, occasional strains of E. faecalis produce a plasmid-encoded β-
lactamase similar to that found in Staphylococcus. These isolates are completely
resistant to penicillins, necessitating the combination of a penicillin plus a β-
lactamase inhibitor or the use of imipenem or vancomycin. Any active drug may
be insufficient if used alone for serious infections where high bactericidal
activity is desired (Tables 213.1 and 213.2 ).

Table 213.1

Intrinsic Resistance Mechanisms Among Enterococci

ANTIMICROBIAL MECHANISM
Ampicillin, penicillin Altered binding protein
Aminoglycoside (low level) Decreased permeability, altered ribosomal binding
Clindamycin Altered ribosomal binding
Erythromycin Altered ribosomal binding
Tetracyclines Efflux pump
Trimethoprim-sulfamethoxazole Utilize exogenous folate

Table 213.2

Acquired Resistance Mechanisms Among Enterococci

ANTIMICROBIAL MECHANISM
Ampicillin, penicillin (high level) Mutation of PBP5
Aminoglycoside (high level) Enzyme modification
Quinolones DNA gyrase mutation
Chloramphenicol Efflux pump
Glycopeptide Altered cell wall binding
Quinupristin-dalfopristin Ribosomal modification, efflux pump
Linezolid Point mutation
Daptomycin Unknown

All enterococci have intrinsic low-level resistance to aminoglycosides because

these antibiotics are poorly transported across the Enterococcus cell wall.
Concomitant use of a cell wall active agent, such as a β-lactam or glycopeptide
antibiotic, improves the permeability of the cell wall for the aminoglycosides,
stored contaminated food. Listeriosis is an uncommon but important recognized
etiology of neonatal sepsis and meningitis. Small clusters of nosocomial person-
to-person transmission have occurred in hospital nurseries and obstetric suites.
Sporadic endemic listeriosis is less well characterized. Likely routes include
food-borne infection and zoonotic spread. Zoonotic transmission with
cutaneous infections occurs in veterinarians and farmers who handle sick
animals.
Reported cases of listeriosis are clustered at the extremes of age. Some studies
show higher rates in males and a seasonal predominance in the late summer and
fall in the Northern hemisphere. Outside the newborn period and during
pregnancy, disease is usually reported in patients with underlying
immunosuppression, with a 100-300 times increased risk in HIV-infected
persons and in the elderly population (Table 215.1 ). In a recent surveillance
study from England, malignancies accounted for one third of cases, with special
risk associated with cancer in elderly persons.

Table 215.1
Types of Listeria monocytogenes Infections
Listeriosis in pregnancy
Neonatal listeriosis
Early onset
Late onset
Food-borne outbreaks/febrile gastroenteritis
Listeriosis in normal children and adults (rare)
Focal Listeria infections (e.g., meningitis, endocarditis, pneumonia, liver abscess, osteomyelitis, septic arthritis)
Listeriosis in immunocompromised persons
Lymphohematogenous malignancies
Collagen vascular diseases
Diabetes mellitus
HIV infection
Transplantation
Renal failure with peritoneal dialysis
Listeriosis in elderly persons

The incubation period, which is defined only for common-source food-borne

disease, is 21-30 days but in some cases may be longer. Asymptomatic carriage
and fecal excretion are reported in 1–5% of healthy persons and 5% of abattoir
workers, but duration of excretion, when studied, is short (<1 mo.).

Pathology
Clinical Manifestations
The clinical presentation of listeriosis depends greatly on the age of the patient
and the circumstances of the infection.

Listeriosis in Pregnancy
Pregnant women have increased susceptibility to Listeria infectious
(approximately 20 times higher than nonpregnant women), probably because of
a relative impairment in cell-mediated immunity. L. monocytogenes has been
grown from placental and fetal cultures of pregnancies ending in spontaneous
abortion. The usual presentation in the 2nd and 3rd trimesters is a flulike illness
that may result in seeding of the uterine contents by bacteremia. Rarely is
maternal listeriosis severe, but meningitis in pregnancy has been reported.
Recognition and treatment at this stage are associated with normal pregnancy
outcomes, but the fetus may not be infected even if listeriosis in the mother is
not treated. In other instances, placental listeriosis develops with infection of the
fetus that may be associated with stillbirth or premature delivery. Delivery of an
infected premature fetus is associated with very high infant mortality.
Disseminated disease is apparent at birth, often with a diffuse pustular rash.
Infection in the mother usually resolves without specific therapy after delivery,
but postpartum fever and infected lochia may occur.

Neonatal Listeriosis
Two clinical presentations are recognized for neonatal listeriosis: early-onset
neonatal disease (<5 days, usually within 1-2 days of birth), which is a
predominantly septicemic form, and late onset neonatal disease (>5 days, mean
14 days of life), which is a predominantly meningitic form (Table 215.2 ). The
principal characteristics of the 2 presentations resemble the clinical syndromes
described for group B streptococcus (see Chapter 211 ).

Table 215.2
Characteristic Features of Early- and Late-Onset Neonatal
Listeriosis

EARLY ONSET (<5 DAYS) LATE ONSET (≥5 DAYS)

 Positive result of maternal Listeria culture Negative results of maternal Listeria culture
Obstetric complications Uncomplicated pregnancy
Premature delivery Term delivery
Low birthweight Normal birthweight
Neonatal sepsis Neonatal meningitis
Mean age at onset 1.5 days Mean age at onset 14.2 days
Mortality rate >30% Mortality rate <10%
Nosocomial outbreaks

Early-onset disease occurs with milder transplacental or ascending infections

from the female genital tract. There is a strong association with recovery of L.
monocytogenes from the maternal genital tract, obstetric complications,
prematurity, and neonatal sepsis with multiorgan involvement, including rash,
but without CNS localization (Fig. 215.1 ). The mortality rate is approximately
20–30%.

FIG. 215.1 Listeria monocytogenes. The generalized maculopapular rash present at
birth disappeared within a few hours of life. (From Benitez-Segura I, Fiol-Jaume M,
Balliu PR, Tejedor M: Listeria monocytogenes : generalized maculopapular rash may be
the clue, Arch Dis Child Fetal Neonatal Ed 98(1):F64, 2013, Fig 1.)

The epidemiology of late-onset disease is poorly understood. Onset is usually

after 5 days but before 30 days of age. Affected infants frequently are full-term,
and the mothers are culture negative and asymptomatic. The presenting
syndrome is usually purulent meningitis with parenchymal brain involvement,
which, if adequately treated, has a mortality rate of <20%.

Postneonatal Infections
Listeriosis beyond the newborn period may rarely occur in otherwise healthy
although maternal infection with sparing of the fetus has been reported. There is
no convincing evidence that L. monocytogenes is associated with repeated
spontaneous abortions in humans. The mortality rate is >50% for premature
infants infected in utero, 30% for early-onset neonatal sepsis, 15% for late-onset
neonatal meningitis, and <10% in older children with prompt institution of
appropriate antimicrobial therapy. Mental retardation, hydrocephalus, and other
CNS sequelae are reported in survivors of Listeria meningitis.

Prevention
Listeriosis can be prevented by pasteurization and thorough cooking of foods.
Irradiation of meat products may also be beneficial. Consumption of
unpasteurized or improperly processed dairy products should be avoided,
especially aged soft cheeses, uncooked and precooked meat products that have
been stored at 4°C (39.2°F) for extended periods, and unwashed vegetables
(Table 215.3 ). This avoidance is particularly important during pregnancy and for
immunocompromised persons. Infected domestic animals should be avoided
when possible. Education regarding risk reduction is aimed particularly at
pregnant women and people being treated for cancer.

Table 215.3
Prevention of Food-Borne Listeriosis
GENERAL RECOMMENDATIONS TO PREVENT LISTERIA INFECTION
FDA recommendations for washing and handling food:
• Rinse raw produce, such as fruits and vegetables, thoroughly under running tap water before eating, cutting, or
cooking. Even if the produce will be peeled, it should still be washed first.
• Scrub firm produce, such as melons and cucumbers, with a clean produce brush.
• Dry the produce with a clean cloth or paper towel.
• Separate uncooked meats and poultry from vegetables, cooked foods, and ready-to-eat foods.
Keep your kitchen and environment cleaner and safer.
• Wash hands, knives, countertops, and cutting boards after handling and preparing uncooked foods.
• Be aware that Listeria monocytogenes can grow in foods in the refrigerator. Use an appliance thermometer, such
as a refrigerator thermometer, to check the temperature inside your refrigerator. The refrigerator should be 4.5°C
(40°F) or lower and the freezer −17.8°C (0°F) or lower.
• Clean up all spills in your refrigerator promptly, especially juices from hot dog and lunch meat packages, raw
meat, and raw poultry.
• Clean the inside walls and shelves of your refrigerator with hot water and liquid soap, then rinse.
Cook meat and poultry thoroughly.
• Thoroughly cook raw food from animal sources, such as beef, pork, or poultry to a safe internal temperature. For
a list of recommended temperatures for meat and poultry, visit the safe minimum cooking temperatures chart at
http://www.FoodSafety.gov .
Store foods safely.
 • Use precooked or ready-to-eat food as soon as you can. Do not store the product in the refrigerator beyond the
use-by date; follow USDA refrigerator storage time guidelines:
• Hot dogs: store opened package no longer than 1 wk and unopened package no longer than 2 wk in the
refrigerator.
• Luncheon and deli meat: store factory-sealed, unopened package no longer than 2 wk. Store opened packages
and meat sliced at a local deli no longer than 3-5 days in the refrigerator.
• Divide leftovers into shallow containers to promote rapid, even cooling. Cover with airtight lids or enclose in
plastic wrap or aluminum foil. Use leftovers within 3-4 days.
Choose safer foods.
• Do not drink raw (unpasteurized) milk, and do not eat foods that have unpasteurized milk in them.
RECOMMENDATIONS FOR PERSONS AT HIGHER RISK *
In addition to the recommendations listed above, include:
Meats
• Do not eat hot dogs, luncheon meats, cold cuts, other deli meats (e.g., bologna), or fermented or dry sausages
unless they are heated to an internal temperature of 73.9°C (165°F) or until steaming hot just before serving.
• Avoid getting fluid from hot dog and lunch meat packages on other foods, utensils, and food preparation
surfaces, and wash hands after handling hot dogs, luncheon meats, and deli meats.
• Pay attention to labels. Do not eat refrigerated pâté or meat spreads from a deli or meat counter or from the
refrigerated section of a store. Foods that do not need refrigeration, such as canned or shelf-stable pâté and meat
spreads, are safe to eat. Refrigerate after opening.
Cheeses
• Do not eat soft cheese such as feta, queso blanco, queso fresco, brie, Camembert, blue-veined, or panela (queso
panela) unless it is labeled as made with pasteurized milk. Make sure the label says “MADE WITH
PASTEURIZED MILK.”
Seafood
• Do not eat refrigerated smoked seafood, unless it is contained in a cooked dish, such as a casserole, or unless it
is a canned or shelf-stable product.
• Refrigerated smoked seafood, such as salmon, trout, whitefish, cod, tuna, and mackerel, is most often labeled as
“nova-style,” “lox,” “kippered,” “smoked,” or “jerky.”
• These fish are typically found in the refrigerator section or sold at seafood and deli counters of grocery stores
and delicatessens.
• Canned and shelf stable tuna, salmon, and other fish products are safe to eat.
Follow this general FDA advice for melon safety:
• Consumers and food preparers should wash their hands with warm water and soap for at least 20 sec before and
after handling any whole melon, such as cantaloupe, watermelon, or honeydew.
• Scrub the surface of melons, such as cantaloupes, with a clean produce brush under running water and dry them
with a clean cloth or paper towel before cutting. Be sure that your scrub brush is sanitized after each use, to
avoid transferring bacteria between melons.
• Promptly consume cut melon or refrigerate promptly. Keep your cut melon refrigerated ≤4.5°C (40°F) (0-1.1°C
[32-34°F] is best), for no more than 7 days.
• Discard cut melons left at room temperature for >4 hr.
* Including pregnant women, persons with weakened immune system, and older adults.

FDA, Food and Drug Administration; USDA, U.S. Department of Agriculture.

Adapted from Centers for Disease Control and Prevention: Listeria (listeriosis): prevention.
http://www.cdc.gov/listeria/prevention.html .

Careful handwashing is essential to prevent nosocomial spread within

obstetric and neonatal units. Immunocompromised patients given prophylaxis
with trimethoprim-sulfamethoxazole are protected from Listeria infections.
Cases and especially outbreaks should be reported immediately to public health
authorities so that timely investigation can be initiated in order to interrupt
symptoms, refusal to drink, and vomiting. Less frequently, diarrhea, sore throat,
and chills/shivering are reported. A maculopapular rash, which is
indistinguishable from rashes seen after viral infections, is evident in
approximately 10% of cases early in the course of infection (Fig. 218.2 ). Limb
pain, myalgia, or refusal to walk may occur as the primary complaint in 7% of
otherwise clinically unsuspected cases. As disease progresses, cold hands or feet
and abnormal skin color may be important signs, capillary refill time becomes
prolonged, and a nonblanching or petechial rash will develop in >80% of cases.
In fulminant meningococcal septicemia, the disease progresses rapidly over
several hours from fever with nonspecific signs to septic shock characterized by
prominent petechiae and purpura (purpura fulminans ) with poor peripheral
perfusion, tachycardia (to compensate for reduced blood volume resulting from
capillary leak), increased respiratory rate (to compensate for pulmonary edema),
hypotension (a late sign of shock in young children), confusion, and coma
(resulting from decreased cerebral perfusion). Coagulopathy, electrolyte
disturbance (especially hypokalemia), acidosis, adrenal hemorrhage, renal
failure, and myocardial failure may all develop (Fig. 218.3 ). Meningitis may be
present.

Table 218.1
Prevalence of Symptoms and Signs in Children and Young
People With Meningococcal Septicemia, Meningococcal
Disease, and Bacterial Meningitis

PREVALENCE RANGE (NUMBER OF STUDIES)

SYMPTOM OR SIGN Bacterial Meningococcal Meningococcal
Meningitis Disease Septicemia
Fever 66-97% (10) 58-97% (7) 98% (1)
Vomiting or nausea 18-70% (10) 44-76% (6)
Rash 9-62% (6) 59-100% (9) 70% (1)
Headache 3-59% (7) 16-49% (5) 40% (1)
Lethargy 13-87% (6) 36-65% (3) 59% (1)
Coughing N/A (0) 15-27% (2) 33% (1)
Irritable or unsettled 21-79% (8) 36-67% (3) 32% (1)
Runny nose N/A (0) 24% (1) 31% (1)
Muscle ache or joint pain 23% (1) 7-65% (3) 30% (1)
Refusing food or drink 26-76% (4) 13-60% (3) 27% (1)
Altered mental state* 26-93% (6) 45-81% (3) N/A (0)
Stiff neck 13-74% (13) 5-71% (6) N/A (0)
Impaired consciousness 60-87% (4) 10-72% (2) N/A (0)
Unconsciousness 4-18% (4) N/A (0) N/A (0)
 Chills or shivering N/A (0) 39% (1) N/A (0)
Photophobia 5-16% (2) 2-31% (5) N/A (0)
Respiratory symptoms 25-49% (4) 16-23% (2) N/A (0)
Breathing difficulty 13-34% (4) 11% (1) N/A (0)
Cold hands or feet N/A (0) 43% (1) N/A (0)
Shock 8-16% (2) 27-29% (2) N/A (0)
Seizures 14-38% (12) 7-17% (3) N/A (0)
Diarrhea 21-29% (2) 7-9% (2) N/A (0)
Abdominal pain or distention 17% (1) 4% (1) N/A (0)
Leg pain N/A (0) 11-37% (2) N/A (0)
Thirst N/A (0) 8% (1) N/A (0)
Sore throat, coryza or throat infection 18% (1) 24% (1) N/A (0)
Ill appearance N/A (0) 79% (1) N/A (0)
Capillary refill time >2 sec N/A (0) 83% (1) N/A (0)
Hypotension N/A (0) 28% (1) N/A (0)
Abnormal skin color N/A (0) 19% (1) N/A (0)
Bulging fontanel † 13-45% (4) N/A (0) N/A (0)
Ear infection or ear, nose, and throat 18-49% (5) N/A (0) N/A (0)
infections ‡
Chest infection 14% (1) N/A (0) N/A (0)
Brudzinski sign 11-66% (2) N/A (0) N/A (0)
Kernig sign 10-53% (3) N/A (0) N/A (0)
Abnormal pupils 10% (1) N/A (0) N/A (0)
Cranial nerve pair involvement 4% (1) N/A (0) N/A (0)
Toxic or moribund state 3-49% (2) N/A (0) N/A (0)
Back rigidity 46% (1) N/A (0) N/A (0)
Paresis 6% (1) N/A (0) N/A (0)
Focal neurologic deficit 6-47% (3) N/A (0) N/A (0)
* This includes confusion, delirium, and drowsiness.

†
The age ranges in the 4 studies are 0-14 yr, 0-2 yr, 0-12 mo, and 0-13 wk.
‡ One study reported the number of children and young people with ear, nose, and throat

infections; the 4 other studies reported the number of ear infections only.
Classification of conditions presented in the table reflects the terminology used in the evidence.
N/A, Not applicable.
Adapted from National Collaborating Center for Women's and Children's Health (UK): Bacterial
meningitis and meningococcal septicaemia: management of bacterial meningitis and
meningococcal septicaemia in children and young people younger than 16 years in primary and
secondary care, NICE clinical guidelines, No 102, London, 2010, RCOG Press.
Antibiotics
Empirical antimicrobial therapy should be initiated immediately after the
diagnosis of invasive meningococcal infection is suspected and cultures are
obtained, using a third-generation cephalosporin to cover the most likely
bacterial pathogens until the diagnosis is confirmed. In regions with a high rate
of β-lactam–resistant S. pneumoniae , empirical addition of intravenous (IV)
vancomycin is recommended (see Chapter 621.1 ) while awaiting the outcome
of bacterial identification and sensitivity, but this is unnecessary in other settings
where cephalosporin resistance of pneumococci is very rare (in these settings a
risk assessment of each case should be made). Once the diagnosis of β-lactam–
sensitive meningococcal disease is confirmed in the laboratory, some authorities
recommend a switch to penicillin. Even with no evidence that survival outcomes
are different, however, limited evidence from one study indicates that, in
meningococcal purpura, necrotic skin lesions are less common among children
treated with ceftriaxone than with penicillin. Furthermore, it may be cost-
effective by using a once-daily dose of ceftriaxone for therapy in younger
children, and this is the recommended practice in the United Kingdom (Table
218.2 ). No adequate studies have investigated the optimal duration of therapy
for children, but the course is generally continued for 5-7 days.

Table 218.2
Treatment of Neisseria Meningitidis Invasive Infections

DOSING MAXIMUM
DRUG ROUTE DOSE INTERVAL DAILY NOTES
(hr) DOSE
Penicillin G IM or 300,000 4-6 12-24 Does not clear carriage, and
IV units/kg/day million units “prophylaxis” is required at the end of
treatment.
Ampicillin IM or 200-400 6 6-12 g Does not clear carriage, and
IV mg/kg/day “prophylaxis” is required at the end of
treatment.
Cefotaxime IM or 200-300 6-8 8-12 g Recommended in the neonate
IV mg/kg/day
Ceftriaxone IM or 100 12-24 2-4 g
Preferred treatment as only once or
IV mg/kg/day twice daily, and may reduce skin
complications.
ALTERNATIVE THERAPY IN THE FACE OF LIFE-THREATENING β-LACTAM ALLERGY
Chloramphenicol* IV 50-100 6 2-4 g
mg/kg/day
Meropenem † IV 60-120 8 1.5-6 g
mg/kg/day
Prevention
Secondary Prevention
Close contacts of patients with meningococcal disease are at increased risk of
infection because such individuals are likely to be colonized with the index
case's (hyperinvasive) strain. Antibiotic prophylaxis should be offered as soon as
possible to individuals who have been exposed directly to a patient's oral
secretions, for whom risk may be 1,000 times the background rate in the
population. This includes household, kissing, and close family contacts of cases,
as well as childcare and recent preschool contacts in the United States. Up to
30% of cases occur in the 1st wk, but risk persists for up to 1 yr after
presentation of the index case. Although prophylaxis is effective in preventing
secondary cases, co-primary cases may occur in the days after presentation of
the index case, and contacts should be carefully evaluated if they develop
symptoms. Advice on management of nonclose contacts, such as those in
daycare, nursery settings, or school and other institutions, varies in different
countries because the risk of a secondary case in this situation is low and opinion
on risk assessment varies. Ceftriaxone and ciprofloxacin are the most effective
agents for prophylaxis, with ciprofloxacin the drug of choice in some countries.
Rifampin is most widely used but fails to eradicate colonization in 15% of cases
(Table 218.3 ). Prophylaxis is not routinely recommended for medical personnel
except those with exposure to aerosols of respiratory secretions, such as through
mouth-to-mouth resuscitation, intubation, or suctioning before or in the 24 hr
after antibiotic therapy is initiated in the index case.

Table 218.3
Antibiotic Prophylaxis to Prevent Neisseria Meningitidis
Infection*

AGE-GROUP DOSE DURATION EFFICACY

Rifampin †
Infants <1 mo 5 mg/kg PO every 12 hr 2 days (4 doses)
Children ≥1 mo 10 mg/kg PO every 12 hr (max 600 mg) 2 days (4 doses) 90-95%
Adults 600 mg PO every 12 hr 2 days (4 doses) 90-95%
Ceftriaxone
Children <15 yr 125 mg IM 1 dose 90-95%
Children ≥15 yr 250 mg IM 1 dose 90-95%
Ciprofloxacin
 Children ≥1 mo † ‡ 20 mg/kg (max 500 mg) PO 1 dose 90-95%
Azithromycin (Not Recommended Routinely)
All ages 10 mg/kg (max 500 g) PO 1 dose 90%
* Recommended for household and kissing contacts. In the United States, chemoprophylaxis is
recommended for:

• Household contact, especially children <2 yr old

• Childcare or preschool contact at any time during 7
days before onset of illness
• Direct exposure to index patient's secretions through
kissing, sharing toothbrushes or eating utensils at any
time during 7 days before onset of illness
• Mouth-to-mouth resuscitation, unprotected contact
during endotracheal intubation during 7 days before
onset of illness
• Frequently slept in same dwelling as index patient
during 7 days before onset of illness
• Passengers seated directly next to the index case
during airline flights lasting >8 hr
†
Not recommended for pregnant women (ceftriaxone is agent of choice in this setting).
‡ Not recommended routinely for young people <18 yr old; use only if fluoroquinolone-resistant
strains of N. meningitidis have not been identified in the community.
IM, Intramuscularly; PO, orally (by mouth).

Neither penicillin nor ampicillin treatment eradicates nasopharyngeal carriage

and should not be routinely used for prophylaxis. Patients with meningococcal
infection treated solely with penicillin or ampicillin are therefore at risk of
relapse or transmission to a close contact and should receive antimicrobial
prophylaxis with one of the agents listed in Table 218.3 before hospital
discharge. The preference is to use ceftriaxone for treatment of the index case, in
which case further prophylaxis is not required. Droplet infection control
precautions should be observed for hospitalized patients for 24 hr. after initiation
of effective therapy. All confirmed or probable cases of meningococcal infection
must be reported to the local public health department according to national or
individual and population immunity.
Quadrivalent meningococcal A, C, Y, W conjugate vaccines (MenACWY )
have been available since 2005 and are routinely used for U.S. adolescents and
as a single adolescent booster dose in some countries that had established MenC
infant programs more than a decade ago. MenACWY was initially introduced as
a single dose at 11 yr of age in the United States, but concerns about waning
immunity led to the adoption of a 2nd dose. The initial reports on effectiveness
(>80%) of MenACWY in the U.S. program indicates that these vaccines are
likely to provide control of disease caused by capsular groups C, W, and Y
(capsular group A being unimportant currently), although the program has taken
some time to become fully established. As the population of immunized
adolescents and young adults in the United States grows, the effects of these
vaccines on carriage of meningococci likely will reduce disease among other
segments of the population through herd immunity, assuming the transmission
dynamics of Y and W meningococci are the same as for capsular group C.
Although MenACWY vaccines are not currently recommended in the United
States for routine use in younger age-groups in view of the low rate of disease
caused by these capsular groups in infancy, they may provide broader protection
in countries that are already using MenC vaccines in infant programs. Other
combination vaccines containing various conjugates, including Hib-MenC (used
in the United Kingdom as 12 mo booster) and Hib-MenCY, may have a role in
broadening protection beyond MenC, in early life. Table 218.4 outlines the
current U.S. programmatic recommendations.

Table 218.4
Recommendations for Meningococcal Vaccination (United
States, 2017)
GENERAL POPULATION
<2 YR 2-10 YR 11-18 YR 19-55 YR
Not recommended Not A single dose of MenACWY-D or Not recommended
recommended MenACWY-CRM at age 11-12 yr with a
booster dose at age 16 yr
SPECIAL POPULATIONS AT INCREASED RISK OF MENINGOCOCCAL DISEASE
RISK FACTOR 2-18 7-23 MONTHS 2-55 YR
MONTHS
Persistent complement 4 doses of 2 doses of MenACWY-CRM, with 2nd dose 2 doses of
deficiencies, MenACWY- administered at age ≥12 mo and ≥3 mo after MenACWY-CRM or
functional or anatomic CRM at 2, 4, 1st dose, or 2 doses of MenACWY-D (not MenACWY-D 8-12
asplenia 6, and 12-15 indicated for functional or anatomic asplenia wk apart* §
 mo* ‡ ) at age 9 and 12 mo* † and MenB vaccine (2
doses of 4CMenB or 3
doses of 2fHbp) †
At risk during a 4 doses of 2 doses of MenACWY-CRM, with 2nd dose 1 dose of MenACWY-
community outbreak MenACWY- administered at age ≥12 mo and ≥3 mo after CRM or MenACWY-
with a vaccine CRM at 2, 4, 1st dose, or 2 doses of MenACWY-D at age 9 D
capsular group 6, and 12-15 and 12 mo † MenB vaccine (2
covered by the mo doses of 4CMenB or 3
relevant vaccine doses of 2fHbp)
depending on capsular
group associated with
the outbreak †
Travel to or resident 4 doses of 2 doses of MenACWY-CRM, with 2nd dose 1 dose of MenACWY-
of countries where MenACWY- administered at age ≥12 mo and ≥3 mo after CRM or MenACWY-D* †
meningococcal CRM at 2, 4, 1st dose, or 2 doses of MenACWY-D at 9
disease is 6, and 12-15 and age 12 mo (could be reduced to 8 wk if
hyperendemic or mo* required for travel)* †
epidemic ǁ
Have HIV 4 doses of 2 doses of MenACWY-CRM or 2 doses of 2 doses of MenACWY-
MenACWY- MenACWY-D at age 9-23 mo, 12 wk apart* † CRM or MenACWY-D 8-
CRM at 2, 4, 12 wk apart* † ǁ
6, and 12-15
mo*
Other risk factors — — 1 dose MenACWY
* Booster every 5 yr if ongoing risk (after 3 yr if <7 yr old).

‡ Because of high risk for invasive pneumococcal disease, children with functional or anatomic
asplenia should not be immunized with MenACWY-D before age 2 yr, to avoid interference with
the immune response to the pneumococcal conjugate vaccine (PCV).
§ If MenACWY-D is used, it should be administered at least 4 wk. after completion of all PCV

doses.
ǁ For example, visitors to the “meningitis belt” of sub-Saharan Africa. Vaccination also is required
by the government of Saudi Arabia for all travelers to Mecca during the annual Hajj.
† Assuming not previously vaccinated.

Adapted from https://www.cdc.gov/vaccines/hcp/acip-recs/vacc-specific/mening.html .

Individuals at high risk of meningococcal disease, such as those with

complement deficiency and travelers to regions where there is a risk of epidemic
meningococcal disease caused by A or W, should receive MenACWY (see Table
218.4 ). The risk of disease among close contacts of cases of disease caused by
vaccine capsular groups may be further reduced if they are offered MenACWY
in addition to antimicrobial prophylaxis. A possible association between
MenACWY-diphtheria and Guillain-Barré syndrome, which caused concern
early after the vaccine was first used in the United States, has not been
substantiated.
A capsular group A meningococcal conjugate vaccine (MenA ) has been
as antibiotic resistance threat level “Urgent” by the CDC. Surveillance data from
the CDC Gonococcal Isolate Surveillance Project reveal concerning fluctuations
in minimum inhibitory concentration (MIC) for the oral cephalosporin cefixime
and the injectable third-generation cephalosporin ceftriaxone , leading the CDC
to revise its U.S. gonorrhea treatment guidelines in 2012 to dual therapy in an
attempt to preserve the last commercially available effective treatment. A
theoretical basis exists for using 2 antimicrobials with different molecular targets
to improve treatment efficacy and potentially delay emergence and spread of
resistance to cephalosporins.
Table 219.1 summarizes first-line treatment regimens for neonate, child
(weight ≤45 kg), adolescent, and adult gonococcal regimens. Mucosal, localized
infections are treatable with single doses; disseminated infections are treated for
a minimum of 1 wk. Although dual therapy is not recommended for neonatal and
childhood infections, it is recommended for all adult and adolescent infections
(inclusive of children >45 kg). The use of azithromycin as the 2nd antimicrobial
is preferred to doxycycline because of the convenience and compliance
advantages of single-dose therapy and the higher prevalence of gonococcal
resistance to tetracycline compared to azithromycin among gonococcal
surveillance isolates, particularly in strains with elevated MIC to cefixime.

Table 219.1
Recommended Treatment of Gonococcal Infections

LENGTH
INFECTION TREATMENT REGIMEN OF
THERAPY
Neonates Ophthalmia Ceftriaxone,* 25-50 mg/kg IV or IM (max 250 mg), plus Once
neonatorum lavage infected eye frequently until discharge eliminated
Disseminated Ceftriaxone,* 25-50 mg/kg IV or IM qd 7 days
infection or
Scalp abscess Cefotaxime, 25-50 mg/kg IV or IM q8–12h †
Septic
arthritis
Meningitis Ceftriaxone,* 25-50 mg/kg IV or IM qd 10-14 days
or
Cefotaxime, 25-50 mg/kg IV or IM q8-12h †
Endocarditis Ceftriaxone,* 25-50 mg/kg IV or IM qd Minimum 28
or days
Cefotaxime, 25-50 mg/kg IV or IM q8-12h †
Children ≤45 kg Pharyngeal Ceftriaxone, 25-50 mg/kg IV or IM (max 250 mg) Once
infection
Anorectal
infection
 Urogenital
infection
Conjunctivitis Ceftriaxone, 50 mg/kg IM (max 1 g) ‡ Once
Disseminated Ceftriaxone, 50 mg/kg IV or IM qd (max 1 g daily) 7 days
infection
Septic
arthritis
Meningitis Ceftriaxone, 50 mg/kg IV or IM q12-24h (max 4 g daily) 10-14 days
Endocarditis Ceftriaxone, 50 mg/kg IV or IM q12-24h (max 4 g daily) Minimum 28
days
Adults, adolescents, Pharyngeal Ceftriaxone, 250 mg IM Once
and children >45 kg infection plus
Anorectal Azithromycin, 1 g PO
infection
Urogenital
infection
Conjunctivitis Ceftriaxone, 1 g IM Once
plus
Azithromycin, 1 g PO ‡
Disseminated Ceftriaxone, 1 g IV or IM qd § 7 days
infection plus
Septic Azithromycin, 1 g PO Once
arthritis
Meningitis Ceftriaxone, 1-2 g IV q12-24h 10-14 days
plus
Azithromycin, 1 g PO Once
Endocarditis Ceftriaxone, 1-2 g IV q12-24h Minimum 28
plus days
Azithromycin, 1 g PO Once
* When available, cefotaxime should be substituted for ceftriaxone in neonates with
hyperbilirubinemia (particularly those who are premature) and in those <28 days old if receiving
calcium-containing intravenous fluids. Consult neonatal dosing references.
† Dose and/or dosing frequency change after postnatal age >7 days. Consult neonatal dosing
references.
‡ Plus lavage of the infected eye with saline solution (once).

§ Ceftriaxone should be continued for 24-48 hr after clinical improvement begins, at which time
the switch may be made to an oral agent (e.g., cefixime or a quinolone) if antimicrobial
susceptibility is documented by culture. If no organism is isolated and the diagnosis is secure,
treatment with ceftriaxone should be continued for at least 7 days.
IM, Intramuscularly; IV, intravenously; PO, orally (by mouth); qd, every day; q8-12h, every 8 to 12
hours.
From Hsu KK, Wangu Z: Neisseria gonorrhoeae. In Long SS, Prober CG, Fischer M, editors:
Principles and practice of pediatric infectious diseases, ed 5, Philadelphia, 2018, Elsevier, Table
126.1.

Alternative regimens exist for adolescents and adults but are extremely
limited. For patients with cephalosporin allergy, the combination of gentamicin
(240 mg intramuscularly [IM]) plus azithromycin (2 g orally [PO]) cured 100%
mo to 3 yr old in at least some countries. With the exception of patients with
endocarditis, the presentation of invasive K. kingae infections is frequently mild,
and a body temperature <38°C (100.4°F), a normal C-reactive protein (CRP)
level, and a normal white blood cell (WBC) count are common, requiring a high
index of clinical suspicion.

Table 220.1

Clinical Spectrum and Relative Frequency of Kingella kingae Infections

CLINICAL DISEASE FREQUENCY
SKELETAL SYSTEM +++
Septic arthritis +++
Osteomyelitis ++
Spondylodiscitis +
Tenosynovitis ±
Dactylitis ±
Bursitis ±
Bacteremia with no focus +++
CARDIAC +
Endocarditis +
Pericarditis ±
Meningitis ±
Peritonitis ±
Cellulitis ±
Soft tissue abscesses ±
LOWER RESPIRATORY TRACT ±
Laryngotracheobronchitis ±
Pneumonia ±
Pleural empyema ±
OCULAR ±
Keratitis ±
Corneal abscess ±
Endophthalmitis ±
Eyelid abscess ±
+++, Very common; ++, common; +, infrequent; ±, exceptional.

Septic Arthritis
Although K. kingae –driven arthritis especially affects the large, weight-bearing
joints, involvement of the small metacarpophalangeal, sternoclavicular, and
tarsal joints is not unusual (see Chapter 704 ). The disease has an acute
presentation, and children are brought to medical attention after a median of 3
days. The leukocyte count in the synovial fluid shows <50,000 WBCs/µL in
almost 25% of the patients, and the Gram stain of synovial fluid is positive in
in the immunologic response to thymus-independent type 2 antigens such as
unconjugated PRP, presumably explaining the high incidence of type b
infections in infants and young children in the prevaccine era.
The conjugate vaccines act as thymus-dependent antigens and elicit serum
antibody responses in infants and young children (Table 221.1 ). These vaccines
are believed to prime memory antibody responses on subsequent encounters with
PRP. The concentration of circulating anti-PRP antibody in a child primed by a
conjugate vaccine may not correlate precisely with protection, presumably
because a memory response may occur rapidly on exposure to PRP and provide
protection.

Table 221.1
Haemophilus influenzae Type b (Hib) Conjugate Vaccines
Available in the United States

VACCINE TRADE NAME COMPONENTS MANUFACTURER

PRP-T ActHib PRP conjugated to tetanus toxoid Sanofi
PRP-T Hibrix PRP conjugated to tetanus toxoid GlaxoSmithKline Biologicals
PRP-OMP PedvaxHIB PRP conjugated to OMP Merck
PRP-T/DTaP-IPV Pentacel PRP-T + DTaP-IPV vaccines Sanofi Pasteur
DTaP, Diphtheria and tetanus toxoids and acellular pertussis vaccine; HepB, hepatitis B vaccine;
IPV, trivalent inactivated polio vaccine; OMP, outer membrane protein complex from Neisseria
meningitidis ; PRP, polyribosylribitol phosphate.

Much less is known about immunity to other H. influenzae serotypes or to

nontypeable isolates. For nontypeable isolates, evidence suggests that antibodies
directed against 1 or more outer membrane proteins are bactericidal and protect
against experimental challenge. A variety of antigens have been evaluated in an
attempt to identify vaccine candidates for nontypeable H. influenzae, including
outer membrane proteins (P1, P2, P4, P5, P6, D15, and Tbp A/B), LPS, various
adhesins, and lipoprotein D.

Diagnosis
Presumptive identification of H. influenzae is established by direct examination
of the collected specimen after staining with Gram reagents. Because of its small
size, pleomorphism, and occasional poor uptake of stain, as well as the tendency
for proteinaceous fluids to have a red background, H. influenzae is sometimes
cardiac, pulmonary, muscular, or neurologic disorders have increased risk of
poor outcome beyond infancy. Table 224.1 lists caveats in assessment and care
of infants with pertussis. The specific, limited goals of hospitalization are to (1)
assess progression of disease and likelihood of life-threatening events at peak of
disease; (2) maximize nutrition; (3) prevent or treat complications; and (4)
educate parents in the natural history of the disease and in care that will be given
at home. Heart rate, respiratory rate, and pulse oximetry are monitored
continuously with alarm settings so that paroxysms can be witnessed and
recorded by healthcare personnel. Detailed cough records and documentation of
feeding, vomiting, and weight change provide data to assess severity. Typical
paroxysms that are not life threatening have the following features: duration <45
sec; red but not blue color change; tachycardia, bradycardia (not <60 beats/min
in infants), or oxygen desaturation that spontaneously resolves at the end of the
paroxysm; whooping or strength for brisk self-rescue at the end of the paroxysm;
self-expectorated mucus plug; and posttussive exhaustion but not
unresponsiveness. Assessing the need to provide oxygen, stimulation, or
suctioning requires skilled personnel who can watchfully observe an infant's
ability for self-rescue but who will intervene rapidly and expertly when
necessary. The benefit of a quiet, dimly lighted, undisturbed, comforting
environment cannot be overestimated or forfeited in a desire to monitor and
intervene. Feeding children with pertussis is challenging. The risk of
precipitating cough by nipple feeding does not warrant nasogastric, nasojejunal,
or parenteral alimentation in most infants. The composition or thickness of
formula does not affect the quality of secretions, cough, or retention. Large-
volume feedings are avoided.

Table 224.1
Caveats in Assessment and Care of Infants With Pertussis
• Infants with potentially fatal pertussis may appear well between episodes.
• A paroxysm must be witnessed before a decision is made between hospital and home care.
• Only analysis of carefully compiled cough record permits assessment of severity and progression of illness.
• Suctioning of nose, oropharynx, or trachea should not be performed on a “preventive” schedule.
• Feeding in the period following a paroxysm may be more successful than after napping.
• Family support begins at the time of hospitalization with empathy for the child's and family's experience to date,
transfer of the burden of responsibility for the child's safety to the healthcare team, and delineation of
assessments and treatments to be performed.
• Family education, recruitment as part of the team, and continued support after discharge are essential.

Within 48-72 hr, the direction and severity of disease are obvious from
analysis of recorded information. Hospital discharge is appropriate if, over 48 hr,
disease severity is unchanged or diminished, intervention is not required during
paroxysms, nutrition is adequate, no complication has occurred, and parents are
adequately prepared for care at home. Apnea and seizures occur in the
incremental phase of illness and in patients with complicated disease. Portable
oxygen, monitoring, or suction apparatus should not be needed at home.
Infants who have apnea, paroxysms that lead to life-threatening events, or
respiratory failure require escalating respiratory support and frequently require
intubation and pharmaceutically induced paralysis.

Antibiotics
An antimicrobial agent always is given when pertussis is suspected or confirmed
to decrease contagiousness and to afford possible clinical benefit. Azithromycin
is the drug of choice in all age-groups, for treatment or postexposure
prophylaxis (Table 224.2 ). Macrolide resistance has been reported rarely, and
recent isolates have retained susceptibility despite genetic strain adaptations.
Infantile hypertrophic pyloric stenosis (IHPS) is associated with macrolide
use in young infants, especially in those <14 days old, with highest risk in those
receiving erythromycin vs azithromycin. Benefits of postexposure prophylaxis
or treatment of infants far outweigh risk of IHPS. Young infants should be
managed expectantly if projectile vomiting occurs. The FDA also warns of risk
of fatal heart rhythms with use of azithromycin in patients already at risk for
cardiovascular events, especially those with prolongation of the QT interval.
Trimethoprim-sulfamethoxazole (TMP-SMX) is an alternative to azithromycin
for infants >2 mo old and children unable to receive azithromycin. Because of
limited effectiveness, treatment of B. parapertussis is based on clinical judgment
and is considered in high-risk populations. Agents are the same as for B.
pertussis . Treatment of infections caused by other Bordetella spp. should be
undertaken with consultation of a subspecialist.

Table 224.2
Recommended Antimicrobial Treatment and Postexposure
Prophylaxis for Pertussis

AGE- PRIMARY AGENTS ALTERNATE AGENT*

GROUP Azithromycin Erythromycin Clarithromycin TMP-SMX
 <1 mo Recommended agent Not preferred Not Contraindicated for infants
10 mg/kg/day in a Erythromycin is recommended <2 mo of age (risk for
single dose for 5 days substantially (safety data kernicterus)
associated with unavailable)
infantile
hypertrophic pyloric
stenosis.
Use if azithromycin
is unavailable; 40-50
mg/kg/day in 4
divided doses for 14
days.
1-5 mo 10 mg/kg/day in a single 40-50 mg/kg/day in 4 15 mg/kg/day in Contraindicated at age
dose for 5 days divided doses for 14 days 2 divided doses <2 mo
for 7 days For infants age ≥2 mo:
TMP 8 mg/kg/day plus
SMX 40 mg/kg/day in 2
divided doses for 14
days
Infants 10 mg/kg in a single dose 40-50 mg/kg/day (max 2 15 mg/kg/day in TMP 8 mg/kg/day plus SMX
age ≥6 on day 1 (max 500 mg), g/day) in 4 divided doses 2 divided doses 40 mg/kg/day in 2 divided
mo and then 5 mg/kg/day (max 250 for 14 days (max 1 g/day) doses (max TMP: 320
children mg) on days 2-5 for 7 days mg/day) for 14 days
Adults 500 mg in a single dose on 2 g/day in 4 divided 1 g/day in 2 TMP 320 mg/day–SMX
day 1, then 250 mg/day on doses for 14 days divided doses 1600 mg/day in 2 divided
days 2-5 for 7 days doses for 14 days
* Trimethoprim-sulfamethoxazole (TMP-SMX) can be used as an alternative agent to macrolides

in patients ≥2 mo old who are allergic to macrolides, who cannot tolerate macrolides, or who are
infected with a rare macrolide-resistant strain of Bordetella pertussis .
Adapted from Centers for Disease Control and Prevention (CDC): Recommended antimicrobial
agents for treatment and postexposure prophylaxis of pertussis: 2005 CDC guidelines, MMWR
54:1–16, 2005.

Adjunct Therapies
No rigorous clinical trial has demonstrated a beneficial effect of β2 -adrenergic
stimulants such as salbutamol and albuterol. Fussing associated with aerosol
treatment triggers paroxysms. No randomized, blinded clinical trial of sufficient
size has been performed to evaluate the usefulness of corticosteroids in the
management of pertussis; their clinical use is not warranted. A randomized,
double-blind, placebo-controlled trial of pertussis immunoglobulin intravenous
(IGIV) was halted prematurely because of expiration/lack of additional supply of
study product; there was no indication of clinical benefit. Standard
immunoglobulin has not been studied and should not be used for treatment or
prophylaxis.
alteration in the expression of a number of host genes, including those encoding
proinflammatory mediators (inducible nitric oxide synthase, chemokines, IL-1β),
receptors or adhesion molecules (tumor necrosis factor [TNF]-α receptor, CD40,
intercellular adhesion molecule 1), and antiinflammatory mediators
(transforming growth factor-β1, TGF-β2). Other upregulated genes include those
involved in cell death or apoptosis (intestinal epithelial cell protease, TNF-R1,
Fas) and transcription factors (early growth response 1, interferon [IFN]
regulatory factor 1). S. Typhimurium can induce rapid macrophage death in
vitro, which depends on the host cell protein caspase-1 and is mediated by the
effector protein SipB (Salmonella invasion protein B). Intracellular S.
Typhimurium is found within specialized vacuoles that have diverged from the
normal endocytic pathway. This ability to survive within
monocytes/macrophages is essential for S. Typhimurium to establish a systemic
infection in the mouse. The mucosal proinflammatory response to S.
Typhimurium infection and the subsequent recruitment of phagocytic cells to the
site may also facilitate systemic spread of the bacteria.
Some virulence traits are shared by all salmonellae, but others are serotype
restricted. These virulence traits have been defined in tissue culture and murine
models, and it is likely that clinical features of human Salmonella infection will
eventually be related to specific DNA sequences. With most diarrhea-associated
nontyphoidal salmonelloses, the infection does not extend beyond the lamina
propria and the local lymphatics. Specific virulence genes are related to the
ability to cause bacteremia. These genes are found significantly more often in
strains of S. Typhimurium isolated from the blood than in strains recovered from
stool. Although both S. dublin and S. choleraesuis have a greater propensity to
rapidly invade the bloodstream with little or no intestinal involvement, the
development of disease after infection with Salmonella depends on the number
of infecting organisms, their virulence traits, and several host defense factors.
Various host factors may also affect the development of specific complications
or clinical syndromes (Table 225.1 ); of these factors, HIV infections are
assuming greater importance in Africa in all age-groups.

Table 225.1
Host Factors and Conditions Predisposing to Development
of Systemic Disease with Nontyphoidal Salmonella (NTS)
Strains
 Neonates and young infants (≤3 mo old)
HIV/AIDS
Other immunodeficiencies and chronic granulomatous disease
Defects in interferon γ production or action
Immunosuppressive and corticosteroid therapies
Malignancies, especially leukemia and lymphoma
Hemolytic anemia, including sickle cell disease, malaria, and bartonellosis
Collagen vascular disease
Inflammatory bowel disease
Achlorhydria or use of antacid medications
Impaired intestinal motility
Schistosomiasis, malaria
Malnutrition

Bacteremia is possible with any Salmonella serotype, especially in

individuals with reduced host defenses and especially in those with altered
reticuloendothelial or cellular immune function. Thus, children with HIV
infection, chronic granulomatous disease, and leukemia are more likely to
develop bacteremia after Salmonella infection, although the majority of children
with Salmonella bacteremia are HIV-negative. Children with Schistosoma
mansoni infection and hepatosplenic involvement, as well as chronic malarial
anemia, are also at a greater risk for development of chronic salmonellosis.
Children with sickle cell disease are at increased risk for Salmonella septicemia
and osteomyelitis. This risk may be related to the presence of numerous
infarcted areas in the gastrointestinal (GI) tract, bones, and RES, as well as
reduced phagocytic and opsonizing capacity of patients.

Clinical Manifestations
Acute Enteritis
The most common clinical presentation of salmonellosis is acute enteritis. After
an incubation period of 6-72 hr (mean: 24 hr), there is an abrupt onset of nausea,
vomiting, and crampy abdominal pain, located primarily in the periumbilical
area and right lower quadrant, followed by mild to severe watery diarrhea and
sometimes by diarrhea containing blood and mucus. A large proportion of
children with acute enteritis are febrile, although younger infants may exhibit a
normal or subnormal temperature. Symptoms usually subside within 2-7 days in
healthy children, and fatalities are rare. However, some children experience
severe disease with a septicemia-like picture (high fever, headache, drowsiness,
confusion, meningismus, seizures, abdominal distention). The stool typically
contains a moderate number of PMNs and occult blood. Mild leukocytosis may
necessary to perform susceptibility tests on all human isolates. Infections with
suspected drug-resistant Salmonella should be closely monitored and treated
with appropriate antimicrobial therapy.

Table 225.2
Treatment of Salmonella Gastroenteritis
ORGANISM AND INDICATION
Salmonella infections in infants <3 mo old or in immunocompromised persons (in addition to appropriate
treatment for underlying disorder)
DOSE AND DURATION OF TREATMENT
Cefotaxime, † 100-200 mg/kg/day every 6-8 hr for 5-14 days*
or
Ceftriaxone, 75 mg/kg/day once daily for 7 days*
or
Ampicillin, 100 mg/kg/day every 6-8 hr for 7 days*
or
Cefixime, 15 mg/kg/day for 7-10 days*
* A blood culture should be obtained prior to antibiotic therapy. In a well appearing
immunocompetent child without evidence of disseminated disease, a single dose of ceftriaxone
may be given followed by oral azithromycin; ampicillin, trimethoprim-sulfamethoxazole, or a
fluoroquinolone may be substituted once sensitivities are known.
† If available.

Prognosis
Most healthy children with Salmonella gastroenteritis recover fully. However,
malnourished children and children who do not receive optimal supportive
treatment are at risk for development of prolonged diarrhea and complications.
Young infants and immunocompromised patients often have systemic
involvement, a prolonged course, and extraintestinal foci. In particular, children
with HIV infection and Salmonella infections can have a florid course.
After infection, NTS are excreted in feces for a median of 5 wk. A prolonged
carrier state after nontyphoidal salmonellosis is rare but may be seen in children,
particularly those with biliary tract disease and cholelithiasis after chronic
hemolysis. During the period of Salmonella excretion, the individual may infect
others, directly by the fecal-oral route or indirectly by contaminating foods.
Prevention
Control of the transmission of Salmonella infections to humans requires control
of the infection in the animal reservoir, judicious use of antibiotics in dairy and
livestock farming, prevention of contamination of foodstuffs prepared from
animals, and use of appropriate standards in food processing in commercial and
private kitchens. Because large outbreaks are often related to mass food
production, it should be recognized that contamination of just one piece of
machinery used in food processing may cause an outbreak; meticulous cleaning
of equipment is essential. Clean water supply and education in handwashing and
food preparation and storage are critical to reducing person-to-person
transmission. Salmonella may remain viable when cooking practices prevent
food from reaching a temperature >65.5°C (150°F) for >12 min. Parents should
be advised of the risk of various pets(classically including reptiles and
amphibians but also rodents) and be given recommendations for preventing
transmission from these frequently infected hosts (Table 225.3 ).

Table 225.3
Recommendations for Preventing Transmission of
Salmonella from Reptiles and Amphibians to Humans
Pet store owners, healthcare providers, and veterinarians should provide information to owners and potential
purchasers of reptiles and amphibians about the risks for and prevention of salmonellosis from these pets.
Persons at increased risk for infection or serious complications from salmonellosis (e.g., children <5 yr old,
immunocompromised persons) should avoid contact with reptiles and amphibians and any items that have been
in contact with reptiles and amphibians.
Reptiles and amphibians should be kept out of households that include children <5 yr old or immunocompromised
persons. A family expecting a child should remove any pet reptile or amphibian from the home before the infant
arrives.
Reptiles and amphibians should not be allowed in childcare centers.
Persons should always wash their hands thoroughly with soap and water after handling reptiles and amphibians or
their cages.
Reptiles and amphibians should not be allowed to roam freely throughout a home or living area.
Pet reptiles and amphibians should be kept out of kitchens and other food preparation areas. Kitchen sinks should
not be used to bathe reptiles and amphibians or to wash their dishes, cages, or aquariums. If bathtubs are used
for these purposes, they should be cleaned thoroughly and disinfected with bleach.
Reptiles and amphibians in public settings (e.g., zoos, exhibits) should be kept from direct or indirect contact with
patrons except in designated “animal contact” areas equipped with adequate handwashing facilities. Food and
drink should not be allowed in animal contact areas.
From Centers for Disease Control and Prevention: Reptile-associated salmonellosis—selected
states, 1998–2002, MMWR 52:1206–1210, 2003.

In contrast to the situation in developed countries, relatively little is known

crops of 10-15 on the lower chest and abdomen and last 2-3 days (Fig. 225.6 ).
These lesions may be difficult to see in dark-skinned children. Patients managed
as outpatients present with fever (99%) but have less emesis, diarrhea,
hepatomegaly, splenomegaly, and myalgias than patients who require hospital
admission.

Table 225.4

Common Clinical Features of Typhoid Fever in Children*

FEATURE RATE (%)
High-grade fever 95
Coated tongue 76
Anorexia 70
Vomiting 39
Hepatomegaly 37
Diarrhea 36
Toxicity 29
Abdominal pain 21
Pallor 20
Splenomegaly 17
Constipation 7
Headache 4
Jaundice 2
Obtundation 2
Ileus 1
Intestinal perforation 0.5
* Data collected in Karachi, Pakistan, from 2,000 children.
 If no complications occur, the symptoms and physical findings gradually
resolve within 2-4 wk; however, the illness may be associated with malnutrition
in a number of affected children. Although enteric fever caused by S. Paratyphi
organisms has been classically regarded as a milder illness, there have been
several outbreaks of infection with drug-resistant S. Paratyphi A, suggesting that
paratyphoid fever may also be severe, with significant morbidity and
complications.

Complications
Although altered liver function is found in many patients with enteric fever,
clinically significant hepatitis, jaundice, and cholecystitis are relatively rare and
may be associated with higher rates of adverse outcome. Intestinal hemorrhage
(<1%) and perforation (0.5–1%) are infrequent among children. Intestinal
perforation may be preceded by a marked increase in abdominal pain (usually in
the right lower quadrant), tenderness, vomiting, and features of peritonitis.
Intestinal perforation and peritonitis may be accompanied by a sudden rise in
pulse rate, hypotension, marked abdominal tenderness and guarding, and
subsequent abdominal rigidity. A rising white blood cell count with a left shift
and free air on abdominal radiographs may be seen in such cases.
Rare complications include toxic myocarditis, which may manifest as
arrhythmias, sinoatrial block, or cardiogenic shock (Table 225.5 ). Neurologic
complications are also relatively uncommon among children; they include
delirium, psychosis, increased intracranial pressure, acute cerebellar ataxia,
chorea, deafness, and Guillain-Barré syndrome. Although case fatality rates may
be higher with neurologic manifestations, recovery usually occurs with no
sequelae. Other reported complications include fatal bone marrow necrosis, DIC,
hemolytic-uremic syndrome, pyelonephritis, nephrotic syndrome, meningitis,
endocarditis, parotitis, orchitis, and suppurative lymphadenitis.

Table 225.5
Extraintestinal Infectious Complications of Typhoid Fever
Caused by Salmonella enterica Serotype Typhi

ORGAN PREVALENCE
RISK FACTORS COMPLICATIONS
SYSTEM (%)
Central 3-35 Residence in endemic region, Encephalopathy, cerebral edema,
 nervous malignancy, endocarditis, congenital subdural empyema, cerebral abscess,
system heart disease, paranasal sinus meningitis, ventriculitis, transient
infections, pulmonary infections, Parkinsonism, motor neuron disorders,
meningitis, trauma, surgery, ataxia, seizures, Guillain-Barré
osteomyelitis of skull syndrome, psychosis
Cardiovascular 1-5 Cardiac abnormalities—e.g., Endocarditis, myocarditis, pericarditis,
system existing valvular abnormalities, arteritis, congestive heart failure
rheumatic heart disease, congenital
heart defects
Pulmonary 1-6 Residence in endemic region, past Pneumonia, empyema, bronchopleural
system pulmonary infection, sickle cell fistula
anemia, alcohol abuse, diabetes,
HIV infection
Bone and joint <1 Sickle cell anemia, diabetes, Osteomyelitis, septic arthritis
systemic lupus erythematosus,
lymphoma, liver disease, previous
surgery or trauma, extremes of age,
corticosteroid use
Hepatobiliary 1-26 Residence in endemic region, Cholecystitis, hepatitis, hepatic
system pyogenic infections, intravenous abscesses, splenic abscess, peritonitis,
drug use, splenic trauma, HIV, paralytic ileus
hemoglobinopathy
Genitourinary <1 Urinary tract abnormalities, pelvic Urinary tract infection, renal abscess,
system pathology, systemic abnormalities pelvic infections, testicular abscess,
prostatitis, epididymitis
Soft tissue At least 17 cases Diabetes Psoas abscess, gluteal abscess,
infections reported in cutaneous vasculitis
English-
language
literature
Hematologic At least 5 cases Hemophagocytosis syndrome
reported in
English-
language
literature
From Huang DB, DuPont HL: Problem pathogens: extra-intestinal complications of Salmonella
enterica serotype Typhi infection, Lancet Infect Dis 5:341–348, 2005.

The propensity to become a carrier follows the epidemiology of gallbladder

disease, increasing with patient age and the antibiotic resistance of the prevalent
strains. Although limited data are available, rates of chronic carriage are
generally lower in children than adults.

Diagnosis
The mainstay of the diagnosis of typhoid fever is a positive result of culture from
the blood or another anatomic site. Results of blood cultures are positive in 40–
60% of the patients seen early in the course of the disease, and serial blood
cultures may be required to identify Salmonella bacteremia. Stool and urine
viral infections such as Dengue fever, acute hepatitis, and infectious
mononucleosis.
Infection by Salmonella in general, and typhoid or paratyphoid fever in
particular, should be thoroughly considered in the differential diagnosis and
workup for fever in a returned traveler.

Treatment
An early diagnosis of typhoid fever and institution of appropriate treatment are
essential. The vast majority of children with typhoid fever can be managed at
home with oral antibiotics and close medical follow-up for complications or
failure of response to therapy. Patients with persistent vomiting, severe diarrhea,
and abdominal distention may require hospitalization and parenteral antibiotic
therapy.
There are general principles of typhoid fever management. Adequate rest,
hydration, and attention are important to correct fluid and electrolyte imbalance.
Antipyretic therapy (acetaminophen 10-15 mg/kg every 4-6 hr PO) should be
provided as required. A soft, easily digestible diet should be continued unless the
patient has abdominal distention or ileus. Antibiotic therapy is critical to
minimize complications (Table 225.6 ). It has been suggested that traditional
therapy with either chloramphenicol or amoxicillin is associated with relapse
rates of 5–15% and 4–8%, respectively, whereas use of the azithromycin,
quinolones and third-generation cephalosporins is associated with higher cure
rates. The antibiotic treatment of typhoid fever in children is also influenced by
the prevalence of antimicrobial resistance. Over the past 2 decades, emergence
of MDR strains of S. Typhi (i.e., isolates fully resistant to amoxicillin,
trimethoprim-sulfamethoxazole, and chloramphenicol) has necessitated
treatment with fluoroquinolones , which are the antimicrobial drug of choice for
treatment of salmonellosis in adults, with cephalosporins as an alternative. Some
regions are also reporting S. Typhi that produce extended-spectrum β-lactamases.
Fig. 225.7 shows known worldwide distribution patterns of antimicrobial
resistance among S. Typhi isolates.

Table 225.6
Treatment of Typhoid Fever in Children
 OPTIMAL THERAPY ALTERNATIVE EFFECTIVE DRUGS
SUSCEPTIBILITY
Daily Dose Daily Dose
Antibiotic Days Antibiotic Days
(mg/kg/day) (mg/kg/day)
UNCOMPLICATED TYPHOID FEVER
Fully sensitive Chloramphenicol 50-75 14- Fluoroquinolone, e.g., 15 5-7*
21 ofloxacin or ciprofloxacin
Amoxicillin 75-100 14
Multidrug resistant Fluoroquinolone 15 5-7 Azithromycin 8-10 7
or
Cefixime 15-20 7-14 Cefixime 15-20 7-14
Quinolone resistant † Azithromycin 8-10 7 Cefixime 20 7-14
or
Ceftriaxone 75 10-
14
SEVERE TYPHOID FEVER
Fully sensitive Fluoroquinolone 15 10- Chloramphenicol 100 14-
(e.g., ofloxacin) 14 21
Amoxicillin 100
Multidrug resistant Fluoroquinolone 15 10- Ceftriaxone 60 10-
14 14
or
Cefotaxime ‡ 80 10-
14
Quinolone resistant Ceftriaxone 60 10- Azithromycin 10-20 7
14
Cefotaxime ‡ 80 10- Fluoroquinolone 20 7-14
14
* A 3-day course is also effective, particularly for epidemic containment.

†
The optimum treatment for quinolone-resistant typhoid fever has not been determined.
Azithromycin, third-generation cephalosporins, or high-dose fluoroquinolones for 10-14 days is
effective.
‡ If available.

Adapted from World Health Organization: Treatment of typhoid fever. In Background document:
the diagnosis, prevention and treatment of typhoid fever. Communicable disease surveillance and
response: vaccines and biologicals, Geneva, 2003, WHO, pp 19–23.
http://whqlibdoc.who.int/hq/2003/WHO_V&B_03.07.pdf .
reduced antigen-specific antibody-secreting cells with late and reduced mucosa
IgA production against Shigella . Less effective adaptive immunity may put
children at more risk for increased disease severity, mortality, and recurrences.

Clinical Manifestations and

Complications
Shigellae produce intra- and extraintestinal symptoms. Bacillary dysentery is
clinically similar regardless of infecting serotype . However, different species
produce illnesses with different severity and risk for mortality, with S.
dysenteriae type 1 most likely to produce any single manifestation and with
greater severity. Ingestion of shigellae is followed by an incubation period of 12
hr to several days before symptoms ensue. Severe abdominal pain, emesis,
anorexia, generalized toxicity, urgency, and painful defecation characteristically
occur (Table 226.1 ). The typically high fever with shigellosis distinguishes it
from EHEC. The diarrhea may be watery and of large volume initially,
evolving into frequent, small-volume, bloody mucoid stools. Most children
never progress to the stage of bloody diarrhea, but some have bloody stools from
the outset. Significant dehydration is related to the fluid and electrolyte losses in
feces and emesis. Untreated diarrhea can last 7-10 days; only approximately
10% of patients have diarrhea persisting for >10 days. Persistent diarrhea occurs
in malnourished infants, children with AIDS, and occasionally previously
normal children. Even nondysenteric disease can be complicated by persistent
illness.

Table 226.1

Acute Clinical Manifestations of Shigellosis in Children <5 Yr Old

DYSENTERY WATERY DIARRHEA
MANIFESTATION
(n = 757) (n = 288)
Fever 607 (80%) 207 (72%)
Abdominal cramps 616 (81%) 137 (48%)
Vomiting 136 (18%) 89 (31%)
WHO-defined dehydration 95 (13%) 134 (47%)
Tenesmus 511 (68%) 32 (11%)
Rectal prolapse 19 (3%) 4 (1%)
From Kotloff KL, Riddle MS, Platts-Mills JA, et al: Shigellosis, Lancet 391:801–810, 2018.
 Physical examination initially shows abdominal distention and tenderness,
hyperactive bowel sounds, and a tender rectum on digital examination. Rectal
prolapse may be present, particularly in malnourished children. Neurologic
findings are among the most common extraintestinal manifestations of bacillary
dysentery, occurring in as many as 40% of hospitalized children. EIEC can cause
similar neurologic toxicity. Convulsions, headache, lethargy, confusion, nuchal
rigidity, or hallucinations may be present before or after the onset of diarrhea.
The cause of these neurologic findings is not understood. Infections with Shiga
toxin positive and negative strains can lead to neurologic features. Seizures
sometimes occur when little fever is present, suggesting that simple febrile
convulsions do not explain their appearance. Hypocalcemia or hyponatremia
may be associated with seizures in a small number of patients. Although
symptoms often suggest central nervous system infection, and cerebrospinal
fluid pleocytosis with minimally elevated protein levels can occur, meningitis
caused by shigellae is rare. Based on animal studies, it has been suggested that
proinflammatory mediators, including TNF-α and IL-1β, nitric oxide, and
corticotropin-releasing hormone, all play a role in the enhanced susceptibility to
Shigella -mediated seizures and encephalopathy.
The most common complication of shigellosis is dehydration (Table 226.2 ).
Inappropriate secretion of antidiuretic hormone with profound hyponatremia can
complicate dysentery, particularly when S. dysenteriae is the etiologic agent.
Hypoglycemia and protein-losing enteropathy are common and are decreased by
early appropriate antibiotic therapy. Severe protein-losing enteropathy is
associated with prolonged illness and linear growth shortfalls. Bacteremia is
uncommon except in girls or women infected with HIV, malnourished children,
young infants, and children with S. dysenteriae serotype 1 infection. When
bacteremia occurs with dysentery (<5%), it is as likely to be caused by other
enteric bacteria as by Shigella itself. The presence of E. coli, Klebsiella , and
other enteric bacteria in blood cultures of children with shigellosis may reflect
the loss of the barrier function during severe colitis. The mortality rate is high
(approximately 20%) when sepsis occurs, with a greater likelihood of occurrence
in HIV-infected persons. Other major complications include disseminated
intravascular coagulation (DIC), particularly in very young, malnourished
children. Despite the extent to which the intestinal epithelial barrier is lost,
bacteremia and DIC are uncommon.

Table 226.2
Clinical Complications of Shigellosis
INTESTINAL COMPLICATIONS
Rectal prolapse*
Toxic megacolon
Intestinal perforation
Intestinal obstruction
Appendicitis
Persistent diarrhea
EXTRAINTESTINAL COMPLICATIONS
Dehydration
Severe hyponatremia (serum sodium <126 mmol/L)*
Hypoglycemia
Focal infections (e.g., meningitis, osteomyelitis, arthritis, splenic abscesses, vaginitis)
Sepsis, usually in malnourished or immunocompromised persons
Seizure or encephalopathy
Leukemoid reaction (peripheral leukocytes >40 000/µL)*
POSTINFECTIOUS MANIFESTATIONS
Hemolytic-uremic syndrome (HUS)*
Reactive arthritis †
Irritable bowel syndrome (IBS) ‡
Malnutrition
* Significantly more common in episodes with Shigella dysenteriae type 1 than with all other
Shigella spp. among Bangladeshi children younger than 15 yr during the 1990s (rectal prolapse
[52% vs 15%], severe hyponatremia [58% vs 26%], leukemoid reaction [22% vs 2%], and HUS
[8% vs 1%]).
† Typical acute symptoms include asymmetric oligoarthritis (usually lower limb), enthesitis,

dactylitis, and back pain. Extraarticular manifestations include conjunctivitis and uveitis; urethritis
and other genitourinary tract manifestations; oral, skin, and nail lesions; and rarely, cardiac
abnormalities.
‡ IBS follows approximately 4% of Shigella episodes in studies from high-resource settings.

Adapted from Kotloff KL, Riddle MS, Platts-Mills JA, et al: Shigellosis, Lancet 391:801–810, 2018.

Neonatal shigellosis is rare, particularly among the exclusively breastfed.

Neonates may have only low-grade fever with mild, nonbloody diarrhea.
However, complications occur more often in neonates than in older children and
include septicemia, meningitis, dehydration, colonic perforation, and toxic
megacolon.
S. dysenteriae serotype 1 infection is frequently complicated by hemolysis,
anemia, and hemolytic-uremic syndrome . HUS is caused by Shiga toxin–
mediated vascular endothelial injury. Shiga- toxin–producing non-dysenteriae
Shigella and E. coli that produce Shiga toxins (e.g., E. coli O157:H7, E. coli
O111:NM, E. coli O26:H11, and less often, many other serotypes) also cause
HUS (see Chapter 538.5 ).
contains many serotypes (e.g., 117 ETEC serotypes have been identified), and
some serotypes can belong to more than 1 pathotype (e.g., O26:H11 can be
either EPEC or EHEC, depending on which specific virulence genes are
present), serotyping frequently does not provide definitive identification of
pathotypes.
Because E. coli are normal fecal flora, pathogenicity is defined by
demonstration of virulence characteristics and association of those traits with
illness (Table 227.1 ). The mechanism by which E. coli produces diarrhea
typically involves adherence of organisms to a glycoprotein or glycolipid
receptor on a target intestinal cell, followed by production of a factor that injures
or disturbs the function of intestinal cells. The genes for virulence properties and
antibiotic resistance are often carried on transferable plasmids, pathogenicity
islands, or bacteriophages. In the developing world, the various diarrheagenic E.
coli strains cause frequent infections in the 1st years of life; diarrheagenic E. coli
as a group are responsible for 30-40% of all diarrhea cases in children
worldwide. They occur with increased frequency during the warm months in
temperate climates and during rainy season months in tropical climates. Most
diarrheagenic E. coli strains (except STEC) require a large inoculum of
organisms to induce disease, thus necessitating exposure to grossly contaminated
ingestible materials. Infection is most likely when food-handling or sewage-
disposal practices are suboptimal. The diarrheagenic E. coli pathotypes are also
important in North America and Europe, although their epidemiology is less well
defined in these areas than in the developing world. In North America, the
various diarrheagenic E. coli strains may cause as much as 30% of infectious
diarrhea in children <5 yr old.

Table 227.1
Clinical Characteristics, Pathogenesis, and Diagnosis of
Diarrheagenic E. coli

CHARACTERISTICS OF MAIN VIRULENCE

POPULATIONS DIARRHEA FACTORS
PATHOGEN DIAGNOSIS
AT RISK Adherence
Watery Bloody Duration Toxins
Factors
ETEC >1 yr old and +++ — Acute Colonization Heat-labile Detection of
travelers factor enterotoxin enterotoxins
antigens (LT) (LT and ST) by
(CFs or Heat-stable enzyme
CFAs); ECP enterotoxin immunoassays
 (ST) or PCR (lt, st )
EIEC >1 yr old + ++ Acute Invasion Detection of
plasmid invasion
antigen plasmid
(IpaABCD) antigen of
Shigella (ipaH
) by PCR
EPEC <2 yr old +++ + Acute, A/E lesion, EspF, Map, Detection of
prolonged intimin/Tir, EAST1, intimin gene
or EspABD, SPATEs (EspC (eae ) ±
persistent Bfp ) bundle-
forming pili
(bfp A) by
PCR, and
absence of
Shiga toxins;
HEp-2 cells
adherence
assay (LA,
LLA)
STEC 6 mo-10 yr and + +++ Acute A/E lesion, Shiga toxins Detection of
(EHEC/VTEC) elderly persons intimin/Tir, (Stx1, Stx2, Shiga toxins
EspABD and variants of by enzyme
Stx2) immunoassays
or PCR (Stx 1,
Stx 2); stool
culture on
MacConkey-
sorbitol media
to detect E.
coli O157.
Simultaneous
culture for
O157 and
nonculture
assays to detect
Shiga toxins
EAEC <2 yr old, HIV- +++ + Acute, Aggregative SPATEs (Pic, Detection of
infected patients, prolonged, adherence Pet), ShET1, AggR , AA
and travelers or fimbriae EAST1 plasmid, and
persistent (AAF) other virulence
genes: aap , aa
tA , astA ,
set1A by PCR;
HEp-2 cells
adherence
assay (AA)
DAEC >1 yr old and ++ — Acute Afa/Dr, SPATEs (Sat) Detection of
travelers AIDA-I Dr adhesins
(daaC or daaD)
and Dr-
associated
genes by PCR;
HEp-2 cells
adherence
 assay (DA)
—, Not present; +, present; ++, common; +++, very common; A/E lesion, attaching and effacing
lesion; AA, aggregative adherence; Bfp, bundle-forming pili; DA, diffuse adherence; DAEC,
diffusely adherent E. coli; EAEC, enteroaggregative E. coli; EAST1, enteroaggregative heat-stable
toxin; ECP, E. coli common pilus; EHEC, enterohemorrhagic E. coli; EIEC, enteroinvasive E. coli;
EPEC, enteropathogenic E. coli ; EspABD, E. coli –secreted proteins A, B, and D; ETEC,
enterotoxigenic E. coli; LA, localized adherence; LLA, localized-like adherence; PCR, polymerase
chain reaction; ShET1, Shigella enterotoxin 1; SPATEs, serine-protease autotransporter of
Enterobacteriaceae; STEC, Shiga toxin–producing E. coli ; Tir, translocated intimin receptor;
VTEC, verotoxin-producing E. coli.

Many studies have found diarrheagenic E. coli pathotypes in a significant

proportion of asymptomatic healthy children living in developing countries.
Fecal contamination (human and animal), which is common in the low-
resource environments where many young children live, facilitates the
transmission of pathogens. Also, with modern, highly sensitive microbiologic
methods, small numbers of bacteria can be detected in stool samples. Therefore,
it is important to assess the prevalence of various enteropathogens in children
with and without diarrhea to interpret results. Excretion of enteropathogens by
children without diarrhea may be explained by characteristics of the pathogens
(virulence heterogeneity), the host (host susceptibility, age, nutritional status,
breastfeeding, immunity), and environmental factors (inoculum size).

Enterotoxigenic Escherichia coli

ETEC accounts for a sizable fraction of dehydrating infantile diarrhea in the
developing world (10–30%) and of traveler's diarrhea (20–60% of cases);
ETEC is the most common cause of traveler's diarrhea. In the Global Enteric
Multicenter Study (GEMS) conducted across Asia and Africa, heat-stable
enterotoxin (ST)–expressing ETEC (with or without coexpression of heat-labile
enterotoxin [LT]) was among the most important causes of diarrhea in young
children in developing countries and was associated with increased risk of death.
The typical signs and symptoms include explosive watery, nonmucoid,
nonbloody diarrhea; abdominal pain; nausea; vomiting; and little or no fever.
The illness is usually self-limited and resolves in 3-5 days but occasionally lasts
>1 wk.
ETEC causes few or no structural alterations in the gut mucosa. Diarrhea
follows colonization of the small intestine and elaboration of enterotoxins.
ETEC strains secrete an LT and/or an ST. LT, a large molecule consisting of 5
Treatment
Rehydration is the mainstay of therapy (see Chapter 69 ). Effective and timely
case management decreases mortality considerably. Children with mild or
moderate dehydration may be treated with oral rehydration solution (ORS)
unless the patient is in shock, is obtunded, or has intestinal ileus. Vomiting is not
a contraindication to ORS. Severely dehydrated patients require intravenous
fluid, ideally with lactated Ringer solution. When available, rice-based ORS
should be used during rehydration, because this fluid has been shown to be
superior to standard ORS in children and adults with cholera. Close monitoring
is necessary, especially during the 1st 24 hr of illness, when large amounts of
stool may be passed. After rehydration, patients should be reassessed every 1-2
hr, or more frequently if profuse diarrhea is ongoing. Feeding should not be
withheld during diarrhea. Frequent, small feedings are better tolerated than less
frequent, large feedings.
Antibiotics should only be given in patients with moderately severe to severe
dehydration (Table 228.1 ). As soon as vomiting stops (usually within 4-6 hr
after initiation of rehydration therapy), an antibiotic to which local V. cholerae
strains are sensitive must be administered. Antibiotics shorten the duration of
illness, decrease fecal excretion of vibrios, decrease the volume of diarrhea, and
reduce the fluid requirement during rehydration. Single-dose antibiotics increase
compliance; doxycycline, ciprofloxacin, and azithromycin are effective against
cholera. There are increasing reports of resistance to tetracyclines, trimethoprim-
sulfamethoxazole, and other drugs. Because of these multidrug-resistant strains,
antibiotic treatment must be tailored based on available susceptibility results
from the area. The 2013 WHO guidelines recommend cotrimoxazole (4 mg
trimethoprim/kg and 20 mg/kg sulfamethoxazole/kg twice daily) and
chloramphenicol (20 mg/kg IM every 6 hr for 3 days) as possible alternative
antibiotics for treatment. A recent systematic review, however, recommended the
use of single-dose azithromycin (20 mg/kg) due to widespread antimicrobial
resistance. Cephalosporins and aminoglycosides are not clinically effective
against cholera and therefore should not be used, even if in vitro tests show
strains to be sensitive.

Table 228.1
Recommended Antimicrobials for Cholera*
 RECOMMENDING BODY ANTIBIOTIC OF CHOICE ALTERNATIVE
WHO † (antibiotics Adults Adults
recommended for cases with Doxycycline, 300 mg given as a Erythromycin, 250 mg 4 times a day
severe dehydration) single dose orally (PO) × 3 days PO
or
Tetracycline, 500 mg 4 times a
day × 3 days PO
Children Children
Tetracycline, 12.5 mg/kg/dose 4 Erythromycin, 12.5 mg/kg/dose 4
times a day × 3 days (up to 500 times a day × 3 days (up to 250 mg
mg/dose × 3 days) PO 4 times a day × 3 days) PO
PAHO ‡ (antibiotics Adults Adults
recommended for cases with Doxycycline, 300 mg PO given Ciprofloxacin, 1 g PO single dose
moderate to severe dehydration) as a single dose or
Azithromycin, 1 g PO single dose
(first line for pregnant women)
Children Children
Erythromycin, 12.5 mg/kg/dose Ciprofloxacin, 20 mg/kg PO as a
4 times a day × 3 days (up to single dose
500 mg/dose × 3 days) or
or Doxycycline, 2-4 mg/kg PO as a
Azithromycin, 20 mg/kg as a single dose
single dose (up to 1 g)
* Antibiotic selection must be based on sensitivity patterns of strains of Vibrio cholerae O1 or
O139 in the area.
† Adapted from World Health Organization: The treatment of diarrhea: a manual for physicians

and other senior health workers , 4th revision, Geneva, 2005, WHO.
‡ Adapted from Pan American Health Organization: Recommendations for clinical management of

cholera, Washington, DC, 2010. http://new.paho.org/hq/index.php?

option=com_docman&task=doc_download&gid=10813&Itemid= .

Zinc should be given as soon as vomiting stops . Zinc deficiency is common

among children in many developing countries. Zinc supplementation in children
<5 yr old shortens the duration of diarrhea and reduces subsequent diarrhea
episodes when given daily for 14 days at the time of the illness. Children <6 mo
old should receive 10 mg of oral zinc daily for 2 wk, and children >6 mo should
receive 20 mg of oral zinc daily for 2 wk.

Prevention
Improved personal hygiene, access to clean water, and sanitation are the
mainstays of cholera control. Appropriate case management substantially
decreases case fatalities to <1%. Travelers from developed countries often have
no prior exposure to cholera and are therefore at risk of developing the disease.
Children traveling to cholera-affected areas should avoid drinking potentially
contaminated water and eating high-risk foods such as raw or undercooked fish
and shellfish. No country or territory requires vaccination against cholera as a
condition for entry.
In 2016, a live oral cholera vaccine, CVD 103 Hg-R (Vaxchora, PaxVax), was
licensed in the United States for use in adults age 18-64 yr traveling to cholera-
affected areas.
Alarmed by the increasing prevalence of cholera, in 2011 the World Health
Assembly recommended the use of oral cholera vaccines to complement existing
water, sanitation, and hygiene initiatives for cholera control. Older-generation
parenteral cholera vaccines have not been recommended by World Health
Organization (WHO) because of the limited protection they confer and their high
reactogenicity. Oral cholera vaccines are safe, are protective for approximately
2-5 yr duration, and confer moderate herd protection. Three oral cholera
vaccines are currently available internationally and recognized by WHO (Table
228.2 ). An internationally licensed killed whole cell oral cholera vaccine with
recombinant B subunit (Dukoral, Crucell) has been available in >60 countries,
including the European Union, and provides protection against cholera in
endemic areas as well as cross-protection against certain strains of
enterotoxigenic E. coli . The 2 other vaccines (Shanchol, Shantha Biotech; and
Euvichol, Eubiologics) are variants of the 1st vaccine and contain the V. cholerae
O1 and O139 antigens but do not contain the B subunit. Without the B subunit,
these vaccines do not require buffer for administration, thereby reducing
administration costs and resources, making them easier to deploy.

Table 228.2

Available Oral Cholera Vaccines*

VACCINE
CONTENTS DOSING SCHEDULE
TRADE NAME
Dukoral (Crucell) 1 mg of recombinant B subunit of cholera toxin plus 2.5 × Children 2-6 yr old: 3
1010 colony-forming units of the following strains of V. doses, 1-6 wk apart
cholerae : Adults and children >6
Formalin-killed El Tor Inaba (Phil 6973) yr old: 2 doses, 1-6 wk
Heat-killed classical Inaba (Cairo 48) apart
Heat-killed classical Ogawa (Cairo 50)
Formalin-killed classical Ogawa (Cairo 50)
Shanchol V. cholerae O1: Adults and children ≥1 yr
(Shantha 600 EU Formalin-killed El Tor Inaba (Phil 6973) old: 2 doses, 2 wk apart
Biotech) 300 EU Heat-killed classical Inaba (Cairo 48)
Euvichol 300 EU Heat-killed classical Ogawa (Cairo 50)
(Eubiologics) 300 EU Formalin-killed classical Ogawa (Cairo 50)
 V. cholerae O139-600 EU of Formalin-killed strain 4260B
* WHO-prequalified vaccines.

Oral cholera vaccines have been available for >2 decades, and with the WHO
declaration, countries are now using oral cholera vaccines in mass vaccination
campaigns where cholera remains a substantial problem. A cholera vaccine
stockpile, established by WHO, is now available and can be accessed by
countries at risk for cholera, supplementing efforts to lessen the impact of this
ongoing cholera scourge.

Bibliography
Ali M, Nelson AR, Lopez AL, Sack DA. Updated global burden
of cholera in endemic countries. PLoS Negl Trop Dis .
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Clemens JD, Nair GB, Ahmed T, et al. Cholera. Lancet .
2017;390:1539–1548.
Desai SN, Pezzoli L, Martin S, et al. A second affordable oral
cholera vaccine: implications for the global vaccine stockpile.
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Hall V, Medus C, Wahl G, et al. Vibrio cholerae serogroup O1,
serotype Inaba—Minnesota, August 2016. MMWR Morb
Mortal Wkly Rep . 2017;66(36):961–962.
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Cholera incidence and mortality in sub-Saharan African sites
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paediatric cholera infection: a systematic review of the
CHAPTER 229

Campylobacter
Ericka V. Hayes

Campylobacter , typically Campylobacter jejuni and Campylobacter coli , are

found globally and are among the most common causes of human intestinal
infections. Clinical presentation varies by age and underlying conditions.

Etiology
Twenty-six species and 9 subspecies of Campylobacter are recognized (as of
December 2014). Most of these have been isolated from humans, and many are
considered pathogenic. The most significant of these are C. jejuni and C. coli,
which are believed to cause the majority of human enteritis. More than 100
serotypes of C. jejuni have been identified. C. jejuni has been subspeciated into
C. jejuni subsp. jejuni and C. jejuni subsp. doylei. Although C. jejuni subsp.
doylei has been isolated from humans, it is much less common, less hardy, and
more difficult to isolate. Other species, including Campylobacter fetus,
Campylobacter lari, and Campylobacter upsaliensis, have been isolated from
patients with diarrhea, although much less frequently (Table 229.1 ). Emerging
Campylobacter spp. have been implicated in acute gastroenteritis, inflammatory
bowel disease, and peritonitis, including C. concisus , and C. ureolyticus .
Additional Campylobacter spp. have been isolated from clinical specimens, but
their roles as pathogens have not been established.

Table 229.1

Campylobacter Species Associated With Human Disease

SPECIES DISEASES IN HUMANS COMMON SOURCES
C. jejuni Gastroenteritis, bacteremia, Guillain-Barré Poultry, raw milk, cats, dogs, cattle, swine,
 syndrome monkeys, water
C. coli Gastroenteritis, bacteremia Poultry, raw milk, cats, dogs, cattle, swine,
monkeys, oysters, water
C. fetus Bacteremia, meningitis, endocarditis, mycotic Sheep, cattle, birds, dogs
aneurysm, diarrhea
C. Diarrhea, bacteremia, proctitis Swine, cattle, deer, hamsters, raw milk, oysters
hyointestinalis
C. lari Diarrhea, colitis, appendicitis, bacteremia, UTI Seagulls, water, poultry, cattle, dogs, cats,
monkeys, oysters, mussels
C. upsaliensis Diarrhea, bacteremia, abscesses, enteritis, Cats, dogs, other domestic pets
colitis, hemolytic-uremic syndrome
C. concisus Diarrhea, gastritis, enteritis, periodontitis Human oral cavity, dogs
C. sputorum Diarrhea, bedsores, abscesses, periodontitis Human oral cavity, cattle, swine, dogs
C. rectus Periodontitis
C. mucosalis Enteritis Swine, dogs
C. jejuni Diarrhea, colitis, appendicitis, bacteremia, UTI Swine
subsp. doylei
C. curvus Gingivitis, alveolar abscess Poultry, raw milk, cats, dogs, cattle, swine,
monkeys, water, human oral cavity
C. gracilis Head and neck abscesses, abdominal abscesses, Dogs
empyema
C. Diarrhea Swine
cryaerophila
UTI, Urinary tract infection.

Campylobacter organisms are gram-negative, curved, thin (0.2-0.8 µm wide),

non–spore-forming rods (0.5-5 µm long) that usually have tapered ends. They
are smaller than most other enteric bacterial pathogens and have variable
morphology, including short, comma-shaped or S -shaped organisms and long,
multispiraled, filamentous, seagull-shaped organisms. Individual organisms are
usually motile with a flagellum at one or both poles depending on the species.
Such morphology enables these bacteria to colonize the mucosal surfaces of both
the gastrointestinal (GI) and respiratory tracts and move through them in a
spiraling motion. Most Campylobacter organisms are microaerophilic,
occasionally partially anaerobic, and oxidase positive. Most can transform into
coccoid forms under adverse conditions, especially oxidation.

Epidemiology
Worldwide, Campylobacter enteritis is a leading cause of acute diarrhea. Efforts
to reduce Campylobacter contamination and use of safe handling practices have
led to decreased incidence. Campylobacter infections can be both food-borne
and water-borne and most frequently result from ingestion of contaminated
poultry (chicken, turkey) or raw milk . Less often, the bacteria come from
communities of bacteria encased in an extracellular matrix that protects the
organisms from the host immune response and the effects of antibiotics. Biofilm
formation requires pilus-mediated attachment to a surface, proliferation of the
organism, and production of exopolysaccharide as the main bacterial component
of the extracellular matrix. A mature biofilm can persist despite an intense host
immune response, is resistant to many antimicrobials, and is difficult to eradicate
with current therapies.

Clinical Manifestations
Most clinical patterns are related to opportunistic infections in
immunocompromised hosts (see Chapter 205 ) or are associated with shunts and
indwelling catheters (Chapter 206 ). P. aeruginosa may be introduced into a
minor wound of a healthy person as a secondary invader, and cellulitis and a
localized abscess that exudes green or blue pus may follow. The characteristic
skin lesions of P. aeruginosa, ecthyma gangrenosum , whether caused by direct
inoculation or a metastatic focus secondary to septicemia, begin as pink macules
and progress to hemorrhagic nodules and eventually to ulcers with ecchymotic
and gangrenous centers with eschar formation, surrounded by an intense red
areola (Table 232.1 and Fig. 232.1 ).

Table 232.1

Pseudomonas aeruginosa Infections

INFECTION COMMON CLINICAL CHARACTERISTICS
Endocarditis Native right-sided (tricuspid) valve disease with intravenous drug abuse
Pneumonia Compromised local (lung) or systemic host defense mechanisms; nosocomial (respiratory),
bacteremic (malignancy), or abnormal mucociliary clearance (cystic fibrosis) may be
pathogenetic; cystic fibrosis is associated with mucoid P. aeruginosa organisms producing
capsular slime
Central nervous Meningitis, brain abscess; contiguous spread (mastoiditis, dermal sinus tracts, sinusitis);
system infection bacteremia or direct inoculation (trauma, surgery)
External otitis Swimmer's ear; humid warm climates, swimming pool contamination
Malignant otitis Invasive, indolent, febrile toxic, destructive necrotizing lesion in young infants,
externa immunosuppressed neutropenic patients, or diabetic patients; associated with 7th nerve
palsy and mastoiditis
Chronic mastoiditis Ear drainage, swelling, erythema; perforated tympanic membrane
Keratitis Corneal ulceration; contact lens keratitis
Endophthalmitis Penetrating trauma, surgery, penetrating corneal ulceration; fulminant progression
Osteomyelitis/septic Puncture wounds of foot and osteochondritis; intravenous drug abuse; fibrocartilaginous
arthritis joints, sternum, vertebrae, pelvis; open fracture osteomyelitis; indolent pyelonephritis and
vertebral osteomyelitis
 Urinary tract Iatrogenic, nosocomial; recurrent UTIs in children, instrumented patients, and those with
infection obstruction or stones
Intestinal tract Immunocompromised, neutropenia, typhlitis, rectal abscess, ulceration, rarely diarrhea;
infection peritonitis in peritoneal dialysis
Ecthyma Metastatic dissemination; hemorrhage, necrosis, erythema, eschar, discrete lesions with
gangrenosum bacterial invasion of blood vessels; also subcutaneous nodules, cellulitis, pustules, deep
abscesses
Primary and Local infection; burns, trauma, decubitus ulcers, toe web infection, green nail (paronychia);
secondary skin whirlpool dermatitis; diffuse, pruritic folliculitis; vesiculopustular or maculopapular,
infections erythematous lesions

FIG. 232.1 Round, nontender skin lesion on 2 yr old female's buttock.
Note the black ulcerated center of the lesion and its red margin. (From
Ghanaiem H, Engelhard D: A healthy 2-year-old child with a round black
skin lesion, J Pediatr 163:1225, 2013.)

Outbreaks of dermatitis and urinary tract infections (UTIs) caused by P.

aeruginosa have been reported in healthy persons after use of pools or hot tubs.
Skin lesions of folliculitis develop several hours to 2 days after contact with
these water sources. Skin lesions may be erythematous, macular, papular, or
pustular. Illness may vary from a few scattered lesions to extensive truncal
involvement. In some children, malaise, fever, vomiting, sore throat,
conjunctivitis, rhinitis, and swollen breasts may be associated with dermal
lesions. UTIs caused by P. aeruginosa are most often nosocomial and are often
associated with the presence of an indwelling urinary catheter, urinary tract
malformations, and previous antibiotic use. UTIs may be minimized or
prevented by prompt removal of the catheter and by early identification and
corrective surgery of obstructive lesions when present.

Burns and Wound Infection

shows the frequency of various symptoms and examination findings.

Table 233.1

Common Clinical Manifestations of Tularemia in Children

SIGN OR SYMPTOM FREQUENCY
Lymphadenopathy 96%
Fever (>38.3°C [100.9°F]) 87%
Ulcer/eschar/papule 45%
Pharyngitis 43%
Myalgias/arthralgias 39%
Nausea/vomiting 35%
Hepatosplenomegaly 35%

The clinical manifestations of tularemia have been divided into 6 major

clinical syndromes (Table 233.2 ). Ulceroglandular and glandular disease are
the 2 most common forms of tularemia diagnosed in children. Infections
following the bites of ticks or deer flies take these forms. Mortality with these
forms of tularemia is rare, especially with implementation of effective treatment.
Glandular disease, which is associated with lymphadenopathy without skin
ulceration, may also result from minor skin abrasions. Within 48-72 hr after
inoculation of the skin, an erythematous, tender, or pruritic papule may appear at
the portal of entry. This papule may enlarge and form an ulcer with a black base.
Ulcers are generally erythematous and painful with raised borders and may last
several weeks, especially if untreated. Various other skin lesions have been
described, including erythema multiforme and erythema nodosum.
Approximately 20% of patients may develop a generalized maculopapular rash
that occasionally becomes pustular.

Table 233.2

Clinical Syndromes of Tularemia in Children

CLINICAL
CHARACTERISTICS OF SYNDROME FREQUENCY
SYNDROME
Ulceroglandular Skin ulcer/eschar, painful regional adenopathy 45%
Glandular Regional adenopathy without detectable skin ulceration 25%
Pneumonia Nonproductive cough, dyspnea, pleuritic chest pain; multilobar/diffuse 14%
infiltrates > lobar infiltrates on chest radiography
Oropharyngeal Pharyngitis, mucosal ulcers, cervical adenopathy 4%
Oculoglandular Unilateral, painful, and often purulent conjunctivitis; chemosis; conjunctival 2%
ulcers; preauricular adenopathy
Typhoidal Severe systemic disease (sepsis-like syndrome): high fever, headaches, 2%
 myalgias, arthralgias, neurologic symptoms

The unifying manifestation of glandular and ulceroglandular forms of

tularemia is painful regional lymphadenopathy . Adenopathy may develop
before, concurrent with, or after skin ulceration in ulceroglandular disease.
Cervical or posterior auricular nodes are involved following bites on the head or
neck, whereas enlarged axillary or epitrochlear nodes signal exposure on the
arms. Nodes may vary in size from 0.5-10 cm ( inches) and appear singly or
in clusters. These affected nodes may become fluctuant and drain spontaneously
and are often associated with overlying skin changes. Late suppuration of the
involved nodes has been described in 25–30% of patients despite effective
therapy. Examination of this material from such lymph nodes usually reveals
sterile necrotic material.
Oropharyngeal tularemia results from consumption of poorly cooked meats
or contaminated water. This syndrome is characterized by acute pharyngitis, with
or without tonsillitis, and cervical lymphadenitis. Infected tonsils may become
large and develop a yellowish white membrane that may resemble the
membranes associated with diphtheria. GI disease may also occur and usually
presents with mild, unexplained diarrhea or emesis but may progress to rapidly
fulminant and fatal disease. GI bleeding can develop in more severe forms
associated with intestinal ulcers.
Oculoglandular tularemia is uncommon, but when it does occur, the portal
of entry is the conjunctiva. Contact with contaminated fingers or debris from
crushed insects is the most common mechanism of this form of tularemia.
Disease is generally unilateral, and the conjunctiva is painful and inflamed with
yellowish nodules and pinpoint ulcerations. Purulent conjunctivitis with
ipsilateral preauricular or submandibular lymphadenopathy can develop and is
referred to as Parinaud oculoglandular syndrome . Corneal ulceration and
perforation are uncommon but serious complications of this form of disease.
Typhoidal tularemia is usually associated with a large inoculum of
organisms and is a term used to describe severe, bacteremic disease regardless of
the mode of transmission or portal of entry. Patients are critically ill, and
symptoms mimic those with other forms of sepsis: high fevers, confusion, rigors,
myalgias, vomiting, and diarrhea. Clinicians practicing in tularemia-endemic
regions must always consider this diagnosis in critically ill children.
Complications of bacteremia with F. tularensis can include the development of
meningitis, pericarditis, hepatitis, peritonitis, endocarditis, skin/soft tissue
abscesses, and osteomyelitis. Because of its increased virulence, F. tularensis
Table 234.1
Recommended Therapy for Treatment of Brucellosis

ANTIMICROBIAL DURATION
AGE/CONDITIONS DOSE ROUTE*
AGENT †
≥8 yr Doxycycline 4.4 mg/kg/day divided twice daily; PO ≥6 wk
max 200 mg/day
plus
Rifampin 15-20 mg/kg/day in 1 or 2 divided PO ≥6 wk
doses; max 600-900 mg/day
Alternative:
Doxycycline 4.4 mg/kg/day divided twice daily; PO ≥6 wk
max 200 mg/day
plus
Streptomycin 20-40 mg/kg/day in 2-4 divided IM 2-3 wk
doses; max 1 g/day
or
Gentamicin 6-7.5 mg/kg/day in 3 divided IM/IV 1-2 wk
doses
<8 yr Trimethoprim- TMP (10 mg/kg/day; max 480 PO ≥6 wk
sulfamethoxazole mg/day) and SMX (50 mg/kg/day;
(TMP-SMX) max 2.4 g/day)
plus
Rifampin 15-20 mg/kg/day in 1 or 2 divided PO ≥6 wk
doses; max 600-900 mg/day
Meningitis, Doxycycline 4.4 mg/kg/day divided twice daily; PO ≥4-6 mo
osteomyelitis/spondylitis max 200 mg/day
endocarditis plus
Gentamicin 6-7.5 mg/kg/day in 3 divided IV 1-2 wk
doses
plus
Rifampin 15-20 mg/kg/day in 1 or 2 divided PO ≥4-6 mo
doses; max 600-900 mg/day
* PO, Oral (by mouth): IM, intramuscular; IV, intravenous.

† Longer courses of therapy may be needed for more severe or complicated cases.

In more serious infections (e.g., endocarditis, meningitis, osteoarticular), 3-

drug therapy is advised. An aminoglycoside (streptomycin, gentamicin) should
be administered for the 1st 7-14 days along with doxycycline or TMP-SMX plus
rifampin, which are then continued for 4-6 mo. Treatment may need to be
continued for up to 1 yr in severe cases of central nervous system (CNS) disease.
Although relapse occurs in approximately 5–15% of cases, antimicrobial
resistance is rare. Relapse is confirmed by isolation of Brucella within weeks to
months after therapy has ended. Prolonged treatment is the key to preventing
disease relapse, and steps should be taken to assure compliance with the long
courses of therapy needed to achieve eradication.
CHAPTER 236

Bartonella
Rachel C. Orscheln

The spectrum of disease resulting from human infection with Bartonella species
includes the association of bacillary angiomatosis and cat-scratch disease with
Bartonella henselae. There are more than 30 validated species of Bartonella ,
but 6 major species are responsible for most human disease: B. henselae,
B.quintana, B. bacilliformis, B. elizabethae, B. vinsonii, and B. clarridgeiae
(Table 236.1 ). The remaining Bartonella spp. have been found primarily in
animals, particularly rodents and moles. However, zoonotic infections from
animal-associated strains of Bartonella spp. have been reported. In 2013 a novel
Bartonella agent with the proposed name Candidatus Bartonella ancashi
(Bartonella ancashensis) was described as a cause of verruga peruana .

Table 236.1
Bartonella Species Causing Majority of Human Disease

DISEASE ORGANISM VECTOR PRIMARY RISK FACTOR

Bartonellosis (Carrión B. bacilliformis Sandfly (Lutzomyia Living in endemic areas (Andes
disease) verrucarum) Mountains)
Cat-scratch disease B. henselae Cat Cat scratch or bite
B.
clarridgeiae
Trench fever B. quintana Human body louse Body louse infestation during
outbreak
Bacteremia, endocarditis B. henselae Cat for B. henselae Severe immunosuppression
B. Rat for B. elizabethae
elizabethae Vole for B. vinsonii
B. vinsonii Human body louse for B.
B. quintana quintana
Bacillary angiomatosis B. henselae Cat for B. henselae Severe immunosuppression
B. quintana Human body louse for B.
quintana
Peliosis hepatis B. henselae Cat for B. henselae Severe immunosuppression
 B. quintana Human body louse for B.
quintana

Members of the genus Bartonella are gram-negative, oxidase-negative,

fastidious aerobic rods that ferment no carbohydrates. B. bacilliformis is the only
species that is motile, achieving motility by means of polar flagella. Optimal
growth is obtained on fresh media containing ≥5% sheep or horse blood in the
presence of 5% carbon dioxide. The use of lysis centrifugation for specimens
from blood on chocolate agar for extended periods (2-6 wk) enhances recovery.

236.1
Cat-Scratch Disease (Bartonella
henselae)
Rachel C. Orscheln

Keywords
Bartonella
B. henselae
CSD
encephalopathy
endocarditis
flea
granuloma
hepatosplenomegaly
inoculation papule
lymphadenitis
Parinaud oculoglandular syndrome
stellate macular retinopathy
Table 237.1
Diagnoses Considered in Subsequently Laboratory-
Confirmed Cases of Infant Botulism

ADMISSION DIAGNOSIS SUBSEQUENTLY CONSIDERED DIAGNOSES

Suspected sepsis, meningitis Guillain-Barré syndrome
Pneumonia Myasthenia gravis
Dehydration Disorders of amino acid metabolism
Viral syndrome Hypothyroidism
Hypotonia of unknown etiology Drug ingestion
Organophosphate poisoning
Constipation Brainstem encephalitis
Failure to thrive Heavy metal poisoning (Pb, Mg, As)
Spinal muscular atrophy type 1 (Werdnig-Hoffmann Poliomyelitis
disease) Viral polyneuritis
Hirschsprung disease
Metabolic encephalopathy
Medium-chain acetyl–coenzyme A dehydrogenase
deficiency

Differential Diagnosis
Botulism is frequently misdiagnosed, most often as a polyradiculoneuropathy
(Guillain-Barré or Miller Fisher syndrome), myasthenia gravis, or a central
nervous system (CNS) disease (Table 237.2 ). In the United States, botulism is
more likely than Guillain-Barré syndrome , intoxication, or poliomyelitis to
cause a cluster of cases of acute flaccid paralysis. Botulism differs from other
flaccid paralyses in its initial and prominent cranial nerve palsies that are
disproportionate to milder weakness and hypotonia below the neck; in its
symmetry; and in its absence of sensory nerve damage. Spinal muscular atrophy
may closely mimic infant botulism at presentation.

Table 237.2
Conditions Considered in Differential Diagnosis of
Foodborne Botulism and Wound Botulism
Acute gastroenteritis
Myasthenia gravis
Guillain-Barré syndrome
Organophosphate poisoning
Meningitis
 Encephalitis
Psychiatric illness
Cerebrovascular accident
Poliomyelitis
Hypothyroidism
Aminoglycoside-associated paralysis
Tick paralysis
Hypocalcemia
Hypermagnesemia
Carbon monoxide poisoning
Hyperemesis gravidarum
Laryngeal trauma
Diabetic complications
Inflammatory myopathy
Overexertion

Additional diagnostic procedures may be useful in rapidly excluding botulism

as the cause of paralysis. The CSF is unchanged in botulism but is abnormal in
many CNS diseases. Although the CSF protein concentration is eventually
elevated in Guillain-Barré syndrome, it may be normal early in illness. Imaging
of the brain, spine, and chest may reveal hemorrhage, inflammation, or
neoplasm. A test dose of edrophonium chloride briefly reverses paralytic
symptoms in many patients with myasthenia gravis and, reportedly, in some with
botulism, although this is rarely performed in infants. A close inspection of the
skin, especially the scalp, may reveal an attached tick that is causing paralysis.
Possible organophosphate intoxication should be pursued aggressively, because
specific antidotes (oximes) are available and because the patient may be part of a
commonly exposed group, some of whom have yet to demonstrate illness. Other
tests that require days for results include stool culture for Campylobacter jejuni
as a precipitant of Guillain-Barré syndrome, spinal muscular atrophy and other
genetic (including mitochondrial) disorders, and assays for the autoantibodies
that cause myasthenia gravis, Lambert-Eaton syndrome, and Guillain-Barré
syndrome.

Treatment
Human botulism immune globulin, given intravenously (BIG-IV, also referred to
as BabyBIG), is licensed for the treatment of infant botulism caused by type A or
B botulinum toxin. Treatment with BIG-IV consists of a single intravenous
infusion of 50-100 mg/kg (see package insert) that should be given as soon as
possible after infant botulism is suspected so as to immediately end the toxemia
that is the cause of the illness and arrest progression of paralysis. When the
Table 237.3
Complications of Infant Botulism
Acute respiratory distress syndrome
Aspiration
Clostridium difficile enterocolitis
Hypotension
Inappropriate antidiuretic hormone secretion
Long bone fractures
Misplaced or plugged endotracheal tube
Nosocomial anemia
Otitis media
Pneumonia
Pneumothorax
Recurrent atelectasis
Seizures secondary to hyponatremia
Sepsis
Subglottic stenosis
Tracheal granuloma
Tracheitis
Transfusion reaction
Urinary tract infection

Prognosis
When the regenerating nerve endings have induced formation of a new motor
end plate, neuromuscular transmission is restored. In the absence of
complications, particularly those related to hypoxia, the prognosis in infant
botulism is for full and complete recovery. Hospital stay in untreated infant
botulism averages 5.7 wk but differs significantly by toxin type, with patients
with untreated type B disease being hospitalized a mean of 4.2 wk and those
with untreated type A disease being hospitalized a mean of 6.7 wk.
In the United States, the case fatality ratio for hospitalized cases of infant
botulism is <1%. After recovery, patients with untreated infant botulism appear
to have an increased incidence of strabismus that requires timely screening and
treatment.
The case fatality ratio in foodborne and wound botulism varies by age, with
younger patients having the best prognosis. Some adults with botulism have
reported chronic weakness and fatigue for >1 yr as sequelae.

Prevention
associated with deposition of immune complexes and activation of complement,
are reported rarely after tetanus vaccination. Mass immunization campaigns in
developing countries have occasionally provoked a widespread hysterical
reaction.

Wound Management
Tetanus prevention measures after trauma consist of inducing active immunity to
tetanus toxin and of passively providing antitoxic antibody (Table 238.1 ).
Tetanus prophylaxis is an essential part of all wound management, but specific
measures depend on the nature of the injury and the immunization status of the
patient. Prevention of tetanus must be included in planning for the consequences
of bombings, natural disasters, and other possible civilian mass-casualty events.

Table 238.1
Tetanus Vaccination and Immune Globulin Use in Wound
Management

CLEAN, MINOR WOUNDS ALL OTHER WOUNDS*

HISTORY OF ABSORBED
TETANUS TOXOID TIG TIG
DTaP, Tdap, or Td † ‡ DTaP, Tdap, or TD † ‡
Uncertain or <3 doses Yes No Yes Yes
≥3 doses No if <10 yr since last dose of No No if <5 yr since last tetanus- No
tetanus-containing vaccine containing vaccine §
Yes if ≥10 yr since last dose of No Yes if ≥5 yr since last tetanus- No
tetanus-containing vaccine containing vaccine dose
* Such as, but not limited to, wounds contaminated with dirt, feces, and saliva; puncture wounds;
avulsions; and wounds resulting from missiles, crushing, burns, and frostbite.
† DTaP is used for children <7 yr old. Tdap is preferred over Td for underimmunized children ≥7 yr
old who have not received Tdap previously.
‡ Intravenous immune globulin should be used when TIG is unavailable.

§ More frequent boosters are not needed and can accentuate adverse events.

DT, Diphtheria and tetanus toxoid vaccine; DTaP, combined diphtheria toxoid–tetanus toxoid–
acellular pertussis vaccine; Td, tetanus toxoid and reduced diphtheria toxoid vaccine; Tdap,
tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine; TIG, tetanus immune
globulin.
Data from Tetanus (lockjaw). In Kimberlin DW, Brady MT, Jackson MA, Long SS, editors: Red
book: 2015 report of the Committee on Infectious Diseases, ed 30, Elk Grove Village, IL, 2015,
American Academy of Pediatrics.
eliminating certain high carrier populations from testing (e.g., children under 1
yr of age) will increase the positive predictive value of laboratory testing.
Culture for organism isolation is a sensitive test but is labor intensive, taking
several days. Culture alone is not specific because it does not differentiate
between toxin-producing and non–toxin-producing strains.
Pseudomembranous nodules and characteristic plaques may be seen on
colonoscopy or sigmoidoscopy.

Treatment
Initial treatment of CDI involves discontinuation of any nonvital antibiotic
therapy and administration of fluid and electrolyte replacement. For mild cases,
this treatment may be curative. Persistent symptoms or moderate to severe
disease warrant antimicrobial therapy directed against C. difficile.
Oral metronidazole remains the first-line therapy for mild to moderate CDI in
children (Table 239.1 ). For more severe infection, oral vancomycin is approved
by the U.S. Food and Drug Administration (FDA) for CDI. Vancomycin exhibits
ideal pharmacologic properties for treatment of this enteric pathogen, since it is
not absorbed in the gut. Vancomycin is suggested as a first-line agent for severe
disease, as manifested by hypotension, peripheral leukocytosis, or severe
pseudomembranous colitis. Concerns about cost and the emergence of
vancomycin-resistant enterococci limit its use as first-line therapy in mild to
moderate disease. Fidaxomicin , a second-line agent not yet approved for
pediatric use, is a narrow-spectrum macrolide antibiotic with noninferior
efficacy to vancomycin but superior recurrence prevention. The cost of a course
of fidaxomicin can be twice that of vancomycin and 125-fold higher than
metronidazole. Reports have demonstrated high treatment efficacy for donor
(unaffected) fecal therapy (transplant).

Table 239.1
Recommendations for the Treatment of Clostridium difficile
Infection in Children

STRENGTH OF
CLINICAL RECOMMENDED PEDIATRIC MAXIMUM
RECOMMENDATION/QUALITY
DEFINITION TREATMENT DOSE DOSE
OF EVIDENCE
Initial episode, Metronidazole × 7.5 mg/kg/dose 500 mg tid or Weak/Low
 nonsevere 10 days PO tid or qid qid
or
Vancomycin × 10 10 mg/kg/dose 125 mg qid Weak/Low
days PO qid
Initial episode, Vancomycin × 10 mg/kg/dose 500 mg qid Strong/Moderate
severe/fulminant 10 days PO or qid
PR
with or without
Metronidazole × 10 10 mg/kg/dose 500 mg tid Weak/Low
days IV* tid
First recurrence, Metronidazole × 7.5 mg/kg/dose 500 mg tid or Weak/Low
nonsevere 10 days PO tid or qid qid
or
Vancomycin × 10 10 mg/kg/dose 125 mg qid Weak/Low
days PO qid
Second or Vancomycin in a 10 mg/kg/dose 125 mg qid Weak/Low
subsequent tapered and qid
recurrence pulsed regimen †
or
Vancomycin × Vancomycin, 10 Vancomycin, Weak/Low
10 days, mg/kg/dose qid; 500 mg qid;
followed by rifaximin: no rifaximin, 400
rifaximin ‡ × 20 pediatric dosing mg tid
days
or
Fecal microbiota Weak/Very low
transplantation
* In cases of severe or fulminant Clostridium difficile infection associated with critical illness,
consider addition of intravenous metronidazole to oral vancomycin.
† Tapered and pulsed regimen: vancomycin, 10 mg/kg with max of 125 mg 4 times daily for 10-14

days, then 10 mg/kg with max of 125 mg twice daily for 1 wk, then 10 mg/kg with max of 125 mg
once daily for 1 wk, and then 10 mg/kg with max of 125 mg every 2 or 3 days for 2-8 wk.
‡ No pediatric dosing for rifaximin; not approved by the U.S. Food and Drug Administration for use
in children <12 yr old.
IV, Intravenously; PO, orally; PR, rectally; tid, 3 times daily; qid, 4 times daily.
Adapted from McDonald LC, Gerding DN, Johnson S, et al: Clinical practice guidelines for
Clostridium difficile infection in adults and children: 2017 update by the Infectious Diseases
Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA), Clin
Infect Dis 66(7):e1–e48, 2018 (Table 2).

Treatment of adults is different (Table 239.2 ). Because treatment of CDI

continues to evolve, adult-based protocols may be relevant to older children and
adolescents.

Table 239.2
Recommendations for the Treatment of Clostridium difficile
Infection in Adults

STRENGTH OF
CLINICAL SUPPORTIVE RECOMMENDED
RECOMMENDATION/QUALITY
DEFINITION CLINICAL DATA TREATMENT*
OF EVIDENCE
Initial episode, Leukocytosis with VAN, 125 mg qid × 10 days Strong/High
nonsevere white blood cell or
count of ≤15,000 FDX, 200 mg bid × 10 days Strong/High
cells/mL and serum Alternate if above agents are Weak/High
creatinine level unavailable: metronidazole, 500 mg
<1.5 mg/dL tid PO × 10 days
Initial episode, Leukocytosis with VAN, 125 mg qid PO × 10 days Strong/High
severe † a white blood cell or
count of ≥15,000 FDX, 200 mg bid × 10 days Strong/High
cells/mL or a serum
creatinine level
>1.5 mg/dL
Initial episode, Hypotension or VAN, 500 mg qid PO or by Strong/Moderate (oral VAN)
fulminant shock, ileus, nasogastric tube. If ileus, consider Weak/Low (rectal VAN)
megacolon adding rectal instillation of VAN. Strong/Moderate (intravenous
Intravenous metronidazole (500 mg metronidazole)
every 8 hr) should be administered
with oral or rectal VAN, particularly
if ileus is present.
First VAN, 125 mg qid × 10 days, if Weak/Low
recurrence metronidazole was used for the
initial episode
or
Use prolonged tapered and Weak/Low
pulsed VAN regimen if standard
regimen was used for initial
episode (e.g., 125 mg qid for
10-14 days, bid for 1 wk, qd for
1 wk, and then every 2 or 3 days
for 2-8 wk)
or
FDX, 200 mg bid ×for 10 days if Weak/Moderate
VAN was used for the initial episode
Second or VAN in a tapered and pulsed Weak/Low
subsequent regimen
recurrence or
VAN, 125 mg qid PO × 10 days, Weak/Low
followed by rifaximin, 400 mg
tid × 20 days
or
FDX, 200 mg bid × 10 days Weak/Low
or
Fecal microbiota transplantation ‡ Strong/Moderate
* All randomized trials have compared 10-day treatment courses, but some patients (particularly

those treated with metronidazole) may have delayed response to treatment, and clinicians should
consider extending treatment duration to 14 days in those circumstances.
Clinical Manifestations
Anaerobic infections occur in a variety of sites throughout the body (Table 240.1
). Anaerobes often coexist synergistically with aerobes. Infections with
anaerobes are usually polymicrobial, including an aerobic component.

Table 240.1
Infections Associated With Anaerobic Bacteria

ANAEROBIC
SITE AND INFECTION MAJOR RISK FACTORS
BACTERIA*
CENTRAL NERVOUS SYSTEM
Cerebral abscess Cyanotic heart disease Polymicrobial
Cystic fibrosis Prevotella
Penetrating trauma Porphyromonas
Bacteroides
Fusobacterium
Peptostreptococcus
Epidural and subdural Direct extension from contiguous sinusitis, otitis Bacteroides fragilis †
empyemas, meningitis media, mastoiditis, or anatomic defect involving the Fusobacterium
dura Peptostreptococcus
Veillonella
UPPER RESPIRATORY TRACT
Dental abscess Poor periodontal hygiene Peptostreptococcus
Ludwig angina (cellulitis of Drugs producing gingival hypertrophy Fusobacterium
sublingual-submandibular
space)
Necrotizing gingivitis Prevotella
(Vincent stomatitis) melaninogenica
Fusobacterium
Chronic otitis-mastoiditis- Tympanic perforation Prevotella
sinusitis Tympanostomy tubes Bacteroides
Fusobacterium
Peptostreptococcus
Peritonsillar abscess Streptococcal pharyngitis Fusobacterium
Retropharyngeal abscess Penetrating injury Prevotella
Porphyromonas
Lemierre syndrome Preexisting viral or bacterial pharyngitis Fusobacterium
LOWER RESPIRATORY TRACT
Aspiration pneumonia Periodontal disease Polymicrobial
Prevotella
Porphyromonas
Fusobacterium
Peptostreptococcus
Necrotizing pneumonitis Bronchial obstruction P. melaninogenica
Lung abscess Altered gag or consciousness Bacteroides intermedius
Aspirated foreign body Fusobacterium
Sequestered lobe Peptostreptococcus
Vascular anomaly Eubacterium
 B. fragilis
Veillonella
Septic pulmonary emboli Fusobacterium
INTRAABDOMINAL
Abscess Appendicitis Polymicrobial
B. fragilis
Bilophila wadsworthia
Peptostreptococcus
Clostridium spp.
Secondary peritonitis Penetrating trauma (especially of the colon) Bacteroides
Clostridium
Peptostreptococcus
Eubacterium
Fusobacterium
FEMALE GENITAL TRACT
Bartholin abscess Vaginosis B. fragilis
Tuboovarian abscess Intrauterine device Bacteroides bivius
Endometritis Peptostreptococcus
Pelvic thrombophlebitis Clostridium
Salpingitis Mobiluncus
Chorioamnionitis Actinomyces
Septic abortion Clostridium
SKIN AND SOFT TISSUE
Cellulitis Decubitus ulcers Varies with site and
contamination with oral or
enteric flora
Perirectal cellulitis Abdominal wounds Clostridium perfringens
(myonecrosis)
Myonecrosis (gas gangrene) Pilonidal sinus Bacteroides
Clostridium
Necrotizing fasciitis and Trauma Fusobacterium
synergistic gangrene Human and animal bites Clostridium tertium
Immunosuppressed or neutropenic patients Clostridium septicum
Varicella Anaerobic streptococci
BLOOD
Bacteremia Intraabdominal infection, abscesses, myonecrosis, B. fragilis
necrotizing fasciitis Clostridium
Peptostreptococcus
Fusobacterium
* Infections may also be from or may involve aerobic bacteria as the sole agent or as part of a

mixed infection; brain abscess may contain microaerophilic streptococci; intraabdominal infections
may contain gram-negative enteric organisms and enterococci; and salpingitis may contain
Neisseria gonorrhoeae and Chlamydia trachomatis .
† Bacteroides fragilis is usually isolated from infections below the diaphragm except for brain
abscesses.

Bacteremia
Anaerobes account for approximately 5% of bloodstream bacterial isolates in
adults, but this rate is lower in children. The most common blood isolates of
caused by Clostridium welchii type C (an organism not usually present in the
human intestine), the organism being transmitted by contaminated pig meat.
Anaerobic osteomyelitis , particularly of fingers and toes, can complicate any
process capable of producing hypoxic necrosis, including diabetes, neuropathies,
vasculopathies, and coagulopathies.

Diagnosis
The diagnosis of anaerobic infection requires a high index of suspicion and the
collection of appropriate and adequate specimens for anaerobic culture (Table
240.2 ). Culture specimens should be obtained in a manner that protects them
from contamination with mucosal bacteria and from exposure to ambient
oxygen. Swab samples from mucosal surfaces, nasal secretions, respiratory
specimens, and stool should not be sent for anaerobic culture because these sites
normally harbor anaerobic flora. Aspirates of infected sites, abscess material,
and biopsy specimens are appropriate for anaerobic culturing. Specimens should
be protected from atmospheric oxygen and transported to the laboratory
immediately. Anaerobic transport medium is used to increase the likelihood of
recovery of obligate anaerobes. Gram staining of abscess fluid from suspected
anaerobic infections is useful because even if the organisms do not grow in
culture, they can be seen on the smear.

Table 240.2
Clues to Presumptive Diagnosis of Anaerobic Infections*
Infection contiguous to or near a mucosal surface colonized with anaerobic bacteria (oropharynx, intestinal-
genitourinary tract)
Putrid odor
Severe tissue necrosis, abscesses, gangrene, or fasciitis
Gas formation in tissues (crepitus on exam or visible on plain radiograph)
Failure to recover organisms using conventional aerobic microbiologic methods, despite the presence of mixed
pleomorphic organisms on smears
Failure of organisms to grow after pretreatment with antibiotics effective against anaerobes
Failure of clinical response to antibiotic therapy poorly effective against anaerobic bacteria (e.g.,
aminoglycosides)
“Sulfur granules” in discharges caused by actinomycosis
Toxin-mediated syndromes: botulism, tetanus, gas gangrene, food poisoning, pseudomembranous colitis
Infections associated with anaerobic bacteria (see Table 240.1 )
Septic thrombophlebitis
Septicemic syndrome with jaundice or intravascular hemolysis
Typical appearance on Gram stain:
Bacteroides spp.—small, delicate, pleomorphic, pale, gram-negative bacilli
 Fusobacterium nucleatum —thin, gram-negative bacilli with fusiform shape, pointed ends
Fusobacterium necrophorum —pleomorphic gram-negative bacilli with rounded ends
Peptostreptococcus —chained, gram-positive cocci similar to aerobic cocci
Clostridium perfringens —large, short, fat (boxcar-shaped) gram-positive bacilli
* Suspicion of anaerobic infection is critical before specimens are sampled for culture, to ensure

optimal microbiologic techniques and prompt, appropriate therapy.

Antimicrobial resistance among anaerobes has consistently increased over

time, and the susceptibility of anaerobic agents to antimicrobial agents has
become less predictable. A rapid and simple screening test for antibiotic
susceptibility can be used to detect β-lactamase production and presumptive
penicillin resistance. More detailed susceptibility testing, available at reference
laboratories, is recommended for isolates recovered from sterile body sites or
those that are clinically important and are known to have variable or unique
susceptibilities.
Recent advances in direct detection of anaerobes from clinical samples
include 16S ribosomal RNA (16S rRNA) gene-based methods, DNA
hybridization, matrix-assisted laser desorption/ionization time-of-flight mass
spectrometry (MALDI-TOF MS), multiplex PCR, and oligonucleotide array
technologies. MALDI-TOF MS has been used as a rapid method to identify
infectious agents, including many anaerobes. 16S rRNA gene sequencing can be
used for isolates whose identification by MS is unreliable.

Treatment
Treatment of anaerobic infections usually requires adequate drainage and
appropriate antimicrobial therapy. Antibiotic therapy varies depending on the
suspected or proven anaerobe involved. Many oral anaerobic bacterial species
are susceptible to penicillins, although some strains may produce a β-lactamase.
Drugs that are active against such strains include metronidazole, penicillins
combined with β-lactamase inhibitors (ampicillin-sulbactam, ticarcillin-
clavulanate, piperacillin-tazobactam), carbapenems (imipenem, meropenem,
doripenem, ertapenem), clindamycin, tigecycline, linezolid, and cefoxitin.
Penicillin and vancomycin are active against the gram-positive anaerobes.
Increasing resistance to antimicrobials has been noted among anaerobes,
particularly with Bacteroides spp. Clindamycin is no longer recommended in the
empirical treatment of abdominal infections due to increasing resistance among
Bacteroides. Aerobes are usually present with the anaerobes, necessitating
broad-spectrum antibiotic combinations for empirical therapy. Specific therapy is
bovis. The pediatric dosage is 10-15 mg/kg/day orally (PO) in a single dose, not
to exceed 300 mg/day. The adult dosage is 5 mg/kg/day PO in a single dose, not
to exceed 300 mg/day. Alternative pediatric dosing is 20-30 mg/kg PO in a
single dose, not to exceed 900 mg/dose, given twice weekly under directly
observed therapy (DOT) , in which patients are observed to ingest each dose of
antituberculosis medication to maximize the likelihood of completing therapy.
The duration of treatment depends on the disease being treated (Table 241.1 ).
INH needs to be taken 1 hr before or 2 hr after meals because food decreases
absorption. It is available in liquid, tablet, intravenous (IV; not approved by the
FDA), and intramuscular (IM) preparations.

Table 241.1
Recommended Usual Treatment Regimens for Drug-
Susceptible Tuberculosis in Infants, Children, and
Adolescents

INFECTION/DISEASE
REGIMEN COMMENTS
CATEGORY
LATENT MYCOBACTERIUM TUBERCULOSIS INFECTION a
Isoniazid susceptible 12 weeks of isoniazid plus rifapentine,
once a week
or
4 mo of rifampin, once a day Continuous daily therapy is required.
or Intermittent therapy even by DOT is
not recommended.
9 mo of isoniazid, once a day If daily therapy is not possible, DOT
twice a week can be used for 9 mo.
Isoniazid resistant 4 mo of rifampin, once a day Continuous daily therapy is required.
Intermittent therapy even by DOT is
not recommended.
Isoniazid-rifampin Consult a tuberculosis specialist. Moxifloxacin or levofloxacin with or
resistant without ethambutol or pyrazinamide.
PULMONARY AND EXTRAPULMONARY INFECTION
Except meningitis b 2 mo of isoniazid, rifampin, pyrazinamide, Some experts recommend a 3-
and ethambutol daily or twice weekly, drug initial regimen (isoniazid,
followed by 4 mo of isoniazid and rifampin c rifampin, and pyrazinamide) if the
by DOT d for drug-susceptible M. tuberculosis risk of drug resistance is low.
DOT is highly desirable.
If hilar adenopathy only and the
risk of drug resistance is low, 6
mo course of isoniazid and
rifampin is sufficient.
Drugs can be given 2 or 3
times/wk under DOT.
9-12 mo of isoniazid and rifampin for drug-
susceptible Mycobacterium bovis
 Meningitis 2 mo of isoniazid, rifampin, For patients who may have acquired
pyrazinamide, and an aminoglycoside e or tuberculosis in geographic areas where
ethionamide, once daily, followed by 7-10 resistance to streptomycin is common,
mo of isoniazid and rifampin, once daily kanamycin, amikacin, or capreomycin
or twice weekly (9-12 mo total) for drug- can be used instead of streptomycin.
susceptible M. tuberculosis
At least 12 mo of therapy without
pyrazinamide for drug-susceptible M.
bovis
a
Positive TST or IGRA result, no disease. See text for comments and additional
acceptable/alternative regimens.
b
Duration of therapy may be longer for human immunodeficiency virus (HIV)-infected people, and
additional drugs and dosing intervals may be indicated
c Medications should be administered daily for the 1st 2 wk to 2 mo of treatment and then can be

administered 2-3 times/wk by DOT. (Twice-weekly therapy is not recommended for HIV-infected
people.)
d If initial chest radiograph shows pulmonary cavities, and sputum culture after 2 mo of therapy

remains positive, the continuation phase is extended to 7 mo, for a total treatment duration of 9
mo.
e
Streptomycin, kanamycin, amikacin, or capreomycin.
DOT, Directly observed therapy; IGRA, interferon-γ release assay; TST, tuberculin skin test.
Adapted from American Academy of Pediatrics: Red book: 2018–2021 report of the Committee on
Infectious Diseases, ed 31, Elk Grove Village, IL, 2018, AAP (Table 3.85).

Major adverse effects include hepatotoxicity in 1% of children and

approximately 3% of adults (increasing with age) and dose-related peripheral
neuropathy. Pyridoxine can prevent the peripheral neuropathy and is indicated
for breastfeeding infants and their mothers, children and youth on milk- or meat-
deficient diets, pregnant adolescents, and symptomatic HIV-infected children.
Minor adverse events include rash, worsening of acne, epigastric pain with
occasional nausea and vomiting, decreased vitamin D levels, and dizziness. The
liquid formulation of INH contains sorbitol, which often causes diarrhea and
stomach upset.
INH is accompanied by significant drug-drug interactions (Table 241.2 ). The
metabolism of INH is by acetylation. Acetylation rates have minimal effect on
efficacy, but slow acetylators have an increased risk for hepatotoxicity,
especially when used in combination with rifampin. Routine baseline liver
function testing or monthly monitoring is only indicated for persons with
underlying hepatic disease or receiving concomitant hepatotoxic drugs,
including other antimycobacterial agents, acetaminophen, or alcohol. Monthly
clinic visits while taking INH alone are encouraged to monitor adherence,
adverse effects, and worsening of infection.

Table 241.2

Isoniazid Drug-Drug Interactions

DRUG USED WITH ISONIAZID EFFECTS
Acetaminophen, alcohol, rifampin Increased hepatotoxicity of isoniazid or listed drugs
Aluminum salts (antacids) Decreased absorption of isoniazid
Carbamazepine, phenytoin, theophylline, Increased level, effect, or toxicity of listed drugs due to
diazepam, warfarin decreased metabolism
Itraconazole, ketoconazole, oral hypoglycemic Decreased level or effect of listed drugs due to increased
agents metabolism
Cycloserine, ethionamide Increased central nervous system adverse effects of cycloserine
and ethionamide
Prednisolone Increased isoniazid metabolism

Rifamycins
The rifamycins (rifampin, rifabutin, rifapentine) are a class of macrolide
antibiotics developed from Streptomyces mediterranei. Rifampin is a synthetic
derivative of rifamycin B, and rifabutin is a derivative of rifamycin S.
Rifapentine is a cyclopentyl derivative. The rifamycins inhibit the DNA-
dependent RNA polymerase of mycobacteria, resulting in decreased RNA
synthesis. These agents are generally bactericidal at treatment doses, but they
may be bacteriostatic at lower doses. Resistance is from a mutation in the DNA-
dependent RNA polymerase gene (rpoB ) that is often induced by previous
incomplete therapy. Cross-resistance between rifampin and rifabutin has been
demonstrated.
Rifampin is active against M. tuberculosis, M. leprae, M. kansasii, and M.
avium complex. Rifampin is an integral drug in standard combination treatment
of active M. tuberculosis disease and can be used as an alternative to INH in the
treatment of latent tuberculosis infection in children who cannot tolerate INH.
Rifabutin has a similar spectrum, with increased activity against M. avium
complex. Rifapentine is undergoing pediatric clinical trials and appears to have
activity similar to the activity of rifampin. The pediatric dosage of rifampin is
10-15 mg/ kg/day PO in a single dose, not to exceed 600 mg/day. The adult
dosage of rifampin is 5-10 mg/kg/day PO in a single dose, not to exceed 600
mg/day. Commonly used rifampin preparations include 150 and 300 mg capsules
and a suspension that is usually formulated at a concentration of 10 mg/mL. The
shelf life of rifampin suspension is short (approximately 4 wk), so it should not
Clofazimine
Clofazimine is a synthetic phendimetrazine tartrate derivative that acts by
binding to the mycobacterial DNA at guanine sites. It has a slow bactericidal
activity against M. leprae. Mechanisms of resistance are not well studied. No
cross-resistance between clofazimine and dapsone or rifampin has been shown.
Clofazimine is indicated as part of a combination therapy for the treatment of
M. leprae. It appears there may be some activity against other mycobacteria such
as M. avium complex, although treatment failures are common. Safety and
efficacy of clofazimine are poorly studied in children. The pediatric dosage is 1
mg/kg/day PO as a single dose, not to exceed 100 mg/day, in combination with
dapsone and rifampin, for 2 yr and then additionally as a single agent for >1 yr.
The adult dosage is 100 mg/day PO. Clofazimine should be taken with food to
increase absorption.
The most common adverse effect is a dosage-related, reversible, pink to tan-
brown discoloration of the skin and conjunctiva. Other adverse effects include a
dry, itchy skin rash, headache, dizziness, abdominal pain, diarrhea, vomiting,
peripheral neuropathy, and elevated hepatic transaminases.
Routine laboratory monitoring includes periodic liver function tests.

Agents Used Against Nontuberculous

Mycobacteria
Cefoxitin
Cefoxitin, a cephamycin derivative, is a second-generation cephalosporin that,
like other cephalosporins, inhibits cell wall synthesis by linking with penicillin-
binding proteins to create an unstable bacterial cell wall. Resistance develops by
alterations in penicillin-binding proteins.
Cefoxitin is often used in combination therapy for mycobacterial disease
(Table 241.3 ). Pediatric dosing is based on disease severity, with a range of 80-
160 mg/kg/day divided every 4-8 hr, not to exceed 12 g/ day. Adult dosages are
1-2 g/day, not to exceed 12 g/day. Cefoxitin is available in IV and IM
formulations. Increased dosing intervals are needed with renal insufficiency.

Table 241.3
Treatment of Nontuberculous Mycobacteria Infections in
Children
ORGANISM DISEASE INITIAL TREATMENT
SLOWLY GROWING SPECIES
Mycobacterium Lymphadenitis Complete excision of lymph nodes; if excision incomplete or disease recurs,
avium complex clarithromycin or azithromycin plus ethambutol and/or rifampin (or rifabutin).
(MAC); Pulmonary Clarithromycin or azithromycin plus ethambutol with rifampin or rifabutin
Mycobacterium infection (pulmonary resection in some patients who fail to respond to drug therapy).
haemophilum ; For severe disease, an initial course of amikacin or streptomycin often is
Mycobacterium included. Clinical data in adults with mild to moderate disease support that 3-
lentiflavum times-weekly therapy is as effective as daily therapy, with less toxicity. For
patients with advanced or cavitary disease, drugs should be given daily.
Mycobacterium Prosthetic Valve removal, prolonged antimicrobial therapy based on susceptibility
chimaera valve testing.
endocarditis
Disseminated See text.
Mycobacterium Pulmonary Rifampin plus ethambutol with isoniazid daily. If rifampin resistance is
kansasii infection detected, a 3-drug regimen based on drug susceptibility testing should be
used.
Osteomyelitis Surgical debridement and prolonged antimicrobial therapy using rifampin plus
ethambutol with isoniazid.
Mycobacterium Cutaneous None, if minor; rifampin, TMP-SMX, clarithromycin, or doxycycline* for
marinum infection moderate disease; extensive lesions may require surgical debridement.
Susceptibility testing not routinely required.
Mycobacterium Cutaneous and Daily intramuscular streptomycin and oral rifampin for 8 wk; excision to
ulcerans bone remove necrotic tissue, if present; potential response to thermotherapy.
infections
RAPIDLY GROWING SPECIES
Mycobacterium Cutaneous Initial therapy for serious disease is amikacin plus meropenem IV, followed
fortuitum group infection by clarithromycin, doxycycline,* TMP-SMX, or ciprofloxacin PO, on the
basis of in vitro susceptibility testing; may require surgical excision. Up to
50% of isolates are resistant to cefoxitin.
Catheter Catheter removal and amikacin plus meropenem IV; clarithromycin, TMP-
infection SMX, or ciprofloxacin, orally, on the basis of in vitro susceptibility testing.
Mycobacterium Otitis media; There is no reliable antimicrobial regimen because of variability in drug
abscessus cutaneous susceptibility. Clarithromycin plus initial course of amikacin plus cefoxitin or
infection imipenem/meropenem; may require surgical debridement on the basis of in
vitro susceptibility testing (50% are amikacin resistant).
Pulmonary Serious disease, clarithromycin, amikacin, and cefoxitin or
infection (in imipenem/meropenem on the basis of susceptibility testing; most isolates have
cystic fibrosis) very low MIC to tigecycline; may require surgical resection.
Mycobacterium Catheter Catheter removal; debridement, removal of foreign material; valve
chelonae infection, replacement; and tobramycin (initially) plus clarithromycin, meropenem, and
prosthetic linezolid.
valve
endocarditis
Disseminated Tobramycin and meropenem or linezolid (initially) plus clarithromycin.
cutaneous
infection
* Doxycycline can be used for short durations (i.e., ≤21 days) without regard to patient age, but for
longer treatment durations is not recommended for children <8 yr old. Only 50% of isolates of M.
can transmit M. tuberculosis to children, and children with HIV infection are at
increased risk for developing tuberculosis after infection. Specific groups are at
high risk for acquiring TBI and progressing to tuberculosis (Table 242.1 ).

Table 242.1
Groups at High Risk for Acquiring Tuberculosis Infection
and Developing Disease in Countries With Low Incidence
RISK FACTORS FOR TUBERCULOSIS INFECTION
Children exposed to high-risk adults
Foreign-born persons from high-prevalence countries
Homeless persons
Persons who inject drugs
Present and former residents or employees of correctional institutions, homeless shelters, and nursing homes
Healthcare workers caring for high-risk patients (if infection control is not adequate)
RISK FACTORS FOR PROGRESSION OF TUBERCULOSIS INFECTION TO TUBERCULOSIS
DISEASE
Infants and children ≤4 yr old, especially those <2 yr old
Adolescents and young adults
Persons co-infected with human immunodeficiency virus
Persons with skin test conversion in the past 1-2 yr
Persons who are immunocompromised, especially in cases of malignancy and solid-organ transplantation,
immunosuppressive medical treatments including anti–tumor necrosis factor therapies, diabetes mellitus,
chronic renal failure, silicosis, and malnutrition
RISK FACTORS FOR DRUG-RESISTANT TUBERCULOSIS
Personal or contact history of treatment for tuberculosis
Contacts of patients with drug-resistant tuberculosis
Birth or residence in a country with a high rate of drug resistance
Poor response to standard therapy
Positive sputum smears (acid-fast bacilli) or culture ≥2 mo after initiating appropriate therapy

The incidence of drug-resistant tuberculosis has increased dramatically

throughout the world. MDR-TB is defined as resistance to at least isoniazid and
rifampin; extensively drug-resistant tuberculosis includes MDR-TB plus
resistance to any fluoroquinolone and at least 1 of 3 injectable drugs
(kanamycin, capreomycin, amikacin). In 2015 the estimate for MDR-TB was
3.9% of incident cases, but rates as high as 32% have been reported in countries
formerly part of the Soviet Union. In 2015 in the United States, a total of 89
patients with MDR-TB were reported, 70.8% of whom were foreign-born (Fig.
242.5 ). The CDC reported that among children with culture-confirmed
tuberculosis in the United States in 2014, 17.4% had resistance to at least 1 first-
line drug, and 0.9% had MDR-TB.
and recommend targeted tuberculin testing of children at risk identified through
periodic screening questionnaires (Table 242.2 ). Possible exposure to an adult
with or at high risk for infectious pulmonary tuberculosis is the most crucial risk
factor for children. Reaction size limits for determining a positive TST result
vary with the person's risk for infection (Table 242.3 ). In those at highest risk of
progression to TB disease, TST sensitivity is most important, whereas specificity
is more important for persons at low risk of progression.

Table 242.2
Tuberculin Skin Test (TST) or Interferon-γ Release Assay
(IGRA): Recommendations for Infants, Children, and
Adolescents*

CHILDREN FOR WHOM IMMEDIATE TST OR IGRA IS INDICATED †

Contacts of people with confirmed or suspected contagious tuberculosis (contact investigation)
Children with radiographic or clinical findings suggesting tuberculosis disease
Children immigrating from countries with endemic infection (e.g., Asia, Middle East, Africa, Latin America,
countries from former Soviet Union), including international adoptees
Children with travel histories to countries with endemic infection and substantial contact with indigenous people
from such countries ‡
Children who should have annual TST or IGRA:
• Children infected with human immunodeficiency virus
CHILDREN AT INCREASED RISK FOR PROGRESSION OF TUBERCULOSIS INFECTION TO
TUBERCULOSIS DISEASE
Children with other medical conditions, including diabetes mellitus, chronic renal failure, malnutrition, and
congenital or acquired immunodeficiencies and children receiving tumor necrosis factor (TNF) antagonists
deserve special consideration. Without recent exposure, these children are not at increased risk of acquiring
tuberculosis infection. Underlying immune deficiencies associated with these conditions theoretically would
enhance the possibility for progression to severe disease. Initial histories of potential exposure to tuberculosis
should be included for all of these patients. If these histories or local epidemiologic factors suggest a possibility
of exposure, immediate and periodic TST or IGRA should be considered. An initial TST or IGRA should be
performed before initiation of immunosuppressive therapy, including prolonged corticosteroid
administration, organ transplantation, or use of TNF-α antagonists or blockers, or immunosuppressive
therapy in any child requiring these treatments.
* Bacille Calmette-Guérin immunization is not a contraindication to a TST.

† Beginning as early as 3 mo of age.

‡ If the child is well and has no history of exposure, the TST or IGRA should be delayed up to 10
wk after return.
From American Academy of Pediatrics: Red book: 2018 report of the Committee on Infectious
Diseases , ed 30, Elk Grove Village, IL, 2015, AAP, p 831.

Table 242.3
Definitions of Positive Tuberculin Skin Test (TST) Results
in Infants, Children, and Adolescents*
INDURATION ≥5 mm
Children in close contact with known or suspected contagious people with tuberculosis disease
Children suspected to have tuberculosis disease:
• Findings on chest radiograph consistent with active or previously tuberculosis disease
• Clinical evidence of tuberculosis disease †
Children receiving immunosuppressive therapy ‡ or with immunosuppressive conditions, including HIV infection
INDURATION ≥10 mm
Children at increased risk of disseminated tuberculosis disease:
• Children <4 yr old
• Children with other medical conditions, including Hodgkin disease, lymphoma, diabetes mellitus, chronic
renal failure, or malnutrition (see Table 242.2 )
Children with increased exposure to tuberculosis disease:
• Children born in high-prevalence regions of the world
• Children often exposed to adults with HIV infection, homeless, users of illicit drugs, residents of nursing
homes, incarcerated or institutionalized, or migrant farm workers
• Children who travel to high-prevalence regions of the world
INDURATION ≥15 mm
Children ≥4 yr old without any risk factors
* These definitions apply regardless of previous BCG immunization; erythema at TST site does
not indicate a positive test result. Tests should be read at 48-72 hr after placement.
† Evidence by physical examination or laboratory assessment that would include tuberculosis in

the working differential diagnosis (e.g., meningitis).

‡ Including immunosuppressive doses of corticosteroids or tumor necrosis factor-α antagonists.

BCG, Bacille Calmette-Guérin; HIV, human immunodeficiency virus.

From American Academy of Pediatrics: Red book: 2015 report of the Committee on Infectious
Diseases , ed 30, Elk Grove Village, IL, 2018, American Academy of Pediatrics, p 830.

Interferon-γ Release Assay (IGRA)

Two blood tests—T-SPOT.TB (Oxford Immunotec; Marlborough, MA) and
QuantiFERON-TB (QFT, Qiagen; Germantown, MD) detect IFN-γ generation
by the patient's T cells in response to specific M. tuberculosis antigens (ESAT-6,
CFP-10, and TB7.7). The QFT test measures whole blood concentrations of
IFN-γ, and the T-SPOT.TB test measures the number of lymphocytes/monocytes
producing IFN-γ. The test antigens are not present on M. bovis –BCG and
Mycobacterium avium complex, the major group of environmental
mycobacteria, so one would expect higher specificity compared with the TST
and fewer false-positive results. Both IGRAs have internal positive and negative
controls. Internal positive controls allows for detection of an anergic test
have shown no consistent, significant difference between the 2 commercially
available IGRAs, and the CDC recommends no preference. Because of cost
constraints, WHO does not indorse IGRA use in low- and middle-income
countries, even in those with a high prevalence of tuberculosis.

Table 242.4
Recommendations for Use of Tuberculin Skin Test (TST)
and Interferon-γ Release Assay (IGRA) in Children
TST preferred, IGRA acceptable
• Children <2 yr of age*
IGRA preferred, TST acceptable
• Children >2 yr of age who have received BCG vaccine
• Children >2 yr of age who are unlikely to return for TST reading
TST and IGRA should be considered when:
The initial and repeat IGRAs are indeterminate or invalid.
The initial test (TST or IGRA) is negative, and:
• Clinical suspicion for TB disease is moderate to high. †
• The child has TB risk factor and is at high risk of progression and poor outcome (especially therapy with
immunomodulating biologic agent, e.g., TNF-α antagonist). †
The initial TST is positive and:
• >2 yr old and history of BCG vaccination.
• Additional evidence needed to increase adherence with therapy.
* Some experts do not use an IGRA for children younger than 2 yr because of a relative lack of
data for this age-group and the high risk of progression to disease.
† Positive result of either test is considered significant in these groups.

BCG, Bacille Calmette-Guérin; TB, tuberculosis, TNF, tumor necrosis factor.

Adapted from Starke JR, AAP Committee of Infectious Diseases: Interferon-γ release assays for
diagnosis of tuberculosis infection and disease in children, Pediatrics 134(6):e1771, 2014.

Mycobacterial Sampling, Susceptibility

and Culture
The most specific confirmation of pulmonary tuberculosis is isolation of M.
tuberculosis from a clinical sample. Sputum specimens for culture should be
collected from adolescents and older children who are able to expectorate.
Induced sputum with a jet nebulizer, inhaled saline, and chest percussion
followed by nasopharyngeal suctioning is effective in children as young as 1 yr.
Sputum induction provides samples for both culture and acid-fast bacilli
Table 242.5
Commonly Used Drugs for Treatment of Tuberculosis in
Infants, Children, and Adolescents

TWICE-
DAILY
DOSAGE WEEKLY MAXIMUM
DRUG DOSAGE ADVERSE REACTIONS
FORMS DOSAGE DOSE
(mg/kg)
(mg/kg/dose)
Ethambutol Tablets: 20 50 2.5 g Optic neuritis (usually reversible),
100 mg decreased red-green color
400 mg discrimination, gastrointestinal tract
disturbances, hypersensitivity
Isoniazid* Scored 10-15 † 20-30 Daily: Mild hepatic enzyme elevation,
tablets: 300 mg hepatitis, † peripheral neuritis,
100 mg Twice hypersensitivity
300 mg weekly:
Syrup: 10 900 mg
mg/mL
Pyrazinamide* Scored tablets: 30-40 50 2 g Hepatotoxic effects, hyperuricemia,
500 mg arthralgias, gastrointestinal tract upset
Rifampin* Capsules: 15-20 15-20 600 mg Orange discoloration of
150 mg secretions or urine, staining of
300 mg contact lenses, vomiting,
Syrup hepatitis, influenza-like reaction,
formulated thrombocytopenia, pruritus
from Oral contraceptives may be
capsules ineffective.
* Rifamate is a capsule containing 150 mg of isoniazid and 300 mg of rifampin. Two capsules

provide the usual adult (i.e., person weighing >50 kg) daily doses of each drug. Rifater, in the
United States, is a capsule containing 50 mg of isoniazid, 120 mg of rifampin, and 300 mg of
pyrazinamide. Isoniazid and rifampin also are available for parenteral administration. Many
experts recommend using a daily rifampin dose of 20–30 mg/kg/day for infants and toddlers and
for serious forms of tuberculosis such as meningitis and disseminated disease.
† When isoniazid in a dosage exceeding 10 mg/kg/day is used in combination with rifampin, the
incidence of hepatotoxic effects may be increased.
From American Academy of Pediatrics: Red book: 2018 report of the Committee on Infectious
Diseases , ed 30, Elk Grove Village, IL, 2015, AAP, p 842.

Table 242.6
Less Commonly Used Drugs for Treating Drug-Resistant
Tuberculosis in Infants, Children, and Adolescents*

DOSAGE, MAXIMUM
DRUGS DAILY DOSAGE (mg/kg) ADVERSE REACTIONS
FORMS DOSE
Vials: 500 15-30 (IV or IM 1 g Auditory and vestibular toxic
Amikacin † mg, 1 g administration) effects, nephrotoxic effects

Bedaquiline Tablets: 100 Adults and children ≥12 yr, QTc prolongation, reduced levels
mg >33 kg: 400 mg for 14 with efavirenz co-administration
days, then 200 mg 3 times
weekly for 22 wk
Capreomycin † Vials: 1 g 15-30 (IM administration) 1 g Auditory and vestibular toxicity
and nephrotoxic effects
Clofazimine Gelcaps: 2-3 mg/kg per day 100 mg QTc prolongation, reversible skin
50 mg pigmentation
100 mg
Cycloserine Capsules: 10-20, given in 2 divided 1 g Psychosis, personality changes,
250 mg doses seizures, rash
Delamanid Tablets: Adults and children QTc prolongation, adverse events
50 mg ≥13 yr, ≥35 kg: 100 with hypoalbuminemia, avoid if
100 mg mg twice daily metronidazole allergic
Children 6-12 yr, 20-
34 kg: 50 mg twice
daily
Ethionamide Tablets: 250 15-20, given in 2-3 divided 1 g GI tract disturbances, hepatotoxic
mg doses effects, hypersensitivity reactions,
hypothyroidism
Kanamycin Vials: 15-30 (IM or IV 1 g Auditory and vestibular toxic
75 mg/2 administration) effects, nephrotoxic effects
mL
500
mg/2
mL
1 g/3
mL
Levofloxacin Tablets: Adults: 750-1000 mg 1 g Theoretic effect on growing
250 mg (daily) cartilage, joint pain, GI tract
500 mg Children: 15-20 mg/kg disturbances, rash, headache,
750 mg daily restlessness, confusion
Oral
solution:
25/mL
Vials: 25
mg/mL
Linezolid Tablets: Children ≥12 yr: 10 600 mg Bone marrow suppression,
400 mg mg/kg daily peripheral neuropathy, lactic
600 mg Children <12 yr: 10 acidosis, potential overlapping
Syrup: mg/kg twice daily toxicity with nucleoside reverse
20 transcriptase inhibitors
mg/mL
Ofloxacin Tablets: Adults/adolescents: 800 mg Arthropathy, arthritis
200 mg 800 mg
300 mg Children 15-20 mg/kg
400 mg daily
Vials:
20
mg/mL
40
mg/mL
 Moxifloxacin Tablets: Adults/adolescents: 400 mg Arthropathy, arthritis
400 mg 400 mg
IV Children: 7.5-10
solution: mg/kg daily
400
mg/250
mL in
0.8%
saline
Paraaminosalicylic Packets: 3 g 200-300 (2-4 times a day) 10 g GI tract disturbances,
acid (PAS) hypersensitivity, hepatotoxic
effects
Streptomycin † Vials: 20-40 (IM administration) 1 g Auditory and vestibular toxic
1 g effects, nephrotoxic effects, rash
4 g
* These drugs should be used in consultation with a specialist in tuberculosis.

† Dose adjustment in renal insufficiency.

GI, Gastrointestinal; IM, intramuscular; IV, intravenous.

From American Academy of Pediatrics: Red book: 2018 Report of the Committee on Infectious
Diseases , ed 30. Elk Grove Village, IL, 2015, AAP, p 843–844; and Harausz EP, Garcia-Prats AJ,
Seddon JA, et al: New/repurposed drugs for pediatric multidrug-resistant tuberculosis: practice-
based recommendations, Am J Respir Crit Care Med 195(10):1300-1310, 2017.

Extrapulmonary tuberculosis is usually caused by small numbers of

mycobacteria. In general, the treatment for most forms of extrapulmonary
tuberculosis in children, including cervical lymphadenopathy, is the same as for
pulmonary tuberculosis. Exceptions are bone and joint, disseminated, and CNS
tuberculosis, for which there are inadequate data to recommend 6 mo of therapy;
these conditions are treated for 9-12 mo. Surgical debridement in bone and joint
disease and ventriculoperitoneal shunting in CNS disease may be necessary
adjuncts to medical therapy.
The optimal treatment of tuberculosis in HIV-infected children has not been
established. HIV-seropositive adults with tuberculosis can be treated successfully
with standard regimens that include isoniazid, rifampin, pyrazinamide, and
ethambutol. The total duration of therapy should be 6-9 mo, or 6 mo after culture
of sputum becomes sterile, whichever is longer. Data for children are limited to
relatively small series. Most experts believe that HIV-infected children with
drug-susceptible tuberculosis should receive the standard 4-drug regimen for the
1st 2 mo followed by isoniazid and rifampin, for a total duration of at least 9 mo.
However, all treatment should be daily, not intermittent. Children with HIV
infection appear to have more frequent adverse reactions to antituberculosis
drugs and must be monitored closely during therapy. Co-administration of
rifampin and some antiretroviral agents results in subtherapeutic blood levels of
through the National Hansen's Disease Program (NHDP ;
http://www.hrsa.gov/hansens or 800-642-2477). Specimens (formalin or paraffin
embedded) can be sent to the NHDP for pathologic analysis free of charge. A
polymerase chain reaction (PCR) test for M. leprae is not readily available in
clinical practice but may be performed at the NHDP. In nonendemic areas, PCR
may be useful for diagnosis when AFB are discernible in tissue, but clinical and
histopathologic features are not typical. M. leprae DNA is detectable by PCR in
95% of lepromatous disease (sensitivity >90%) and 55% of tuberculoid lepra
(sensitivity of 34–80%). PCR has also allowed detection of the organism in nasal
secretions from asymptomatic people. Molecular testing for mutations causing
drug resistance is also available through the NHDP and is usually used in the
setting of relapse.
Antibodies to M. leprae are present in 90% of patients with untreated
lepromatous disease, 40–50% of patients with paucibacillary disease, and 1–5%
of healthy controls. However, serologic testing is insensitive and is not used for
diagnosis.

Treatment
The primary goal of treatment is early antimicrobial therapy to prevent
permanent neuropathy. Leprosy is curable. Effective treatment requires
multidrug therapy (MDT) with dapsone , clofazimine , and rifampin .
Combination therapy is employed to prevent antimicrobial resistance. In the
United States, clinical providers considering a diagnosis and treatment of a
patient with HD should obtain consultation from the NHDP. The recommended
combination MDT can be obtained free of charge from the NHDP (Table 243.1 )
and in other countries through WHO (Table 243.2 ). Compared to WHO, the
NHDP advocates for a longer duration of treatment and daily rather than
monthly administration of rifampin, because shorter antimicrobial regimens have
been associated with greater risk of relapse. The recommended duration by the
WHO for tuberculoid disease is 6 mo and for lepromatous disease, 12 mo.

Table 243.1
NHDP-Recommended Multidrug Therapy Regimens for
Hansen Disease in the United States
 TYPE OF LEPROSY PATIENT ANTIMICROBIAL DURATION OF
POPULATION THERAPY THERAPY
Multibacillary (LL, BL, Adult Dapsone, 100 mg/day, and 24 mo
BB) Rifampin, 600 mg/day, and
Clofazimine, 50 mg/day
Pediatric* Dapsone, 1 mg/kg/day, and
Rifampin, 10-20 mg/kg/day,
and
Clofazimine, 1 mg/kg/day †
Paucibacillary (TT, BT) Adult Dapsone, 100 mg/day, and 12 mo
Rifampin, 600 mg/day
Pediatric* Dapsone, 1 mg/kg/day, and
Rifampin, 10-20 mg/kg/day
*
Daily pediatric mg/kg dose should not exceed adult daily maximum.
† Clofazimine is only available through NHDP Investigational New Drug (IND) program; minimum
formulation is 50 mg, and capsules should not be cut. Alternative dosing includes clofazimine, 2
mg/kg every other day, or clarithromycin, 7.5 mg/kg/day.
NHDP multidrug therapy is daily and of longer duration than WHO-recommended regimen. All
drugs are administered orally.
NHDP, National Hansen's Disease Program; BB, Borderline; BL, borderline lepromatous; BT,
borderline tuberculoid; LL, lepromatous; TT, tuberculoid.

Table 243.2
WHO-Recommended Multidrug Therapy (MDT) Regimens
for Hansen Disease

TYPE OF PATIENT DURATION OF

ANTIMICROBIAL THERAPY
LEPROSY POPULATION THERAPY
Multibacillary (LL, Adult Rifampicin, 600 mg once monthly, and 12 mo
BL, BB) Dapsone, 100 mg/day, and
Clofazimine, 300 mg once monthly and 50
mg/day
Pediatric* Rifampicin, 450 mg once monthly, and
Dapsone, 50 mg/day, and
Clofazimine, 150 mg once monthly and 50
mg every other day
Paucibacillary (TT, Adult Rifampicin, 600 mg once monthly, and 6 mo
BT) Dapsone, 100 mg/day
Pediatric* Rifampicin, 450 mg once monthly, and
Dapsone, 50 mg/day
* In children <10 yr old, MDT dosages should be in mg/kg, not to exceed the adult daily maximum:

rifampicin, 10 mg/kg once monthly; dapsone, 2 mg/kg/day; and clofazimine, 1 mg/kg on alternate
days.
WHO, World Health Organization; BB, Borderline; BL, borderline lepromatous; BT, borderline
tuberculoid; LL, lepromatous; TT, tuberculoid.
 Observed differences in pathogenicity, clinical relevance, and spectrum of
clinical disease associated with the various NTM species emphasize the
importance of bacterial factors in the pathogenesis of NTM disease, although
exact virulence factors remain largely unknown.

Clinical Manifestations
Lymphadenitis of the superior anterior cervical or submandibular lymph nodes
is the most common manifestation of NTM infection in children (Table 244.1 ).
Preauricular, posterior cervical, axillary, and inguinal nodes are involved
occasionally. Lymphadenitis is most common in children 1-5 yr of age and has
been related to soil exposure (e.g., playing in sandboxes) and teething, although
exact predisposing conditions have not been found. Given the constant
environmental exposure to NTM, the occurrence of these infections might also
reflect an atypical immune response of a subset of the infected children during or
after their first contact with NTM. However, in healthy children with isolated
NTM lymphadenitis, immunodeficiency is very rare.

Table 244.1

Major Clinical Syndromes Associated with Nontuberculous Mycobacterial Infection

MOST
SYNDROME COMMON LESS FREQUENT CAUSES*
CAUSES
Chronic nodular MAC (M. M. xenopi, M. malmoense, M. szulgai, M. smegmatis, M. celatum, M. simiae, M.
disease (adults intracellulare, goodii, M. asiaticum, M. heckeshornense, M. branderi, M. lentiflavum, M.
with M. avium ), triplex, M. fortuitum, M. arupense, M. abscessus subsp. bolletii, M. phocaicum,
bronchiectasis; M. kansasii, M. aubagnense, M. florentinum, M. abscessus subsp. massiliense, M.
cystic fibrosis) M. abscessus nebraskense, M. saskatchewanense, M. seoulense, M. senuense, M.
paraseoulense, M. europaeum, M. sherrisii, M. kyorinense, M. noviomagense,
M. mantenii, M. shinjukuense, M. koreense, M. heraklionense, M.
parascrofulaceum, M. arosiense
Cervical or MAC M. scrofulaceum, M. malmoense (northern Europe), M. abscessus, M. fortuitum,
other M. lentiflavum, M. tusciae, M. palustre, M. interjectum, M. elephantis, M.
lymphadenitis heidelbergense, M. parmense, M. bohemicum, M. haemophilum, M. europaeum,
(especially M. florentinum, M. triplex, M. asiaticum, M. kansasii, M. heckeshornense
children)
Skin and soft M. fortuitum M. kansasii, M. haemophilum, M. porcinum, M. smegmatis, M. genavense, M.
tissue disease group, M. lacus, M. novocastrense, M. houstonense, M. goodii, M. immunogenum, M.
chelonae, M. mageritense, M. abscessus subsp. massiliense, M. arupense, M. monacense, M.
abscessus, M. bohemicum, M. branderi, M. shigaense, M. szulgai, M. asiaticum, M. xenopi,
marinum, M. M. kumamotense, M. setense, M. montefiorense (eels), M. pseudoshottsii (fish),
ulcerans M. shottsii (fish)
(Australia,
 tropical
countries
only)
Skeletal (bone, M. marinum, M. haemophilum, M. scrofulaceum, M. heckeshornense, M. smegmatis, M.
joint, tendon) MAC, M. terrae/chromogenicum complex, M. wolinskyi, M. goodii, M. arupense, M.
infection kansasii, M. xenopi, M. triplex, M. lacus, M. arosiense
fortuitum
group, M.
abscessus, M.
chelonae
Disseminated M. genavense, M. haemophilum, M. xenopi
infection
HIV- M. avium, M. M. marinum, M. simiae, M. intracellulare, M. scrofulaceum, M. fortuitum, M.
seropositive kansasii conspicuum, M. celatum, M. lentiflavum, M. triplex, M. colombiense, M.
host sherrisii, M. heckeshornense
HIV- M. abscessus, M. marinum, M. kansasii, M. haemophilum, M. chimaera, M. conspicuum, M.
seronegative M. chelonae shottsii (fish), M. pseudoshottsii (fish)
host
Catheter-related M. fortuitum, M. mucogenicum, M. immunogenum, M. mageritense, M. septicum, M.
infections M. abscessus, porcinum, M. bacteremicum, M. brumae
M. chelonae
Hypersensitivity Metal M. immunogenum M. avium
pneumonitis workers; hot
tub
*
The available information is sparse for selected pathogens such as M. xenopi, M. malmoense,
M. szulgai, M. celatum, and M. asiaticum and the newly described species.
HIV, Human immunodeficiency virus; MAC, Mycobacterium avium complex.
From Brown-Elliott BA, Wallace Jr. RJ: Infections caused by nontuberculous mycobacteria other
than Mycobacterium avium complex. In Bennett JF, Dolin R, Blaser MJ, editors: Mandell, Douglas,
and Bennett's principles and practice of infectious diseases, ed 8, Philadelphia, 2015, Elsevier
(Table 254-1).

Affected children usually lack constitutional symptoms and present with a

unilateral subacute and slowly enlarging lymph node or group of closely
approximated nodes >1.5 cm in diameter that are firm, painless, freely movable,
and not erythematous (Fig. 244.1 ). The involved nodes occasionally resolve
without treatment, but most undergo rapid suppuration after several weeks (Fig.
244.2 ). The center of the node becomes fluctuant, and the overlying skin thins
and becomes erythematous and often even violaceous. Eventually, the nodes
rupture and can form cutaneous sinus tracts that can drain persistently,
reminiscent of scrofula from tuberculosis (Fig. 244.3 ).
exceedingly rare.

Diagnosis
For infections of lymph nodes, skin, bone, and soft tissues, isolation of the
causative NTM bacteria by Mycobacterium culture, preferably with histologic
confirmation of granulomatous inflammation, normally suffices for diagnosis
(Table 244.2 ). The differential diagnosis of NTM lymphadenitis includes acute
bacterial lymphadenitis, tuberculosis, cat-scratch disease (Bartonella henselae) ,
mononucleosis, toxoplasmosis, brucellosis, tularemia, and malignancies,
especially lymphomas. Differentiation between NTM and M. tuberculosis may
be difficult, but children with NTM lymphadenitis usually have a Mantoux
tuberculin skin test reaction of <15 mm induration, unilateral anterior cervical
node involvement, a normal chest radiograph, and no history of exposure to
adult tuberculosis. Definitive diagnosis requires excision of the involved nodes
for culture and histology. Fine-needle aspiration for PCR and culture can enable
earlier diagnosis, before excisional biopsy.

Table 244.2
American Thoracic Society Diagnostic Criteria for
Nontuberculous Mycobacteria (NTM) Lung Disease
The minimum evaluation of a patient for NTM lung disease should include:
1. Chest radiograph or, when no cavitation is present, HRCT
2. At least 3 sputum or respiratory samples for AFB culture
3. Exclusion of other disease, such as tuberculosis
Clinical diagnosis of NTM is based on pulmonary symptoms, presence of nodules or cavities, as seen on chest
radiograph or an HRCT scan, with multifocal bronchiectasis with multiple small nodules, and exclusion of other
diagnoses.
Microbiologic diagnosis of NTM:
At least 2 expectorated sputa (or at least 1 bronchial wash or lavage) with positive cultures for NTM, or
transbronchial or other lung biopsy showing the presence of granulomatous inflammation or AFB, with 1 or
more sputum or bronchial washings that are culture positive for NTM.
AFB, Acid-fast bacilli; HRCT, high-resolution computed tomography.
Data from Griffith DE, Aksamit T, Brown-Elliott BA, et al: An official ATS/IDSA statement:
diagnosis, treatment and prevention of nontuberculous mycobacterial diseases, Am J Respir Crit
Care Med 175:367–416, 2007.
From Brown-Elliott BA, Wallace Jr. RJ: Infections caused by nontuberculous mycobacteria other
than Mycobacterium avium complex. In Bennett JF, Dolin R, Blaser MJ, editors: Mandell, Douglas,
and Bennett's principles and practice of infectious diseases, ed 8, Philadelphia, 2015, Elsevier
(Table 254-3).
Table 245.1

Late Manifestations of Congenital Syphilis

SYMPTOM/SIGN DESCRIPTION/COMMENTS
Olympian brow Bony prominence of the forehead caused by persistent or recurrent periostitis
Clavicular or Unilateral or bilateral thickening of the sternoclavicular third of the clavicle
Higoumenaki's sign
Saber shins Anterior bowing of the midportion of the tibia
Scaphoid scapula Convexity along the medial border of the scapula
Hutchinson teeth Peg-shaped upper central incisors; they erupt during 6th yr of life with abnormal enamel,
resulting in a notch along the biting surface
Mulberry molars Abnormal 1st lower (6 yr) molars characterized by small biting surface and excessive
number of cusps
Saddle nose* Depression of the nasal root, a result of syphilitic rhinitis destroying adjacent bone and
cartilage
Rhagades Linear scars that extend in a spoke-like pattern from previous mucocutaneous fissures of the
mouth, anus, and genitalia
Juvenile paresis Latent meningovascular infection; it is rare and typically occurs during adolescence with
behavioral changes, focal seizures, or loss of intellectual function
Juvenile tabes Rare spinal cord involvement and cardiovascular involvement with aortitis
Hutchinson triad Hutchinson teeth, interstitial keratitis, and 8th nerve deafness
Clutton joint Unilateral or bilateral painless joint swelling (usually involving knees) from synovitis with
sterile synovial fluid; spontaneous remission usually occurs after several weeks
Interstitial keratitis Manifests with intense photophobia and lacrimation, followed within weeks or months by
corneal opacification and complete blindness
8th nerve deafness May be unilateral or bilateral, appears at any age, manifests initially as vertigo and high-tone
hearing loss, and progresses to permanent deafness
* A perforated nasal septum may be an associated abnormality.

FIG. 245.6 Hutchinson teeth as a late manifestation of congenital syphilis.
Table 245.2

Clues That Suggest a Diagnosis of Congenital Syphilis

EPIDEMIOLOGIC BACKGROUND CLINICAL FINDINGS
Untreated early syphilis in the mother Osteochondritis, periostitis
Untreated latent syphilis in the mother Snuffles, hemorrhagic rhinitis
An untreated mother who has contact with a known Condylomata lata
syphilitic during pregnancy Bullous lesions, palmar or plantar rash
Mother treated less than 30 days prior to delivery Mucous patches
Mother treated for syphilis during pregnancy with a drug Hepatomegaly, splenomegaly
other than penicillin Jaundice
Mother treated for syphilis during pregnancy without Nonimmune hydrops fetalis
follow-up to demonstrate 4-fold decrease in titer Generalized lymphadenopathy
Mother coinfected with HIV Central nervous system signs; elevated cell
count or protein in cerebrospinal fluid
Hemolytic anemia, diffuse intravascular
coagulation, thrombocytopenia
Pneumonitis
Nephrotic syndrome
Placental villitis or vasculitis (unexplained
enlarged placenta)
Intrauterine growth restriction
Arranged in decreasing order of confidence of diagnosis.
Modified from Remington JS, Klein JO, Wilson CB, et al., editors: Infectious diseases of the fetus
and newborn infant , ed 6, Philadelphia, 2006, WB Saunders, p. 556.

Diagnosis of neurosyphilis in the newborn with syphilitic infection is

confounded by poor sensitivity of the CSF VDRL test in this age group and lack
of CSF abnormalities. A positive CSF VDRL test in a newborn warrants
treatment for neurosyphilis, even though it might reflect passive transfer of
antibodies from serum to CSF. It is now accepted that all infants with a
presumptive diagnosis of congenital syphilis should be treated with regimens
effective for neurosyphilis because central nervous system involvement cannot
be reliably excluded. Diagnosis of syphilis beyond early infancy should lead to
consideration of possible child abuse.
For infants with proven or highly probable disease or abnormal physical
findings, complete evaluation, including serologic tests (RPR or VDRL),
complete blood count with differential and platelet count, liver function tests,
long-bone radiographs, ophthalmology examination, auditory brainstem
response, and other tests as indicated, should be performed. For infants with a
positive VDRL or RPR test result and normal physical examination whose
mothers were inadequately treated, further evaluation is not necessary if 10 days
of parenteral therapy are administered.
Treatment
The goals of early detection and treatment include treatment of current infection
and prevention of both late stage disease and sexual or vertical transmission. T.
pallidum remains extremely sensitive to penicillin, with no evidence of emerging
penicillin resistance, and thus penicillin remains the treatment drug of choice
(Table 245.3 and http://www.cdc.gov/std/treatment ). Parenteral penicillin G is
the only documented effective treatment for congenital syphilis, syphilis during
pregnancy, and neurosyphilis. Aqueous crystalline penicillin G is preferred over
procaine penicillin, because it better achieves and sustains the minimum
concentration of 0.018 µg/mL (0.03 units/mL) needed for 7-10 days to achieve
the prolonged treponemicidal levels required for the long dividing time of T .
pallidum . Although nonpenicillin regimens are available to the penicillin-
allergic patient, desensitization followed by standard penicillin therapy is the
most reliable strategy. Success of treatment also depends upon the integrity of
the host immune response. A transient acute systemic febrile reaction called the
Jarisch-Herxheimer reaction (caused by massive release of endotoxin-like
antigens during bacterial lysis) occurs in 15–20% of patients with acquired or
congenital syphilis treated with penicillin. It is not an indication for
discontinuing penicillin therapy.

Table 245.3

Recommended Treatment for Syphilis in People Older Than 1 Mo

STATUS CHILDREN ADULTS
Congenital Aqueous crystalline penicillin G, 200,000-300,000
syphilis U/kg/day, IV, administered as 50,000 U/kg, every 4-6 hr
for 10 days*
Primary, Penicillin G benzathine, ‡ 50,000 U/kg, IM, up to the Penicillin G benzathine, 2.4
secondary, adult dose of 2.4 million U in a single dose million U, IM, in a single dose
and early OR
latent syphilis If allergic to penicillin and not
† pregnant , Doxycycline, 100 mg,
orally, twice a day for 14 days
OR
Tetracycline, 500 mg, orally, 4
times/day for 14 days
Late latent Penicillin G benzathine, 50,000 U/kg, IM, up to the adult Penicillin G benzathine, 7.2
syphilis § dose of 2.4 million U, administered as 3 single doses at 1- million U total, administered as 3
wk intervals (total 150,000 U/kg, up to the adult dose of doses of 2.4 million U, IM, each at
7.2 million U) 1-wk intervals
OR
If allergic to penicillin and not
 pregnant , Doxycycline, 100 mg,
orally, twice a day for 4 wk
OR
Tetracycline, 500 mg, orally, 4
times/day for 4 wk
Tertiary Penicillin G benzathine 7.2
million U total, administered as 3
doses of 2.4 million U, IM, at 1-
wk intervals
If allergic to penicillin and not
pregnant, consult an infectious
diseases expert
Neurosyphilis Aqueous crystalline penicillin G, 200,000-300,000 Aqueous crystalline penicillin G,
|| U/kg/day, IV, every 4-6 hr for 10-14 days, in doses not to 18-24 million U per day,
exceed the adult dose administered as 3-4 million U, IV,
every 4 hr for 10-14 days ¶
OR
Penicillin G procaine, ‡ 2.4
million U, IM, once daily PLUS
probenecid, 500 mg, orally, 4
times/day, both for 10-14 days ¶
* If the patient has no clinical manifestations of disease, the cerebrospinal fluid (CSF) examination

is normal, and the CSF Venereal Disease Research Laboratory (VDRL) test result is negative,
some experts would treat with up to 3 weekly doses of penicillin G benzathine, 50,000 U/kg, IM.
Some experts also suggest giving these patients a single dose of penicillin G benzathine, 50,000
U/kg, IM, after the 10-day course of intravenous aqueous penicillin.
†
Early latent syphilis is defined as being acquired within the preceding year.

‡ Penicillin G benzathine and penicillin G procaine are approved for intramuscular administration
only.
§ Late latent syphilis is defined as syphilis beyond 1 yr duration.

|| Patients who are allergic to penicillin should be desensitized.

¶ Some experts administer penicillin G benzathine, 2.4 million U, IM, once per week for up to 3 wk
after completion of these neurosyphilis treatment regimens.
IV , intravenously; IM , intramuscularly.
From American Academy of Pediatrics: Red book: 2015 report of the committee on infectious
diseases , ed 30, Elk Grove Village, IL, 2015, American Academy of Pediatrics, Table 3.74.

Acquired Syphilis
Primary, secondary, and early latent disease is treated with a single dose of
benzathine penicillin G (50,000 units/kg IM, maximum 2.4 million units).
Persons with late latent or tertiary disease require 3 doses at 1 wk intervals.
Nonpregnant penicillin-allergic patients without neurosyphilis may be treated
with either doxycycline (100 mg PO twice daily for 2 wk) or tetracycline (500
have an immunogenetic basis. Persons with certain HLA-DR allotypes may be
genetically predisposed to develop chronic Lyme arthritis. An autoinflammatory
response in the synovium can result in clinical symptoms long after the bacteria
have been killed by antibiotics.

Clinical Manifestations
The clinical manifestations of Lyme disease are divided into early and late stages
(Table 249.1 ). Early Lyme disease is further classified as early localized or early
disseminated disease. Untreated patients can progressively develop clinical
symptoms of each stage of the disease, or they can present with early
disseminated or with late disease without apparently having had any symptoms
of the earlier stages of Lyme disease.

Table 249.1

Clinical Stages of Lyme Disease

DISEASE TIMING AFTER
TYPICAL CLINICAL MANIFESTATIONS
STAGE TICK BITE
Early 3-30 days Erythema migrans (single), variable constitutional symptoms (headache,
localized fever, myalgia, arthralgia, fatigue)
Early 3-12 wk Erythema migrans (single or multiple), worse constitutional symptoms,
disseminated cranial neuritis, meningitis, carditis, ocular disease
Late >2 mo Arthritis

Early Localized Disease

The first clinical manifestation of Lyme disease in most patients is erythema
migrans (Fig. 249.2 ). Although it usually occurs 7-14 days after the bite, the
onset of the rash has been reported from 3 to 30 days later. The initial lesion
occurs at the site of the bite. The rash is generally either uniformly erythematous
or a target lesion with central clearing; rarely, there are vesicular or necrotic
areas in the center of the rash. Occasionally the rash is itchy or painful, although
usually it is asymptomatic. The lesion can occur anywhere on the body, although
the most common locations are the axilla, periumbilical area, thigh, and groin. It
is not unusual for the rash to occur on the neck or face, especially in young
children. Without treatment, the rash gradually expands (hence the name
migrans ) to an average diameter of 15 cm and typically remains present for 1-2
in endemic areas. Finally, because antibodies against B. burgdorferi persist after
successful treatment, there is no reason to obtain follow-up serologic tests.

Treatment
Table 249.2 provides treatment recommendations. Most patients can be treated
with an oral regimen of antibiotic therapy. Young children are generally treated
with amoxicillin. Doxycycline has the advantages of good central nervous
system penetration and activity against A. phagocytophilum , which may be
transmitted at the same time as B. burgdorferi in certain geographic areas. In
general, children younger than 8 yr of age should not be treated with
doxycycline because of the risk of permanent staining of the teeth (although
courses of ≤2 wk are usually safe in this regard). Patients who are treated with
doxycycline should be alerted to the risk for developing photosensitivity in sun-
exposed areas while taking the medication; long sleeves, long pants, and hat are
recommended for activities in direct sunlight. The only oral cephalosporin
proved to be effective for the treatment of Lyme disease is cefuroxime axetil,
which is an alternative for persons who cannot take doxycycline or who are
allergic to penicillin. Macrolide antibiotics, including azithromycin, appear to
have limited activity.

Table 249.2
Recommended Treatment of Lyme Disease

DRUG PEDIATRIC DOSING

Amoxicillin 50 mg/kg/day in 3 divided doses (max: 1,500 mg/day)
Doxycycline 4.4 mg/kg/day in 2 divided doses (max: 200 mg/day) (see text regarding
doxycycline use in children)
Cefuroxime axetil 30 mg/kg/day in 2 divided doses (max: 1,000 mg/day)
Ceftriaxone (IV)* , † 50-75 mg/kg/day once daily (max: 2,000 mg/day)
Azithromycin ‡ 10 mg/kg/day once daily ×7 days
RECOMMENDED THERAPY BASED ON CLINICAL MANIFESTATION
Erythema migrans Doxycycline ×10 days
Amoxicillin ×14 days
Meningitis Doxycycline ×14 days or
Ceftriaxone ×14 days (14-21 for hospitalized patients)
Cranial nerve palsy § Doxycycline ×14 days
Cardiac disease Oral regimen or ceftriaxone, 14-21 days (see text for specifics)
Arthritis Oral regimen, 28 days
Persistent arthritis after initial Oral regimen ×28 days or
treatment Ceftriaxone, 14-28 days
Genital mycoplasmas can cause chronic inflammation of the genitourinary tract
and amniotic membranes. These bacteria usually live in a state of adherence to
the respiratory or urogenital tract, but can disseminate to other organs when there
is a disruption of the mucosa or a weakened or immature immune system, such
as in premature infants. Ureaplasma spp. can infect the amniotic sac early in
gestation without rupturing the amniotic membranes, resulting in a clinically
silent, chronic chorioamnionitis characterized by an intense inflammatory
response. Attachment to fetal human tracheal epithelium can cause ciliary
disarray, clumping, and loss of epithelial cells. In vitro studies show that
Ureaplasma spp. stimulates macrophage production of interleukin (IL)-6 and
tumor necrosis factor-α. In addition, high concentrations of proinflammatory
cytokines possibly associated with development of bronchopulmonary dysplasia
(BPD) of prematurity, such as monocyte chemoattractant protein-1 and IL-8,
have been found in tracheal secretions from very-low-birthweight infants
colonized with Ureaplasma spp. Immunity appears to require serotype-specific
antibody. Thus, lack of maternal antibodies might account for a higher disease
risk in premature newborns.

Clinical Manifestations
The main syndromes associated with Ureaplasma spp., M. genitalium, and M.
hominis are displayed in Table 251.1 .

Table 251.1
Clinical Syndromes and Antibiotic Therapy for
Ureaplasmas and Mycoplasmas Infection

UREAPLASMA SPP. M. HOMINIS M. GENITALIUM

INTRAUTERINE AND NEONATAL INFECTIONS
Chorioamnionitis ++ ++ –
Preterm delivery ++ ++ ++
Postpartum fever ++ +++ UK
BPD +++ + UK
CNS infections + + UK
NEC + UK UK
GENITOURINARY INFECTIONS
NGU (acute/chronic) ++* – +++
Cervicitis – – +++
PID + ++ +++
NON-NEONATAL/NON-GENITOURINARY INFECTIONS
 CNS disease † + ++ –
Bacteremia + ++ –
Surgical wound infections ++ ++ –
Arthritis + ++ –
TREATMENT
Macrolides ++ – ++
Quinolones ‡ + ++ +
Clindamycin – ++ +
Tetracyclines (doxycycline) ++ + +
* Only Ureaplasma urealyticum (not parvum ).

† CNS disease includes: meningitis, brain abscess, subdural empyema, and nonfunctioning CNS

shunts.
‡ The most commonly used quinolones are ciprofloxacin and moxifloxacin.

BPD : bronchopulmonary dysplasia; CNS : central nervous system; NEC : necrotizing

enterocolitis; NGU : nongonococcal urethritis; PID : pelvic inflammatory disease; UK : unknown.

Intrauterine and Neonatal Infections

Chorioamnionitis and Early Onset Infections
Genital mycoplasmas are associated with a variety of fetal and neonatal
infections. Ureaplasma spp. can cause clinically inapparent chorioamnionitis,
resulting in spontaneous abortion, increased fetal death, or premature delivery.
The role of Ureaplasma in clinical chorioamnionitis is still unclear. The
association between preterm birth and ureaplasmas remains uncertain. Studies
have shown that women with Ureaplasma spp. detected by PCR in amniotic
fluid between 12 to 20 wk of gestation have an increased risk of preterm labor
and delivery. Ureaplasma spp. can also be recovered from tracheal, blood,
cerebrospinal fluid (CSF), or lung biopsy specimens in up to 50% of sick infants
younger than 34 wk gestation. In a study of 351 mother/infant dyads, isolation of
Ureaplasma spp. or M. hominis from cord blood was documented in 23% of
infants born between 23 and 32 wk gestation, and correlated with the
development of systemic inflammatory response syndrome.

Bronchopulmonary Dysplasia
The role of these organisms in causing severe respiratory insufficiency, the need
for mechanical ventilation, the development of BPD, or death remains
controversial. Nevertheless, meta-analyses of published studies have identified
respiratory colonization with Ureaplasma spp. as an independent risk factor for
in humans where Amblyomma ticks frequently contain R. amblyommatis suggest
that the full range of agents that can cause spotted fever is still to be discerned.

Table 255.1
Summary of Rickettsial Diseases of Humans, Including
Rickettsia, Orientia, Ehrlichia, Anaplasma, Neorickettsia,
and Coxiella

PRESENTING
ARTHROPOD VECTOR, GEOGRAPHIC
GROUP OR DISEASE AGENT CLINICAL
TRANSMISSION HOSTS DISTRIBUTION
FEATURES*
SPOTTED FEVER GROUP
Rocky Mountain Rickettsia Tick bite: Dogs Western Fever, headache,
spotted fever rickettsii Dermacentor Rodents hemisphere rash,* emesis,
species (wood diarrhea, myalgias
tick, dog tick)
Rhipicephalus
sanguineus
(brown dog
tick)
Mediterranean Rickettsia Tick bite: R. Dogs Africa, Painless eschar
spotted fever conorii sanguineus (brown Rodents Mediterranean, (tache noir) with
(boutonneuse dog tick) India, Middle East regional
fever) lymphadenopathy,
fever, headache,
rash,* myalgias
African tick-bite Rickettsia Tick bite Cattle Sub-Saharan Fever, single or
fever africae Goats? Africa, Caribbean multiple eschars,
regional
lymphadenopathy,
rash* (can be
vesicular)
Tickborne Rickettsia Tick bite: ? Europe Eschar (scalp),
lymphadenopathy slovaca, Dermacentor painful
(TIBOLA); Rickettsia lymphadenopathy
Dermacentor- raoultii,
borne necrosis Rickettsia
and sibirica
lymphadenopathy mongolotimonae
(DEBONEL)
Rickettsia sp , “Rickettsia Dermacentor California Eschar, fever,
364D genotype philippi ” occidentalis headache,
(Pacific coast tick) lymphadenopathy,
malaise
Flea-borne Rickettsia felis Flea bite Opossums Western Fever, rash,*
spotted fever Cats hemisphere, headache
Dogs Europe
TRANSITIONAL GROUP
Rickettsialpox Rickettsia akari Mite bite Mice North America, Painless eschar,
Russia, Ukraine, ulcer or papule;
 Adriatic, Korea, tender regional
South Africa lymphadenopathy,
fever, headache,
rash* (can be
vesicular)
Queensland tick Rickettsia Ixodes holocyclus, Bandicoots Australia, Fever, eschar,
typhus australis I. tasmani and Rodents Tasmania headache, myalgia,
lymphadenopathy

TYPHUS GROUP
Murine typhus Rickettsia typhi Flea feces Rats Worldwide Fever, headache,
Opossums rash,* myalgias,
emesis,
lymphadenopathy,
hepatosplenomegaly
Epidemic (louse- Rickettsia Louse feces Humans South America, Fever, headache,
borne) typhus prowazekii Central America, abdominal pain,
(recrudescent Mexico, Africa, rash,* CNS
form: Brill- Asia, Eastern involvement
Zinsser disease) Europe
Flying squirrel Rickettsia Louse feces? Flying Eastern United Same as above
(sylvatic) typhus prowazekii Flea feces or squirrels States (often milder)
bite?
SCRUB TYPHUS
Scrub typhus Orientia Chigger bite: Rodents? South Asia, Fever, rash,*
tsutsugamushi Leptotrombidium Japan, Indonesia, headache, painless
Korea, China, eschar,
Russia, Australia hepatosplenomegaly,
gastrointestinal
symptoms

EHRLICHIOSIS AND ANAPLASMOSIS

Human Ehrlichia Tick bite: Deer United States Fever, headache,
monocytic chaffeensis Amblyomma Dogs Europe? malaise, myalgias,
ehrlichiosis americanum (lone Africa? Asia? rash* ‡ ,
star tick) hepatosplenomegaly,
‡ swollen hands/feet
‡
Human Anaplasma Tick bite: Rodents United States, Fever, headache,
granulocytic phagocytophilum Ixodes species Deer Europe, Asia malaise, myalgias
anaplasmosis Haemaphysalis Ruminants
longicornis
Ewingii Ehrlichia ewingii Tick bite: Dogs United States Fever, headache,
ehrlichiosis Amblyomma Deer (south-central, malaise, myalgias
americanum (lone southeast)
star tick)
Ehrlichia muris Ehrlichia muris Ixodes scapularis ? Minnesota, Fever, headache,
euclairensis euclairensis Wisconsin malaise, myalgias
infection

Sennetsu Neorickettsia Ingestion of fish fish, Japan, Malaysia, Fever,

neorickettsiosis sennetsu helminth?, trematodes Laos “mononucleosis”
 ingestion of symptoms,
fermented fish postauricular and
posterior cervical
lymphadenopathy
Q FEVER
Q Fever: acute Coxiella burnetii Inhalation of Cattle Worldwide Fever, headache,
(for chronic, see infected aerosols: Sheep arthralgias,
text) contact with Goats myalgias,
parturient animals, Cats gastrointestinal
abattoir, Rabbits symptoms, cough,
contaminated pneumonia, rash
cheese and milk, ? (children)
ticks
* Rash is infrequently present at initial presentation but appears during the 1st wk of illness.

† Preferred treatment is in bold .

‡ Often present in children but not adults.

ALT, alanine aminotransferase; ANC, absolute neutrophil count; AST, aspartate aminotransferase;
CNS, central nervous system; DFA, direct fluorescent antibody; IFA, indirect fluorescent antibody;
IgG, immunoglobulin G; IgM, immunoglobulin M; IH, immunohistochemistry; PCR, polymerase
chain reaction; WBC, white blood cell count.

Infections with other members of the spotted fever and transitional groups are
clinically similar to MSF, with fever, maculopapular rash, and eschar at the site
of the tick bite. Israeli spotted fever is generally associated with a more severe
course, including death, in children. African tick bite fever is relatively mild, can
include a vesicular rash, and often manifests with multiple eschars. New
potentially pathogenic rickettsial species have been identified, including R.
slovaca, the cause of tickborne lymphadenopathy or Dermacentor -borne
necrosis and lymphadenopathy. R. aeschlimannii, R. heilongjiangensis, R.
helvetica, R. massiliae, and R. raoultii are all reported to cause mild to moderate
illnesses in humans, although few cases have been described. Fortunately, the
vast majority of infections respond well to doxycycline treatment if instituted
early in illness; however, this is a significant challenge.

255.1
Rocky Mountain Spotted Fever
(Rickettsia rickettsii)
CHAPTER 260

Principles of Antifungal Therapy

William J. Steinbach, Michael Cohen-Wolkowiez, Daniel K. Benjamin Jr.

Invasive fungal infections are a major cause of morbidity and mortality in the
growing number of immunocompromised children. Fortunately, the therapeutic
armamentarium for invasive fungal infections has markedly increased since the
turn of the century (Tables 260.1 and 260.2 ).

Table 260.1
Suggested Dosing of Antifungal Agents in Children and
Neonates
SUGGESTED
DRUG FORMULATIONS PEDIATRIC COMMENTS
DOSAGE
Amphotericin IV 1 mg/kg/day Generally less toxicity in children than adults; do not
B start with smaller test doses
deoxycholate
Lipid IV 5 mg/kg/day Generally, all lipid formulations are dosed the same;
amphotericin there is no clear indication of one formulation over
B another for clinical efficacy
formulations
Fluconazole IV, PO 12 mg/kg/day Loading dose (25 mg/kg) is recommended in neonates
based on pharmacokinetic simulations and likely
suggested in children, but insufficiently studied
Itraconazole PO 2.5 mg/kg/dose Divide dosage twice daily in children; follow trough
bid levels
Voriconazole IV, PO 8 mg/kg/dose Linear pharmacokinetics in children requires higher
bid IV dosing than in adults; 9 mg/kg/dose bid IV loading,
maintenance; 9 followed by maintenance dosing; follow trough levels
mg/kg/dose bid
oral maintenance
Posaconazole IV, PO Suspected to be Dosage unclear in children at present.
12-24 mg/kg/day In adults, max dosage for oral suspension is 800
divided tid (oral mg/day, and optimally divide this into 2 or 3 doses;
suspension) follow trough levels. Adult dosing for IV and
extended-release tablet is 300 mg twice on 1st day,
 then 300 mg once daily.
Isavuconazole PO, IV No dosing in Adult dosing for IV and tablet is 200 mg 3 times on 1st
children day, then 200 mg once daily.
Micafungin IV 2-10 mg/kg/day Highest dosages in neonates (10 mg/kg/day), and lower
dosages in children; >8 yr of age, use adult dosage
Anidulafungin IV 1.5 mg/kg/day Loading dose of 3 mg/kg/day
Caspofungin IV 50 mg/m2 /day Load with 70 mg/m2 /day, then 50/mg/m2 /day as
maintenance dosage

Table 260.2
Suggested Antifungals for Specific More Common Fungal
Pathogens

AMPHOTERICIN
FUNGAL
B FLUCONAZOLE ITRACONAZOLE VORICONAZOLE POSACONAZOLE
SPECIES
FORMULATIONS
Aspergillus ++ − − − −
calidoustus
Aspergillus + − +/− ++ +
fumigatus
Aspergillus − − + ++ +
terreus
Blastomyces ++ + ++ + +
dermatitidis
Candida + ++ + + +
albicans
Candida + − +/− +/− +/−
glabrata
Candida + − − + +
krusei
Candida − ++ + + +
lusitaniae
Candida ++ ++ + + +
parapsilosis
Coccidioides ++ + ++ + ++
immitis
Cryptococcus ++ + + + +
spp.
Fusarium +/− − − ++ +
spp.
Histoplasma ++ + ++ + +
capsulatum
Mucor spp. ++ − +/− − +
Scedosporium − − +/− + +
apiospermum
Scedosporium − − +/− +/− +/−
prolificans
++ , preferred therapy(ies); +, usually active; +/−, variably active; −, usually not active.
C. krusei and some isolates of C. glabrata. Additionally, in centers where
fluconazole prophylaxis is used, another agent, such as amphotericin B
deoxycholate, should be used for treatment. The echinocandins have excellent
activity against most Candida species and have been used successfully in
patients with resistant organisms or in whom other therapies have failed. Several
studies have described the pharmacokinetics of antifungals in infants (Table
261.1 ).

Table 261.1

Dosing of Antifungal Agents in Infants* and Number of Infants Younger Than 1 Yr of

Age Studied With Reported Pharmacokinetic Parameters
DRUG INFANTS STUDIED SUGGESTED DOSE
Amphotericin B deoxycholate 27 1 mg/kg/day
Amphotericin B lipid complex 28 5 mg/kg/day
Liposomal amphotericin B 17 5 mg/kg/day
Amphotericin B colloidal dispersion 0 5 mg/kg/day
Fluconazole † 65 12 mg/kg/day
Micafungin ‡ 138 10 mg/kg/day
Caspofungin § 22 50 mg/m2 /day
Anidulafungin ‡ 15 1.5 mg/kg/day
* Voriconazole dosing has not been investigated in the nursery.

† A loading dose of 25 mg/kg of fluconazole is necessary to achieve therapeutic serum

concentrations in the early days of therapy.

‡ Micafungin has been studied in infants <120 days of life at this dosage.

§ Caspofungin and anidulafungin should generally be avoided because dosing sufficient to

penetrate brain tissue has not been studied.

Prognosis
Mortality following invasive candidiasis in premature infants has been
consistently reported to be around 20% in large studies but can be as high as
50% in infants <1,500 g birthweight. Candidiasis is also associated with poor
neurodevelopmental outcomes, chronic lung disease, and severe retinopathy of
prematurity.

Bibliography
readily on routine blood culture media, with ≥90% of positive cultures identified
within 72 hr. CT may demonstrate findings consistent with invasive fungal
infection but also is limited by nonspecific findings and false negatives. The role
of screening by CT scan has not been well defined. In high-risk patients, serial
serum assays for (1,3)-β-D -glucan, a polysaccharide component of the fungal
cell wall, may contribute to the diagnosis of invasive Candida infection.
However, this test is not sensitive or specific enough to be used without a careful
assessment of the limitations of the assay.

Treatment
Echinocandins are favored as empirical therapy for moderately or severely ill
children and for those with neutropenia; fluconazole is acceptable for those who
are infected with a susceptible organism and are less critically ill; amphotericin
B products are also acceptable. Definitive antifungal selection should be made
based on susceptibility testing results. Fluconazole is not effective against C.
krusei and some isolates of C. glabrata. C. parapsilosis has occasional resistance
to the echinocandins, but the overall rate is still low. Amphotericin B
deoxycholate is inactive against approximately 20% of the strains of C.
lusitaniae, and therefore susceptibility testing should be performed for all strains
(Table 261.2 ). C. auris , a species first identified in 2009 that has caused
nosocomial infections worldwide, is resistant to most antifungals. An
echinocandin should be used until sensitivity results are available.

Table 261.2

Dosing of Antifungal Agents in Children Older Than 1 Yr of Age for Treatment of

Invasive Disease
DRUG SUGGESTED DOSAGE
Amphotericin B deoxycholate 1 mg/kg/day
Amphotericin B lipid complex 5 mg/kg/day
Liposomal amphotericin B 5 mg/kg/day
Amphotericin B colloidal dispersion 5 mg/kg/day
Fluconazole † 12 mg/kg/day
Voriconazole* , ‡ 8 mg/kg every 12 hr
Micafungin 2-4 mg/kg/day
Caspofungin 50 mg/m2 /day
Anidulafungin 1.5 mg/kg/day
* Use adult dosages in children older than 12 yr of age for voriconazole and older than 8 yr of age
Residual pulmonary coccidioidomycosis includes fibrosis as well as persisting
pulmonary nodules. Nodules are present in 5–7% of infections and sometimes
require differentiation from malignancy in adults.

Disseminated (Extrapulmonary) Infection

Clinically apparent dissemination occurs in 0.5% of patients. Its incidence is
increased in infants; men; persons of Filipino, African, and Latin American
ancestry; and persons from other Asian backgrounds. Primary or acquired
disorders of cellular immunity (Table 267.1 ) markedly increase the risk of
dissemination.

Table 267.1

Risk Factors for Poor Outcome in Patients With Active Coccidioidomycosis

PRIMARY INFECTIONS
Severe, prolonged (≥6 wk), or progressive infection
RISK FACTORS FOR EXTRAPULMONARY DISSEMINATION
Primary or acquired cellular immune dysfunction (including patients receiving tumor necrosis factor inhibitors)
Neonates, infants, the elderly
Male sex (adult)
Filipino, African, Native American, or Latin American ethnicity
Late-stage pregnancy and early postpartum period
Standardized complement fixation antibody titer >1 : 16 or increasing titer with persisting symptoms
Blood group B
Human leukocyte antigen class II allele-DRBI*1301

Symptoms usually occur within 6 mo of primary infection. Prolonged fever,

toxicity, skin lesions, subcutaneous and/or osseous cold abscesses, and laryngeal
lesions can herald the onset. Organism-specific skin lesions have a predilection
for the nasolabial area and appear initially as papules, which evolve to form
pustules, plaques, abscesses, and verrucous plaques. Biopsy of these lesions
demonstrates spherules. Basilar meningitis is the most common manifestation
and may be accompanied by ventriculitis, ependymitis, cerebral vasculitis,
abscess, and syringomyelia. Headache, vomiting, meningismus, and cranial
nerve dysfunction are often present. Untreated meningitis is almost invariably
fatal. Bone infections account for 20–50% of extrapulmonary manifestations, are
area of endemicity should be considered when formulating a plan of
management.

Table 267.2

Indications for Treatment of Coccidioidomycosis in Adults

INDICATION TREATMENT
Acute pneumonia, mild Observe without antifungal treatment
at 1-3 mo intervals for 2 yr; some
experts recommend antifungal
treatment
Weight loss >10%; night sweats >3 wk; infiltrates at least half of 1 lung Treat with an azole daily for 3-6 mo,
or parts of both lungs; prominent or persistent hilar lymphadenopathy; with follow-up at 1-3 mo intervals for
complement fixation titers >1 : 16; inability to work, symptoms >2 mo 2 yr
Uncomplicated acute pneumonia, special circumstances: Treat with an azole daily for 3-6
immunosuppression, late pregnancy, Filipino or African ancestry, age mo, with follow-up at 1-3 mo
>55 yr, other chronic diseases (diabetes, cardiopulmonary disease), intervals for 2 yr
symptoms >2 mo Treat with amphotericin B if in
late pregnancy
Diffuse pneumonia: reticulonodular or miliary infiltrates suggest Treat initially with amphotericin B
underlying immunodeficiency and possible fungemia, pain if significant hypoxia or rapid
deterioration, followed by an azole
for ≥1 yr
In mild cases, an azole for ≥1 yr
Chronic pneumonia Treat with an azole for ≥1 yr
Disseminated disease, nonmeningeal Treat with an azole for ≥1 yr except in
severe or rapidly worsening cases, for
which amphotericin B is recommended
Disseminated disease, meningeal Treat with fluconazole (some add
intrathecal amphotericin B) and treat
indefinitely

Patients should be followed closely because late relapse can occur, especially
in patients who are immunosuppressed or have severe manifestations. Treatment
is recommended for all HIV-infected patients with active coccidioidomycosis
and CD4 counts <250/µL. Following successful treatment, antifungals may be
stopped if the CD4 count exceeds 250/µL. Treatment should be continued if the
CD4 count remains less than 250/µL and should be given indefinitely in all HIV-
infected patients with coccidioidal meningitis.
First-line agents include oral and intravenous preparations of fluconazole (12
mg/kg/day IV or PO) and itraconazole (10 mg/kg/day). Serum levels of
itraconazole should be monitored.
Amphotericin B is preferred for initial treatment of severe infections.
Amphotericin B deoxycholate is less costly than lipid formulations and is often
well tolerated in children. Once a daily dose of amphotericin B deoxycholate of
CHAPTER 272

Principles of Antiviral Therapy

Mark R. Schleiss

Antiviral chemotherapy typically requires a delicate balance between targeting

critical steps in viral replication without interfering with host cellular function.
Because viruses require cellular functions to complete replication, many antiviral
agents exert significant host cellular toxicity, a limitation that has hindered
antiviral drug development. In spite of this limitation, a number of agents are
licensed for use against viruses, particularly herpesviruses, respiratory viruses,
and hepatitis viruses (Table 272.1 ).

Table 272.1
Currently Licensed Antiviral Drugs

ANTIVIRAL TRADE NAME MECHANISM OF ACTION

Acyclovir Zovirax Inhibits viral DNA polymerase
Adefovir Hepsera Nucleotide reverse transcriptase inhibitor
Amantadine* Symmetrel Blocks M2 protein ion channel
Baloxavir Xofluza Inhibits polymerase acidic endonuclease, blocking viral
replication
Beclabuvir BMS-791325 Inhibitor of HCV NS5B
Boceprevir † Victrelis Inhibitor of HCV NS3 serine protease
Active against HCV genotype 1
Cidofovir Vistide Inhibits viral DNA polymerase
Daclatasvir Daklinza Inhibitor of HCV NS5A
Used in varying combinations with sofosbuvir, ribavirin, and
interferon
Dasabuvir Exviera Inhibitor of HCV NS5B
Used together with the combination medication
ombitasvir/paritaprevir/ritonavir (Vikiera Pak)
Activity limited to HCV genotype 1
Elbasvir (Zepatier) Inhibitor of HCV NS5A
Used in combination with the NS3/4A protease inhibitor
grazoprevir under the trade name Zepatier, either with or
without ribavirin
Entecavir Baraclude Nucleoside reverse transcriptase inhibitor
Active against HBV
Famciclovir Generic Inhibits viral DNA polymerase
Fomivirsen ‡ Vitravene Phosphorothioate oligonucleotide inhibits viral replication via
antisense mechanism
Foscarnet Foscavir Inhibits viral DNA polymerase and reverse transcriptase at
pyrophosphate-binding site
Ganciclovir Cytovene Inhibits viral DNA polymerase
Grazoprevir (Zepatier) Inhibitor of HCV NS3-4A serine protease Used in combination
with elbasvir under the trade name Zepatier, either with or
without ribavirin
Idoxuridine Herplex Inhibits viral DNA polymerase
Interferon-α Intro-A (interferon- Produces multiple effector proteins that exert antiviral effects;
α2b) also directly interacts with immune system components
Roferon-A
(interferon-α2a)
Infergen (interferon
alfacon-1)
Interferon-α2b plus Rebetron Not established
ribavirin
Lamivudine (3TC) Epivir Inhibits viral DNA polymerase and reverse transcriptase; active
against HBV
Ledipasvir (with Sofosbuvir: Inhibitor of HCV NS5A
Harvoni)
Ombitasvir (Viekira Pak) Inhibitor of HCV NS5A
Used in combination with paritaprevir, ritonavir and
dasabuvir in Viekira Pak
Active against HCV genotype 1
Oseltamivir Tamiflu Neuraminidase inhibitor; interference with deaggregation and
release of viral progeny
Paritaprevir (Viekira Pak) Inhibitor of HCV NS3-4A serine protease Used in combination
(Technivie/Viekirax) with ombitasvir, ritonavir and dasabuvir (Viekira Pak), or in
combination with ombitasvir and ritonavir (Technivie/Viekirax)
Pegylated interferon PEG-Intron (α2b), Same as interferon
Pegasys (α2a)
Penciclovir Denavir Inhibits viral DNA polymerase
Peramivir Rapivab Neuraminidase inhibitor
Ribavirin Virazole, Rebetol, Interference with viral messenger RNA
Copegus
Rimantadine* Flumadine Blocks M2 protein ion channel
Simeprevir Olysio Inhibitor of HCV NS3-4A serine protease Active against
genotype 1 ± genotype 4
Used with include sofosbuvir or ribavirin and pegylated
interferon-alfa
Sofosbuvir (Harvoni) Inhibitor of HCV NS5B
Used in combination with Ledipasvir (Harvoni)
Telaprevir Incivek Inhibitor of HCV NS3-4A serine protease
Incivio Active against HCV genotype 1
Telbivudine Tyzeka Interferes with HBV DNA replication
Tenofovir Viread Nucleoside reverse transcriptase inhibitor
Active against HBV
Trifluridine Viroptic Inhibits viral DNA polymerase
Valacyclovir Valtrex Same as acyclovir
Valganciclovir Valcyte Same as ganciclovir
 Velpatasvir (Epclusa, Sofosvel, Inhibitor of HCV NS5A
Velpanat) Used in combination with sofosbuvir (Epclusa, Sofosvel,
Velpanat)
Active against all 6 HCV genotypes
Vidarabine ara-A Inhibits viral DNA polymerase (and to lesser extent, cellular
DNA polymerase)
Zanamivir Relenza Neuraminidase inhibitor; interference with deaggregation and
release of viral progeny
FDA-APPROVED COMBINATION THERAPIES
Interferon-α2b + Rebetron (Intron-A plus
ribavirin Rebetol)
Interferon-α2a + Roferon-A + ribavirin
ribavirin
Pegylated PEG-Intron + Rebetol
interferon-α2b +
ribavirin (3 yr and
older)
Pegylated Pegasys + Copegus
interferon-α2a +
ribavirin (5 yr and
older)
* No longer recommended by Centers for Disease Control and Prevention for treatment of
influenza.
†
No longer marketed in United States.
‡ No longer available.

In making the decision to commence antiviral drugs, it is important for the

clinician to obtain appropriate diagnostic specimens, which can help clarify the
antiviral of choice. The choice of a specific antiviral is based on the
recommended agent of choice for a particular clinical condition,
pharmacokinetics, toxicities, cost, and the potential for development of
resistance (Table 272.2 ). Intercurrent conditions in the patient, such as renal
insufficiency, should also be considered. Clinicians must monitor antiviral
therapy closely for adverse events or toxicities, both anticipated and
unanticipated.

Table 272.2
Antiviral Therapies for Non-HIV Clinical Conditions*

ANTIVIRAL
VIRUS CLINICAL SYNDROME AGENT OF ALTERNATIVE ANTIVIRAL AGENTS
CHOICE
Influenza A Treatment Oseltamivir Zanamivir (>7 yr old)
and B (>2 wk old) Peramivir (>2 yr old)
Prophylaxis Oseltamivir Zanamivir (>5 yr old)
(>3 mo old)
Respiratory Bronchiolitis or pneumonia in Ribavirin
syncytial high-risk host aerosol
virus
Adenovirus In immunocompromised Cidofovir
patients:
Pneumonia
Viremia
Nephritis
Hemorrhagic cystitis
CMV Congenital CMV infection Ganciclovir Valganciclovir (if oral therapy appropriate; long-
(IV) term oral valganciclovir investigational but may
improve developmental and hearing outcomes)
Retinitis in AIDS patients Valganciclovir Ganciclovir
Cidofovir
Foscarnet
Ganciclovir ocular insert
Pneumonitis, colitis; Ganciclovir Foscarnet
esophagitis in (IV) Cidofovir
immunocompromised patients Valganciclovir
HSV Neonatal herpes Acyclovir
(IV)
Suppressive therapy following Acyclovir
neonatal herpes with central (PO)
nervous system involvement
HSV encephalitis Acyclovir
(IV)
HSV gingivostomatitis Acyclovir Acyclovir (IV)
(PO)
First episode genital infection Acyclovir Valacyclovir
(PO) Famciclovir
Acyclovir (IV) (severe disease)
Recurrent genital herpes Acyclovir Valacyclovir
(PO) Famciclovir
Suppression of genital herpes Acyclovir Valacyclovir
(PO) Famciclovir
Cutaneous HSV (whitlow, Acyclovir Penciclovir (topical)
herpes gladiatorum) (PO)
Eczema herpeticum Acyclovir Acyclovir (IV) (severe disease)
(PO)
Mucocutaneous infection in Acyclovir Acyclovir (PO) (if outpatient therapy acceptable)
immunocompromised host (IV)
(mild)
Mucocutaneous infection in Acyclovir
immunocompromised host (IV)
(moderate to severe)
Prophylaxis in bone marrow Acyclovir Valacyclovir
transplant recipients (IV)
Acyclovir-resistant HSV Foscarnet Cidofovir
Keratitis or keratoconjunctivitis Trifluridine Vidarabine
Varicella- Chickenpox, healthy child Supportive Acyclovir (PO)
zoster virus care
Chickenpox, Acyclovir
immunocompromised child (IV)
Zoster (not ophthalmic branch Supportive Acyclovir (PO)
 of trigeminal nerve), healthy care
child
Zoster (ophthalmic branch of Acyclovir
trigeminal nerve), healthy child (IV)
Zoster, immunocompromised Acyclovir Valacyclovir
child (IV)
*
For antiviral agents for hepatitis B and hepatitis C, see Table 272.1 .
CMV, cytomegalovirus; HSV, herpes simplex virus.

In vitro sensitivity testing of virus isolates to antiviral compounds usually

involves a complex tissue culture system. The potency of an antiviral is
determined by the 50% inhibitory dose (ID50 ), which is the antiviral
concentration required to inhibit the growth in cell culture of a standardized viral
inoculum by 50%. Because of the complexity of these assays, the results vary
widely, and the actual relationship between antiviral sensitivity testing and
antiviral therapy outcomes is sometimes unclear. Because these assays are often
not readily available and take considerable time to complete, genotypic analysis
for antiviral susceptibility is increasingly being offered. Such assays may be
useful for patients on long-term antiviral therapy.
Clinical context is essential in making decisions about antiviral treatment,
along with knowledge of a patient's immune status. For example, antiviral
treatment is rarely if ever indicated in an immunocompetent child shedding
cytomegalovirus (CMV) but may be lifesaving when administered to an
immunocompromised solid organ transplant (SOT) or hematopoietic stem cell
transplant (HSCT) patient. Antivirals can be used with a variety of clinical goals
in mind. Antivirals can be used for treatment of active end-organ disease, as
prophylaxis to prevent viral infection or disease, or as preemptive therapy
aimed at reducing risk of progression to disease (i.e., a positive signal indicating
viral replication but in the absence of clinical evidence of end-organ disease). In
preemptive therapy, a patient will usually have a positive signal for polymerase
chain reaction–based identification of viral nucleic acids in a clinical sample
(blood or body fluid) but have no symptoms. However, SOT and HSCT patients
are at high risk of developing disease in this setting (particularly due to CMV
infection), a scenario that warrants preemptive treatment with an antiviral agent.
In contrast, prophylaxis is administered to seropositive patients who are at risk to
reactivate latent viral infection but do not yet have evidence of active viral
replication or shedding.
A fundamental concept important in the understanding of the mechanism of
action of most antivirals is that viruses must use host cell components to
rashes similar to that of measles. Kawasaki syndrome can cause many of the
same findings as measles but lacks discrete intraoral lesions (Koplik spots) and a
severe prodromal cough and typically leads to elevations of neutrophils and
acute-phase reactants. In addition, the characteristic thrombocytosis of Kawasaki
syndrome is absent in measles (see Chapter 191 ). Drug eruptions may
occasionally be mistaken for measles.

Complications
Complications of measles are largely attributable to the pathogenic effects of the
virus on the respiratory tract and immune system (Table 273.1 , Fig. 273.2 ).
Several factors make complications more likely. Morbidity and mortality from
measles are greatest in individuals younger than 5 yr of age (especially <1 yr of
age) and older than 20 yr of age. In developing countries, higher case fatality
rates have been associated with crowding, possibly attributable to larger
inoculum doses after household exposure. Severe malnutrition in children results
in a suboptimal immune response and higher morbidity and mortality with
measles infection. Low serum retinol levels in children with measles are
associated with higher measles morbidity and mortality in developing countries
and in the United States. Measles infection lowers serum retinol concentrations,
so subclinical cases of hyporetinolemia may be made symptomatic during
measles. Measles infection in immunocompromised persons is associated with
increased morbidity and mortality. Among patients with malignancy in whom
measles develops, pneumonitis occurs in 58% and encephalitis occurs in 20%.

Table 273.1
Complications by Age for Reported Measles Cases, United
States, 1987–2000

NO. (%) OF PERSONS WITH COMPLICATION

BY AGE GROUP
OVERALL (67,032 CASES
COMPLICATION
WITH AGE INFORMATION) <5 yr (N 5-9 yr 10-19 yr 20-29 yr <30 yr
(N = (N = (N = (N =
= 28,730)
6,492) 18,580) 9,161) 4,069)
Any 19,480 (29.1) 11,883 1,173 2,369 2,656 1,399
(41.4) (18.1) (12.8) (29.0) (34.4)
Death 177 (0.3) 97 (0.3) 9 (0.1) 18 (0.1) 26 (0.3) 27 (0.7)
Diarrhea 5,482 (8.2) 3,294 408 (6.3) 627 (3.4) 767 (8.4) 386 (9.5)
(11.5)
 Encephalitis 97 (0.1) 43 (0.2) 9 (0.1) 13 (0.1) 21 (0.2) 11 (0.3)
Hospitalization 12,876 (19.2) 7,470 612 (9.4) 1,612 (8.7) 2,075 1,107
(26.0) (22.7) (27.2)
Otitis media 4,879 (7.3) 4,009 305 (4.7) 338 (1.8) 157 (1.7) 70 (1.7)
(14.0)
Pneumonia 3,959 (5.9) 2,480 183 (2.8) 363 (2.0) 554 (6.1) 379 (9.3)
(8.6)
From Perry RT, Halsey NA: The clinical significance of measles: a review, Clin Infect Dis
189(Suppl. 1):S4–S16, 2004.

Pneumonia is the most common cause of death in measles. It may manifest as

giant cell pneumonia caused directly by the viral infection or as superimposed
bacterial infection. The most common bacterial pathogens are Streptococcus
pneumoniae, Haemophilus influenzae, and Staphylococcus aureus . Following
severe measles pneumonia, the final common pathway to a fatal outcome is
often the development of bronchiolitis obliterans.
Croup, tracheitis, and bronchiolitis are common complications in infants and
toddlers with measles. The clinical severity of these complications frequently
requires intubation and ventilatory support until the infection resolves.
Acute otitis media is the most common complication of measles and was of
particularly high incidence during the epidemic of the late 1980s and early 1990s
because of the relatively young age of affected children. Sinusitis and mastoiditis
also occur as complications. Viral and/or bacterial tracheitis is seen and can be
life-threatening. Retropharyngeal abscess has also been reported.
Measles infection is known to suppress skin test responsiveness to purified
tuberculin antigen. There may be a higher rate of activation of pulmonary
tuberculosis in populations of individuals infected with Mycobacterium
tuberculosis who are then exposed to measles.
Diarrhea and vomiting are common symptoms associated with acute measles,
and diffuse giant cell formation is found in the epithelium in the gastrointestinal
tract. Dehydration is a common consequence, especially in young infants and
children. Appendicitis or abdominal pain may occur from obstruction of the
appendiceal lumen by lymphoid hyperplasia.
Febrile seizures occur in <3% of children with measles. Encephalitis
following measles is a long-associated complication, often with an unfavorable
outcome. Rates of 1-3 per 1,000 cases of measles have been reported, with
greater numbers occurring in adolescents and adults than in preschool- or
school-age children. Encephalitis is a postinfectious, immunologically mediated
process and is not the result of a direct effect by the virus. Clinical onset begins
during the exanthem and manifests as seizures (56%), lethargy (46%), coma
Prevention
Patients shed measles virus from 7 days after exposure to 4-6 days after the onset
of rash. Exposure of susceptible individuals to patients with measles should be
avoided during this period. In hospitals, standard and airborne precautions
should be observed for this period. Immunocompromised patients with measles
will shed virus for the duration of the illness, so isolation should be maintained
throughout the disease.

Vaccine
Vaccination against measles is the most effective and safe prevention strategy.
Measles vaccine in the United States is available as a combined vaccine with
measles-mumps-rubella vaccine, the last of which is the recommended form in
most circumstances (Table 273.2 ). Following the measles resurgence of 1989-
1991, a 2nd dose of measles vaccine was added to the schedule. The current
recommendations include a 1st dose at 12-15 mo of age, followed by a 2nd dose
at 4-6 yr of age. However, the 2nd dose can be given any time after 30 days
following the 1st dose, and the current schedule is a convenience schedule.
Seroconversion is slightly lower in children who receive the 1st dose before or at
12 mo of age (87% at 9 mo, 95% at 12 mo, and 98% at 15 mo) because of
persisting maternal antibody; however, this is an evolving situation, with
children currently as young as 6 mo unprotected from maternal antibodies and
susceptible to measles infection. For children who have not received 2 doses by
11-12 yr of age, a 2nd dose should be provided. Infants who receive a dose
before 12 mo of age should be given 2 additional doses at 12-15 mo and 4-6 yr
of age. Children who are traveling should be offered either primary measles
immunization even as young as 6 mo or a 2nd dose even if <4 yr.

Table 273.2

Recommendations for Measles Immunization

CATEGORY RECOMMENDATIONS
Unimmunized, no history of MMR or MMRV vaccine is recommended at 12-15 mo of age; a 2nd dose is
measles (12-15 mo of age) recommended at least 28 days after the 1st dose (or 90 days for MMRV) and
usually is administered at 4 through 6 yr of age
Children 6-11 mo of age in Immunize with MMR vaccine, but this dose is not considered valid, and 2 valid
epidemic situations or doses administered on or after the 1st birthday are required. The 1st valid dose
before international travel should be administered at 12-15 mo of age; the 2nd valid dose is recommended at
 least 28 days later and usually is administered at 4 through 6 yr of age. MMRV
should not be administered to children <12 mo of age.
Students in kindergarten, Administer the 2nd dose
elementary, middle, and
high school who have
received 1 dose of measles
vaccine at 12 mo of age or
older
Students in college and Administer the 2nd dose
other postsecondary
institutions who have
received 1 dose of measles
vaccine at 12 mo of age or
older
History of immunization Dose not considered valid; immunize (2 doses)
before the 1st birthday
History of receipt of Dose not considered valid; immunize (2 doses)
inactivated measles vaccine
or unknown type of vaccine,
1963–1967
Further attenuated or Dose not considered valid; immunize (2 doses)
unknown vaccine
administered with IG
Allergy to eggs Immunize; no reactions likely
Neomycin allergy, Immunize; no reactions likely
nonanaphylactic
Severe hypersensitivity Avoid immunization
(anaphylaxis) to neomycin
or gelatin
Tuberculosis Immunize; if patient has untreated tuberculosis disease, start antituberculosis
therapy before immunizing
Measles exposure Immunize or give IG, depending on circumstances
HIV infected Immunize (2 doses) unless severely immunocompromised; administration of IG if
exposed to measles is based on degree of immunosuppression and measles vaccine
history
Personal or family history of Immunize; advise parents of slightly increased risk of seizures
seizures
Immunoglobulin or blood Immunize at the appropriate interval
recipient
MMR, measles-mumps-rubella vaccine; MMRV, measles-mumps-rubella-varicella vaccine.
From American Academy of Pediatrics: Measles. In Kimberlin DW, Brady MT, Jackson MA, Long
SS, editors: Red book 2018 report of the committee on infectious diseases, ed 31, Itasca, IL,
2018, American Academy of Pediatrics, Table 3.39, p. 543.

Adverse events from the measles-mumps-rubella vaccine include fever

(usually 6-12 days following vaccination), rash in approximately 5% of
vaccinated persons, and, rarely, transient thrombocytopenia. Children prone to
febrile seizures may experience an event following vaccination, so the risks and
benefits of vaccination should be discussed with parents. Encephalopathy and
autism have not been shown to be causally associated with the measles-mumps-
 Encephalitis 97 (0.1) 43 (0.2) 9 (0.1) 13 (0.1) 21 (0.2) 11 (0.3)
Hospitalization 12,876 (19.2) 7,470 612 (9.4) 1,612 (8.7) 2,075 1,107
(26.0) (22.7) (27.2)
Otitis media 4,879 (7.3) 4,009 305 (4.7) 338 (1.8) 157 (1.7) 70 (1.7)
(14.0)
Pneumonia 3,959 (5.9) 2,480 183 (2.8) 363 (2.0) 554 (6.1) 379 (9.3)
(8.6)
From Perry RT, Halsey NA: The clinical significance of measles: a review, Clin Infect Dis
189(Suppl. 1):S4–S16, 2004.

Pneumonia is the most common cause of death in measles. It may manifest as

giant cell pneumonia caused directly by the viral infection or as superimposed
bacterial infection. The most common bacterial pathogens are Streptococcus
pneumoniae, Haemophilus influenzae, and Staphylococcus aureus . Following
severe measles pneumonia, the final common pathway to a fatal outcome is
often the development of bronchiolitis obliterans.
Croup, tracheitis, and bronchiolitis are common complications in infants and
toddlers with measles. The clinical severity of these complications frequently
requires intubation and ventilatory support until the infection resolves.
Acute otitis media is the most common complication of measles and was of
particularly high incidence during the epidemic of the late 1980s and early 1990s
because of the relatively young age of affected children. Sinusitis and mastoiditis
also occur as complications. Viral and/or bacterial tracheitis is seen and can be
life-threatening. Retropharyngeal abscess has also been reported.
Measles infection is known to suppress skin test responsiveness to purified
tuberculin antigen. There may be a higher rate of activation of pulmonary
tuberculosis in populations of individuals infected with Mycobacterium
tuberculosis who are then exposed to measles.
Diarrhea and vomiting are common symptoms associated with acute measles,
and diffuse giant cell formation is found in the epithelium in the gastrointestinal
tract. Dehydration is a common consequence, especially in young infants and
children. Appendicitis or abdominal pain may occur from obstruction of the
appendiceal lumen by lymphoid hyperplasia.
Febrile seizures occur in <3% of children with measles. Encephalitis
following measles is a long-associated complication, often with an unfavorable
outcome. Rates of 1-3 per 1,000 cases of measles have been reported, with
greater numbers occurring in adolescents and adults than in preschool- or
school-age children. Encephalitis is a postinfectious, immunologically mediated
process and is not the result of a direct effect by the virus. Clinical onset begins
during the exanthem and manifests as seizures (56%), lethargy (46%), coma
Prevention
Patients shed measles virus from 7 days after exposure to 4-6 days after the onset
of rash. Exposure of susceptible individuals to patients with measles should be
avoided during this period. In hospitals, standard and airborne precautions
should be observed for this period. Immunocompromised patients with measles
will shed virus for the duration of the illness, so isolation should be maintained
throughout the disease.

Vaccine
Vaccination against measles is the most effective and safe prevention strategy.
Measles vaccine in the United States is available as a combined vaccine with
measles-mumps-rubella vaccine, the last of which is the recommended form in
most circumstances (Table 273.2 ). Following the measles resurgence of 1989-
1991, a 2nd dose of measles vaccine was added to the schedule. The current
recommendations include a 1st dose at 12-15 mo of age, followed by a 2nd dose
at 4-6 yr of age. However, the 2nd dose can be given any time after 30 days
following the 1st dose, and the current schedule is a convenience schedule.
Seroconversion is slightly lower in children who receive the 1st dose before or at
12 mo of age (87% at 9 mo, 95% at 12 mo, and 98% at 15 mo) because of
persisting maternal antibody; however, this is an evolving situation, with
children currently as young as 6 mo unprotected from maternal antibodies and
susceptible to measles infection. For children who have not received 2 doses by
11-12 yr of age, a 2nd dose should be provided. Infants who receive a dose
before 12 mo of age should be given 2 additional doses at 12-15 mo and 4-6 yr
of age. Children who are traveling should be offered either primary measles
immunization even as young as 6 mo or a 2nd dose even if <4 yr.

Table 273.2

Recommendations for Measles Immunization

CATEGORY RECOMMENDATIONS
Unimmunized, no history of MMR or MMRV vaccine is recommended at 12-15 mo of age; a 2nd dose is
measles (12-15 mo of age) recommended at least 28 days after the 1st dose (or 90 days for MMRV) and
usually is administered at 4 through 6 yr of age
Children 6-11 mo of age in Immunize with MMR vaccine, but this dose is not considered valid, and 2 valid
epidemic situations or doses administered on or after the 1st birthday are required. The 1st valid dose
before international travel should be administered at 12-15 mo of age; the 2nd valid dose is recommended at
 least 28 days later and usually is administered at 4 through 6 yr of age. MMRV
should not be administered to children <12 mo of age.
Students in kindergarten, Administer the 2nd dose
elementary, middle, and
high school who have
received 1 dose of measles
vaccine at 12 mo of age or
older
Students in college and Administer the 2nd dose
other postsecondary
institutions who have
received 1 dose of measles
vaccine at 12 mo of age or
older
History of immunization Dose not considered valid; immunize (2 doses)
before the 1st birthday
History of receipt of Dose not considered valid; immunize (2 doses)
inactivated measles vaccine
or unknown type of vaccine,
1963–1967
Further attenuated or Dose not considered valid; immunize (2 doses)
unknown vaccine
administered with IG
Allergy to eggs Immunize; no reactions likely
Neomycin allergy, Immunize; no reactions likely
nonanaphylactic
Severe hypersensitivity Avoid immunization
(anaphylaxis) to neomycin
or gelatin
Tuberculosis Immunize; if patient has untreated tuberculosis disease, start antituberculosis
therapy before immunizing
Measles exposure Immunize or give IG, depending on circumstances
HIV infected Immunize (2 doses) unless severely immunocompromised; administration of IG if
exposed to measles is based on degree of immunosuppression and measles vaccine
history
Personal or family history of Immunize; advise parents of slightly increased risk of seizures
seizures
Immunoglobulin or blood Immunize at the appropriate interval
recipient
MMR, measles-mumps-rubella vaccine; MMRV, measles-mumps-rubella-varicella vaccine.
From American Academy of Pediatrics: Measles. In Kimberlin DW, Brady MT, Jackson MA, Long
SS, editors: Red book 2018 report of the committee on infectious diseases, ed 31, Itasca, IL,
2018, American Academy of Pediatrics, Table 3.39, p. 543.

Adverse events from the measles-mumps-rubella vaccine include fever

(usually 6-12 days following vaccination), rash in approximately 5% of
vaccinated persons, and, rarely, transient thrombocytopenia. Children prone to
febrile seizures may experience an event following vaccination, so the risks and
benefits of vaccination should be discussed with parents. Encephalopathy and
autism have not been shown to be causally associated with the measles-mumps-
rubella vaccine or vaccine constituents.
A review of the effect of measles vaccination on the epidemiology of SSPE
has demonstrated that measles vaccination protects against SSPE and does not
accelerate the course of SSPE or trigger the disease in those already infected
with wild measles virus.
Passively administered immune globulin may inhibit the immune response to
live measles vaccine, and administration should be delayed for variable amounts
of time based on the dose of Ig (Table 273.3 ).

Table 273.3
Suggested Intervals Between Immunoglobulin
Administration and Measles Immunization*
DOSE
INDICATION FOR IMMUNOGLOBULIN Units (U) or Interval
Route mg IgG/kg
Milliliters (mL) (mo) †
Tetanus (as tetanus Ig) IM 250 U 10 3
Hepatitis A prophylaxis (as Ig):
Contact prophylaxis IM 0.02 mL/kg 3.3 3
International travel IM 0.06 mL/kg 10 3
Hepatitis B prophylaxis (as hepatitis B Ig) IM 0.06 mL/kg 10 3
Rabies prophylaxis (as rabies Ig) IM 20 IU/kg 22 4
Varicella prophylaxis (as VariZIG) IM 125 U/10 kg 20-40 5
(maximum 625 U)
Measles prophylaxis (as Ig):
Standard IM 0.50 mL/kg 80 6
Immunocompromised host IV 400 mg/kg 8
Respiratory syncytial virus prophylaxis (palivizumab IM — 15 mg/kg None
monoclonal antibody) ‡ (monoclonal)
Cytomegalovirus immune globulin IV 3 mL/kg 150 6
Blood transfusion:
Washed RBCs IV 10 mL/kg Negligible 0
RBCs, adenine-saline added IV 10 mL/kg 10 3
Packed RBCs IV 10 mL/kg 20-60 6
Whole blood IV 10 mL/kg 80-100 6
Plasma or platelet products IV 10 mL/kg 160 7
Replacement (or therapy) of immune deficiencies (as IV — 300-400 8
IVIG)
ITP (as IVIG) IV — 400 8
ITP IV — 1,000 10
ITP or Kawasaki disease IV — 1,600-2,000 11
* Immunization in the form of measles-mumps-rubella (MMR), measles-mumps-rubella-varicella
(MMRV), or monovalent measles vaccine.
† These intervals should provide sufficient time for decreases in passive antibodies in all children
vigilance and maintenance of high levels of immunity in the United States are
necessary.

Pathology
Little information is available on the pathologic findings in rubella occurring
postnatally. The few reported studies of biopsy or autopsy material from cases of
rubella revealed only nonspecific findings of lymphoreticular inflammation and
mononuclear perivascular and meningeal infiltration. The pathologic findings for
CRS are often severe and may involve nearly every organ system (Table 274.1 ).

Table 274.1
Pathologic Findings in Congenital Rubella Syndrome

SYSTEM PATHOLOGIC FINDINGS

Cardiovascular Patent ductus arteriosus
Pulmonary artery stenosis
Ventriculoseptal defect
Myocarditis
Central nervous system Chronic meningitis
Parenchymal necrosis
Vasculitis with calcification
Eye Microphthalmia
Cataract
Iridocyclitis
Ciliary body necrosis
Glaucoma
Retinopathy
Ear Cochlear hemorrhage
Endothelial necrosis
Lung Chronic mononuclear interstitial pneumonitis
Liver Hepatic giant cell transformation
Fibrosis
Lobular disarray
Bile stasis
Kidney Interstitial nephritis
Adrenal gland Cortical cytomegaly
Bone Malformed osteoid
Poor mineralization of osteoid
Thinning cartilage
Spleen, lymph node Extramedullary hematopoiesis
Thymus Histiocytic reaction
Absence of germinal centers
Skin Erythropoiesis in dermis
or only slightly elevated at the outset of CNS disease but usually rises to 50-100
mg/dL by the 2nd wk of illness. In polioencephalitis, the CSF may remain
normal or show minor changes. Serologic testing demonstrates seroconversion
or a 4-fold or greater increase in antibody titers from the acute phase of illness to
3-6 wk later.

Differential Diagnosis
Poliomyelitis should be considered in the differential diagnosis of any case of
paralysis and is only 1 of many causes of acute flaccid paralysis in children and
adults. There are numerous other causes of acute flaccid paralysis (Table 276.1 ).
In most conditions, the clinical features are sufficient to differentiate between
these various causes, but in some cases nerve conduction studies and
electromyograms, in addition to muscle biopsies, may be required.

Table 276.1
Differential Diagnosis of Acute Flaccid Paralysis

REDUCTION
SITE, OR
SENSORY
CONDITION, CLINICAL ONSET OF PROGRESSION ABSENCE RESIDUAL
SIGNS AND
FACTOR, OR FINDINGS PARALYSIS OF PARALYSIS OF DEEP PARALYSIS
SYMPTOMS
AGENT TENDON
REFLEXES
Anterior Horn Cells of Spinal Cord
Poliomyelitis Paralysis Incubation 24-48 hr to onset No Yes Yes
(wild and period 7-14 of full paralysis;
vaccine- days (range: 4- proximal →
associated 35 days) distal,
paralytic asymmetric
poliomyelitis)
Nonpolio Hand-foot-and- As in As in No Yes Yes
enteroviruses mouth disease, poliomyelitis poliomyelitis
(including EV- aseptic
A71, EV D68) meningitis,
acute
hemorrhagic
conjunctivitis,
possibly
idiopathic
epidemic flaccid
paralysis
West Nile virus Meningitis As in As in No Yes Yes
encephalitis poliomyelitis poliomyelitis
Other Neurotropic Viruses
Rabies virus Mo–Yr Acute, Yes Yes No
symmetric,
ascending
Varicella-zoster Exanthematous Incubation Acute, Yes ± ±
virus vesicular period 10-21 symmetric,
eruptions days ascending
Japanese Incubation Acute, proximal, ± ± ±
encephalitis period 5-15 asymmetric
virus days
Guillain-Barré Syndrome
Acute Preceding Hr to 10 days Acute, Yes Yes ±
inflammatory infection, symmetric,
polyradiculo- bilateral facial ascending (days
neuropathy weakness to 4 wk)
Acute motor Fulminant, Hr to 10 days 1-6 days No Yes ±
axonal widespread
neuropathy paralysis,
bilateral facial
weakness,
tongue
involvement
Acute Traumatic Sciatic Neuritis
Intramuscular Acute, Hr to 4 days Complete, Yes Yes ±
gluteal injection asymmetric affected limb
Acute transverse Preceding Acute, Hr to days Yes Yes, early Yes
myelitis Mycoplasma symmetric
pneumoniae, hypotonia of
Schistosoma , lower limbs
other parasitic
or viral
infection
Epidural abscess Headache, back Complete Yes Yes ±
pain, local
spinal
tenderness,
meningismus
Spinal cord Complete Hr to days Yes Yes ±
compression;
trauma
Neuropathies
Exotoxin of In severe cases, Incubation Yes Yes
Corynebacterium palatal period 1-8 wk
diphtheriae paralysis, (paralysis 8-12
blurred vision wk after onset
of illness)
Toxin of Abdominal Incubation Rapid, ± No
Clostridium pain, diplopia, period 18-36 hr descending,
botulinum loss of symmetric
accommodation,
mydriasis
Tick bite Ocular Latency period Acute, No Yes
paralysis symptoms 5-10 days symmetric,
ascending
Diseases of the Neuromuscular Junction
Myasthenia Weakness, Multifocal No No No
 gravis fatigability,
diplopia, ptosis,
dysarthria
Disorders of Muscle
Polymyositis Neoplasm, Subacute, Wk to mo No Yes
autoimmune proximal →
disease distal
Viral myositis Pseudoparalysis Hr to days No No
Metabolic Disorders
Hypokalemic Proximal limb, Sudden No Yes ±
periodic respiratory postprandial
paralysis muscles
Intensive Care Unit Weakness
Critical illness Flaccid limbs Acute, Hr to days ± Yes ±
polyneuropathy and respiratory following
weakness systemic
inflammatory
response
syndrome/sepsis
Modified from Marx A, Glass JD, Sutter RW: Differential diagnosis of acute flaccid paralysis and
its role in poliomyelitis surveillance, Epidemiol Rev 22:298–316, 2000.

The possibility of polio should be considered in any case of acute flaccid

paralysis, even in countries where polio has been eradicated. The diagnoses most
often confused with polio are VAPP, West Nile virus infection, and infections
caused by other enteroviruses (including EV-A71 and EV-D68), as well as
Guillain-Barré syndrome, transverse myelitis, and traumatic paralysis. In
Guillain-Barré syndrome , which is the most difficult to distinguish from
poliomyelitis, the paralysis is characteristically symmetric, and sensory changes
and pyramidal tract signs are common, contrasting with poliomyelitis. Fever,
headache, and meningeal signs are less notable, and the CSF has few cells but an
elevated protein content. Transverse myelitis progresses rapidly over hr to days,
causing an acute symmetric paralysis of the lower limbs with concomitant
anesthesia and diminished sensory perception. Autonomic signs of hypothermia
in the affected limbs are common, and there is bladder dysfunction. The CSF is
usually normal. Traumatic neuritis occurs from a few hr to a few days after the
traumatic event, is asymmetric, is acute, and affects only 1 limb. Muscle tone
and deep tendon reflexes are reduced or absent in the affected limb with pain in
the gluteus. The CSF is normal.
Conditions causing pseudoparalysis do not present with nuchal-spinal rigidity
or pleocytosis. These causes include unrecognized trauma, transient (toxic)
synovitis, acute osteomyelitis, acute rheumatic fever, scurvy, and congenital
syphilis (pseudoparalysis of Parrot).
CHAPTER 277

Nonpolio Enteroviruses
Kevin Messacar, Mark J. Abzug

The genus Enterovirus contains a large number of viruses spread via the
gastrointestinal and respiratory routes that produce a broad range of illnesses in
patients of all ages. Many of the manifestations predominantly affect infants and
young children.

Etiology
Enteroviruses are nonenveloped, single-stranded, positive-sense viruses in the
Picornaviridae (“small RNA virus”) family, which also includes the rhinoviruses,
hepatitis A virus, and parechoviruses. The original human enterovirus subgroups
—polioviruses (see Chapter 276 ), coxsackieviruses, and echoviruses—were
differentiated by their replication patterns in tissue culture and animals (Table
277.1 ). Enteroviruses have been reclassified on the basis of genetic similarity
into 4 species, human enteroviruses A-D. Specific enterovirus types are
distinguished by antigenic and genetic sequence differences, with enteroviruses
discovered after 1970 classified by species and number (e.g., enterovirus D68
and A71). Although more than 100 types have been described, 10-15 account for
the majority of disease. No disease is uniquely associated with any specific
serotype, although certain manifestations are preferentially associated with
specific serotypes. The closely related human parechoviruses can cause clinical
presentations similar to those associated with enteroviruses.

Table 277.1
Classification of Human Enteroviruses
Family Picornaviridae
 Genus Enterovirus
Subgroups* Poliovirus serotypes 1-3
Coxsackie A virus serotypes 1-22, 24 (23 reclassified as echovirus 9)
Coxsackie B virus serotypes 1-6
Echovirus serotypes 1-9, 11-27, 29-33 (echoviruses 10 and 28 reclassified as non-enteroviruses;
echovirus 34 reclassified as a variant of coxsackie A virus 24; echoviruses 22 and 23 reclassified
within the genus Parechovirus )
Numbered enterovirus serotypes (enterovirus 72 reclassified as hepatitis A virus)
* The human enteroviruses have been alternatively classified on the basis of nucleotide and

amino acid sequences into 4 species (human enteroviruses A-D).

Epidemiology
Enterovirus infections are common, with a worldwide distribution. In temperate
climates, annual epidemic peaks occur in summer/fall, although some
transmission occurs year-round. Enteroviruses are responsible for 33–65% of
acute febrile illnesses and 55–65% of hospitalizations for suspected sepsis in
infants during the summer and fall in the United States. In tropical and
semitropical areas, enteroviruses typically circulate year-round. In general, only
a few serotypes circulate simultaneously. Infections by different serotypes can
occur within the same season. Factors associated with increased incidence and/or
severity include young age, male sex, exposure to children, poor hygiene,
overcrowding, and low socioeconomic status. More than 25% of symptomatic
infections occur in children younger than 1 yr of age. Breastfeeding reduces the
risk for infection, likely via enterovirus-specific antibodies.
Humans are the only known natural reservoir for human enteroviruses. Virus
is primarily spread person to person, by the fecal-oral and respiratory routes,
although types causing acute hemorrhagic conjunctivitis may be spread via
airborne transmission. Virus can be transmitted vertically prenatally or in the
peripartum period, or, possibly, via breastfeeding. Enteroviruses can survive on
environmental surfaces, permitting transmission via fomites. Enteroviruses also
can frequently be isolated from water sources, sewage, and wet soil. Although
contamination of drinking water, swimming pools and ponds, and hospital water
reservoirs may occasionally be responsible for transmission, such contamination
is often considered the result rather than the cause of human infection.
Transmission is common within families (≥50% risk of spread to nonimmune
household contacts), daycare centers, playgrounds, summer camps, orphanages,
and hospital nurseries; severe secondary infections may occur in nursery
outbreaks. Transmission risk is increased by diaper changing and decreased by
Except for epidemiologic studies or cases characteristic of specific serotypes
(e.g., enterovirus A71), serology is generally less useful than culture or nucleic
acid detection.

Differential Diagnosis
The differential diagnosis of enterovirus infections varies with the clinical
presentation (Table 277.2 ).

Table 277.2

Differential Diagnosis of Enterovirus Infections

CLINICAL
BACTERIAL PATHOGENS VIRAL PATHOGENS
MANIFESTATION
Nonspecific febrile Streptococcus pneumoniae, Haemophilus Influenza viruses, human herpesviruses 6
illness influenzae type b, Neisseria meningitidis and 7, human parechoviruses
Exanthems/enanthems Group A streptococcus, Staphylococcus Herpes simplex virus, adenoviruses,
aureus , N. meningitidis varicella-zoster virus, Epstein-Barr virus,
measles virus, rubella virus, human
herpesviruses 6 and 7, human
parechoviruses
Respiratory S. pneumoniae, H. influenzae Adenoviruses, influenza viruses, respiratory
illness/conjunctivitis (nontypeable and type b), N. meningitidis, syncytial virus, parainfluenza viruses,
Mycoplasma pneumoniae, Chlamydia rhinoviruses, human metapneumovirus,
pneumoniae coronaviruses
Myocarditis/pericarditis S. aureus, H. influenzae type b, M. Adenoviruses, influenza virus, parvovirus,
pneumoniae cytomegalovirus
Meningitis/encephalitis S. pneumoniae, H. influenzae type b, N. Herpes simplex virus, West Nile virus,
meningitidis, Mycobacterium tuberculosis influenza viruses, adenoviruses, Epstein-
, Borrelia burgdorferi, M. pneumoniae , Barr virus, mumps virus, lymphocytic
Bartonella henselae, Listeria choriomeningitis virus, arboviruses, human
monocytogenes parechoviruses
Neonatal infections Group B streptococcus, Gram-negative Herpes simplex virus, adenoviruses,
enteric bacilli, L. monocytogenes, cytomegalovirus, rubella virus, human
Enterococcus parechoviruses

Human parechoviruses , members of the Picornaviridae family, produce

many manifestations similar to the nonpolio enteroviruses. They are small RNA
viruses that were originally classified as echoviruses. Nineteen parechoviruses
have been identified that infect humans; serotypes 1 and 3 are the most common
causes of symptomatic infection. Parechovirus epidemics occur in the same
season as enterovirus infections, with a biennial pattern of circulation noted in
Europe. Outbreaks have been described in the nursery setting. In young infants,
parechoviruses can cause a sepsis-like illness similar to enterovirus illness and
patient. Infection control practices, including caring for patients with varicella in
isolation rooms with filtered air systems, are essential. All healthcare workers
should have evidence of varicella immunity (Table 280.1 ). Unvaccinated
healthcare workers without other evidence of immunity who have had a close
exposure to VZV should be furloughed for days 8-21 after exposure because
they are potentially infectious during this period.

Table 280.1
Evidence of Immunity to Varicella
Evidence of immunity to varicella consists of any of the following:
• Documentation of age-appropriate vaccination with a varicella vaccine:
• Preschool-age children (i.e., age ≥12 mo): 1 dose
• School-age children, adolescents, and adults: 2 doses*
• Laboratory evidence of immunity † or laboratory confirmation of disease
• Birth in the United States before 1980 ‡
• Diagnosis or verification of a history of varicella disease by a healthcare provider §
• Diagnosis or verification of a history of herpes zoster by a healthcare provider
*
For children who received their 1st dose at younger than age 13 yr and for whom the interval
between the 2 doses was 28 or more days, the 2nd dose is considered valid.
† Commercial assays can be used to assess disease-induced immunity, but they lack sensitivity to

always detect vaccine-induced immunity (i.e., they might yield false-negative results).
‡ For healthcare personnel, pregnant women, and immunocompromised persons, birth before
1980 should not be considered evidence of immunity.
§
Verification of history or diagnosis of typical disease can be provided by any healthcare provider
(e.g., school or occupational clinic nurse, nurse practitioner, physician assistant, or physician). For
persons reporting a history of, or reporting with, atypical or mild cases, assessment by a physician
or his/her designee is recommended, and one of the following should be sought: (1) an
epidemiologic link to a typical varicella case or to a laboratory-confirmed case or (2) evidence of
laboratory confirmation if it was performed at the time of acute disease. When such
documentation is lacking, persons should not be considered as having a valid history of disease,
because other diseases might mimic mild atypical varicella.

Vaccine
Varicella is a vaccine-preventable disease. Varicella vaccine contains live,
attenuated VZV (Oka strain) and is indicated for subcutaneous administration. In
the United States, varicella vaccine is recommended for routine administration
as a 2-dose regimen to healthy children at ages 12-15 mo and 4-6 yr.
Administration of the 2nd dose earlier than 4-6 yr of age is acceptable, but it

FIG. 281.3 Kinetics of antibody responses to Epstein-Barr virus (EBV) antigens in
infectious mononucleosis. EA, early antigen; EBNA, EBV-determined nuclear antigens;
IgG, immunoglobulin G; IgM, immunoglobulin M; VCA, viral capsid antigen.

Table 281.1
Correlation of Clinical Status and Antibody Responses to
Epstein-Barr Virus Infection

CLINICAL STATUS VCA IgM VCA IgG EA IgG EBNA IgG

Susceptible − − − −
Acute primary infection + + +/− −
Recent primary infection +/− + +/− +/−
Past infection − + +/− +
EA, early antigen (typically the diffuse staining component, or EA-D); EBNA, EBV-determined
nuclear antigens; EBV, Epstein-Barr virus; IgG, immunoglobulin G; IgM, immunoglobulin M; VCA,
viral capsid antigen.

Anti-EA IgG antibodies are usually detectable for several months but may
persist or be detected intermittently at low levels for many years. Antibodies to
the diffuse-staining component of EA (EA-D) are found transiently in 80% of
patients during the acute phase of infectious mononucleosis. Antibodies to the
cytoplasmic-restricted component of EA (EA-R) emerge transiently in the
convalescence from infectious mononucleosis. High levels of antibodies to EA-
D or EA-R may be found also in immunocompromised patients with persistent
EBV infections and active EBV replication.
loss associated with congenital CMV infection will pass an initial hearing
screening exam but develop hearing loss in later infancy and early childhood.
Importantly, hearing loss can be progressive in infants with hearing loss
secondary to congenital CMV infections. Lastly, the diagnosis of congenital
CMV infection must be made within the first 2-3 wk of life, and congenital
CMV infection cannot be assumed to be the cause of hearing loss in older infants
without evidence of CMV infection in the newborn period.

Table 282.1
Findings in Infants With Symptomatic Congenital
Cytomegalovirus Infection

FINDINGS % OF INFANTS
CLINICAL FINDINGS
Prematurity (<37 wk) 24
Jaundice (direct bilirubin >2 mg/dL) 42
Petechiae 54
Hepatosplenomegaly 19
Purpura 3
Microcephaly 35
IUGR 28
1 clinical finding 41
2 clinical findings 59
LABORATORY FINDINGS
Elevated ALT (>80 IU/mL) 71
Thrombocytopenia (<100,000 k/mm3 ) 43
Direct hyperbilirubinemia (>2 mg/dL) 54
Head CT abnormalities 42
Findings in 70 infants with symptomatic congenital CMV infection identified during newborn
screening program for infants with congenital CMV infection at the University of Alabama
Hospitals over an approximate 20 yr interval.
CMV, cytomegalovirus; IUGR, in utero growth retardation; ALT, alanine aminotransferase.

An organized plan for follow-up is an important component of the clinical

management of infants with congenital CMV infection. Because permanent
sequelae are limited to disorders of the nervous system, long-term follow-up
should include appropriate assessment of development and neuromuscular
function in infected infants, with referral to specialized care if necessary.
Hearing loss will develop in about 11% of infected infants, and in some infants
hearing loss will progress during infancy. Thus audiologic testing and follow-up
are mandatory in these patients. Other sequelae such as vision loss are
infrequent, but vision testing and comprehensive eye examinations should be
(Table 285.1 ). These include H3N2v viruses, which caused 372 confirmed
human infections in the United States from 2011 to 2016 and were primarily
transmitted through swine contact at agricultural fairs. Influenza viruses that
normally circulate in swine are designated variant (“v”) viruses when detected in
humans, and H3N2v and other variant viruses, including H1N1v and H1N2v,
have sporadically infected humans. In contrast to avian influenza A(H5N1) and
A(H7N9) viruses, variant viruses generally cause mild illness and have been
primarily detected in children. However, none of these viruses has exhibited
sustained, efficient human-to-human transmission.

Table 285.1
Subtypes of Novel Influenza A Viruses and Clinical
Syndromes in Human Infections

VARIANT
LPAI VIRUSES HPAI VIRUSES
VIRUSES*
Conjunctivitis H7N2, H7N3, H7N7, H10N7 H7N3, H7N7 H1N1v, H3N2v
Upper respiratory tract illness H6N1, H7N2, H7N3, H7N9, H5N1, H5N6, H1N1v, H1N2v,
H9N2, H10N7 H7N7 H3N2v
Lower respiratory tract disease, H7N2, H7N9, H9N2, H10N8 H5N1, H5N6, H1N1v, H3N2v
pneumonia H7N7, H7N9
Respiratory failure, acute respiratory H7N9, H10N8 H5N1, H5N6, H1N1v, H3N2v
distress syndrome H7N7, H7N9
Multiorgan failure H7N9, H10N8 H5N1, H5N6, —
H7N7, H7N9
Encephalopathy or encephalitis H7N9 H5N1 —
Fatal outcomes † H7N9, H9N2, H10N8 H5N1, H5N6, H1N1v, H3N2v
H7N7, H7N9
* Variant viruses of swine origin.

† High mortality in reported cases: about 40% for LPAI H7N9, about 50% for HPAI H5N1, and

about 70% for HPAI H5N6.

LPAI, low-pathogenic avian influenza; HPAI, highly pathogenic avian influenza.
From Uyeki TM, Katz JM, Jernigan DB: Novel influenza A viruses and pandemic threats, Lancet
389:2172–2174, 2017.

Seasonal Influenza
An estimated 11,000-45,000 children younger than 18 yr of age are hospitalized
annually in the United States as a result of seasonal influenza-associated
complications, with approximately 6,000-26,000 hospitalizations in children
required for clinical decisions to prescribe antiviral medications, and prompt
suspicion or diagnosis of influenza may allow for early antiviral therapy to be
initiated and may reduce inappropriate use of antibiotics.
A number of diagnostic tests may be used for laboratory confirmation of
influenza (Table 285.2 ). Although rapid influenza diagnostic tests are often
employed because of their ease of use and fast results, they can have suboptimal
sensitivity to detect influenza virus infection, particularly for novel influenza
viruses. Sensitivities of rapid diagnostic tests are generally 50–70% compared to
viral culture or reverse-transcription polymerase chain reaction. Specificities are
higher, approximately 95–100%. Therefore false-negative results occur more
often than false-positive results, particularly when the prevalence of influenza is
high (i.e., during peak influenza activity in the community). The interpretation of
negative results should take into account the clinical characteristics and the
patient's risk for complications. If there is clinical suspicion for influenza in a
patient at high risk for complications (Table 285.3 ), early empiric treatment
should be given regardless of a negative rapid diagnostic test result, and another
type of test (e.g., reverse-transcription polymerase chain reaction or direct
fluorescent antibody testing) may be performed for confirmation.

Table 285.2
Influenza Virus Testing Methods

ACCEPTABLE TEST
METHOD COMMENTS
SPECIMENS TIME
Rapid Influenza Diagnostic Tests (antigen Nasopharyngeal (NP) <15 min Rapid turnaround;
detection) swab, aspirate or wash, suboptimal sensitivity
nasal swab, aspirate, or
wash, throat swab
Rapid Molecular Assay (influenza nucleic NP swab, nasal swab 15-30 min Rapid turnaround, high
acid amplification) sensitivity
Immunofluorescence, Direct (DFA) or NP swab or wash, 1-4 hr Relatively rapid
Indirect (IFA) Fluorescent Antibody bronchial wash, nasal or turnaround; requires
Staining (antigen detection) endotracheal aspirate laboratory expertise and
experience
RT-PCR (singleplex and multiplex; real- NP swab, throat swab, NP Varies by Excellent sensitivity,
time and other RNA-based) and other or bronchial wash, nasal or assay relatively rapid turnaround
molecular assays (influenza nucleic acid endotracheal aspirate, (generally 1- compared with
amplification) sputum 8 hr) conventional methods
Rapid cell culture (shell vials, cell NP swab, throat swab, NP 1-3 day Culture isolates important
mixtures; yields live virus) or bronchial wash, nasal or for strain information and
endotracheal aspirate, antiviral resistance
sputum monitoring
Viral tissue cell culture (conventional; NP swab, throat swab, NP 3-10 day Not recommended for
 yields live virus) or bronchial wash, nasal or routine patient diagnosis
endotracheal aspirate,
sputum
Serologic tests (antibody detection) Paired (appropriately N/A (not Not recommended for
timed) acute and performed routine patient diagnosis,
convalescent serum during acute useful for research studies
specimens infection)
N/A, not applicable; NP, nucleoprotein; RT-PCR, reverse transcription-polymerase chain reaction.
Modified from Centers for Disease Control and Prevention (CDC): Influenza virus testing
methods. Available at https://www.cdc.gov/flu/professionals/diagnosis/table-testing-methods.htm
in Information for Health Professionals (https://www.cdc.gov/flu/professionals/index.htm ); and
from 2018 IDSA Clinical Practice Guidelines.

Table 285.3
Children and Adolescents Who Are at Higher Risk for
Influenza Complications for Whom Antiviral Treatment is
Recommended*

Children younger than 2 yr of age †

Persons with chronic pulmonary (including asthma), cardiovascular (except hypertension alone), renal, hepatic,
hematologic (including sickle cell disease), and metabolic disorders (including diabetes mellitus); or neurologic
and neurodevelopmental conditions (including disorders of the brain, spinal cord, peripheral nerve, and muscle
such as cerebral palsy, epilepsy [seizure disorders], stroke, intellectual disability, moderate to severe
developmental delay, muscular dystrophy, or spinal cord injury)
Persons with immunosuppression, including that caused by medications or by HIV infection
Adolescents who are pregnant, or postpartum (within 2 wk after delivery)
Persons younger than 19 yr of age who are receiving long-term aspirin- or salicylate-containing medications
therapy
American Indians/Alaska Natives
Persons who are extremely obese (body mass index ≥40)
Residents of long-term care facilities
Hospitalized patients at high risk for influenza complications
* Antiviral treatment is recommended for high-risk children with confirmed or suspected influenza;
antivirals are also recommended for children who are hospitalized or have severe or progressive
disease.
† Although all children younger than 5 yr of age are considered at higher risk for complications
from influenza, the highest risk is for those younger than 2 yr of age, with the highest
hospitalization and death rates among infants younger than 6 mo of age.
Current for 2018-2019 influenza season.
Adapted from Centers for Disease Control and Prevention (CDC): Influenza antiviral medications:
summary for clinicians . Available at https://www.cdc.gov/flu/professionals/antivirals/summary-
clinicians.htm . For current details, consult annually updated recommendations at
https://www.cdc.gov/flu/professionals/index.htm .
Treatment
Antiviral medications are an important adjunct to influenza vaccination. Three
classes of antiviral drugs are licensed for treatment of influenza in children. The
neuraminidase inhibitors (NAIs), oral oseltamivir and inhaled zanamivir, may be
used for treatment of children from birth and 7 yr, respectively (Table 285.4 ). In
December 2012, the U.S. Food and Drug Administration (FDA) approved the
use of oseltamivir for the treatment of influenza in infants as young as 2 wk of
age, and the Centers for Disease Control and Prevention (CDC), American
Academy of Pediatrics, and the Infectious Diseases Society of America
recommend its use in infants of any age. A third NAI, peramivir, is given as an
intravenous infusion and is approved for treatment in persons 2 yr of age and
older.

Table 285.4
Recommended Dosage and Schedule of Influenza Antiviral
Medications for Treatment and Chemoprophylaxis in
Children for the 2018-2019 Influenza Season: United States

TREATMENT
MEDICATION CHEMOPROPHYLAXIS DOSING**
DOSING**
ORAL OSELTAMIVIR *
Adults 75 mg twice daily 75 mg once daily
Children ≥12 mo
Body wt
≤15 kg (≤33 lb) 30 mg twice daily 30 mg once daily
>15-23 kg (33-51 lb) 45 mg twice daily 45 mg once daily
>23-40 kg (>51-88 60 mg twice daily 60 mg once daily
lb)
>40 kg (>88 lb) 75 mg twice daily 75 mg once daily
Infants 0-11 mo † 3 mg/kg per dose once 3 mg/kg per dose once daily
daily
Term infants ages 0-8 3 mg/kg per dose twice 3 mg/kg per dose once daily for infants 3-8 mo old; not
mo † daily recommended for infants <3 mo old unless situation judged
critical because of limited safety and efficacy data in this age
group
Preterm infants See details in footnote ‡ Not recommended
INHALED ZANAMIVIR §
Adults 10 mg (two 5 mg 10 mg (two 5 mg inhalations) once daily
inhalations) twice daily
Children (≥7 yr old 10 mg (two 5 mg 10 mg (two 5 mg inhalations) once daily
for treatment; ≥5 yr inhalations) twice daily
old for
chemoprophylaxis)
 INTRAVENOUS PERAMIVIR
Adults 600 mg intravenous Not recommended
infusion once given over
15-30 min
Children (2-12 yr One 12 mg/kg dose, up to Not recommended
old) 600 mg maximum, via
intravenous infusion for 15-
30 min
Children (13-17 yr One 600 mg dose via Not recommended
old) intravenous infusion for 15-
30 min
ORAL BALOXAVIR ††
Adults
40 to <80 kg One 40 mg dose Not recommended
>80 kg One 80 mg dose Not recommended
Children
2-11 yr Not recommended Not recommended
12-17 yr, 40 to <80 One 40 mg dose Not recommended
kg
12-17 yr, >80 kg One 80 mg dose Not recommended
* Oseltamivir is administered orally without regard to meals, although administration with meals

may improve gastrointestinal tolerability. Oseltamivir is available as Tamiflu or as a generic

formulation as capsules and as a powder for oral suspension that is reconstituted to provide a
final concentration of 6 mg/mL.
† Approved by the FDA for children as young as 2 wk of age. Given preliminary pharmacokinetic

data and limited safety data, oseltamivir can be used to treat influenza in both term and preterm
infants from birth because benefits of therapy are likely to outweigh possible risks of treatment.
CDC and US Food and Drug Administration (FDA)–approved dosing is 3 mg/kg per dose twice
daily for children aged 9-11 mo; the American Academy of Pediatrics recommends 3.5 mg/kg per
dose twice daily. The dose of 3 mg/kg provides oseltamivir exposure in children similar to that
achieved by the approved dose of 75 mg orally twice daily for adults, as shown in two studies of
oseltamivir pharmacokinetics in children. The AAP has recommended an oseltamivir treatment
dose of 3.5 mg/kg orally twice daily for infants 9-11 mo, on the basis of data that indicated that a
higher dose of 3.5 mg/kg was needed to achieve the protocol-defined targeted exposure for this
cohort as defined in the CASG 114 study. It is unknown whether this higher dose will improve
efficacy or prevent the development of antiviral resistance. However, there is no evidence that the
3.5 mg/kg dose is harmful or causes more adverse events to infants in this age group.
‡ Oseltamivir dosing for preterm infants. The wt-based dosing recommendation for preterm infants
is lower than for term infants. Preterm infants may have lower clearance of oseltamivir because of
immature renal function, and doses recommended for term infants may lead to high drug
concentrations in this age group. Limited data from the National Institute of Allergy and Infectious
Diseases Collaborative Antiviral Study Group provide the basis for dosing preterm infants by
using their postmenstrual age (gestational age plus chronological age): 1.0 mg/kg per dose orally
twice daily for those <38 wk postmenstrual age; 1.5 mg/kg per dose orally twice daily for those 38-
40 wk postmenstrual age; and 3.0 mg/kg per dose orally twice daily for those >40 wk
postmenstrual age. For extremely preterm infants (<28 wk), please consult a pediatric infectious
diseases physician.
§ Zanamivir is administered by inhalation by using a proprietary Diskhaler device distributed
Pathogenesis
Infection occurs via inoculation of the upper respiratory tract. Infection can
spread rapidly to the lower respiratory tract, but it is not clear whether the
dissemination is mediated by cell-to-cell spread or by aspiration of infected
materials from the upper tract. Severe lower respiratory tract illness, especially
wheezing, occurs mainly during the first year of life, at a time when the airways
are of a very small diameter and thus a high resistance. Maternal serum-
neutralizing antibodies that cross the placenta may afford a relative protection
against severe disease for several weeks or months after birth. Once infection is
established, it is likely that cytotoxic T cells recognize and eliminate virus-
infected cells, thus terminating the infection but also causing some
cytopathology. The virus appears to have specific mechanisms for inhibiting T-
cell responses during acute infection. Individuals with an underlying
predisposition for reactive airways disease (including adults) are susceptible to
severe wheezing during reinfection later in life, suggesting that HMPV may
cause smooth muscle hyperactivity, inflammation, or increased mucus
production in such individuals. Infection in otherwise healthy individuals
resolves without apparent long-term consequences in most cases. HMPV
infection is associated with exacerbations of asthma later in life.

Clinical Manifestations
HMPV is associated with the common cold (complicated by otitis media in
approximately 30% of cases) and with lower respiratory tract illnesses such as
bronchiolitis, pneumonia, croup, and exacerbation of reactive airways disease.
The profile of signs and symptoms caused by HMPV is very similar to that
caused by RSV (Table 288.1 ). Approximately 5–10% of outpatient lower
respiratory tract illnesses in otherwise healthy young children is associated with
HMPV infection, which is second in incidence only to RSV. Children with RSV
or HMPV infection require supplemental oxygen and medical intensive care at
similar frequencies.

Table 288.1

Clinical Manifestations of Human Metapneumovirus in Children

 COMMON (>50%)
Fever > 38°C (100.4°F)
Cough
Rhinitis, coryza
Wheezing
Tachypnea, retractions
Hypoxia (O2 saturation < 94%)
Chest radiograph demonstration of infiltrates or hyperinflation
LESS COMMON
Otitis media
Pharyngitis
Rales
RARE
Conjunctivitis
Hoarseness
Encephalitis
Fatal respiratory failure in immunocompromised children

About half of the cases of HMPV lower respiratory tract illness in children
occur in the first 6 mo of life, suggesting that young age is a major risk factor for
severe disease. Both young adults and the elderly can have HMPV infection that
requires medical care including hospitalization, but severe disease occurs at
much lower frequencies in adults than in young children. Severe disease in
pediatric and older subjects is most common in immunocompromised patients or
those with complications of preterm birth, congenital heart disease, and
neuromuscular disease and can be fatal. A significant number of both adult and
pediatric patients with asthma exacerbations have HMPV infection; it is not clear
whether the virus causes long-term wheezing. RSV and HMPV coinfections
have been reported; coinfections may be more severe than infection with a single
virus, resulting in pediatric intensive care unit admissions. It is difficult to define
true coinfections because these viral RNA genomes can be detected by a reverse
transcriptase polymerase chain reaction (PCR) in respiratory secretions for at
least several weeks after illness, even when virus shedding has terminated.

Laboratory Findings
The virus can be visualized only with electron microscopy. The virus grows in
CHAPTER 289

Adenoviruses
Jason B. Weinberg, John V. Williams

Human adenoviruses (HAdVs) are a common cause of human disease.

Conjunctivitis is a familiar illness associated with the HAdVs, but these viruses
also cause upper and lower respiratory disease, pharyngitis, gastroenteritis, and
hemorrhagic cystitis. HAdVs can cause severe disease in immunocompromised
hosts. Outbreaks of HAdV infection occur in communities and closed
populations, notably the military. No currently approved antiviral drugs are
highly effective against HAdVs. Vaccines are available for HAdV types 4 and 7
but are used only for military populations.

Etiology
Adenoviruses are nonenveloped viruses with an icosahedral protein capsid. The
double-stranded DNA genome is contained within the particle complexed with
several viral proteins. Antigenic variability in surface proteins of the virion and
genomic sequencing define at least 70 serotypes grouped into seven species.
Species differ in their tissue tropism and target organs, causing distinct clinical
infections (Table 289.1 ). HAdVs can be shed from the gastrointestinal tract for
prolonged periods and can establish persistent infection of the tonsils and
adenoids.

Table 289.1

Adenovirus Types With Associated Infections

PREFERRED SITE OF
SPECIES TYPE
INFECTION
A 12, 18, 31, 61 Gastrointestinal
B 3, 7, 11, 14, 16, 21, 34, 35, 50, 55, 66 Respiratory; renal/urinary tract
 epithelium
C 1, 2, 5, 6, 57 Respiratory
D 8-10, 13, 15, 17, 19, 20, 22-30, 32, 33, 36-39, 42-49, 51, 53, 54, Ocular
56, 58-60, 63-67
E 4 Respiratory
F 40, 41 Gastrointestinal
G 52 Gastrointestinal

Epidemiology
HAdVs circulate worldwide and cause endemic infections year-round in
immunocompetent hosts. Asymptomatic infections are also common. Only about
one third of all known HAdV types are associated with clinically apparent
disease. The most prevalent types in recent surveillance studies are HAdV types
3, 2, 1, and 5. Epidemics of conjunctivitis (often severe), pharyngitis, and
respiratory disease occur, especially in schools and military settings. Outbreaks
of febrile respiratory illness caused by HAdV-4 and HAdV-7 are a major source
of morbidity in military barracks, with attack rates ranging from 25% to > 90%.
The spread of HAdV occurs by respiratory and fecal-oral routes. An important
factor in HAdV transmission, especially in epidemics, is the ability of the
nonenveloped particle to survive on inanimate objects in the environment.
Nosocomial outbreaks have been reported.

Pathogenesis
HAdVs bind to cell surface receptors and trigger internalization by endocytosis.
Acidification of the endosome induces conformational changes in the capsid,
leading to eventual translocation of the genome to the cell nucleus. Viral
messenger RNA transcription and genomic replication occur in the nucleus.
Progeny virion particles assemble in the nucleus. Lysis of the cell releases new
infectious particles and causes damage to epithelial mucosa, sloughing of cell
debris, and inflammation. Host responses to HAdV infection include the
recruitment of neutrophils, macrophages, and natural killer cells to the site of
infection and the elaboration by those cells of a number of cytokines and
chemokines. This host immune response is likely to contribute to the symptoms
of HAdV infection, but specific mechanisms of pathogenesis are poorly
understood. The strict species specificity of the adenoviruses has precluded the
development of an animal model for HAdVs, although recent work with HAdV
HPV DNA detected in older women reflects those HPV infections that became
established persistent infections. Persistence is now the known necessary
prerequisite for the development of significant precancerous lesions and cervical
cancer.
Approximately 15–20% of sexually active adolescents have detectable HPV at
any given time and have normal cytologic findings. The most common clinically
detected lesion in adolescent women is the cervical lesion termed low-grade
squamous intraepithelial lesion (LSIL) (Table 293.1 ). LSILs can be found in
25–30% of adolescents infected with HPV. External genital warts are much less
common, occurring in < 1% of adolescents, but approximately 10% of
individuals will develop genital warts in their lifetime. LSIL is a cytologic and
histologic term to reflect the benign changes caused by an active viral infection
and is likely present in most, if not all, women with HPV infection. The majority
of women, however, have very minute or subtle lesions not easily detected by
cytology. As with HPV DNA detection, most LSILs regress spontaneously in
young women and do not require any intervention or therapy. Less commonly,
HPV can induce more severe cellular changes, termed high-grade squamous
intraepithelial lesions (HSILs) (see Chapter 568 ).

Table 293.1
Terminology for Reporting Cervical Cytology and Histology

DESCRIPTIVE DIAGNOSIS OF
EQUIVALENT TERMINOLOGY
EPITHELIAL CELL ABNORMALITIES
SQUAMOUS CELL
Atypical squamous cells of undetermined Squamous atypia
significance (ASC-US)
Atypical squamous cells, cannot exclude
HSIL (ASC-H)
Low-grade squamous intraepithelial lesion Mild dysplasia, condylomatous atypia, HPV-related changes,
(LSIL) koilocytic atypia, cervical intraepithelial neoplasia (CIN) 1
High-grade squamous intraepithelial lesion Moderate dysplasia, CIN 2, severe dysplasia, CIN 3, carcinoma in
(HSIL) situ
GLANDULAR CELL
Endometrial cells, cytologically benign,
in a postmenopausal woman
Atypical
Endocervical cells, NOS
Endometrial cells, NOS
Glandular cells, NOS
Endocervical cells, favor neoplastic
Glandular cells, favor neoplastic

Endocervical adenocarcinoma in situ

 Adenocarcinoma
Endocervical
Endometrial
Extrauterine
NOS
NOS, not otherwise specified.

Although HSILs are considered precancerous lesions, they rarely progress to

invasive cancer. HSILs occur in approximately 0.4–3% of sexually active
women, whereas invasive cervical cancer occurs in 8 cases per 100,000 adult
women. In true virginal populations, including children who are not sexually
abused, rates of clinical disease are close to zero. In the United States, there are
approximately 12,000 new cases and 3,700 deaths from cervical cancer each
year. Worldwide, cervical cancer is the second most common cause of cancer
deaths among women. HPV is also associated with a range of other anogenital
cancers, including an estimated 4,600 cases of anal cancer and 11,100 cases of
oropharyngeal cancers in men and women each year.
Some infants may acquire papillomaviruses during passage through an
infected birth canal, leading to recurrent juvenile laryngeal papillomatosis
(also referred to as respiratory papillomatosis ). Cases also have been reported
after cesarean section. The incubation period for emergence of clinically
apparent lesions (genital warts or laryngeal papillomas) after perinatally
acquired infection is unknown but is estimated to be around 3-6 mo (see Chapter
417.2 ). It may be that infections can also occur during hygienic care from an
infected parent.
Genital warts may represent a sexually transmitted infection even in some
very young children. As such, genital warts appearing in childhood should raise
suspicion for possible sexual abuse with HPV transmission during the abusive
contact. A child with genital warts should therefore be provided with a complete
evaluation for evidence of possible abuse (see Chapter 16.1 ), including the
presence of other sexually transmitted infections (see Chapter 146 ). However,
the presence of genital warts in a child does not confirm sexual abuse, because
perinatally transmitted genital warts may go undetected until the child is older.
Typing for specific genital HPV types in children is not helpful in diagnosis or to
confirm sexual abuse status, because the same genital types occur in both
perinatal transmission and abuse.

Pathogenesis
infection is termed the congenital Zika syndrome (CZS), which consists of
microcephaly, facial disproportion, hypertonia/spasticity, hyperreflexia,
irritability, seizures, arthrogryposis, ocular abnormalities, and sensorineural
hearing loss (Table 294.1 ). A comprehensive understanding of the precise
antecedents to CZS is not known. It appears that the earlier during pregnancy
that ZIKV infections occur, the greater the likelihood of and the more severe the
CZS. Vertical transmission appears to follow viremia with ZIKV, transiting the
uterus to infect the placenta and then the fetus. However, factors that affect the
occurrence or severity of CZS, such as age, ethnicity, or prior immune status of
the mother, are not known. In vitro studies have demonstrated that dengue
antibodies can enhance ZIKV infection in vitro, in Fc-receptor–bearing cells,
but, as yet, there is no evidence that a prior dengue infection alters the chance of
ZIKV crossing the placenta or increases the risk of CZS. Maternal-fetal
transmission of ZIKV can occur during labor and delivery. There are no reports
of ZIKV infection acquired by an infant at the time of delivery leading to
microcephaly. There are no data to contraindicate breastfeeding, although the
virus has been identified in breast milk. Maternal and newborn laboratory testing
is indicated during the first 2 wk of life if the mother had relevant epidemiologic
exposure within 2 wk of delivery and had clinical manifestations of ZIKV
infection (e.g., rash, conjunctivitis, arthralgia, or fever). Infants and children who
acquire ZIKV infection postnatally appear to have a mild course, similar to that
seen in adults.

Table 294.1
Surveillance Case Classification: Children, Neonate to 2
Years of Age, Born to Mothers With Any Evidence of Zika
Virus Infection During Pregnancy
ZIKA-ASSOCIATED BIRTH DEFECTS
Selected structural anomalies of the brain or eyes present at birth (congenital) and detected from birth to age
2 yr. Microcephaly at birth, with or without low birthweight, was included as a structural anomaly.
• Selected congenital brain anomalies: intracranial calcifications; cerebral atrophy; abnormal cortical formation
(e.g., polymicrogyria, lissencephaly, pachygyria, schizencephaly, gray matter heterotopia); corpus callosum
abnormalities; cerebellar abnormalities; porencephaly; hydranencephaly; ventriculomegaly/hydrocephaly.
• Selected congenital eye anomalies: microphthalmia or anophthalmia; coloboma; cataract; intraocular
calcifications; chorioretinal anomalies involving the macula (e.g., chorioretinal atrophy and scarring, macular
pallor, and gross pigmentary mottling), excluding retinopathy of prematurity; optic nerve atrophy, pallor, and
other optic nerve abnormalities.
• Microcephaly at birth: birth head circumference < 3rd percentile for infant sex and gestational age based on
INTERGROWTH-21st online percentile calculator (http://intergrowth21.ndog.ox.ac.uk/ ).
 NEURODEVELOPMENTAL ABNORMALITIES POSSIBLY ASSOCIATED WITH CONGENITAL ZIKA
VIRUS INFECTION
Consequences of neurologic dysfunction detected from birth (congenital) to age 2 yr. Postnatal-onset
microcephaly was included as a neurodevelopmental abnormality.
• Hearing abnormalities: Hearing loss or deafness documented by testing, most frequently auditory brainstem
response (ABR). Includes sensorineural hearing loss, mixed hearing loss, and hearing loss not otherwise
specified. Failed newborn hearing screening is not sufficient for diagnosis.
• Congenital contractures: Multiple contractures (arthrogryposis) and isolated clubfoot documented at birth.
Brain anomalies must be documented for isolated clubfoot but not for arthrogryposis.
• Seizures: Documented by electroencephalogram or physician report. Includes epilepsy or seizures not otherwise
specified; excludes febrile seizures.
• Body tone abnormalities: Hypertonia or hypotonia documented at any age in conjunction with (1) a failed
screen or assessment for gross motor function; (2) suspicion or diagnosis of cerebral palsy from age 1 to 2 yr; or
(3) assessment by a physician or other medical professional, such as a physical therapist.
• Movement abnormalities: Dyskinesia or dystonia at any age; suspicion or diagnosis of cerebral palsy from age
1 to 2 yr.
• Swallowing abnormalities: Documented by instrumented or noninstrumented evaluation, presence of a
gastrostomy tube, or physician report.
• Possible developmental delay: Abnormal result from most recent developmental screening (i.e., failed screen
for gross motor domain or failed screen for two or more developmental domains at the same time point or age);
developmental evaluation; or assessment review by developmental pediatrician. Results from developmental
evaluation are considered the gold standard if available.
• Possible visual impairment: Includes strabismus (esotropia or exotropia), nystagmus, failure to fix and follow
at age < 1 yr; diagnosis of visual impairment at age ≥ 1 yr.
• Postnatal-onset microcephaly: Two most recent head circumference measurements reported from follow-up
care < 3rd percentile for child's sex and age based on World Health Organization child growth standards;
downward trajectory of head circumference percentiles with most recent measurement < 3rd percentile. Age at
measurement was adjusted for gestational age in infants born at < 40 wk of gestational age through age 24 mo
chronologic age.

From Rice ME, Galang RR, Roth NM, et al: Vital signs: Zika-associated birth defects and
neurodevelopmental abnormalities possibly associated with congenital Zika virus infection: US
territories and freely associated states, 2018. MMWR 67(31):858-866, 2018.

Clinical Features
Congenital Zika syndrome may be defined in a fetus with diagnostic evidence
of ZIKV infection, including (1) severe microcephaly (>3 SD below the mean),
partially collapsed skull, overlapping cranial sutures, prominent occipital bone,
redundant scalp skin, and neurologic impairment; (2) brain anomalies, including
cerebral cortex thinning, abnormal gyral patterns, increased fluid spaces,
subcortical calcifications, corpus callosum anomalies, reduced white matter, and
cerebellar vermis hypoplasia; (3) ocular findings, such as macular scarring, focal
pigmentary retinal mottling, structural anomalies (microphthalmia, coloboma,
cataracts, and posterior anomalies), chorioretinal atrophy, or optic nerve
hypoplasia/atrophy; (4) congenital contractures, including unilateral or bilateral
clubfoot and arthrogryposis multiplex congenita; and (5) neurologic impairment,
such as pronounced early hypertonia/spasticity with extrapyramidal symptoms,
motor disabilities, cognitive disabilities, hypotonia, irritability/excessive crying,
tremors, swallowing dysfunction, vision impairment, hearing impairment, and
epilepsy (see Table 294.1 ).
Acquired Zika virus infection may present with nonspecific viral syndrome–
like features. Nonetheless, patients are at increased risk of myelitis and Guillain-
Barré syndrome. In addition, the virus may remain present in the blood and body
fluids for months after resolution of clinical symptoms.

Management
For infants with confirmed Zika virus infection, close follow-up is necessary.
The appropriate follow-up evaluation depends upon whether or not the infant has
clinical signs and symptoms of congenital Zika syndrome. All infants should
have close monitoring of growth and development, repeat ophthalmologic
examinations, and auditory brainstem response testing (see Table 294.1 ).

Laboratory Diagnosis
Laboratory testing for Zika virus infection in the neonate includes the following:
serum and urine for Zika virus RNA via real-time reverse transcription
polymerase chain reaction (rRT-PCR) and serum Zika virus immunoglobulin M
(IgM) enzyme-linked immunosorbent assay (ELISA). If the IgM is positive, the
plaque reduction neutralization test (PRNT) is used to confirm the specificity of
the IgM antibodies against Zika virus and to exclude a false-positive IgM result.
If CSF is available, it should be tested for Zika virus RNA (via rRT-PCR), as
well as Zika virus IgM. CSF specimens need not be collected for the sole
purpose of Zika virus testing but may be reasonable for the evaluation of infants
with microcephaly or intracranial calcifications. A definitive diagnosis of
congenital Zika virus infection is confirmed by the presence of Zika virus RNA
in samples of serum, urine, or CSF collected within the first 2 days of life; IgM
antibodies may be positive or negative. A negative rRT-PCR result with a
positive Zika virus IgM test result indicates probable congenital Zika virus
infection.
Fetuses or infants born to mothers who test positive for ZIKV infection should
be studied sonographically or for clinical evidence of congenital Zika syndrome,
a comprehensive evaluation (including ophthalmologic examination, laboratory
tests, and specialist consultation) should be performed prior to hospital
discharge.

Prognosis
The prognosis of newborns with congenital Zika syndrome is unclear. Reported
acute mortality rates among live-born infants range from 4% to 6%. The
combination of Zika virus–related microcephaly and severe cerebral
abnormalities generally has a poor prognosis, but little is known about the
prognosis for congenitally infected infants with less severe or no apparent
abnormalities at birth.

Differential Diagnosis
The differential diagnosis for congenital Zika virus infection includes other
congenital infections and other causes of microcephaly.

Prevention
The prevention of the congenital Zika syndrome includes avoidance, if possible,
of travel to endemic regions; if travel to endemic regions cannot be avoided,
careful contraception (male and female) is essential, especially with the
knowledge that Zika virus can persist in semen for months after a primary
infection (Table 294.2 ).

Table 294.2

CDC Recommendations for Preconception Counseling and Prevention of Sexual

Transmission of Zika Virus Among Persons With Possible Zika Virus Exposure:
United States, August 2018
EXPOSURE SCENARIO RECOMMENDATIONS (UPDATE STATUS)
Only the male partner The couple should use condoms or abstain from sex for at least 3 mo after the male
travels to an area with risk partner's symptom onset (if symptomatic) or last possible Zika virus exposure (if
for Zika virus transmission asymptomatic). (Updated recommendation)
and couple is planning to
conceive
Only the female partner The couple should use condoms or abstain from sex for at least 2 mo after the
 travels to an area with risk female partner's symptom onset (if symptomatic) or last possible Zika virus
for Zika virus transmission exposure (if asymptomatic). (No change in recommendation) *
and couple is planning to
conceive
Both partners travel to an The couple should use condoms or abstain from sex for at least 3 mo from the male
area with risk for Zika virus partner's symptom onset (if symptomatic) or last possible Zika virus exposure (if
transmission and couple is asymptomatic). (Updated recommendation)
planning to conceive
One or both partners have The couple should talk with their health care provider about their plans for
ongoing exposure (i.e., live pregnancy, their risk for Zika virus infection, the possible health effects of Zika
in or frequently travel to an virus infection on a baby, and ways to protect themselves from Zika. If either
area with risk for Zika virus partner develops symptoms of Zika virus infection or tests positive for Zika virus
transmission) and couple is infection, the couple should follow the suggested timeframes listed above before
planning to conceive trying to conceive. (No change in recommendation) *
Men with possible Zika The couple should use condoms or abstain from sex for the duration of the
virus exposure whose pregnancy. (No change in recommendation) *
partner is pregnant
*
Petersen EE, Meaney-Delman D, Neblett-Fanfair R, et al: Update: interim guidance for
preconception counseling and prevention of sexual transmission of Zika virus for persons with
possible Zika virus exposure—United States, September 2016, MMWR Morb Mortal Wkly Rep
65:1077–1081, 2016.
From Polen KD, Gilboa SM, Hills S, et al: Update: interim guidance for preconception counseling
and prevention of sexual transmission of Zika virus for men with possible Zika virus exposure:
United States, August 2018, MMWR 67(31):868–870, 2018.

Bibliography
Adebanjo T, Godfred-Cato S, Viens L, et al. Update: interim
guidance for the diagnois, evaluation, and management of
infants with possible congenital Zika virus infection—United
States, October 2017. MMWR Morb Mortal Wkly Rep .
2017;66(41):1089–1098.
Baud D, Gubler DJ, Schaub B, et al. An update on Zika virus
infection. Lancet . 2017;390:2099–2109.
Brasil P, Sequeria PC, Freitas AD, et al. Guillain-Barre
syndrome associated with Zika virus infection. Lancet .
2016;387:1482.
Brooks RB, Carlos MP, Myers RA, et al. Likely sexual
transmission of Zika virus from a man with no symptoms of
infection—Maryland, 2016. MMWR Morb Mortal Wkly Rep .
2016;65(34):915–916.
CHAPTER 295

Dengue Fever, Dengue Hemorrhagic

Fever, and Severe Dengue
Scott B. Halstead

Dengue fever is a benign syndrome caused by several arthropod-borne viruses

and is characterized by biphasic fever, myalgia or arthralgia, rash, leukopenia,
and lymphadenopathy. Dengue hemorrhagic fever (Philippine, Thai, or
Singapore hemorrhagic fever; hemorrhagic dengue; acute infectious
thrombocytopenic purpura) is a severe, often fatal, febrile disease caused by one
of four dengue viruses. It is characterized by capillary permeability,
abnormalities of hemostasis, and, in severe cases, a protein-losing shock
syndrome (dengue shock syndrome), which is thought to have an
immunopathologic basis.
A revised case definition adopted by the World Health Organization (WHO) in
2009 includes as severe dengue those cases accompanied by fluid loss leading
to shock, fluid loss with respiratory distress, liver damage evidenced by
elevations of ALT or AST to > 1000 U/L, severe bleeding, and altered
consciousness or significant heart abnormalities.

Etiology
There are at least four distinct antigenic types of dengue virus (dengue 1, 2, 3,
and 4), members of the family Flaviviridae. In addition, three other arthropod-
borne viruses (arboviruses) cause similar dengue fever syndromes with rash
(Table 295.1 ; see also Chapter 294 ).

Table 295.1
Vectors and Geographic Distribution of Dengue-Like
Diseases
GEOGRAPHIC GENUS AND
VIRUS VECTOR DISTRIBUTION
DISEASE
Togavirus Chikungunya Aedes aegypti Africa, India, Southeast Asia, Latin America,
Aedes United States
africanus
Aedes
albopictus
Togavirus O'nyong-nyong Anopheles East Africa
funestus
Flavivirus West Nile fever Culex molestus Europe, Africa, Middle East, India
Culex
univittatus

Epidemiology
Dengue viruses are transmitted by mosquitoes of the Stegomyia family. Aedes
aegypti, a daytime biting mosquito, is the principal vector, and all four virus
types have been recovered from it. Transmission occurs from viremic humans by
bite of the vector mosquito where virus multiplies during an extrinsic incubation
period and then by bite is passed on to a susceptible human in what is called the
urban transmission cycle. In most tropical areas, A. aegypti is highly urbanized,
breeding in water stored for drinking or bathing and in rainwater collected in any
container. Dengue viruses have also been recovered from Aedes albopictus, as in
the 2001 and 2015 Hawaiian epidemics, whereas outbreaks in the Pacific area
have been attributed to several other Aedes species. These species breed in water
trapped in vegetation. In Southeast Asia and West Africa, dengue virus may be
maintained in a cycle involving canopy-feeding jungle monkeys and Aedes
species, which feed on monkeys.
In the 19th and 20th centuries, epidemics were common in temperate areas of
the Americas, Europe, Australia, and Asia. Dengue fever and dengue-like
disease are now endemic in tropical Asia, the South Pacific Islands, northern
Australia, tropical Africa, the Arabian Peninsula, the Caribbean, and Central and
South America (Fig. 295.1 ). Dengue fever occurs frequently among travelers to
these areas. Locally acquired disease has been reported in Florida, Arizona, and
Texas, and imported cases in the United States occur in travelers to endemic
areas. More than 390 million dengue infections occur annually; approximately
96 million have clinical disease.
CHAPTER 297

Ebola and Other Viral Hemorrhagic

Fevers
Scott B. Halstead

Viral hemorrhagic fevers are a loosely defined group of clinical syndromes in

which hemorrhagic manifestations are either common or especially notable in
severe illness. Both the etiologic agents and clinical features of the syndromes
differ, but coagulopathy may be a common pathogenetic feature.

Etiology
Six of the viral hemorrhagic fevers are caused by arthropod-borne viruses
(arboviruses) (Table 297.1 ). Four are caused by togaviruses of the family
Flaviviridae: Kyasanur Forest disease, Omsk hemorrhagic fever, dengue (see
Chapter 295 ), and yellow fever (see Chapter 296 ) viruses. Three are caused by
viruses of the family Bunyaviridae: Congo fever, Hantaan fever, and Rift Valley
fever (RVF) viruses. Four are caused by viruses of the family Arenaviridae:
Junin fever, Machupo fever, Guanarito fever, and Lassa fever. Two are caused by
viruses in the family Filoviridae : Ebola virus and Marburg virus, enveloped,
filamentous RNA viruses that are sometimes branched, unlike any other known
virus.

Table 297.1
Viral Hemorrhagic Fevers

MODE OF TRANSMISSION DISEASE VIRUS

Tick-borne Crimean-Congo hemorrhagic fever (HF)* Congo
Kyasanur Forest disease Kyasanur Forest disease
Omsk HF Omsk
 Mosquito-borne † Dengue HF Dengue (4 types)
Rift Valley fever Rift Valley fever
Yellow fever Yellow fever
Infected animals or materials to humans Argentine HF Junin
Bolivian HF Machupo
Lassa fever* Lassa
Marburg disease* Marburg
Ebola HF* Ebola
HF with renal syndrome Hantaan
* Patients may be contagious; nosocomial infections are common.

† Chikungunya virus is associated infrequently with petechiae and epistaxis. Severe hemorrhagic

manifestations have been reported in some cases.

Epidemiology
With some exceptions, the viruses causing viral hemorrhagic fevers are
transmitted to humans via a nonhuman entity. The specific ecosystem required
for viral survival determines the geographic distribution of disease. Although it
is commonly thought that all viral hemorrhagic fevers are arthropod borne, seven
may be contracted from environmental contamination caused by animals or
animal cells or from infected humans (see Table 297.1 ). Laboratory and hospital
infections have occurred with many of these agents. Lassa fever and Argentine
and Bolivian hemorrhagic fevers are reportedly milder in children than in adults.

Crimean-Congo Hemorrhagic Fever

Sporadic human infection with Crimean-Congo hemorrhagic fever in Africa
provided the original virus isolation. Natural foci are recognized in Bulgaria,
western Crimea, and the Rostov-on-Don and Astrakhan regions; disease occurs
in Central Asia from Kazakhstan to Pakistan. Index cases were followed by
nosocomial transmission in Pakistan and Afghanistan in 1976, in the Arabian
Peninsula in 1983, and in South Africa in 1984. In the Russian Federation, the
vectors are ticks of the species Hyalomma marginatum and Hyalomma
anatolicum, which, along with hares and birds, may serve as viral reservoirs.
Disease occurs from June to September, largely among farmers and dairy
workers.

Kyasanur Forest Disease

the incubation period is 2-21 days (mean: 11 days). The age range in the West
African epidemic was broad, but most patients were between 15 and 44 yr old.

Table 297.2

Clinical Recommendations for Ebola Virus Infection

RECOMMENDATION POPULATION INTERVENTION
1 Oral rehydration Patients with suspected, probable, or confirmed Ebola
virus disease
2 Parenteral administration of Patients with suspected, probable, or confirmed Ebola
fluids virus disease who are unable to drink or who have
inadequate oral intake
3 Systematic monitoring and Patients with suspected, probable, or confirmed Ebola
charting of vital signs and virus disease
volume status
4 Serum biochemistry Patients with suspected, probable, or confirmed Ebola
virus disease
5 Staffing ratio Patients with suspected, probable, or confirmed Ebola
virus disease
6 Communication with family Patients with suspected, probable, or confirmed Ebola
and friends virus disease
7 Analgesic therapy Patients with suspected, probable, or confirmed Ebola
virus disease who are in pain
8 Antibiotics Patients with suspected, probable, or confirmed Ebola
virus disease with high severity of illness
*Confidence is based on the quality of the evidence for the main outcome.
Modified from Lamontagne F, Fowler RA, Adhikari NK, et al: Evidence-based guidelines for
supportive care of patients with Ebola virus disease, Lancet 391:700-708, 2018,Table 2.

Hemorrhagic Fever With Renal Syndrome

The endemic area of hemorrhagic fever with renal syndrome (HFRS), also
known as epidemic hemorrhagic fever and Korean hemorrhagic fever, includes
Japan, Korea, far eastern Siberia, north and central China, European and Asian
Russia, Scandinavia, Czechoslovakia, Romania, Bulgaria, Yugoslavia, and
Greece. Although the incidence and severity of hemorrhagic manifestations and
the mortality rates are lower in Europe than in northeastern Asia, the renal
lesions are the same. Disease in Scandinavia, nephropathia epidemica, is
caused by a different although antigenically related virus, Puumala virus,
associated with the bank vole, Clethrionomys glareolus. Cases occur
predominantly in the spring and summer. There appears to be no age factor in
susceptibility, but because of occupational hazards, young adult men are most
dysphagia, cough, oropharyngeal ulcers, nausea, vomiting, diarrhea, and pains in
the chest and abdomen. Pleuritic chest pain may persist for 2-3 wk. In Argentine
and Bolivian hemorrhagic fevers and less frequently in Lassa fever, a petechial
enanthem appears on the soft palate 3-5 days after onset and at about the same
time on the trunk. The tourniquet test may be positive. The clinical course of
Venezuelan hemorrhagic fever has not been well described.

Table 297.3

Clinical Stages of Lassa Fever

STAGE SYMPTOMS
1 (days General weakness and malaise. High fever > 39°C (102.2°F), constant with peaks of 40-41°C (104-
1-3) 105.8°F)
2 (days Sore throat (with white exudative patches) very common; headache; back, chest, side, or abdominal
4-7) pain; conjunctivitis; nausea and vomiting; diarrhea; productive cough; proteinuria; low blood pressure
(systolic < 100 mm Hg); anemia
3 (after Facial edema; convulsions; mucosal bleeding (mouth, nose, eyes); internal bleeding; confusion or
7 days) disorientation
4 (after Coma and death
14 days)
From Richmond JK, Baglole DJ: Lassa fever: epidemiology, clinical features, and social
consequences, BMJ 327:1271-1275, 2003.

In 35–50% of patients, these diseases may become severe, with persistent high
temperature, increasing toxicity, swelling of the face or neck, microscopic
hematuria, and frank hemorrhages from the stomach, intestines, nose, gums, and
uterus. A syndrome of hypovolemic shock is accompanied by pleural effusion
and renal failure. Respiratory distress resulting from airway obstruction,
pleural effusion, or congestive heart failure may occur. A total of 10–20% of
patients experience late neurologic involvement, characterized by intention
tremor of the tongue and associated speech abnormalities. In severe cases, there
may be intention tremors of the extremities, seizures, and delirium. The
cerebrospinal fluid is normal. In Lassa fever, nerve deafness occurs in early
convalescence in 25% of cases. Prolonged convalescence is accompanied by
alopecia and, in Argentine and Bolivian hemorrhagic fevers, by signs of
autonomic nervous system lability, such as postural hypotension, spontaneous
flushing or blanching of the skin, and intermittent diaphoresis.
Laboratory studies reveal marked leukopenia, mild to moderate
thrombocytopenia, proteinuria, and, in Argentine hemorrhagic fever, moderate
abnormalities in blood clotting, decreased fibrinogen, increased fibrinogen split
Prevention
Primary prevention of rabies infection includes vaccination of domestic animals
and education to avoid wild animals, stray animals, and animals with unusual
behavior.

Immunization and Fertility Control of Animal

Reservoirs
The introduction of routine rabies immunization for domestic pets in the United
States and Europe during the middle of the 20th century virtually eliminated
infection in dogs. In the 1990s, control efforts in Europe and North America
shifted to immunization of wildlife reservoirs of rabies, where rabies was newly
emerging. These programs employed bait laced with either an attenuated rabies
vaccine or a recombinant rabies surface glycoprotein inserted into vaccinia,
distributed by air or hand into areas inhabited by rabid animals. Human contact
with vaccine-laden bait has been infrequent. Adverse events after such contact
have been rare, but the vaccinia vector poses a threat to the same population at
risk for vaccinia itself, namely, pregnant women, immunocompromised patients,
and people with atopic dermatitis. Mass culling of endemic reservoirs has never
worked; vaccination and fertility control stop outbreaks. Bats are ubiquitous and
very important for insect control. Less than 1% of free-flying bats but > 8% of
downed bats and bats found in dwellings are rabid.

Postexposure Prophylaxis
The relevance of rabies for most pediatricians centers on evaluating whether an
animal exposure warrants PEP (Table 300.1 ). No case of rabies has been
documented in a person receiving the recommended schedule of PEP since
introduction of modern cellular vaccines in the 1970s.

Table 300.1
Rabies Postexposure Prophylaxis Guide

EVALUATION AND POSTEXPOSURE PROPHYLAXIS

ANIMAL TYPE
DISPOSITION OF ANIMAL RECOMMENDATIONS
Dogs, cats, and Healthy and available for 10 days Prophylaxis only if animal shows signs of rabies*
ferrets of observation
 Rabid or suspected of being rabid † Immediate immunization and RIG
Unknown (escaped) Consult public health officials for advice
Bats, skunks, Regarded as rabid unless Immediate immunization and RIG
raccoons, foxes, geographic area is known to be free
and most other of rabies or until animal proven
carnivores; negative by laboratory tests †
woodchucks
Livestock, rodents, Consider individually Consult public health officials. Bites of squirrels,
and lagomorphs hamsters, guinea pigs, gerbils, chipmunks, rats, mice
(rabbits, hares, and and other rodents, rabbits, hares, and pikas almost
pikas) never require antirabies treatment
* During the 10-day observation period, at the first sign of rabies in the biting dog, cat, or ferret,

treatment of the exposed person with RIG (human) and vaccine should be initiated. The animal
should be euthanized immediately and tested.
† The animal should be euthanized and tested as soon as possible. Holding for observation is not
recommended. Immunization is discontinued if the immunofluorescent test result for the animal is
negative.
RIG, rabies immunoglobulin.

Given the incubation period for rabies, PEP is a medical urgency, not
emergency. Algorithms have been devised to aid practitioners in deciding when
to initiate rabies PEP (Fig. 300.1 ). The decision to proceed ultimately depends
on the local epidemiology of animal rabies as determined by active surveillance
programs, information that can be obtained from local and state health
departments. In general, bats, raccoons, skunks, coyotes, and foxes should be
considered rabid unless proven otherwise through euthanasia and testing of
brain tissue, whereas bites from small herbivorous animals (squirrels, hamsters,
gerbils, chipmunks, rats, mice, and rabbits) can be discounted. The response to
bites from a pet, particularly a dog, cat, or ferret, depends on local surveillance
statistics and on whether the animal is vaccinated and available for observation.
slower progression of disease.
The CDC Surveillance Case Definition for HIV infection is based on the age-
specific CD4+ T-lymphocyte count or the CD4+ T-lymphocyte percentage of
total lymphocytes (Table 302.1 ), except when a stage 3–defining opportunistic
illness (Table 302.2 ) supersedes the CD4 data. Age adjustment of the absolute
CD4 count is necessary because counts that are relatively high in normal infants
decline steadily until age 6 yr, when they reach adult norms. The CD4 count
takes precedence over the CD4 T-lymphocyte percentage, and the percentage is
considered only if the count is unavailable.

Table 302.1
HIV Infection Stage* Based on Age-Specific CD4+ T-
Lymphocyte Count or CD4+ T-Lymphocyte Percentage of
Total Lymphocytes

AGE ON DATE OF CD4+ T-LYMPHOCYTE TEST

STAGE <1 Yr 1-5 Yr ≥6 Yr
CELLS/µL % CELLS/µL % CELLS/µL %
1 ≥1,500 ≥34 ≥1,000 ≥30 ≥500 ≥26
2 750-1,499 26-33 500-999 22-29 200-499 14-25
3 <750 <26 <500 <22 <200 <14
* Stage is based primarily on the CD4+ T-lymphocyte count. The CD4+ T-lymphocyte count takes

precedence over the CD4+ T-lymphocyte percentage, and the percentage is considered only if the
count is missing.
From Centers for Disease Control and Prevention: Revised surveillance case definition for HIV
infection—United States, 2014, MMWR 63(No RR-3):1-10, 2014.

Table 302.2
Stage 3–Defining Opportunistic Illnesses in HIV Infection
Bacterial infections, multiple or recurrent*
Candidiasis of bronchi, trachea, or lungs
Candidiasis of esophagus
Cervical cancer, invasive †
Coccidioidomycosis, disseminated or extrapulmonary
Cryptococcosis, extrapulmonary
Cryptosporidiosis, chronic intestinal (>1 mo duration)
Cytomegalovirus disease (other than liver, spleen, or nodes), onset at age > 1 mo
Cytomegalovirus retinitis (with loss of vision)
Encephalopathy attributed to HIV ‡
 Herpes simplex: chronic ulcers (>1 mo duration) or bronchitis, pneumonitis, or esophagitis (onset at age > 1 mo)
Histoplasmosis, disseminated or extrapulmonary
Isosporiasis, chronic intestinal (>1 mo duration)
Kaposi sarcoma
Lymphoma, Burkitt (or equivalent term)
Lymphoma, immunoblastic (or equivalent term)
Lymphoma, primary, of brain
Mycobacterium avium complex or Mycobacterium kansasii, disseminated or extrapulmonary
Mycobacterium tuberculosis of any site, pulmonary, † disseminated, or extrapulmonary
Mycobacterium, other species or unidentified species, disseminated or extrapulmonary
Pneumocystis jiroveci (previously known as Pneumocystis carinii ) pneumonia
Pneumonia, recurrent †
Progressive multifocal leukoencephalopathy
Salmonella septicemia, recurrent
Toxoplasmosis of brain, onset at age > 1 mo
Wasting syndrome attributed to HIV ‡
* Only among children aged < 6 yr.

†
Only among adults, adolescents, and children aged ≥ 6 yr.
‡ Suggested diagnostic criteria for these illnesses, which might be particularly important for HIV
encephalopathy and HIV wasting syndrome, are described in the following references: Centers for
Disease Control and Prevention: 1994 Revised classification system for human immunodeficiency
virus infection in children less than 13 years of age, MMWR 43(No. RR-12), 1994; Centers for
Disease Control and Prevention: 1993 Revised classification system for HIV infection and
expanded surveillance case definition for AIDS among adolescents and adults, MMWR 41(No.
RR-17), 1992.
From Centers for Disease Control and Prevention: Revised surveillance case definition for HIV
infection—United States, 2014, MMWR 63(No RR-3):1-10, 2014.

Infections
Approximately 20% of AIDS-defining illnesses in children are recurrent
bacterial infections caused primarily by encapsulated organisms such as
Streptococcus pneumoniae and Salmonella as a result of disturbances in humoral
immunity. Other pathogens, including Staphylococcus, Enterococcus,
Pseudomonas aeruginosa, and Haemophilus influenzae, and other Gram-positive
and Gram-negative organisms may also be seen. The most common serious
infections in HIV-infected children are bacteremia, sepsis, and bacterial
pneumonia, accounting for more than 50% of infections in these patients.
Meningitis, urinary tract infections, deep-seated abscesses, and bone/joint
infections occur less frequently. Milder recurrent infections, such as otitis media,
sinusitis, and skin and soft tissue infections, are very common and may be
chronic with atypical presentations.
Opportunistic infections are generally seen in children with severe
2 wk of age. Plasma HIV RNA PCR assays, which detect viral replication, are as
sensitive as the DNA PCR for early diagnosis. Either the DNA or RNA PCR is
considered acceptable for infant testing. The commercially available HIV-1
assays are not designed for quantification of HIV-2 RNA and thus should not be
used to monitor patients with this infection.

Table 302.3

Laboratory Diagnosis of HIV Infection

TEST COMMENT
HIV Historically preferred test to diagnose HIV-1 subtype B infection in infants and children younger than 24
DNA mo of age; highly sensitive and specific by 2 wk of age and available; performed on peripheral blood
PCR mononuclear cells. False negatives can theoretically occur in non-B subtype HIV-1 infections. Historically
had been preferred for testing in young infants.
HIV Preferred test to identify non–B subtype HIV-1 infections. Similar sensitivity and specificity to HIV DNA
RNA PCR in infants and children younger than 24 mo of age
PCR
PCR, polymerase chain reaction.
Data from American Academy of Pediatrics, Committee of Pediatric AIDS: Diagnosis of HIV-1
infection in children younger than 18 months in the United States, Pediatrics 120:e1547-e1562,
2007.

Viral diagnostic testing should be performed within the first 12-24 hr of life,
particularly for high-risk infants (i.e., those of mothers without sustained
virologic suppression, a late cART start, or a diagnosis with acute HIV during
the pregnancy); the tests can identify almost 40% of HIV-infected children. It
seems that many of these children have a more rapid progression of their disease
and deserve more aggressive therapy. Data suggest that if cART treatment starts
at this point, the outcome will be much better. In exposed children with negative
virologic testing at 1-2 days of life, additional testing should be done at 2-3 wk
of age, 4-8 wk of age, and 4-6 mo of age. For higher-risk infants, additional
virologic diagnostic testing should be considered at 2 to 4 wk after cessation of
ARV prophylaxis (i.e., at 8-10 wk of life) (Fig. 302.4 ). A positive virologic
assay (i.e., detection of HIV by PCR) suggests HIV infection and should be
confirmed by a repeat test on a second specimen as soon as possible because
false-positive tests can occur. A confirmed diagnosis of HIV infection can be
made with two positive virologic test results obtained from different blood
samples. HIV infection can be presumptively excluded in nonbreastfed infants
with two or more negative virologic tests (one at age ≥ 14 days and one at age ≥
4 wk) or one negative virologic test (i.e., negative NAT [RNA or DNA]) at age ≥
catalyzes the incorporation of the viral genome into the host's DNA.

Table 302.4
Summary of Antiretroviral Therapies Available in 2019

DRUG (TRADE
NAMES, DOSING SIDE EFFECTS COMMENTS
FORMULATIONS)
NUCLEOSIDE/NUCLEOTIDE REVERSE Class adverse effects:
TRANSCRIPTASE INHIBITORS Lactic acidosis with
hepatic steatosis,
particularly for older
members of the class
Abacavir Children: ≥3 mo Common: nausea, Can be given with food
(Ziagen, ABC): to 13 yr: 8 vomiting, anorexia, Genetic screening for
tablet: 300 mg; oral mg/kg/dose bid fever, headache, HLAB*5701 must be done prior
solution: 20 mg/mL (maximum dose: diarrhea, rash to initiation of ABC-containing
Trizivir: 300 mg bid) Less common: treatment. If test is positive, avoid
combination of >25 kg: 300 mg hypersensitivity, ABC. Do not restart ABC in
zidovudine (ZDV), bid which can be fatal, patients who had hypersensitivity-
lamivudine, ABC Children with Rare: lactic like symptoms (e.g., flu-like
(300, 150, 300 mg) stable CD4 acidosis with symptoms)
Epzicom: counts and hepatic steatosis,
combination of undetectable pancreatitis,
lamivudine, ABC viral load > 6 mo elevated
(300, 600 mg) while taking triglycerides,
Triumeq: ABC can myocardial
combination of transition to 16 infarction
ABC, lamivudine, mg/kg once daily
dolutegravir (600, (max: 600 mg)
300, 50 mg) Adolescents and
adults: 600 mg
once daily
Trizivir (>40 kg):
1 tablet bid
Epzicom (>25
kg): 1 tablet qd
Triumeq: 1 tablet
qd
Didanosine 2 wk to < 3 mo: Common: diarrhea, Food decreases bioavailability by
(Videx, ddl): 50 mg/m2 /dose abdominal pain, up to 50%. Take 30 min before or
powder for oral bid 3-8 mo: 100 nausea, vomiting 2 hr after meal. Tablets dissolved
solution (prepared mg/m2 /dose bid Less common: in water are stable for 1 hr (4 hr in
with solution >8 mo: 120 pancreatitis, buffered solution)
containing antacid): peripheral Drug interactions: antacids/gastric
10 mg/mL mg/m2 /dose neuropathy, acid antagonists may increase
(max: 200
electrolyte bioavailability; possible decreased
mg/dose) bid
abnormalities, absorption of fluoroquinolones,
Adolescents (>13 lactic acidosis with ganciclovir, ketoconazole,
yr) and adults < hepatic steatosis, itraconazole, dapsone, and some
60 kg: 250 mg hepatomegaly, protease inhibitors. Combination
once daily >60 retinal with d4T enhances toxicity; also
 kg: 400 mg once depigmentation common if combined with
daily (to increase tenofovir.
adherence) Note: Due to increased side
effects compared with other
NRTIs, ddI is no longer
recommended for treatment of
HIV in children in the US.

Enteric-coated 20-25 kg: 200 Same as for ddl Same as for ddl
didanosine (Videx EC): mg once daily
capsule, delayed 25-60 kg: 250
release: 125, 200, 250, mg once daily
400 mg; generic: 200, ≥60 kg: 400 mg
250, 400 mg once daily
Emtricitabine Infants: 0-3 mo: Common: Patient should be tested for
(Emtriva, FTC): 3 mg/kg once headache, hepatitis B virus (HBV) because
capsule: 200 mg; daily insomnia, diarrhea, HBV exacerbation can occur
oral solution: 10 Children ≥ 3 mo nausea, skin when emtricitabine is
mg/mL to 17 yr, oral discoloration discontinued.
Truvada: solution: 6 Less common: Can be given without regard to
combination of mg/kg (max: 240 lactic acidosis with food. Oral solution should be
FTC, tenofovir mg) once daily hepatic steatosis, refrigerated if temperature above
disoproxil fumarate >33 kg, neutropenia 25°C (77°F)
(TDF) (200, 300 adolescents and COBI is a pharmacokinetc
mg) adults: 200 mg enhancer (boosting agent) used to
Truvada Low capsule or 240 optimize drug levels; it is not
Strength: mg solution once interchangeable with ritonavir. It
combinations of daily can alter renal tubular secretion of
FTC/TDF (100, Truvada, Cr, resulting in elevated Cr with
150 mg); (133, 200 Descovy, Atripla, normal GFR. Note oral solution is
mg); (167, 250 mg) Complera, less bioavailable and has a max
Atripla: Descovy, dose of 240 mg, while the max
combination of Stribild, dose for capsules is 200 mg.
FTC, TDF, Genvoya or
efavirenz (EFV) Biktarvy: adult
(200, 300, 600 mg) dose: 1 tablet
Descovy: once daily
combination of
FTC, tenofovir
disoproxil
alafenamide (TAF)
(200, 25 mg)
Complera:
combination of
FTC, TDF,
rilpivirine (RPV)
(200, 300, 25 mg)
Odefsey:
combination of
FTC, TAF, RPV
(25, 200, 25 mg)
Stribild:
combination of
FTC, TDF,
elvitegravir (EVG),
cobicistat (COBI)
(200, 300, 150, 150
mg)
Genvoya:
combination of
FTC, TAF, EVG,
COBI (200, 10,
150, 150 mg)
Biktarvy:
combination of
bictegravir (BIC),
FTC, TAF (50, 200,
25 mg)
Lamivudine Neonates (≥32 Common: No food restrictions
(Epivir, Epivir wk gestational headache, nausea Patient should be tested for
HBV, 3TC): tablet: age through 4 wk Less common: hepatitis B virus (HBV) because
150 (scored), 300 of age for term pancreatitis, HBV exacerbation can occur
mg (Epivir, infants): 2 peripheral when lamivudine is discontinued.
generic), 100 mg mg/kg/dose bid neuropathy, lactic M184V mutation for this drug
(Epivir HBV); ≥4 wk to <3 mo: acidosis with decreases viral fitness and can be
Solution: 5 mg/mL 4 mg/kg/dose bid hepatic steatosis, advantageous to maintain
(Epivir HBV), 10 ≥3 mo to <3 yr: 5 lipodystrophy including inducing AZT
mg/mL (Epivir) mg/kg/dose bid hypersusceptibility.
Combivir: (max 150 mg)
combination of ≥3 yr: 5
ZDV, lamivudine mg/kg/dose bid
(300, 150 mg) (max 150 mg) or
Trizivir, Epzicom, 10 mg/kg/dose
and Triumeq qd (max 300 mg)
combination (see For ≥14 kg with
abacavir) scored tablet
Symfi Lo (150 mg)
combination of 14 to <20 kg: 75
3TC, TDF, EFV mg bid or 150
(300, 300, 400 mg) mg qd (if >3 yr)
≥20 to <25 kg:
75 mg qAM and
150 mg qPM or
225 mg qd (if >3
yr)
≥25 kg: 150 mg
bid or 300 mg qd
Children should
be switched to
once-daily
dosing of
lamivudine (oral
solution or
tablets) from
twice-daily
dosing at ≥3 yr if
clinically stable
for 36 wk with
an undetectable
viral load and
stable CD4 T
lymphocyte
 count
Adolescents and
adults: Combivir
(>30 kg), Trizivir
(>40 kg): 1 tablet
bid
Epzicom (>25
kg): 1 tablet qd
Triumeq (>40
kg): 1 tablet qd
Symfi Lo (>35
kg): 1 tablet qd

Stavudine ≥14 days and < Common: No food restrictions. Should not
(Zerit, d4T): 30 kg: 1 headache, nausea, be administered with ZDV
capsule: 15, 20, 30, mg/kg/dose bid hyperlipidemia, fat because of virologic antagonism.
40 mg; solution: 1 >30 kg: 30 mg maldistribution Higher incidence of lactic
mg/mL bid Less common: acidosis. Increased toxicity if
peripheral combined with ddl.
neuropathy, Note: Due to increased side
pancreatitis, lactic effects compared with other
acidosis, hepatic NRTIs, d4T is no longer
steatosis recommended for treatment of
HIV in children in the US.

Tenofovir 2 to <12 yr: 8 Common: nausea, High-fat meal increases absorption;

disoproxil fumarate mg/kg/dose qd vomiting, diarrhea coadministration with ddl increased
(Viread, TDF): >12 yr and 35 Less common: ddl toxicity, decreases atazanavir
tablet: 150, 200, kg, adolescents lactic acidosis with (ATV) levels (therefore, boosting ATV
250, 300 mg; >12 yr and 35 kg hepatic steatosis, with ritonavir is required). ATV and
powder: 40 mg/1 g and adults: 300 hepatomegaly, lopinavir (LPV) increase TDF levels
powder mg once daily reduced bone and potential toxicity. Screen for HBV
Truvada: Truvada, Atripla, density, renal before TDF is given, because
combination of Complera, Symfi toxicity exacerbation of hepatitis may occur
FTC, TDF (200, Lo, and Stribild: when TDF is discontinued
300 mg) 1 tablet qd
Truvada Low Weight probands
Strength: for ≥2 yr and ≥17
combinations of kg:
FTC/TDF (100, 17 to <22 kg:
150 mg); (133, 200 150 mg qd
mg); (167, 250 mg) 22 to <28 kg:
Atripla: 200 mg qd
Combination of 28 to <35 kg:
FTC, TDF, EFV 250 mg qd
(200, 300, 600 mg) ≥35 kg: 300 mg
Complera: qd
combination of
FTC, TDF, RPV
(200, 300, 25 mg)
Stribild:
combination of
FTC, TDF, EVG,
COBI (200, 300,
150, 150 mg)Symfi
Lo combination of
3TC, TDF, EFV
(300, 300, 400 mg)
Tenofovir Adolescents (≥13 Common: headache, Newer version of TDF that has
alafenamide yr, ≥35 kg): diarrhea, nausea, less renal and bone toxicity.
(Vemlidy, TAF) Descovy, increased serum lipids Screen for HBV before TAF is
Descovy: Genvoya, or given, because exacerbation of
combination of Odefsey: 1 tablet hepatitis may occur when TAF is
TAF, FTC (25, 200 qd discontinued.
mg) Biktarvy: ≥18 yr Concentrates in cells more so than
Genvoya: 1 tablet qd; >12 TDF, so is not approved for
combination of yr to 18 yr and pregnant women given lack of
TAF, FTC, EVG, >35 kg data.
COBI (10, 200, investigational
150, 150 mg) dose 1 tablet qd
Odefsey: based on limited
combination of data
FTC, TAF, RPV
(25, 200, 25 mg)
Biktarvy:
combination of
BIC, FTC, TAF
(50, 200, 25 mg)

Zidovudine Low Risk Common: bone No food restrictions

(Retrovir, AZT, Prophylaxis: marrow Drug interactions: should not be
ZDV): capsule: 100 ≥35 wk gestation suppression (e.g., given with d4T or doxorubicin.
mg; tablet: 300 mg; at birth: macrocytic anemia, Rifampin may increase
syrup: 10 mg/mL; Birth to age 4-6 neutropenia), metabolism.
intravenous wk : 4 headache, nausea, Cimetidine, fluconazole, valproic
injection: 10 mg/kg/dose PO vomiting, anorexia acid may decrease metabolism.
mg/mL (all bid (or 3 Less common: liver Ganciclovir, IFN-α, ribavirin
available generic) mg/kg/dose IV toxicity, lactic increase ZDV toxicity.
Combivir: q12h) acidosis with Only antiretroviral with an IV
combination of ≥30 to <35 wk hepatic steatosis, formulation currently.
ZDV, lamivudine gestation at birth: myopathy, fat
(300, 150 mg) Birth to age 2 wk redistribution
Trizivir: : 2 mg/kg/dose
Combination of PO bid (or 1.5
ZDV, lamivudine, mg/kg/dose IV
ABC (300, 150, q12h)
300 mg) THEN
Age 2 wk to 4-6
wk :
3 mg/kg/dose PO
bid (or 2.3
mg/kg/dose IV
q12h)
<30 wk gestation
at birth
Birth to age 4-6
wk : 2
mg/kg/dose PO
bid (or 1.5
mg/kg/dose IV
q12h)
High Risk
Prophylaxis and
Treatment:
≥35 wk gestation
at birth:
Birth to age 4
wk: 4
mg/kg/dose PO
bid THEN
Age >4 wk: 12
mg/kg/dose PO
bid
≥30 to <35 wk
gestation at birth:
Birth to age 2
wk: 2
mg/kg/dose PO
bid THEN
Age 2 wk to 6-8
wk: 3
mg/kg/dose PO
bid THEN
Age >6-8 wk: 12
mg/kg/dose PO
bid
<30 wk gestation
at birth:
Birth to age 4
wk: 2
mg/kg/dose PO
bid THEN
Age 4 wk to 8-10
wk: 3
mg/kg/dose PO
bid THEN
Age >8-10 wk:
12 mg/kg/dose
PO bid
Infants >4 kg and
≥4 wk post
delivery and
children:
4 kg to <9 kg: 12
mg/kg/dose PO
bid
9 kg to <30 kg: 9
mg/kg/dose PO
bid
>30 kg,
adolescents and
adults: 300 mg
bid
Alternative body
surface area
dosing: 180-240
mg/m2 /dose PO
 bid
Combivir or
Trizivir: 1 tablet
bid
NONNUCLEOSIDE REVERSE Class adverse effects: Rash is mild to severe, usually within first
TRANSCRIPTASE INHIBITORS 6 wk. Discontinue the drug if severe rash (with blistering,
desquamation, muscle involvement, or fever)
Efavirenz Children < 3 yr: Common: skin Capsules can be opened for
(Sustiva, EFV): consult with rashes, CNS mixing in food.
capsule: 50, 200 expert abnormalities (e.g., Administer at bedtime on empty
mg; tablet: 600 mg Children ≥ 3 yr: vivid dreams, stomach to minimize CNS side
Atripla: 10 to < 15 kg: impaired effects. Taking with food,
combination of 200 mg qd concentration, especially fatty meal, can increase
EFV, FTC, TDF 15 to < 20 kg: insomnia, absorption and CNS side effects.
(600, 200, 300 mg) 250 mg qd depression, Drug interactions: Efavirenz
Symfi Lo 20 to < 25 kg: hallucination) induces/inhibits CYP3A4
combination of 300 mg qd Less common: enzymes. Increase clearance of
3TC, TDF, EFV 25 to < 32.5 kg: increased liver drugs metabolized by this
(300, 300, 400 mg) 350 mg qd enzymes; pathway (e.g., antihistamines,
32.5 to < 40 kg: potentially sedatives and hypnotics,
400 mg qd teratogenic, QTc cisapride, ergot derivatives,
≥40 kg: 600 mg prolongation (be warfarin, ethinyl estradiol) and
qd or 367 mg/m 2 careful with other several other ARVs (i.e., protease
body surface QT-prolonging inhibitors). Drugs that induce
area medications), false CYP3A4 (e.g., phenobarbital,
Atripla (>40 kg, positives on some rifampin, rifabutin) decrease
adult dose): 1 cannabinoid and efavirenz levels. Clarithromycin
tablet qd benzodiazepine levels decrease with EFV, and
Symfi Lo (>35 tests azithromycin should be
kg, adult dose): 1 considered.
tablet qd Use with caution in female
adolescents with reproductive
potential because of potential
teratogenicity.
Avoid using in individuals with a
history of past or active
psychiatric issues and use with
caution in adolescents and young
adults owing to possible affective
side effects, including increased
suicidality.

Etravirine (ETR, Children <6 yr: Common: nausea, Always administer following a
Intelence): tablet: 25, consult with rash, diarrhea meal for absorption; taking on
100, 200 mg expert Less common: empty stomach decreases
16 to < 20 kg: hypersensitivity absorption by 50%. Tablets can be
100 mg bid reactions dispersed in water
20 to < 25 kg: Inducer of CYP3A4 enzymes and
125 mg bid inhibitor of CYP2C9 and
25 to < 30 kg: CYP2C19, causing multiple
150 mg bid interactions that should be
>30 kg, checked before initiating ETR.
adolescents and Should not be given in
adults: 200 mg combination with TPV, FPV,
bid ATV, or other nonnucleoside
reverse transcriptase inhibitors
Nevirapine High risk Common: skin No food restrictions
(Viramune, NVP): Prophylaxis: rash, headache, Drug interactions: induces hepatic
tablet: 200 mg; 3-dose series for fever, nausea, CYP450A enzymes (including
extended-release high-risk infants abnormal liver CYP3A and CYP2B6) activity
(XR) tablet: 100, >32 wk gestation function tests and decreases protease inhibitor
400 mg; at birth Less common: concentrations (e.g., IND, SQV,
suspension: 10 (including those hepatotoxicity LPV). Should not be given with
mg/mL born to mothers (rarely life- ATV. Reduces ketoconazole
not taking threatening), concentrations (fluconazole
HAART) hypersensitivity should be used as an alternative).
NOTE: DOSES reactions Rifampin decreases nevirapine
ARE A FLAT serum levels. Anticonvulsants and
DOSE, NOT psychotropic drugs using same
PER KG metabolic pathways as NVP
Dosing intervals: should be monitored. Oral
Within 48 hr of contraceptives may also be
birth, 48 hr after affected. XR formulation must be
first dose, 96 hr swallowed whole.
after second dose For children ≤2 yr, some experts
Birth weight 1.5- start with bid dosing without the
2 kg: 8 mg/dose 14 day lead-in of qd dosing.
PO Lead-in dosing decreases
Birth weight >2 occurrence of rash by allowing
kg: 12 mg/dose induction of cytochrome p450
PO metabolizing enzymes.
Treatment
(including
higher risk
prophylaxis
with empiric
therapy):
≥37 wk gestation
at birth:
Birth to age 4
wk: 6
mg/kg/dose bid
THEN
Age >4 wk: 200
mg/m2 /dose bid
34 to <37 wk
gestation at birth:
Birth to age 1
wk: 4
mg/kg/dose bid
Age 1 to 4 wk: 6
mg/kg/dose bid
Age >4 wk: 200
mg/m2 /dose bid
Note dose
adjustment is
optional at 4 wk
for empiric HIV
therapy for high
risk infants with
negative testing
 ≥1 mo to < 8 yr:
200 mg/m2 once
daily for 14 days;
then same dose
bid (max: 200
mg/dose)
≥8 yr: 120-150
mg/m2 once
daily for 14 days;
then bid (max:
200 mg/dose)
Adolescents and
adults: 200 mg
once daily for 14
days; then 200
mg bid
or
XR 400 mg qd
(after 14 day lead
in)
Rilpivirine Pediatric Headache, insomnia, Given with food only, 500 kcal
(Edurant, RPV): patients: consult rash, depression, mood meal. Do not use with proton
tablet: 25 mg with expert changes pump inhibitors; antacids have to
Complera: Adolescents (>12 be spaced from dose by 2 h before
combination of yr and 35 kg) or 4 h after.
RPV, FTC, TDF and adults: 25 Should not be used if viral load >
(25, 200, 300 mg) mg PO qd 100,000 copies/µL or drugs that
Odefsey: Complera or induce CYP3A or with proton
combination of Odefsey: 1 tablet pump inhibitors
FTC, TAF, RPV qd
(25, 200, 25 mg) Juluca (>18 yr):
Juluca: 1 tablet qd; only
combination of for use in adults
RPV, Dolutegravir with ≥6 mo
(DTG) (25, 50 mg) virologic
suppression with
no resistance to
replace current
regimen
PROTEASE INHIBITORS Class adverse effects: Gi side effects, hyperglycemia,
hyperlipidemia (except atazanavir and darunavir), lipodystrophy,
increased transaminases, increased bleeding disorders in
hemophiliacs. Can induce metabolism of ethinyl estradiol; use
alternate contraception (other than estrogen-containing oral
contraceptives). All of these drugs undergo hepatic metabolism,
mostly by CYP3A4, with many drug interactions. Treatment
note: except in rare instances, always administer with boosting
agent (ritonavir [RTV] or cobicistat [COBI]).
Atazanavir Infants and Common: elevation Administer with food to increase
(Reyataz, ATV): children ≥ 3 mo of indirect absorption. Review drug
powder packet: 50 and ≥ 5 kg: bilirubin; headache, interactions before initiating
mg/packet; capsule: 5 to < 15 kg: arthralgia, because ATV inhibits CYP3A4,
150, 200, 300 mg ATV 200 mg (4 depression, CYP1A2, CYP2C9, and UGT1A1
(Note: capsules and packets) + RTV insomnia, nausea, enzymes. Use with caution with
packets are not 80 mg qd vomiting, diarrhea, cardiac conduction disease or
interchangeable) 15 to < 25 kg: paresthesias liver impairment. Combination
Evotaz: ATV 250 mg (5 Less common: with EFV should not be used in
combination of packets) + RTV prolongation of PR treatment-experienced patients
ATV, COBI (300, 80 mg qd interval on because it decreases ATV levels.
150 mg) Note: Capsules electrocardiogram TDF, antacids, H2 -receptor
are not approved (ECG); rash, rarely antagonists, and proton-pump
for < 6 yr or < 15 Stevens-Johnson inhibitors decrease ATV
kg syndrome, diabetes concentrations. Patients taking
Children ≥6 yr mellitus, buffered ddl should take it at least
and ≥15 kg nephrolithiasis 2 hr before ATV
capsule dosing: COBI is a pharmacokinetc
15 to <35 kg: enhancer (boosting agent) used to
200 mg + RTV optimize drug levels; it is not
100 mg interchangeable with ritonavir. It
≥35 kg: 300 mg can alter renal tubular secretion of
+ RTV 100 mg Cr, resulting in elevated Cr with
Adolescents and normal GFR.
adults:
300 mg + RTV
100 mg
Adults (>18 yr):
Evotaz: 1 tablet
qd

Darunavir <3 yr or < 10 kg: Common: diarrhea, DRV should be given with food.
(Prezista, DRV): do not use nausea, vomiting, Contraindicated for concurrent
tablets: 75, 150, 3 to < 12 yr: abdominal pain, therapy with cisapride, ergot
600, 800 mg; 10 to < 11 kg: fatigue, headache alkaloids, benzodiazepines,
suspension: 100 DRV 200 mg + Less common: skin pimozide, or any major CYP3A4
mg/mL RTV 32 mg bid rashes (including substrates. Use with caution in
Prezcobix: 11 to < 12 kg: Stevens-Johnson patients taking strong CYP3A4
combination DRV, DRV 220 mg + syndrome), lipid inhibitors, or moderate/strong
COBI (800, 150 RTV 32 mg bid and liver enzyme CYP3A4 inducers. Adjust dose
mg) 12 to < 13 kg: elevations, with concurrent rifamycin
DRV 240 mg + hyperglycemia, fat therapy.
RTV 40 mg bid maldistribution Contains sulfa moiety: potential
13 to < 14 kg: for cross-sensitivity with
DRV 260 mg + sulfonamide class
RTV 40 mg bid
14 to < 15 kg:
DRV 280 mg +
RTV 48 mg bid
15 to < 30 kg:
DRB 375 mg +
RTV 48 mg bid
30 to < 40 kg:
DRV 450 mg +
RTV 100 mg bid
≥40 kg: DRV
600 mg + RTV
100 mg bid
Adolescents ≥ 40
kg and adults
with no DRV
mutations: DRV
 800 mg + RTV
100 mg qd
Adults (>18 yr)
with no DRV
mutations:
Prezcobix: 1
tablet qd
Adolescents ≥ 40
kg and adults
with DRV
mutation(s):
DRV 600 mg +
RTV 100 mg bid
Fosamprenavir 6 mo to 18 yr: Common: nausea, Should be given with food. FPV is an
(Lexiva, FPV): <11 kg: FPV 45 vomiting, perioral inhibitor of the CYP450 system and
tablet: 700 mg; mg/kg/dose + paresthesias, an inducer, inhibitor, and substrate of
suspension: 50 RTV 7 headache, rash, CYP3A4, which can cause multiple
mg/mL mg/kg/dose bid lipid abnormalities drug interactions. Use with caution in
11 to < 15 kg: Less common: sulfa-allergic individuals.
FPV 30 Stevens-Johnson
mg/kg/dose + syndrome, fat
RTV 3 redistribution,
mg/kg/dose bid neutropenia,
15 to < 20 kg: elevated creatine
FPV 23 kinase,
mg/kg/dose + hyperglycemia,
RTV 3 diabetes mellitus,
mg/kg/dose bid elevated liver
>20 kg: FPV 18 enzymes,
mg/kg/dose angioedema,
(max: 700 mg) + nephrolithiasis
RTV 3
mg/kg/dose
(max: 100 mg)
bid
Adolescents > 18
yr and adults:
FPV 700 mg +
RTV 100 mg bid
or
FPV 1,400 mg +
RTV 200 mg qd
For protease
inhibitor (PI)–
experienced, the
once-daily dose
is not
recommended

Indinavir Not approved for Common: nausea, Reduce dose (600 mg IDV every 8 hr)
(Crixivan, IDV): use in infants or abdominal pain, with mild to moderate liver
capsule: 100, 200, children hyperbilirubinemia, dysfunction. Adequate hydration (at
400 mg Adolescents and headache, least 48 oz fluid/day in adults)
adults: IDV 800 dizziness, lipid necessary to minimize risk of
mg IDV + RTV abnormalities, nephrolithiasis. IDV is cytochrome
(100 mg to 200 nephrolithiasis, P450 3A4 inhibitor and substrate,
 mg) bid metallic taste which can cause multiple drug
Less common: fat interactions: rifampin reduces levels;
redistribution, ketoconazole, ritonavir, and other
hyperglycemia, protease inhibitors increase IDV
diabetes mellitus, levels. Do not coadminister with EFV,
hepatitis, acute astemizole, cisapride, terfenadine
hemolytic anemia
Lopinavir/Ritonavir 14 days to 18 yr: Common: diarrhea, Do not administer before
(Kaletra, LPV/r): LPV 300 mg/m2 headache, nausea postmenstrual age of 42 wk and
tablet: 100/25 mg, /dose + RTV 75 and vomiting, lipid postnatal age of 14 days owing
200/50 mg; mg/m2 /dose bid elevation to potential severe toxicities.
solution: 80/20 mg In treatment Less common: fat No food restrictions but has better
per/mL (contains naive children >1 redistribution, GI tolerability when given with or
42% alcohol, 15% yr a dose of 230 hyperglycemia, after a meal.
propylene glycol) diabetes mellitus, Pills must be swallowed whole.
mg/m2 /dose bid pancreatitis, Oral solution should be given
can be used. hepatitis, PR with high-fat meal to increase
Adolescents (>18
interval absorption. Poor palatability of
yr) and adults:
prolongation oral solution is difficult to mask
LPV 400 mg + with flavorings or foods. Once-
RTV 100 mg bid
daily dosing is poorly tolerated in
or
most children, and plasma
800 mg LPV + concentration variability makes
200 mg RTV qd
qd dosing contraindicated in
If taken with children. Interacts with drugs
NVP, EFV, FPV, using CYP3A4, which can cause
or NFV:
multiple drug interactions
LPV 600 mg +
RTV 150 mg bid
Nelfinavir <2 yr: not Common: diarrhea, Administer with a meal to
(Viracept, NFV): recommended asthenia, optimize absorption; avoid acidic
tablet: 250, 625 mg Children 2-13 yr: abdominal pain, food or drink (e.g., orange juice).
45-55 skin rashes, lipid Tablet can be crushed or
mg/kg/dose bid abnormalities dissolved in water to administer
(max: 1,250 Less common: as a solution.
mg/dose) exacerbation of Nelfinavir inhibits CYP3A4
Adolescents and liver disease, fat activity, which may cause
adults: 1,250 mg redistribution, multiple drug interactions.
bid hyperglycemia, Rifampin, phenobarbital, and
diabetes mellitus, carbamazepine reduce levels.
elevation of liver Ketoconazole, ritonavir, indinavir,
enzymes and other protease inhibitors
increase levels. Do not
coadminister astemizole,
cisapride, terfenadine.
NFV is no longer recommended
for treatment for HIV due to
inferior potency compared to
newer agents and unpredictable
pharmacokinetics particularly in
adolescents.
Ritonavir Only use is to Common: nausea, Administration with food
(Norvir, RTV): enhance other PIs; headache, enhances bioavailability and
capsule: 100 mg; dose varies (see vomiting, reduces gastrointestinal
tablet: 100 mg; information for abdominal pain, symptoms. RTV solution should
 solution: 80 mg/mL specific PI) diarrhea, taste not be refrigerated (store at 20-
(contains 43% aversion, lipid 25°C)
alcohol) abnormalities, RTV is potent inhibitor of
perioral CYP3A4 and CYP2D6 and
paresthesias inducer of CYP3A4 and CYP1A2
Less common: fat that leads to many drug
redistribution, interactions (e.g., protease
hyperglycemia, inhibitors, antiarrhythmics,
diabetes mellitus, antidepressants, cisapride). Use
pancreatitis, cautiously with inhaled steroids
hepatitis, PR (Cushing syndrome has been
interval reported)
prolongation,
allergic reactions
Saquinavir Infants and Common: diarrhea, Administer with a high-fat meal to
(Invirase, SQV): children < 16 yr: abdominal pain, enhance bioavailability. SQV is
capsule: 200 mg; not approved for headache, nausea, metabolized by CYP3A4, which may
tablet: 500 mg use skin rashes, lipid cause many drug interactions:
Adolescents and abnormalities rifampin, phenobarbital, and
adults: SQV Less common: carbamazepine decrease serum levels.
1,000 mg + RTV exacerbation of Saquinavir may decrease metabolism
100 mg bid chronic liver of calcium channel antagonists, azoles
disease, diabetes (e.g., ketoconazole), macrolides.
mellitus, Pretherapy EKG recommended and
pancreatitis, contraindicated in patients with
elevated liver prolonged QT interval.
transaminases, fat
maldistribution,
increase in both QT
and PR in ECG
Tipranavir <2 yr: not Common: diarrhea, No food restrictions. Better tolerated
(Aptivus, TPV): approved nausea, vomiting, with meal. Can inhibit human platelet
capsule: 250 mg; 2-18 yr fatigue, headache, aggregation: use with caution in
solution: 100 (treatment- skin rashes, patients at risk for increased bleeding
mg/mL (contains experienced elevated liver (trauma, surgery, etc.) or in patients
116 IU vitamin only): TPV 375 enzymes, lipid receiving concurrent medications that
E/mL) mg/m2 /dose + abnormalities may increase the risk of bleeding.
RTV 150 mg/m2 Less common: fat TPV is metabolized by CYP3A4,
(max: TPV 500 redistribution, which may cause many drug
mg + RTV 200 hepatitis, interactions. Contraindicated in
mg) bid hyperglycemia, patients with hepatic insufficiency or
or diabetes mellitus, in those receiving concurrent therapy
TPV 14 intracranial with amiodarone, cisapride, ergot
mg/kg/dose + hemorrhage alkaloids, benzodiazepines, pimozide.
RTV 6 TPV contains sulfonamide moiety, and
mg/kg/dose caution should be taken in patients
(max: same) bid with sulfonamide allergy
Adolescents (>18
yr) and adult:
TPV 500 mg +
RTV 200 mg bid
FUSION INHIBITORS
Enfuvirtide <6 yr: not Common: Local Must be given subcutaneously.
(Fuzeon, ENF): approved injection site Severity of reactions increased if
injection: Children ≥6 yr to reactions in 98% given intramuscularly. Apply ice after
 lyophilized powder 16 yr: 2 (e.g., erythema, injection and massage the area to
of 108 mg mg/kg/dose SQ induration nodules, reduce local reactions. Injection sites
reconstituted in 1.1 (max: 90 mg) bid cysts, ecchymoses) should be rotated; recommended sites
mL of sterile water Adolescents (>16 Less common: are upper arm, anterior thigh, or
delivers 90 mg/mL yr) and adults: 90 increased incidence abdomen.
mg SQ bid of bacterial
pneumonia,
hypersensitivity,
fever, nausea,
vomiting, chills,
elevated liver
enzymes,
hypotension,
immune-mediated
reactions (e.g.,
glomerulonephritis,
Guillain-Barré
syndrome,
respiratory distress)
ENTRY INHIBITORS
Maraviroc Neonates/infants: Common: fever, Testing for CCR5-tropic virus
(Selzentry, MVC): not approved upper respiratory required; virus must not have
oral solution: 20 ≥2 yr and ≥ 10 infection–like mixed tropism (i.e.,
mg/mL; tablet: 25, kg: symptoms, rash, CCR5/CXC4) to have efficacy.
75, 150, 300 mg Given with abdominal pain, No food restrictions. MVC is a
CYP3A musculoskeletal CYP3A4 and P-glycoprotein
inhibitors (EVG, symptoms, (Pgp) substrate, which may cause
RTV, PIs except dizziness many drug interactions.
TPV/r): Less common: Tropism assay to exclude the
10 to < 20 kg: 50 cardiovascular presence of CXCR4 HIV is
mg bid abnormalities, required before using MVC.
20 to < 30 kg: 75 cholestatic Caution should be used when
mg bid jaundice, given to patients with hepatic
30 to < 40 kg: rhabdomyolysis, impairment or cardiac disease or
100 mg bid myositis, receiving CYP3A4 or P-
>40 kg: 150 mg osteonecrosis glycoprotein-modulating drugs.
bid
Given with
NRTIs, T-20,
TPV/r, NVP,
RAL, or other
drugs not
affecting
CYP3A:
10 to < 30 kg:
not
recommended
30 to < 40 kg:
300 mg bid
>40 kg: 300 mg
bid
Given with EFV,
ETR: not
recommended
Adolescents > 16
yr and adults:
 150 mg bid if
given with potent
CYP3A inhibitor
(e.g., protease
inhibitor except
TPV)
300 mg bid if
given with not
potent CYP3A4
inhibitors (e.g.,
NRTI, TPV,
NVP, ENF, RAL)
600 mg bid if
given with potent
CYP3A4 inducer
(e.g., EFV, ETR,
rifampin,
phenobarbital)

INTEGRASE INHIBITORS (INSTI)

Bictegravir (BIC) Biktarvy: ≥18 yr Diarrhea, nausea, No food restrictions
Only available as 1 tablet qd; >12 headache Metabolized by UGT1A1 and
Biktarvy: yr to 18 yr and Insomnia, CYP450 (CYP) 3A
combination of >35 kg: headache, No food restrictions.
BIC, TAF, FTC investigational neuropsychiatric UGT1A1 and CYP450 (CYP) 3A
(50, 25, 200 mg) dose 1 tablet qd illness substrate.
Dolutegravir based on limited Rare: rash, Should be taken 2 hr before or 6
(Tivicay, DTG): data hepatotoxicity, hr after taking laxatives,
tablet: 10, 25, 50 Neonates and hypersensitivity sucralfate, iron or calcium
mg infants: not reactions supplements, or buffered
Triumeq: approved medications.
combination of ≥30 to < 40 kg: DTG decreases tubular secretion
ABC, 3TC, DTG 35 mg qd (ARV- of Cr and slightly increases
(600, 300, 50 mg) naïve or INSTI- measured Cr but does not affect
Juluca: naïve) GFR.
combination of >12 yr and ≥ 40
RPV, Dolutegravir kg adolescents
(DTG) (25, 50 mg) and adults: 50
mg qd (INSTI-
naïve)
If taken with
EFV, FPV/RTV,
TPV/RTV, or
rifampin: 50 mg
bid
If INSTI-
experienced with
associated
resistance or
suspected
resistance: 50 mg
bid
Triumeq: 1 tablet
qd (INSTI-naïve,
≥ 40 kg)
Juluca (>18 yr):
 1 tablet qd; only
for use in adults
with ≥6 mo
virologic
suppression with
no resistance to
replace current
regimen
Elvitegravir Genvoya: Not Nausea, diarrhea, Administer with food.
(EVG): only found approved for <25 headache EVG is metabolized by CYP3A4
in 2 coformulated kg. Child and and modestly induces CYP2D6
fixed-dose Adolescent that can cause multiple drug
combination (FDC) (Weighing ≥25 interactions. Cautiously use with
tablets kg; Any Sexual nephrotoxic drugs. Do not use
Stribild: Maturity Rating Stribild or Genvoya with
combination of [SMR]) and ritonavir.
EVG, FTC, TDF, Adult Dose: 1 COBI is a pharmacokinetc
COBI (150, 200, tablet qd enhancer (boosting agent) used to
300, 150 mg) Stribild: Not optimize drug levels; it is not
Genvoya: approved for <35 interchangeable with ritonavir. It
combination of kg. can alter renal tubular secretion of
FTC, TAF, EVG, Adolescent Cr, resulting in elevated Cr with
COBI (200, 10, (Weighing ≥35 normal GFR.
150, 150 mg) kg and SMR 4 or
5) and Adult
Dose: 1 tablet qd
Raltegravir Treatment and Common: nausea, No food restrictions
(Isentress, RAL): high-risk headache, Oral suspension, film-coated
film-coated tablet: prophylaxis dizziness, diarrhea, tablet and chewable tablet are not
400 mg; HD tablet: (empiric fatigue interchangeable; chewable tablets
600 mg chewable therapy) for Less common: and suspension have better oral
tablet: 25, 100 mg neonates: >37 itching, creatine bioavailability than film-coated
(scored); granules wk gestation at phosphokinase tablet; hence, higher-dose film-
for oral suspension: birth and >2 kg elevation, coated tablet can be taken at 25
100 mg suspended (oral myopathy, kg.
in 10 mL of water suspension): rhabdomyolysis, RAL is metabolized by UGT1A1
for final Birth to Age 1 depression, glucuronidation, and inducers of
concentration of 10 wk: hypersensitivity this system (e.g., rifampin, TPV)
mg/mL approximately Rare: rash will reduce RGV levels, whereas
1.5 mg/kg/dose including Stevens- inhibitors of this system (e.g.,
qd Johnson, TEN, ATV) will increase RGV levels.
2 to <3 kg: 4 mg hypersensitivity Do not administer rifampin with
qd reaction once daily raltegravir (HD).
3 to <4 kg: 5 mg Aluminum and magnesium
qd containing antacids should not be
4 to <5 kg: 7 mg co-administered. UGT1A1
qd metabolism is low at birth and
If mother on increases rapidly over first 4-6 wk
raltegravir in 2- of life. No data for preterm
24 h prior to infants.
delivery, delay
first dose 24 to
48 hr after birth.
Start other ART
ASAP.
Age 1-4 wk:
approximately 3
mg/kg/dose bid
2 to <3 kg: 8 mg
bid
3 to <4 kg: 10
mg bid
4 to <5 kg: 15
mg bid
THEN
Infant and
Pediatrics
dosing
(Oral
suspension)
Children aged ≥4
wk and ≥3 kg to
<20 kg:
approximately 6
mg/kg/dose bid
3 to <4 kg: 25
mg bid
4 to <6 kg: 30
mg bid
6 to <8 kg: 40
mg bid
8 to <11 kg: 60
mg bid
11 to <14 kg: 80
mg bid
14 to <20 kg:
100 mg bid
Chewable tablet:
11 to <14 kg: 75
mg bid
14 to <20 kg:
100 mg bid
20 to <28 kg:
150 mg bid
28 to <40 kg:
200 mg bid
≥40 kg: 300 mg
bid
Child or
adolescent ≥ 25
kg and adults:
400 mg film-
coated tablet bid
Child and
Adolescent
Weighing ≥50 kg
(HD tablet):
1200 mg qd (2
tablets)
For treatment-
naive or
 virologically
suppressed
patients on an
initial regimen of
400 mg twice
daily (HD
tablet): 1200 mg
qd (2 tablets)

Antiretroviral drugs often have significant drug–drug interactions, with each other and with other
classes of medicines, which should be reviewed before initiating any new medication.
The information in this table is not all-inclusive. Updated and additional information on dosages,
drug–drug interactions, and toxicities is available on the AIDSinfo website at
http://www.aidsinfo.nih.gov .
Modified from the Guidelines for use of antiretroviral agents in pediatric HIV infection.
http://aidsinfo.nih.gov/contentfiles/pediatricguidelines.pdf .

By targeting different points in the viral life cycle and stages of cell activation
and by delivering drug to all tissue sites, maximal viral suppression is feasible.
Combinations of three drugs consisting of a two-NRTI backbone of (1) a
thymidine analog NRTI (abacavir or zidovudine) or tenofovir and (2) a
nonthymidine analog NRTI (lamivudine or emtricitabine) to suppress replication
in both active and resting cells added to (3) a ritonavir-boosted PI
(lopinavir/ritonavir, atazanavir, or darunavir), an NNRTI (efavirenz or
nevirapine), or an INSTI (raltegravir or dolutegravir) can produce prolonged
suppression of the virus. The use of three drugs from three different classes
generally should be avoided but may be necessary in children with highly
resistant viruses; the drugs in these regimens should only be chosen by an HIV
specialist with pharmacist input. Combination treatment increases the rate of
toxicities (see Table 302.4 ), and complex drug–drug interactions occur among
many of the antiretroviral drugs. Many PIs are inducers or inhibitors of the
cytochrome P450 system and are therefore likely to have serious interactions
with multiple drug classes, including nonsedating antihistamines and
psychotropic, vasoconstrictor, antimycobacterial, cardiovascular, anesthetic,
analgesic, and gastrointestinal drugs (cisapride). Whenever new medications are
added to an antiretroviral treatment regimen, especially a protease inhibitor or
cobicistat containing regimen, a pharmacist and/or HIV specialist should be
consulted to address possible drug interactions. The inhibitory effect of ritonavir
(a PI) on the cytochrome P450 system has been exploited, and small doses of the
drug are added to several other protease inhibitors (e.g., lopinavir, atazanavir,
darunavir) to slow their metabolism by the P450 system and to improve their
pharmacokinetic profile. This strategy provides more effective drug levels with
Table 302.5

Recommendations for PJP Prophylaxis and CD4 Monitoring for HIV-Exposed Infants
and HIV-Infected Children, by Age and HIV Infection Status
AGE/HIV INFECTION PJP PROPHYLAXIS CD4 MONITORING
STATUS
Birth to 4-6 wk, HIV-exposed No prophylaxis None
HIV infection reasonably No prophylaxis None
excluded*
<1 yr, HIV-infected or HIV- Prophylaxis regardless of CD4 According to local practice for initiation or
indeterminate count or percentage follow-up of cART
1-5 yr, HIV-infected Prophylaxis if CD4 < 500 cells/µL According to local practice for initiation or
or < 15% † follow-up of cART
>6 yr, HIV-infected Prophylaxis if CD4 < 200 cells/µL According to local practice for initiation or
or < 15% † ‡ follow-up of cART
* See text.

† More frequent monitoring (e.g., monthly) is recommended for children whose CD4 counts or
percentages are approaching the threshold at which prophylaxis is recommended.
‡ Prophylaxis should be considered on a case-by-case basis for children who might otherwise be
at risk for PJP, such as children with rapidly declining CD4 counts or percentages or children with
category C conditions. Children who have had PJP should receive PJP prophylaxis until their CD4
count is ≥200 cells/mm3 for patients aged ≥6 yr, CD4 percentage is ≥15% or CD4 count is ≥500
cells/mm3 for patients aged 1 to <6 yr for >3 consecutive mo after receiving cART for ≥6 mo.
The National Perinatal HIV Hotline (1-888-448-8765) provides consultation on all aspects of
perinatal HIV care.
cART, combined antiretroviral therapy; PJP, Pneumocystis jiroveci pneumonia.

Table 302.6
Prophylaxis to Prevent First Episode of Opportunistic
Infections Among HIV-Exposed and HIV-Infected Infants
and Children, United States*

PREVENTIVE REGIMEN
PATHOGEN
INDICATION FIRST CHOICE ALTERNATIVE
STRONGLY RECOMMENDED AS STANDARD OF CARE
Pneumocystis HIV-infected or HIV-indeterminate TMP-SMX , 150/750 Dapsone: age ≥
pneumonia † infants aged 1-12 mo; HIV-infected mg/m2 body surface area 1 mo: 2 mg/kg
children aged 1-5 yr with CD4 count per day or 5-10 mg/kg/day (max: 100 mg)
of < 500 cells/µL or CD4 percentage (TMP)/25-50 mg/kg/day orally qd; or 4
of < 15%; HIV-infected children (SMX) (max: 320/1,600 mg/kg (max: 200
aged 6-12 yr with CD4 count of < mg) orally qd or bid 3 times mg) orally once
200 cells/µL or CD4 percentage of < weekly on consecutive days a week
15%; >13 yr with CD4 count <200 or Atovaquone:
 <15% or age 1-3 mo and
qd or bid orally 3 times > 24 mo-12 yr:
weekly on alternate days 30-40 mg/kg
orally qd with
food; age 4-24
mo: 45 mg/kg
orally qd with
food; ≥ 13 yr
1500 mg orally
qd
Aerosolized
pentamidine:
age ≥ 5 yr: 300
mg once a
month by
Respirgard II
(Marquest,
Englewood, CO)
nebulizer

Malaria Living or traveling to area in which Same for HIV-infected and Doxycycline,
malaria is endemic HIV-uninfected children. 2.2 mg/kg body
Refer to weight
http://www.cdc.gov/malaria/ (maximum 100
for the most recent mg) orally qd for
recommendations. children >8 yr
Mefloquine , 5 mg/kg Chloroquine, 5
orally 1 time weekly (max: mg/kg base
250 mg) (equal 7.5 mg/kg
Atovaquone/proguanil chloroquine
(Malarone) qd phosphate)
11-20 kg: 62.5 mg/25 mg (1 orally up to 300
pediatric tablet) mg weekly (only
21-30 kg: 2 pediatric tablets for regions
31-40 kg: 3 pediatric tablets where the
>40 kg: 1 adult tablet parasite is
(250 mg/100 mg) sensitive)
Mycobacterium
tuberculosis
Isoniazid- TST reaction ≥ 5 mm Isoniazid, 10-15 mg/kg Rifampin, 10-20
sensitive or body weight (max: 300 mg) mg/kg body weight
Prior positive TST result without qd for 9 mo (max: 600 mg) orally
treatment or daily for 4-6 mo
or 20-30 mg/kg body weight
Close contact with any person (max: 900 mg) orally 2
who has contagious TB. TB times weekly for 9 mo;
disease must be excluded before DOT highly recommended
start of treatment
Isoniazid- Same as previous pathogen; Rifampin, 10-20 mg/kg body Consult TB expert
resistant increased probability of exposure to weight (max: 600 mg) orally
isoniazid-resistant TB daily for 4-6 mo
Multidrug- Same as previous pathogen; Choice of drugs requires
resistant increased probability of exposure to consultation with public health
(isoniazid and multidrug-resistant TB authorities and depends on
rifampin) susceptibility of isolate from
 source patient
Mycobacterium For children age ≥ 6 yr with CD4 Clarithromycin, 7.5 mg/kg Azithromycin, 5
avium complex ‡ count of < 50 cells/µL; age 2-5 yr (max: 500 mg) orally bid mg/kg body
with CD4 count of < 75 cells/µL; age or weight (max:
1-2 yr with CD4 count of < 500 cells/ Azithromycin, 20 mg/kg 250 mg) orally
µL; age < 1 yr with CD4 count of < (max: 1,200 mg) orally once qd
750 cells/µL a week or
Children age ≥ 5
yr
Rifabutin, 300
mg orally qd
Varicella-zoster Exposure to varicella or shingles Varicella-zoster immunoglobulin If VariZIG is not
virus § with no history of varicella (VariZIG), 125 IU/10 kg (max: available and <
or 625 IU) IM, administered ideally 96 hr from
Zoster or seronegative status for within 96 hr after exposure; exposure,
VZV potential benefit up to 10 days acyclovir 20
or after exposure mg/kg (max: 800
Lack of evidence for age- mg) 4 times a
appropriate vaccination day for 5-7 days
or
IVIG, 400
mg/kg,
administered
once
Vaccine- Standard recommendations for HIV- Routine vaccinations (see Fig.
preventable exposed and HIV-infected children 302.5 )
pathogens
USUALLY RECOMMENDED
Toxoplasma Seropositive IgG to Toxoplasma and TMP-SMX, 150/750 mg/m2 Dapsone, age ≥
gondii ¶ severe immunosuppression: age < 6 orally qd or divided bid 1 mo: 2 mg/kg
yr with CD4 percentage < 15%; age or or 15 mg/m2
≥ 6 yr with CD4 count < 100 cells/µL Same dosage qd 3 times (max: 25 mg)
weekly on consecutive days orally qd
or plus
bid 3 times weekly on Pyrimethamine,
alternate days 1 mg/kg (max:
25 mg) orally qd
plus
Leucovorin, 5
mg orally every
3d
Invasive Hypogammaglobulinemia (i.e., IgG < IVIG 400 mg/kg body weight
bacterial 400 mg/dL) every 2-4 wk
infections
Cytomegalovirus CMV antibody positivity and Valganciclovir, 900 mg orally
severe immunosuppression (CD4 qd with food for older children
count < 50 cells/µL for >6 yr; who can receive adult dosing
CD4 percentage <5% for ≤6 yr)
For children aged 4 mo–16 yr,
valganciclovir oral solution 50
mg/mL at dose in milligrams = 7
× BSA × CrCl (up to maximum
CrCl of 150 mL/min/1.73 m2 )
orally qd with food (maximum
 dose 900 mg/day)
* Information in these guidelines might not represent FDA approval or FDA-approved labeling for

products or indications. Specifically, the terms safe and effective might not be synonymous with
the FDA-defined legal standards for product approval.
† Daily trimethoprim-sulfamethoxazole (TMP-SMX) reduces the frequency of certain bacterial

infections. Compared with weekly dapsone, daily dapsone is associated with a lower incidence of
PCP but higher hematologic toxicity and mortality rates. Patients receiving therapy for
toxoplasmosis with sulfadiazine-pyrimethamine are protected against PCP and do not need TMP-
SMX. TMP-SMX, dapsone-pyrimethamine, and possibly atovaquone (with or without
pyrimethamine), protect against toxoplasmosis; however, data have not been prospectively
collected.
‡
Substantial drug interactions can occur between rifamycins (i.e., rifampin and rifabutin) and
protease inhibitors and nonnucleoside reverse transcriptase inhibitors. A specialist should be
consulted.
§ Children routinely being administered intravenous immunoglobulin (IVIG) should receive VariZIG
if the last dose of IVIG was administered more than 21 days before exposure.
¶ Protection against toxoplasmosis is provided by the preferred anti-Pneumocystis regimens and

possibly by atovaquone.
CMV, cytomegalovirus; FDA, U.S. Food and Drug Administration; HIV, human immunodeficiency
virus; IgG, immunoglobulin G; IM, intramuscularly; IVIG, intravenous immunoglobulin; PCP,
Pneumocystis pneumonia; TB, tuberculosis; TMP-SMX, trimethoprim-sulfamethoxazole; TST,
tuberculin skin test; VZV, varicella-zoster virus.
From Centers for Disease Control and Prevention (CDC): Guidelines for the prevention and
treatment of opportunistic infections among HIV-exposed and HIV-infected children, MMWR
Recomm Rep 58(RR-11):127-128, 2009, Table 1.

Prophylaxis against MAC should be offered to HIV-infected children with

advanced immunosuppression (i.e., CD4 lymphocyte count < 750 cells/µL in
children younger than 1 yr of age, < 500 cells/µL in children 1-2 yr of age, < 75
cells/µL in children 2-5 yr of age, and < 50 cells/µL in children > 6 yr of age)
(see Table 302.6 ). The drugs of choice are azithromycin (20 mg/kg [maximum:
1,200 mg] once a week orally or 5 mg/kg [maximum: 250 mg] once daily orally)
or clarithromycin (7.5 mg/kg bid orally). In rare situations, rifabutin 300 mg qd
can be an alternative for children older than 6 yr of age though efficacy data in
children is very limited.
Based on adult data, primary prophylaxis against most opportunistic infections
may be discontinued if patients have experienced sustained (>6 mo duration)
immune reconstitution with cART, even if they had previous opportunistic
infections such as Pneumocystis pneumonia or disseminated MAC. HIV-infected
children are at higher risk for TB and thus should have tuberculin skin testing (5
tuberculin units purified protein derivation) or interferon gamma release assay
CHAPTER 304

Transmissible Spongiform
Encephalopathies
David M. Asher

The transmissible spongiform encephalopathies (TSEs, prion diseases) are slow

infections of the human nervous system, consisting of at least four diseases of
humans (Table 304.1 ): kuru; Creutzfeldt-Jakob disease (CJD) with its variants—
sporadic CJD (sCJD), familial CJD (fCJD), iatrogenic CJD (iCJD), and new-
variant or variant CJD (vCJD); Gerstmann-Sträussler-Scheinker syndrome
(GSS); and fatal familial insomnia (FFI), or the even more rare sporadic fatal
insomnia syndrome. TSEs also affect animals; the most common and best-
known TSEs of animals are scrapie in sheep, bovine spongiform encephalopathy
(BSE or mad cow disease) in cattle, and a chronic wasting disease (CWD) of
deer, elk, and moose found in parts of the United States, Canada, Norway, and
Finland. All TSEs have similar clinical and histopathologic manifestations, and
all are slow infections with very long asymptomatic incubation periods (often
years), durations of several months or more, and overt disease affecting only the
nervous system. TSEs are relentlessly progressive after illness begins and are
invariably fatal. The most striking neuropathologic change that occurs in each
TSE, to a greater or lesser extent, is spongy degeneration of the cerebral cortical
gray matter.

Table 304.1
Clinical and Epidemiologic Features of Human
Transmissible Spongiform Encephalopathies (Prion
Diseases)

GEOGRAPHIC USEFUL DURATION

CLINICAL SOURCE OF
DISEASE FEATURES INFECTION DISTRIBUTION AND ANCILLARY OF
PREVALENCE TESTS ILLNESS
sCJD Dementia, Unknown Worldwide; ≈1/1 million/yr; 85– EEG— 1-24 mo
myoclonus, 95% of all CJD cases in United PSWCs; CSF (mean: 4-6
ataxia States 14-3-3; mo)
MRI/DWI
fCJD Dementia, Genetic Worldwide—geographic clusters; Gene testing; Mean ≈15
myoclonus, association >100 known families; 5–15% of EEG—PSWC mo
ataxia (PRNP CJD cases rare;
mutations) MRI/DWI (?)
?? Possible
exogenous
source of
infection
iCJD Incoordination, Cadaver dural ≈1% of CJD cases in toto (cadaver 1 mo-10 yr
dementia (late) grafts, human dural grafts), > 100 cases (human
pituitary pituitary hormones), > 100 cases;
hormones, corneal transplantation, 3 cases;
corneal neurosurgical instruments, 6 cases,
transplantation,
including 2 from cortical depth
neurosurgical electrodes; RBC transfusions, 4
instruments, cases of vCJD infection, 3 clinical,
EEG depth 1 preclinical (United Kingdom);
electrodes human plasma–derived factor VIII,
1 preclinical case of vCJD (United
Kingdom)
vCJD Mood and Linked to BSE >230 clinical cases (see iatrogenic Tonsil biopsy 8-36 mo
behavioral in cattle, vCJD, above): none living, May may show (mean 14
abnormalities, transfusion 2017 PrPTSE mo)
paresthesias, plasma MRI/FLAIR
dementia products
Kuru Incoordination, Linked to Fore people of Papua New Guinea EEG—no 3-24 mo
ataxia, tremors, cannibalism (≈2,600 known cases) PSWCs; CSF
dementia (late) 14-3-3 often
negative; MRI
(?)
GSS Incoordination, 90% genetic Worldwide; >50 families; ≈1- PRNP gene 2-12 yr
chronic (PRNP 10/100 million/yr sequencing (mean ≈ 57
progressive mutations) mo)
ataxia,
corticospinal
tract signs,
dementia (late),
myoclonus
(rare)
FFI Disrupted sleep, PRNP ≈27 families in Europe, United EEG— 8 mo to
intractable gene Kingdom, United States, Finland, PSWCs only 6 yr
insomnia; mutation Australia, China, Japan rarely (mean:
autonomic (D 178L); positive; MRI PRNP
hyperactivation; very rare —no DWI 129 MM
myoclonus, sporadic abnormalities; 12 ± 4
ataxia; cases CSF 14-3-3 mo
corticospinal positive in ≈ 129 MV
tract signs; 50% 21 ± 15
dementia mo)
 No case of vCJD has been confirmed in anyone born in the United Kingdom
after 1989. However, examination of resected appendixes in the United Kingdom
for evidence of subclinical infection with prions suggested that about 1 in 2,000
people tested had a detectable accumulation of PrPTSE in lymphoid follicles. It
remains controversial whether those accumulations resulted from subclinical
vCJD or another TSE; none of the subjects to date has presented to medical
attention with overt TSE.
Iatrogenic transmissions of CJD have been recognized for more than 30 yr
(Table 304.2 ). Such accidental transmissions of CJD have been attributed to use
of contaminated neurosurgical instruments (no case reported since 1980) or
operating facilities, use of cortical electrodes contaminated during epilepsy
surgery, injections of human cadaveric pituitary growth hormone and
gonadotropin (no longer marketed in the United States), and transplantation of
contaminated corneas and allografts of human dura mater, still in limited use in
the United States as a surgical patching material. Pharmaceuticals and tissue
grafts derived from or contaminated with human neural tissues, particularly if
obtained from unselected donors and large pools of donors, pose special risks.

Table 304.2
Iatrogenic Transmission of Creutzfeldt-Jakob Disease by
Products of Human Origin

INCUBATION TIME
PRODUCT NO. OF PATIENTS
Mean Range
Cornea 3 17 mo 16-18 mo
Dura mater allograft >100 7.4 yr 1.3-16 yr
Pituitary extract
Growth hormone >100* 12 yr 5-38.5 yr
Gonadotropin 4 13 yr 12-16 yr
Red blood cells 4 ? 6 yr 6.3-8.5 yr †
Plasma-derived coagulation factor VIII 1 ? > 11 yr ‡
* There have been 28 cases reported among approximately 8,000 recipients of human cadaveric
growth hormone in the United States; the remaining cases have been reported in other countries.
† The second transfusion-transmitted case of vCJD (Peden AH, Head MW, Ritchie DL, et al:
Preclinical vCJD after blood transfusion in a PRNP codon 129 heterozygous patient, Lancet
364:527-529, 2004) died of unrelated causes about 5 yr after transfusion but was found to have
accumulations of abnormal PrP in the spleen and cervical lymph node—a finding unique to vCJD
and interpreted as probable preclinical infection.
‡ The diagnosis of vCJD infection attributed to treatment with human plasma–derived coagulation
Clinical Manifestations
Kuru, no longer seen, is a progressive degenerative disease of the cerebellum
and brainstem with less obvious involvement of the cerebral cortex. The first
sign of kuru was usually cerebellar ataxia followed by progressive
incoordination. Coarse, shivering tremors were characteristic. Variable
abnormalities in cranial nerve function appeared, frequently with impairment in
conjugate gaze and swallowing. Patients died of inanition and pneumonia or of
burns from cooking fires, usually within 1 yr after onset. Although changes in
mentation were common, there was no frank dementia or progression to coma,
as in CJD. There were no signs of acute encephalitis, such as fever, headaches,
and convulsions.
CJD occurs throughout the world. Patients initially have either sensory
disturbances (most often visual) or confusion and inappropriate behavior,
progressing over weeks or months to frank dementia, akinetic mutism, and,
ultimately, coma. Some patients have cerebellar ataxia early in the disease, and
most patients experience myoclonic jerking movements. The mean survival time
of patients with sCJD has been < 1 yr from the earliest signs of illness, although
approximately 10% live for 2 yr. Variant CJD (Table 304.3 ) differs from the
more common sCJD; patients with vCJD are much younger at onset (as young as
12 yr) and more often present with complaints of dysesthesia and subtle
behavioral changes, often mistaken for psychiatric illness. Severe mental
deterioration occurs later in the course of vCJD. Patients with vCJD have
survived substantially longer than those with sCJD. Attempts have been made to
subclassify cases of CJD based on the electrophoretic differences in PrPTSE and
variation in its sensitivity to digestion with the proteolytic enzyme proteinase
(PK); the different variants are said to have somewhat different clinical features,
including the duration of illness, though all are ultimately fatal.

Table 304.3

Clinical and Histopathologic Features of Patients With Variant and Typical Sporadic
Creutzfeldt-Jakob Disease
SPORADIC CJD
FEATURE VARIANT CJD (FIRST 10 PATIENTS)
(185 PATIENTS)
Years of age at 29 (19-74) 65
death* (range)
Duration of 12 (8-23) 4
illness, mo
 (range)
Presenting Abnormal behavior, dysesthesia Dementia
signs
Later signs Dementia, ataxia, myoclonus Ataxia, myoclonus
Periodic Rare Most
complexes on
EEG
PRNP 129 All tested (except one transfusion-transmitted case, one plasma- 83%
Met/Met derivative transmitted case; one possible clinical case in United
Kingdom where no tissue was available to confirm)
Histopathologic Vacuolation, neuronal loss, astrocytosis, plaques (100%) Vacuolation, neuronal
changes loss, astrocytosis,
plaques (≤15%)
Florid PrP 100% 0
plaques †
PrPTSE BSE-like ‡ Not BSE-like
glycosylation
pattern
* Median age and duration for variant CJD; averages for typical sporadic CJD.

† Dense plaques with a pale periphery of surrounding vacuolated cells.

‡ Characterized by an excess of high-molecular-mass band (diglycosylated) and 19-kDa

nonglycosylated band glycoform of PrP-res (Collinge J, Sidle KC, Meads J, et al: Molecular
analysis of prion strain variation and the aetiology of “new variant” CJD, Nature 383:685-690,
1996).
BSE, bovine spongiform encephalopathy; CJD, Creutzfeldt-Jakob disease; EEG,
electroencephalogram; Met, codon 129 of one PRNP gene encoding for methionine; PRNP , prion
protein–encoding gene; PrP, prion protein.
Modified from Will RG, Ironside JW, Zeidler M, et al: A new variant of Creutzfeldt-Jakob disease in
the UK, Lancet 347:921-925, 1996.

GSS is a familial disease resembling CJD but with more prominent cerebellar
ataxia and amyloid plaques. Dementia may appear only late in the course, and
the average duration of illness is longer than typical sCJD. Progressively severe
insomnia and dysautonomia, as well as ataxia, myoclonus, and other signs
resembling those of CJD and GSS, characterize FFI and sporadic fatal insomnia.
A case of sporadic fatal insomnia has been described in a young adolescent.
GSS has not been diagnosed in children or adolescents.
A novel prion disease has been reported that is expressed in several
generations with an autosomal dominant pattern associated with a unique
mutation in the PRNP gene. The affected persons were middle-aged with a
history of chronic diarrhea for years plus autonomic neuropathy and modest
mental impairment but without full-blown dementia; PK-resistant PrP deposits
with amyloid properties occurred in the brain, lymphoid tissues, kidney, spleen,
and intestinal tract. The disease was not successfully transmitted to three lines of
CHAPTER 305

Principles of Antiparasitic Therapy

Beth K. Thielen, Mark R. Schleiss

Parasites are divided into three main groups taxonomically: protozoans, which
are unicellular, and helminths and ectoparasites, which are multicellular.
Chemotherapeutic agents appropriate for one group may not be appropriate for
the others, and not all drugs are readily available (Table 305.1 ). Some drugs are
not available in the United States, and some are available only from the
manufacturer, specialized compounding pharmacies, or the Centers for Disease
Control and Prevention (CDC). Information on the availability of drugs and
expert guidance in management can be obtained by contacting the CDC Parasitic
Diseases Branch (1-404-718-4745; e-mail [email protected] (M-F, 8 AM -4 PM ,
Eastern time). For assistance in the management of malaria, healthcare providers
should call the CDC Malaria Hotline: 1-770-488-7788 or 1-855-856-4713 toll-
free (M-F, 9 AM -5 PM , Eastern time). For all emergency consultations after
hours, clinicians can contact the CDC Emergency Operations Center at 1-770-
488-7100 and request to speak with a CDC Malaria Branch clinician or on-call
parasitic diseases physician. Some antiparasitic drugs are not licensed for use in
the United States but can be obtained as investigational new drugs (INDs) from
the CDC; providers should call the CDC Drug Service, Division of Scientific
Resources and Division of Global Migration and Quarantine, at 1-404-639-3670.

Table 305.1
Drugs for Parasitic Infections
Parasitic infections are found throughout the world. With increasing travel, immigration, use of
immunosuppressive drugs, and the spread of HIV, physicians anywhere may see infections caused by previously
unfamiliar parasites. The table below lists first-choice and alternative drugs for most parasitic infections.
INFECTION DRUG ADULT DOSAGE PEDIATRIC DOSAGE
Acanthamoeba keratitis
Drug of choice: See footnote 1
Amebiasis (Entamoeba histolytica)
Asymptomatic infection
Drug of choice: Iodoquinol (Yodoxin) 2 650 mg PO tid × 20 days 30-40 mg/kg/day (max
1950 mg) in 3 doses PO ×
20 days
or Paromomycin 25-35 mg/kg/day PO in 3 doses × 25-35 mg/kg/day PO in 3
7 days doses × 7 days
Alternative: Diloxanide furoate 3 500 mg tid PO × 10 days 20 mg/kg/day PO in 3
doses × 10 days
Mild to moderate intestinal disease
Drug of choice: Metronidazole 500-750 mg tid PO × 7-10 days 35-50 mg/kg/day PO in 3
doses × 7-10 days
or Tinidazole 4 2 g PO once daily × 3 days 50 mg/kg/day PO (max 2 g)
in 1 dose × 3 days
Either followed by: Iodoquinol 2 650 mg PO tid × 20 days 30-40 mg/kg/day PO in 3
doses × 20 days (max 2 g)
or Paromomycin 25-35 mg/kg/day PO in 3 doses × 25-35 mg/kg/day PO in 3
7 days doses × 7 days
Alternative: Nitazoxanide 5 500 mg bid × 3 days 1-3 yr: 100 mg bid × 3 days
4-11 yr: 100 mg bid × 3
days
12+ yr: use adult dosing
Severe intestinal and extraintestinal disease
Drug of choice: Metronidazole 750 mg PO tid × 7-10 days 35-50 mg/kg/day PO in 3
doses × 7-10 days
or Tinidazole 4 2 g PO once daily × 5 days 50 mg/kg/day PO (max 2 g)
× 5 days
Either followed by: Iodoquinol 2 650 mg PO tid × 20 days 30-40 mg/kg/day PO in 3
doses × 20 days (max 2 g)
or Paromomycin 25-35 mg/kg/day PO in 3 doses × 25-35 mg/kg/day PO in 3
7 days doses × 7 days
Amebic meningoencephalitis, primary and granulomatous
Naegleria fowleri
Drug of choice: Amphotericin B 1.5 mg/kg/day IV in 2 divided 1.5 mg/kg/day IV in 2
deoxycholate 6 , 7 doses × 3 days, then 1 mg/kg divided doses × 3 days,
daily IV × 11 days then 1 mg/kg daily IV × 11
days
plus Amphotericin B 1.5 mg/kg intrathecally daily × 2 1.5 mg/kg intrathecally
deoxycholate 6 , 7 days, then 1 mg/kg intrathecally daily × 2 days, then 1
every other day × 8 days mg/kg intrathecally every
other day × 8 days
plus Rifampin 7 10 mg/kg (max 600 mg) IV or PO 10 mg/kg (max 600 mg) IV
daily × 28 days or PO daily × 28 days
plus Fluconazole 7 10 mg/kg (max 600 mg) IV or PO 10 mg/kg (max 600 mg) IV
daily × 28 days or PO daily × 28 days
plus Azithromycin 7 500 mg IV or PO daily × 28 days 10 mg/kg (max 500 mg) IV
or PO daily × 28 days
plus Miltefosine 6 , 7 , 8 50 mg PO tid × 28 days <45 kg: 50 mg bid (max 2.5
mg/kg) × 28 days
≥45 kg: use adult dosing
plus Dexamethasone 0.6 mg/kg/day IV in 4 divided 0.6 mg/kg/day IV in 4
doses × 4 days divided doses × 4 days
Acanthamoeba
Drug of choice: See footnotes 7 , 8
Balamuthia mandrillaris
Drug of choice: See footnotes 7 , 9a , 9b
Sappinia diploidea
Drug of choice: See footnote 10
Ancylostoma caninum (eosinophilic enterocolitis)
Drug of choice: Albendazole 7 400 mg PO once <10 kg/2 yr: 11
≥2 yr: see adult dosing
or Mebendazole 100 mg PO bid × 3 days 100 mg PO bid × 3 days 12
or Pyrantel pamoate (OTC) 7 11 mg/kg PO (max 1 g) × 3 days 11 mg/kg PO (max 1 g) × 3
days
or Endoscopic removal
Ancylostoma duodenale, see Hookworm
Angiostrongyliasis (Angiostrongylus cantonensis, Angiostrongylus costaricensis)
Drug of choice: See footnote 13
Anisakiasis (Anisakis spp.)
Treatment of Surgical or endoscopic removal
choice:
Alternative: Albendazole 7 , 14 400 mg PO bid × 6-21 days <10 kg/2 yr: 11
≥2 yr: see adult dosing
Ascariasis (Ascaris lumbricoides, roundworm)
Drug of choice: Albendazole 7 400 mg PO once <10 kg/2 yr: see adult
dosing 11
≥2 yr: see adult dosing
or Mebendazole 100 mg PO bid × 3 days or 500 100 mg PO bid × 3 days or
mg PO once 500 mg PO once 12
or Ivermectin 7 150-200 µg/kg PO once <15 kg: not indicated
≥15 kg: see adult dosing
Babesiosis (Babesia microti)
Drugs of choice: 15 Atovaquone 7 750 mg PO bid × 7-10 days 20 mg/kg (max 750 mg) PO
bid × 7-10 days
plus Azithromycin 7 500-1000 mg once, then 250 mg 10 mg/kg PO on day 1
daily × 7-10 days. Higher doses (max 500 mg/dose), then 5
(600-1000 mg) and/or prolonged mg/kg/day (max 250
therapy (6 wk or longer) may be mg/dose) PO on days 2-10
required for immunocompromised
patients.
or Clindamycin 7 300-600 mg IV qid or 600 mg tid 20-40 mg/kg/day IV or PO
PO × 7-10 days in 3 or 4 doses × 7-10 days
(max 600 mg/dose)
plus Quinine 7 648 mg tid PO × 7-10 days 10 mg/kg (max 648 mg) PO
tid × 7-10 days
Balamuthia mandrillaris, see Amebic meningoencephalitis, primary
Balantidiasis (Balantidium coli)
Drug of choice: Tetracycline 7 , 16 500 mg PO qid × 10 days <8 yr: not indicated
≥8 yr: 10 mg/kg (max 500
mg) PO qid × 10 days
Alternative: Metronidazole 7 750 mg PO tid × 5 days 35-50 mg/kg/day PO in 3
divided doses × 5 days
or Iodoquinol 2 , 7 650 mg PO tid × 20 days 30-40 mg/kg/day (max 2 g)
PO in 3 divided doses × 20
days
or 500 mg PO bid × 3 days 1-3 yr: 100 mg PO bid × 3
 Nitazoxanide 4 , 7 days

4-11 yr: 200 mg PO bid × 3

days
12+ yr: see adult dosing
Baylisascariasis (Baylisascaris procyonis)
Drug of choice: Albendazole 7 , 17 400 mg PO BID × 10-20 days <10 kg/2 yr: 25-50
mg/kg/day PO in 1-2
divided doses × 10-20 days
11
≥2 yr: 25-50 mg/kg/day PO
in 1-2 divided doses × 10-
20 days
Blastocystis hominis infection
Drug of choice: See footnote 18
Capillariasis (Capillaria philippinensis)
Drug of choice: Mebendazole 7 200 mg PO bid × 20 days 200 mg PO bid × 20 days 12
Alternative: Albendazole 7 400 mg PO daily × 10 days <10 kg/2 yr: 11
≥2 yr: see adult dosing
Chagas disease, see Trypanosomiasis
Clonorchis sinensis, see Fluke infection
Cryptosporidiosis (Cryptosporidium parvum)
Immunocompetent
Drug of choice: Nitazoxanide 4 500 mg PO bid × 3 days 1-3 yr: 100 mg PO bid × 3
days
4-11 yr: 200 mg PO bid × 3
days
12+ yr: see adult dosing
HIV infected
Drug of choice: See footnote 19
Cutaneous larva migrans (Ancylostoma braziliense, A. caninum, dog and cat hookworm, creeping eruption)
Drug of choice: Albendazole 7 , 20 400 mg PO daily × 3-7 days <10 kg/2 yr: 200 mg PO
daily × 3 days 11
≥2 yr: see adult dosing
or Ivermectin 7 200 µg/kg PO daily × 1-2 days <15 kg: not indicated
≥15 kg: see adult dosing
Alternative: Thiabendazole Apply topically tid × 7 days Apply topically tid × 7 days
Cyclosporiasis (Cyclospora cayetanensis)
Drug of choice: Trimethoprim- TMP 160 mg/SMX 800 mg (1 DS 4-5 mg/kg TMP component
sulfamethoxazole (TMP- tab) PO bid × 7-10 days (max 160 mg) PO bid × 7-
SMX) 7 , 21 10 days
Cysticercosis, see Tapeworm infection
Cystoisosporiasis (Cystoisospora belli, formerly known as Isospora)
Drug of choice: Trimethoprim- TMP 160 mg/SMX 800 mg (1 DS 4-5 mg/kg TMP component
sulfamethoxazole (TMP- tablet) PO bid × 10 days (max 160 mg) PO bid × 10
SMX) 7 days
Alternative: Pyrimethamine 50-75 mg PO divided bid × 10 —
days
plus Leukovorin 10-25 mg PO daily × 10 days —
or Ciprofloxacin 7 500 mg PO bid × 7-10 days —
Dientamoeba fragilis infection 22
Paromomycin 7 25-35 mg/kg/day PO in 3 doses × 25-35 mg/kg/day PO in 3
 7 days divided doses × 7 days
or Iodoquinol 2 650 mg PO tid × 20 days 30-40 mg/kg/day PO (max
2 g) in 3 divided doses × 20
days
or Metronidazole 7 500-750 mg tid × 10 days 35-50 mg/kg/day in 3
divided doses × 10 days
Diphyllobothrium latum, see Tapeworm infection
Dracunculus medinensis (guinea worm) infection
Treatment of Slow mechanical extraction of worm 23
choice:
Echinococcus, see Tapeworm infection
Entamoeba histolytica, see Amebiasis
Enterobius vermicularis (pinworm) infection 24
Drug of choice: Albendazole 7 400 mg PO once; repeat in 2 wk <10 kg/2 yr: 200 mg PO
once; repeat in 2 wk 11
≥2 yr: see adult dosing
or Mebendazole 100 mg PO once; repeat in 3 wk 100 mg PO once; repeat in
3 wk 12
or Pyrantel pamoate (OTC) 11 mg/kg base PO once (max 1 11 mg/kg base PO once
g); repeat in 2 wk (max 1 g); repeat in 2 wk
Fasciola hepatica, see Fluke infection
Filariasis 25
Lymphatic filariasis (Wuchereria bancrofti, Brugia malayi, Brugia timori)
Drug of choice: 26 Diethylcarbamazine 27 , 28 6 mg/kg once or 6 mg/kg PO in 3 <18 mo: no indication
divided doses × 12 days 29 ≥18 mo: see adult dosing
Loa loa
<8,000 microfilaria/mL 28
Drug of choice: Diethylcarbamazine 27 , 28 9 mg/kg PO in 3 doses × 14 days <18 mo: no indication
29 ≥18 mo: see adult dosing
Alternative: Albendazole 27 200 mg PO bid × 21 days <10 kg/2 yr: 11
≥2 yr: see adult dosing
≥8,000 microfilaria/mL 28 , 30
Treatment of Apheresis
choice:
or Albendazole 27 200 mg PO bid × 21 days <10 kg/2 yr: 11
≥2 yr: see adult dosing
Either followed by: Diethylcarbamazine 27 , 28 8-10 mg/kg PO in 3 doses × 21 <18 mo: no indication
days 29 ≥18 mo: see adult dosing
Mansonella ozzardi
Drug of choice: See footnote 31
Mansonella perstans
Drug of choice: Doxycycline 7 , 16 , 32 100 mg bid PO × 6 wk 4 mg/kg/day in 2 doses PO
× 6 wk
Mansonella streptocerca 33
Drug of choice: Diethylcarbamazine 6 mg/kg/day PO × 14 days 6 mg/kg/day PO × 14 days
or Ivermectin 7 150 µg/kg PO once <15 kg: not indicated
≥15 kg: see adult dosing
Tropical pulmonary eosinophilia (TPE) 34

Drug of choice: Diethylcarbamazine 27 6 mg/kg once or 6 mg/kg PO in 3 <18 mo: no indication

divided doses × 14-21 days 26 ≥18 mo: see adult dosing
Onchocerca volvulus (river blindness)
Drug of choice: Ivermectin 35 150 µg/kg PO once, repeated <15 kg: not indicated
every 6-12 mo until asymptomatic ≥15 kg: see adult dosing
Fluke, hermaphroditic, infection
Clonorchis sinensis (Chinese liver fluke)
Drug of choice: Praziquantel 25 mg/kg PO tid × 2 days 25 mg/kg PO tid × 2 days
36
or Albendazole 7 10 mg/kg PO × 7 days <10 kg/2 yr: 11
≥2 yr: see adult dosing
Fasciola hepatica (sheep liver fluke)
Drug of choice: Triclabendazole 7 , 37 , 38 10 mg/kg PO once or twice 10 mg/kg PO once or twice
Alternative: Nitazoxanide 7 500 mg PO bid × 7 days 1-3 yr: 100 mg PO bid
4-11 yr: 200 mg PO bid
≥12 yr: see adult dosing
or Bithionol 3 , 7 30-50 mg/kg PO on alternate days 30-50 mg/kg PO on
× 10-15 doses alternate days × 10-15
doses
Fasciolopsis buski, Heterophyes heterophyes, Metagonimus yokogawai (intestinal flukes)
Drug of choice: Praziquantel 7 25 mg/kg PO tid × 1 day 25 mg/kg PO tid × 1 day 36
Metorchis conjunctus (North American liver fluke) 39

Drug of choice: Praziquantel 7 25 mg/kg PO tid × 1 day 25 mg/kg PO tid × 1 day 36

Nanophyetus salmincola
Drug of choice: Praziquantel 7 20 mg/kg PO tid × 1 day 20 mg/kg PO tid × 1 day 36
Opisthorchis viverrini (Southeast Asian liver fluke), O. felineus (cat liver fluke)
Drug of choice: Praziquantel 25 mg/kg PO tid × 2 days 25 mg/kg PO tid × 2 days
36
or Albendazole 7 10 mg/kg PO × 7 days <10 kg/2 yr: 11
≥2 yr: see adult dosing
Paragonimus westermani (lung fluke)
Drug of choice: Praziquantel 7 25 mg/kg PO tid × 2 days 25 mg/kg PO tid × 2 days
36
or Triclabendazole 7 , 40 10 mg/kg PO bid × 1 day or 5 10 mg/kg PO bid × 1 day or
mg/kg daily × 3 days 5 mg/kg daily × 3 days
or Bithionol 3 , 7 30-50 mg/kg PO on alternate days 30-50 mg/kg PO on
× 10-15 doses alternate days × 10-15
doses
Giardiasis (Giardia intestinalis, also known as G. duodenalis or G. lamblia)
Drug of choice: Metronidazole 7 250 mg PO tid × 5 days 5 mg/kg (max 250 mg) PO
tid × 5 days
or Nitazoxanide 5 500 mg PO bid × 3 days 1-3 yr: 100 mg PO every 12
hr × 3 days
4-11 yr: 200 mg PO every
12 hr × 3 days
12+ yr: see adult dosing
or Tinidazole 4 2 g PO once 50 mg/kg PO once (max 2
g)
Alternative: 41 Paromomycin 7 , 42 25-35 mg/kg/day PO in 3 doses × 25-35 mg/kg/day PO in 3
7 days doses × 7 days
or Furazolidone 3 100 mg PO qid × 7-10 days 6 mg/kg/day PO in 4 doses
× 7-10 days
or Quinacrine 2 100 mg PO tid × 5 days 2 mg/kg tid PO × 5 days
(max 300 mg/day)
Gnathostomiasis (Gnathostoma spinigerum)
Treatment of Albendazole 7 400 mg PO bid × 21 days <10 kg/2 yr: 11
choice: 43
≥2 yr: see adult dosing
or Ivermectin 7 200 µg/kg/day PO × 2 days <15 kg: not indicated
≥15 kg: see adult dosing
± Surgical removal
Gongylonemiasis (Gongylonema sp.) 44
Treatment of Surgical removal
choice:
or Albendazole 7 400 mg PO daily × 3 days 10 mg/kg/day PO × 3 days
Hookworm infection (Ancylostoma duodenale, Necator americanus)
Drug of choice: Albendazole 7 400 mg PO once <10 kg/2 yr: 11
≥2 yr: see adult dosing
or Mebendazole 100 mg PO bid × 3 days or 500 100 mg PO bid × 3 days or
mg once 500 mg once 12
or Pyrantel pamoate (OTC) 7 11 mg/kg (max 1 g) PO × 3 days 11 mg/kg (max 1 g) PO × 3
days
Hydatid cyst, see Tapeworm infection
Hymenolepis nana, see Tapeworm infection
Leishmania infection 45
Visceral 46
Drug of choice: Liposomal amphotericin B 3 mg/kg/day IV on days 1-5, 14, 3 mg/kg/day IV on days 1-
(AmBisome) 47 , 48 and 21 (total dose 21 mg/kg) 5, 14, and 21 (total dose 21
mg/kg)
or Miltefosine 49 30-44 kg: 50 mg PO bid × 28 <12 yr: 2.5 mg/kg daily ×
days 28 days 7
≥45 kg: 50 mg PO tid × 28 days 12 yr: see adult dosing
or Sodium stibogluconate 20 mg/kg/day IV or IM × 28 days 20 mg/kg/day IV or IM ×
(Pentostam) 27 , 50 28 days
or Amphotericin B 1 mg/kg IV daily or every 2 days 1 mg/kg IV daily or every 2
deoxycholate 7 for 15-20 doses days for 15-20 doses
Alternative: Meglumine antimoniate 3 , 20 mg pentavalent 20 mg pentavalent
50 antimony/kg/day IV or IM × 28 antimony/kg/day IV or IM
days × 28 days
or Pentamidine 7 4 mg/kg IV or IM daily or every 2 4 mg/kg IV or IM daily or
days for 15-30 doses every 2 days for 15-30
doses
Cutaneous 51 , 52
Drug of choice: Sodium stibogluconate 27 , 20 mg/kg/day IV or IM × 20 days 20 mg/kg/day IV or IM ×
50 20 days
or Liposomal amphotericin B 3 mg/kg/day IV on days 1-5 and 3 mg/kg/day IV on days 1-5
(AmBisome) 7 10 or 1-7 (total dose 18-21 and 10 or 1-7 (total dose
mg/kg) 18-21 mg/kg)
or Amphotericin B 0.5-1 mg/kg IV daily or every 2 0.5-1 mg/kg IV daily or
deoxycholate 7 days (total dose 15-30 mg/kg) every 2 days (total dose 15-
30 mg/kg)
or Miltefosine 49 30-44 kg: 50 mg PO bid × 28 <12 yr: 2.5 mg/kg daily ×
days 28 days 7
≥45 kg: 50 mg PO tid × 28 days 12 yr: see adult dosing
Alternatives: Meglumine antimoniate 20 mg pentavalent 20 mg pentavalent
3,50 antimony/kg/day IV or IM × 20 antimony/kg/day IV or IM
 days × 20 days
or Pentamidine 7 , 53 3-4 mg/kg IV or IM every 2 days 2-3 mg/kg IV or IM daily
× 3-4 doses or every 2 days × 4-7 doses
or Paromomycin 7 , 54 Topically 2×/day × 10-20 days Topically 2×/day × 10-20
days
or Ketoconazole 7 600 mg daily × 28 days
or Fluconazole 7 200 mg daily × 6 wk
or Local therapy, including cryotherapy, thermotherapy, intralesional SbV , topical
paromomycin, photodynamic or laser therapy
Mucosal 54, 55
Drug of choice: Sodium stibogluconate 27 , 20 mg/kg/day IV or IM × 28 days 20 mg/kg/day IV or IM ×
50 28 days
or Liposomal amphotericin B 3 mg/kg/day IV × 10 days or 4 2-4 mg/kg/day IV × 10
(AmBisome) 7 mg/kg on days 1-5, 10, 17, 24, 31, days or 4 mg/kg on days 1-
and 38 (total dose 20-60 mg/kg) 5, 10, 17, 24, 31, and 38
(total dose 20-60 mg/kg)
or Amphotericin B 0.5-1 mg/kg IV daily or every 2 0.5-1 mg/kg IV daily or
deoxycholate 7 days (total dose 20-45 mg/kg) every 2 days (total dose 20-
45 mg/kg)
or Miltefosine 49 30-44 kg: 50 mg PO bid × 28 <12 yr: 2.5 mg/kg daily ×
days 28 days 7
≥45 kg: 50 mg PO tid × 28 days 12 yr: see adult dosing
Alternative: Meglumine antimoniate 3 , 20 mg pentavalent 20 mg pentavalent
50 antimony/kg/day IV or IM × 28 antimony/kg/day IV or IM
days × 28 days
Lice (head and body) infestation (Pediculus humanus capitis, Pediculus humanus humanus)
Drug of choice: 0.5% Malathion (Ovide) 56 Topically 2x, 1 wk apart Topically 2x, 1 wk apart,
approved for ≥ 6 yr
or 1% Permethrin (Nix) Topically 2x, 1 wk apart Topically 2x, 1 wk apart,
(OTC) 56 approved for ≥ 2 mo
or Pyrethrins with piperonyl Topically 2x, 1 wk apart Topically 2x, 1 wk,
butoxide (A-200, Pronto, approved for ≥ 2 yr
R&C, Rid, Triple X)
(OTC) 57
or 0.5% Ivermectin lotion Topically, once Topically once, approved
(Sklice) for ≥ 6 mo
or 0.9% Spinosad suspension Topically once, 2nd dose in 1 wk Topically once, 2nd dose in
(Natroba) if live adult lice seen 1 wk if live adult lice seen,
approved for ≥ 6 mo
or Ivermectin
7 , 58 200-400 µg/kg PO 2x, 1 wk apart <15 kg: not indicated
≥15 kg: see adult dosing
or 5% Benzyl alcohol lotion Topically 2x, 1 wk apart Topically 2x, 1 wk apart
(Ulesfia)
Lice (pubic) infestation (Phthirus pubis) 59
Drug of choice: 1% Permethrin (Nix) Topically 2x, 1 wk apart Topically 2x, 1 wk apart,
(OTC) 56 approved for ≥ 2 mo
or Pyrethrins with piperonyl Topically 2x, 1 wk apart Topically 2x, 1 wk apart,
butoxide (A-200, Pronto, approved for ≥ 2 yr
R&C, Rid, Triple X)
(OTC) 52
or 0.5% Malathion (Ovide) 56 Topically 2x, 1 wk apart Topically 2x, 1 wk apart,
approved for ≥ 6 yr
or 0.5% Ivermectin lotion Topically, once Topically once, approved
(Sklice) for ≥ 6 mo
or Ivermectin 7 , 58 200-400 µg/kg PO 2x, 1 wk apart <15 kg: not indicated
≥15 kg: see adult dosing
Loa loa, see Filariasis
Malaria (Plasmodium falciparum, Plasmodium ovale, Plasmodium vivax, and Plasmodium malariae)
Treatment
Uncomplicated infection due to P. falciparum or species not identified acquired in areas of chloroquine
resistance or unknown resistance 60
Drug of choice: 61 Atovaquone/proguanil 4 adult tablets PO once daily or 2 <5 kg: not indicated
(Malarone) adult tablets PO bid × 3 days 63 5-8 kg: 2 pediatric tablets
Adult tablets: 50 mg PO daily × 3 days
atovaquone/100 mg 9-10 kg: 3 pediatric tablets
proguanil PO daily × 3 days
Pediatric tablets: 62.5 11-20 kg: 1 adult tablet PO
mg atovaquone/25 mg daily × 3 days
proguanil 62 21-30 kg: 2 adult tablets PO
daily × 3 days
31-40 kg: 3 adult tablets PO
daily × 3 days
>40 kg: 4 adult tablets PO
daily × 3 days
or Coartem (artemether- 4 tablets per dose. A 3- day 5 to < 15 kg: 1 tablet PO
lumefantrine) treatment schedule with a total of per dose
Fixed dose of 20 mg 6 oral doses is recommended for 15 to < 25 kg: 2 tablets PO
artemether and 120 both adult and pediatric patients per dose
mg lumefantrine per based on weight. These 6 doses 25 to < 35 kg: 3 tablets per
tablet should be administered over 3 dose
days at 0, 8, 24, 36, 48, and 60 h5. ≥35 kg: 4 tablets PO per
dose
or Quinine sulfate 648 mg salt PO tid × 3-7 days 63 10 mg salt/kg PO tid × 3-7
days 64
plus Doxycycline 7 , 16 100 mg PO bid × 7 days 4 mg/kg/day PO in 2 doses
× 7 days
or plus Tetracycline 7
, 16 250 mg PO qid × 7 days 6.25 mg/kg PO qid × 7 days
or plus Clindamycin
7 , 65 20 mg/kg/day PO in 3 divided 20 mg/kg/day PO in 3
doses × 7 days 66 doses × 7 days
Alternative: Mefloquine 67 , 68 750 mg PO followed 12 hr later 15 mg/kg PO followed 12
by 500 mg hr later by 10 mg/kg
Uncomplicated infection due to P. falciparum or species not identified acquired in areas of chloroquine
sensitivity or uncomplicated P. malariae or P. knowlesi
Drug of choice: Chloroquine phosphate 600 mg base PO, then 300 mg 10 mg/kg base PO, then 5
(Aralen) base PO at 6, 24, and 48 hr mg/kg base PO at 6, 24, and
48 hr
or Hydroxychloroquine 620 mg base PO, then 310 mg 10 mg/kg base PO, then 5
(Plaquenil) 71 base PO at 6, 24, and 48 hr mg/kg base PO at 6, 24, and
48 hr
Uncomplicated infection with P. vivax acquired in areas of chloroquine resistance 68
Drug of choice: Atovaquone/proguanil 4 adult tablets PO once daily × 3 <5 kg: not indicated
(Malarone) days 5-8 kg: 2 pediatric tablets
Adult tablets: 50 mg PO daily × 3 days
atovaquone/100 mg
proguanil 9-10 kg: 3 pediatric tablets
 Pediatric tablets: 62.5 PO daily × 3 days
mg atovaquone/25 mg 11-20 kg: 1 adult tablet PO
proguanil 62 daily × 3 days
21-30 kg: 2 adult tablets PO
daily × 3 days
31-40 kg: 3 adult tablets PO
daily × 3 days
>40 kg: 4 adult tablets PO
daily × 3 days
plus Primaquine 70 30 mg base PO daily × 14 days 0.5 mg/kg/day PO × 14
days
or Quinine sulfate 648 mg salt PO tid × 3-7 days 63 10 mg salt/kg PO tid × 3-7
days 57
plus Doxycycline 7 , 16 100 mg PO bid × 7 days 4 mg/kg/day PO in 2 doses
× 7 days
or plus Tetracycline 7 , 16 250 mg PO qid × 7 days 6.25 mg/kg PO qid × 7 days
or plus Clindamycin 7 , 65 20 mg/kg/day PO in 3 divided 20 mg/kg/day PO in 3
doses × 7 days 66 doses × 7 days
plus Primaquine 69 30 mg base PO daily × 14 days 0.5 mg/kg/day PO × 14
days
or Mefloquine 67 750 mg PO followed 12 hr later 15 mg/kg PO followed 12
by 500 mg PO hr later by 10 mg/kg PO
plus Primaquine 70 30 mg base PO daily × 14 days 0.5 mg/kg/day PO × 14
days
Uncomplicated infection with P. ovale and P. vivax acquired in areas without chloroquine resistance 68
Drug of choice: Chloroquine phosphate 600 mg base PO, then 300 mg 10 mg/kg base PO, then 5
(Aralen) base PO at 6, 24, and 48 hr mg/kg base PO at 6, 24, and
48 hr
plus Primaquine 70 30 mg base PO daily × 14 days 0.5 mg/kg/day PO × 14
days
or Hydroxychloroquine 620 mg base PO, then 310 mg 10 mg/kg base PO, then 5
(Plaquenil) 71 base PO at 6, 24, and 48 hr mg/kg base PO at 6, 24, and
48 hr
plus Primaquine 70 30 mg base PO daily × 14 days 0.5 mg/kg/day PO × 14
days
Severe malaria due to all Plasmodium spp.
Drug of choice: 72 Quinidine gluconate 73 10 mg salt/kg IV in normal saline 10 mg salt/kg IV in normal
loading dose (max 600 mg) over saline loading dose (max
1-2 hr, followed by continuous 600 mg) over 1-2 hr,
infusion of 0.02 mg salt/kg/min followed by continuous
until PO therapy can be started infusion of 0.02 mg
salt/kg/min until PO
therapy can be started
plus Doxycycline 7
, 16 100 mg PO or IV bid × 7 days 4 mg/kg/day PO or IV in 2
doses × 7 days
or plus Tetracycline 7
, 16 250 mg PO qid × 7 days 6.25 mg/kg PO qid × 7 days
or plus Clindamycin 7 , 65 20 mg/kg/day PO in 3 divided 20 mg/kg/day PO in 3
doses × 7 days or 10 mg/kg IV divided doses × 7 days or
loading dose, then 5 mg/kg tid 10 mg/kg IV loading dose,
until able to take PO 60 then 5 mg/kg tid until able
to take PO 60
Alternative: Artesunate 27 , 74 2.4 mg/kg/dose IV × 3 days, at 0, 2.4 mg/kg/dose IV × 3
12, 24, 48, and 72 hr days, at 0, 12, 24, 48, and
Followed by: Atovaquone-proguanil, 72 hr
doxycycline, clindamycin,
or mefloquine as above
Prevention of relapses: P. vivax and P. ovale only
Drug of choice: Primaquine phosphate 70 30 mg base/day PO × 14 days 0.6 mg base/kg/day PO ×
14 days
Malaria: Prevention 75
Chloroquine-sensitive areas 60
Drug of choice Chloroquine phosphate 76 , 500 mg salt (300 mg base), PO 5 mg/kg base once/wk, up
77 , 78 once/wk beginning 1-2 wk before to adult dose of 300 mg
travel to malarious area and 4 wk base beginning 1-2 wk
after leaving before travel to malarious
area and 4 wk after leaving
or Hydroxychloroquine 400 mg (310 mg base) PO 5 mg/kg base once/wk, up
(Plaquenil) 71 once/wk beginning 1-2 wk before to adult dose of 310 mg
travel to malarious area and 4 wk base beginning 1-2 wk
after leaving before travel to malarious
area and 4 wk after leaving
Chloroquine-resistant areas 60
Drug of choice: Atovaquone/proguanil 62 , 1 adult tablet PO q day beginning 11-20 kg: 1 pediatric tablet
77 , 79 , 80 1-2 days before travel to PO/day
malarious area and 7 days after 21-30 kg: 2 pediatric tablets
leaving PO/day
31-40 kg: 3 pediatric tablets
PO/day
>40 kg: 1 adult tablet
PO/day
or Mefloquine 67 , 77 , 78 , 81 1 adult tablet PO q day beginning <9 kg: 5 mg/kg salt
1-2 wk before travel to malarious once/wk
area and 4 wk after leaving 9-19 kg: ¼ tablet once/wk
19-30 kg: ½ tablet once/wk
31-45 kg: ¾ tablet once/wk
>45 kg: 1 tablet once/wk
or Doxycycline 7 , 82 100 mg PO daily ≥8 yr: 2 mg/kg/day, up to
100 mg/day
Alternative for Primaquine 7 , 83 30 mg base PO daily beginning 1- 0.5 mg/kg base (max 30
areas with primarily 2 days before travel to malarious mg) daily beginning 1-2
P. vivax: area and 7-14 days after leaving days before travel to
malarious area and 7-14
days after leaving
Malaria: Presumptive self-treatment 84
Drug of choice: Atovaquone/proguanil 4 adult tablets PO once daily × 3 <5 kg: not indicated
(Malarone) days 5-8 kg: 2 pediatric tablets
Adult tablets: 50 mg PO daily × 3 days
atovaquone/100 mg 9-10 kg: 3 pediatric tablets
proguanil PO daily × 3 days
Pediatric tablets 62.5 11-20 kg: 1 adult tablet PO
mg atovaquone/25 mg daily × 3 days
proguanil 62
21-30 kg: 2 adult tablets PO
daily × 3 days
31-40 kg: 3 adult tablets PO
daily × 3 days
>40 kg: 4 adult tablets PO
 daily × 3 days
or Quinine sulfate 63 648 mg salt PO tid × 3-7 days 10 mg salt/kg PO tid × 3-7
days
plus Doxycycline 7 , 16 100 mg PO bid × 7 days 4 mg/kg/day PO in 2
divided doses × 7 days
or Mefloquine 67 , 68 750 mg PO followed 12 hr later 15 mg/kg PO followed 12
by 500 mg hr later by 10 mg/kg
Microsporidiosis
Ocular (Encephalitozoon hellem, Encephalitozoon cuniculi, Vittaforma corneae [Nosema corneum])
Drug of choice: Albendazole 7 , 85 400 mg PO bid <10 kg/2 yr: 11
≥2 yr: see adult dosing
plus Fumagillin 86

Intestinal (Enterocytozoon bieneusi, Encephalitozoon [Septata] intestinalis)

E. bieneusi 87
Drug of choice: Fumagillin 60 mg/day PO × 14 days in 3
divided doses
E. intestinalis
Drug of choice: Albendazole 7 , 85 400 mg PO bid × 21 days <10 kg/2 yr: 11
≥2 yr: see adult dosing
Disseminated (E. hellem, E. cuniculi, E. intestinalis, Pleistophora sp., Trachipleistophora sp., and Brachiola
vesicularum)
Drug of choice: 88 Albendazole 7 , 85 400 mg PO bid <10 kg/2 yr: 11
≥2 yr: see adult dosing
Mites, see Scabies
Moniliformis moniliformis infection
Drug of choice: Pyrantel pamoate (OTC) 7 11 mg/kg PO once, repeat twice, 2 11 mg/kg PO once, repeat
wk apart twice, 2 wk apart
Naegleria species, see Amebic meningoencephalitis, primary
Necator americanus, see Hookworm infection
Oesophagostomum bifurcum
Drug of choice: See footnote 89
Onchocerca volvulus, see Filariasis
Opisthorchis viverrini, see Fluke infection
Paragonimus westermani, see Fluke infection
Pediculus capitis, Pediculus humanus, Phthirus pubis, see Lice
Pinworm, see Enterobius
Pneumocystis jiroveci (formerly Pneumocystis carinii ) pneumonia (PCP) 90
Moderate to severe disease
Drug of choice: Trimethoprim- 15-20 mg/kg/day TMP 15-20 mg/kg/day TMP
sulfamethoxazole (TMP- component IV in 3-4 divided component IV in 3-4
SMX) doses × 21 days (change to PO divided doses × 21 days
after clinical improvement) (change to PO after clinical
improvement)
Alternative: Pentamidine 3-4 mg IV daily × 21 days 3-4 mg IV daily × 21 days
or Primaquine 30 mg base PO daily × 21 days 0.3 mg/kg base PO (max 30
mg) daily × 21 days
plus Clindamycin 7 600-900 mg IV tid or qid × 21 15-25 mg/kg IV tid or qid ×
days, or 300-450 mg PO tid or qid 21 days, or 10 mg/kg PO
× 21 days (change to PO after tid or qid (max 300-450
clinical improvement) mg/dose) × 21 days (change
to PO after clinical
improvement)
Mild to moderate disease
Drug of choice: Trimethoprim- 320 mg/1600 mg (2 DS tablets) TMP 15-20 mg/kg/day PO
sulfamethoxazole (TMP- PO tid × 21 days in 3 or 4 doses × 21 days
SMX)
Alternatives: Dapsone 100 mg PO daily × 21 days 2 mg/kg/day (max 100 mg)
PO × 21 days
plus Trimethoprim 15 mg/kg/day PO in 3 doses 15 mg/kg/day PO in 3
doses
or Primaquine 30 mg base PO daily × 21 days 0.3 mg/kg base PO daily
(max 30 mg) × 21 days
plus Clindamycin 300-450 mg PO tid or qid × 21 10 mg/kg PO tid or qid
days (max 300-450 mg/dose) ×
21 days
or Atovaquone 750 mg PO bid × 21 days 1-3 mo: 30 mg/kg/day PO
in 2 doses × 21 days
Primary and secondary prophylaxis 91
Drug of choice: Trimethoprim- 1 tablet (single strength or TMP 150 mg/m 2 in 1-2
sulfamethoxazole (TMP- greater) PO daily or 1 DS tablet doses daily or on 3
SMX) PO 3 days/wk consecutive days per wk 92
Alternatives: 91 Dapsone 7 50 mg PO bid, or 100 mg PO 2 mg/kg/day (max 100 mg)
daily PO or 4 mg/kg (max 200
mg) PO each wk
or Dapsone 7 50 mg PO daily or 200 mg PO
each wk
plus Pyrimethamine 93 50 mg PO or 75 mg PO each wk
or Pentamidine aerosol 300 mg inhaled monthly via ≥5 yr: 300 mg inhaled
Respirgard II nebulizer monthly via Respirgard II
nebulizer
or Atovaquone 7 1,500 mg/day PO in 1 or 2 doses 1-3 mo: 30 mg/kg/day PO
4-24 mo: 45 mg/kg/day PO
in 2 doses × 21 days
>24 mo: 30 mg/kg/day PO
in 2 doses × 21 days
Roundworm, see Ascariasis
Sappinia diploidea, see Amebic meningoencephalitis, primary
Scabies (Sarcoptes scabiei)
Drug of choice: 5% Permethrin 94 Topically, 2× at least 1 wk apart Topically 2x, 1 wk apart,
approved for ≥ 2 mo
Alternative: 94 , 95 Ivermectin 7 , 94 , 96 200 µg/kg PO x2 at least 1 wk <15 kg: not indicated
apart ≥15 kg: see adult dosing
10% Crotamiton Topically overnight on days 1, 2, Topically overnight on days
3, 8 1, 2, 3, 8
Schistosomiasis (Bilharziasis)
Schistosoma haematobium or S. intercalatum
Drug of choice: Praziquantel 40 mg/kg/day PO in 1 or 2 doses 40 mg/kg/day PO in 1 or 2
× 1 day doses × 1 day 36
Schistosoma japonicum or S. mekongi
Drug of choice: Praziquantel 60 mg/kg/day PO in 2 or 3 doses 60 mg/kg/day PO in 3
× 1 day doses × 1 day 36
Schistosoma mansoni
Drug of choice: Praziquantel 40 mg/kg/day PO in 1 or 2 doses 40 mg/kg/day PO in 1 or 2
× 1 day doses × 1 day 36
Alternative: Oxamniquine 97 , 98 15 mg/kg PO once 20 mg/kg/day PO in 2
doses × 1 day
Sleeping sickness, see Trypanosomiasis
Strongyloidiasis (Strongyloides stercoralis)
Drug of choice: 99 Ivermectin 200 µg/kg/day PO × 2 days <15 kg: not indicated
≥15 kg: see adult dosing
Alternative: Albendazole 7 , 100 400 mg PO bid × 7 days <10 kg/2 yr: 11
≥2 yr: see adult dosing
Tapeworm infection
Adult (intestinal stage)
Diphyllobothrium latum (fish), Taenia saginata (beef), Taenia solium (pork), Dipylidium caninum (dog)
Drug of choice: Praziquantel 7 5-10 mg/kg PO once 5-10 mg/kg PO once 36
Alternative: Niclosamide 2 g PO once 50 mg/kg PO once
Hymenolepis nana (dwarf tapeworm)
Drug of choice: Praziquantel 7 25 mg/kg PO once 25 mg/kg PO once 36
Alternative: Niclosamide 101 2 g PO daily × 7 days 11-34 kg: 1 g PO on day 1,
then 500 mg/day PO × 6
days
>34 kg: 1.5 g PO on day 1,
then 1 g/day PO × 6 days
Larval (tissue stage)
Echinococcus granulosus (hydatid disease cystic echinococcosis)
Drug of choice: 102 Albendazole 7 400 mg PO bid × 1-6 mo <10 kg/2 yr: 5-7.5 mg/kg
PO bid (max 400 mg) 11
≥2 yr: 5-7.5 mg/kg PO bid
(max 400 mg) × 1-6 mo
Echinococcus multilocularis (alveolar echinococcosis)
Treatment of See footnote 103
choice:
Taenia solium (cysticercosis)
Treatment of Albendazole 400 mg bid PO × 8-30 days; can <10 kg/2 yr: 7.5 mg/kg PO
choice: 104 be repeated as necessary bid × 8-30 days; can be
repeated as necessary 11
≥2 yr: 7.5 mg/kg PO (max
400 mg) bid × 8-30 days;
can be repeated as
necessary
plus Steroids
Alternative: Praziquantel 7 50 mg/kg/day PO in 3 divided 50 mg/kg/day PO in 3
doses × 15 days divided doses × 15 days 36
or Surgical removal
Toxocariasis, see Visceral larva migrans
Toxoplasmosis (Toxoplasma gondii) 105
Drug of choice: 106 Pyrimethamine 108 200 mg PO × 1, then 50-75 2 mg/kg/day × 3 days, then
, 107 mg/day × 3-6 wk 1 mg/kg/day (max 25
mg/day) × 3-6 wk 109
plus Sulfadiazine 1.5 g PO qid × 3-6 wk 100-200 mg/kg/day in 4
divided doses × 3-6 wk
or plus Clindamycin 1.8-2.4 g/day IV or PO in 3-4 5-7.5 mg/kg IV or PO tid or
doses × 3-6 wk qid (max 600 mg/dose) × 3-
6 wk
or plus Atovaquone 1,500 mg PO bid 1,500 mg PO bid
Alternative: Trimethoprim- 15-20 mg/kg/day TMP 15-20 mg/kg TMP
sulfamethoxazole (TMP- component PO or IV in 3-4 component PO or IV in 3 or
SMX) 7 divided doses × 3-6 wk 4 doses × 3-6 wk
Trichinellosis (Trichinella spiralis)
Drug of choice: Steroids for severe Prednisone 30-60 mg PO daily ×
symptoms 10-15 days
plus Albendazole 7 400 mg PO bid × 8-14 days <10 kg/2 yr: 11
≥2 yr: see adult dosing
Alternative: Mebendazole 7 200-400 mg PO tid × 3 days, then 200-400 mg PO tid × 3
400-500 mg PO tid × 10 days days, then 400-500 mg PO
tid × 10 days 12
Trichomoniasis (Trichomonas vaginalis)
Drug of choice: 110 Metronidazole 2 g PO once or 500 mg PO bid × 15 mg/kg/day PO in 3
7 days doses × 7 days
or Tinidazole 4 2 g PO once 50 mg/kg PO once (max 2
g)
Trichostrongylus infection
Drug of choice: Pyrantel pamoate 7 11 mg/kg base PO once (max 1 g) 11 mg/kg PO once (max 1
g)
Alternative: Mebendazole 7 100 mg PO bid × 3 days 100 mg PO bid × 3 days 12
or Albendazole 7 400 mg PO once <10 kg/2 yr: 11
≥2 yr: 15 mg/kg/day PO
(max 800 mg) × 1-6 mo
Trichuriasis (Trichuris trichiura, whipworm)
Drug of choice: Mebendazole 100 mg PO bid × 3 days 100 mg PO bid × 3 days 12
Alternative: Albendazole 7 400 mg PO × 3 days <10 kg/2 yr: 11
≥2 yr: see adult dosing
or Ivermectin 7 200 µg/kg PO daily × 3 days <15 kg: not indicated
≥15 kg: see adult dosing
Trypanosomiasis 111
Trypanosoma cruzi (American trypanosomiasis, Chagas disease)
Drug of choice: Benznidazole 27 5-7 mg/kg/day PO in 2 divided ≤12 yr: 5-7.5 mg/kg/day
doses × 60 days PO in 2 divided doses × 60
days
>12 yr: see adult dosing
Alternative: Nifurtimox 27 , 112 8-10 mg/kg/day PO in 3-4 doses × ≤10 yr: 15-20 mg/kg/day
90 days PO in 3-4 doses × 90 days
11-16 yr: 12.5-15
mg/kg/day in 3-4 doses ×
90 days
>16 yr: see adult dosing
Trypanosoma brucei gambiense (West African trypanosomiasis, sleeping sickness)
Hemolymphatic stage
Drug of choice: 113 Pentamidine isethionate 7 4 mg/kg/day IM × 7-10 days 4 mg/kg/day IM or IV × 7-
10 days
Alternative: Suramin 27 100 mg (test dose) IV, then 1 g IV 2 mg/kg (test dose) IV, then
on days 1, 3, 7, 14, and 21 20 mg/kg IV on days 1, 3,
7, 14, and 21
Late disease with CNS involvement
Drug of choice: Eflornithine 27 , 114 100 mg/kg IV qid × 14 days 100 mg/kg IV qid × 14 days
Alternative: Melarsoprol
27 , 115 2-3.6 mg/kg (max 200 mg) daily 2-3.6 mg/kg (max 200 mg)
IV (progressively increased daily IV (progressively
 during series) × 3 days. After 7 increased during series) × 3
days, 3.6 mg/kg daily × 3 days. days. After 7 days, 3.6
After 7 days, give a 3rd series of
mg/kg daily × 3 days. After
3.6 mg/kg daily × 3 days. 7 days, give a 3rd series of
3.6 mg/kg daily × 3 days.
Trypanosoma brucei rhodesiense (East African trypanosomiasis, sleeping sickness)
Hemolymphatic stage
Drug of choice: Suramin 27 100 mg (test dose) IV, then 1 g IV 2 mg/kg (test dose), then 20
on days 1, 3, 7, 14, and 21 mg/kg IV on days 1, 3, 7,
14, and 21
Late disease with CNS involvement
Drug of choice: Melarsoprol 27 , 114 2-3.6 mg/kg (max 200 mg) daily 2-3.6 mg/kg (max 200 mg)
IV (progressively increased daily IV (progressively
during series) × 3 days. After 7 increased during series) × 3
days, 3.6 mg/kg daily × 3 days. days. After 7 days, 3.6
After 7 days, give a 3rd series of mg/kg daily × 3 days. After
3.6 mg/kg daily × 3 days. 7 days, give a 3rd series of
3.6 mg/kg daily × 3 days.
Visceral larva migrans (Toxocariasis) 116
Drugs of choice: Albendazole 7 400 mg PO bid × 5 days <10 kg/2 yr: 11
≥2 yr: see adult dosing
or Mebendazole 7 100-200 mg PO bid × 5 days 100-200 mg PO bid × 5
days 12
Whipworm, see Trichuriasis
Wuchereria bancrofti, see Filariasis
1 For treatment of keratitis caused by Acanthamoeba, 0.02% topical polyhexamethylene

biguanide (PHMB) and 0.02% chlorhexidine have been successfully used individually and in
combination in a large number of patients (Tabin G, et al: Cornea 20:757, 2001; Wysenbeek YS,
et al: Cornea 19:464, 2000). The expected treatment course is 6-12 mo. PHMB is no longer
available from Leiter's Park Avenue Pharmacy but is available from the O'Brien Pharmacy (1-800-
627-4360; distributes in many states) and the Greenpark Pharmacy (1-713-432-9855; Texas
only). Combinations with either 0.1% propamidine isethionate (Brolene) or hexamidine
(Desmodine) have been used (Seal DV: Eye 17:893, 2003) successfully, but these are not
available in the United States. Neomycin is no longer recommended due to high levels of
resistance (Acanthamoeba keratitis: Treatment guidelines from The Medical Letter 143, 8/1/2013).
In addition, the combination of chlorhexidine, natamycin (pimaricin), and debridement also has
been successful (Kitagawa K, et al: Jpn J Ophthalmol 47:616, 2003).
2 The drug is not available commercially but can be compounded by Expert Compounding
Pharmacy, 6744 Balboa Blvd, Lake Balboa, CA 91406 (1-800-247-9767 or 1-818-988-7979 or
[email protected] ).
3 The drug is not available commercially in the United States.

4 A nitroimidazole similar to metronidazole, tinidazole was approved by the FDA in 2004 and

appears to be as effective and better tolerated than metronidazole. It should be taken with food to
minimize GI adverse effects. For children and patients unable to take tablets, a pharmacist may
crush the tablets and mix them with cherry syrup (Humco, and others). The syrup suspension is
good for 7 days at room temperature and must be shaken before use. Ornidazole, a similar drug,
is also used outside the United States.
5 Nitazoxanide is FDA approved as a pediatric oral suspension for treatment of Cryptosporidium in
should be followed by treatment with a luminal agent, such as paromomycin
(which is preferred) or iodoquinol. Diloxanide furoate can also be used in
children > 2 yr of age, but it is no longer available in the United States.
Paromomycin should not be given concurrently with metronidazole or
tinidazole, because diarrhea is a common side effect of paromomycin and may
confuse the clinical picture. Asymptomatic intestinal infection with E. histolytica
should be treated, preferably with paromomycin or alternatively with either
iodoquinol or diloxanide furoate. For fulminant cases of amebic colitis, some
experts suggest adding dehydroemetine (1 mg/kg/ day subcutaneously or
intramuscularly, never intravenously), available only through the Centers for
Disease Control and Prevention. Patients should be hospitalized for monitoring
if dehydroemetine is administered. Dehydroemetine should be discontinued if
tachycardia, T-wave depression, arrhythmia, or proteinuria develops.

Table 307.1
Drug Treatment for Amebiasis

MEDICATION ADULT DOSAGE (ORAL) PEDIATRIC DOSAGE (ORAL)*

INVASIVE DISEASE
Metronidazole Colitis or liver abscess: 750 mg tid Colitis or liver abscess: 35-50 mg/kg/day in 3 divided
for 7-10 days doses for 7-10 days
Or
Tinidazole Colitis: 2 g once daily for 3 days Colitis: 50 mg/kg/day once daily for 3 days
Liver abscess: 2 g once daily for 3-5 Liver abscess: 50 mg/kg/day once daily for 3-5 days
days
Followed by:
Paromomycin 500 mg tid for 7 days 25-35 mg/kg/day in 3 divided doses for 7 days
(preferred)
Or
Diloxanide furoate 500 mg tid for 10 days 20 mg/kg/day in 3 divided doses for 7 days
†
Or
Iodoquinol 650 mg tid for 20 days 30-40 mg/kg/day in 3 divided doses for 20 days
ASYMPTOMATIC INTESTINAL COLONIZATION
Paromomycin As for invasive disease As for invasive disease
(preferred)
Or
Diloxanide furoate
†
Or
Iodoquinol
* All pediatric dosages are up to a maximum of the adult dose.

† Not available in the United States.

abdominal distention and cramps, bloating, malaise, flatulence, nausea, anorexia,
and weight loss develops (Table 308.1 ). Stools initially may be profuse and
watery and later become greasy and foul smelling and may float. Stools do not
contain blood, mucus, or fecal leukocytes. Varying degrees of malabsorption
may occur. Abnormal stool patterns may alternate with periods of constipation
and normal bowel movements. Malabsorption of sugars, fats, and fat-soluble
vitamins is well documented and may be responsible for substantial weight loss.
Giardia has been associated with iron deficiency in internationally adopted
children. Extraintestinal manifestations of Giardia appear to be more common in
adults than children and include arthritis and, in one report after an outbreak,
chronic fatigue syndrome. Giardiasis in children has been associated with
growth stunting, and repeated Giardia infections correlate with a decrease in
cognitive function in children in endemic areas.

Table 308.1

Clinical Signs and Symptoms of Giardiasis

SYMPTOM FREQUENCY (%)
Diarrhea 64-100
Malaise, weakness 72-97
Abdominal distention 42-97
Flatulence 35-97
Abdominal cramps 44-81
Nausea 14-79
Foul-smelling, greasy stools 15-79
Anorexia 41-73
Weight loss 53-73
Vomiting 14-35
Fever 0-28
Constipation 0-27

Diagnosis
Giardiasis should be considered in children who have acute nondysenteric
diarrhea, persistent diarrhea, intermittent diarrhea and constipation,
malabsorption, chronic crampy abdominal pain and bloating, failure to thrive, or
weight loss. It should be particularly high in the differential diagnosis of children
in child care, children in contact with an index case, children with a history of
recent travel to an endemic area, and children with humoral immunodeficiencies.
Testing for giardiasis should be standard for internationally adopted children
Treatment
Children with acute diarrhea in whom Giardia organisms are identified should
receive therapy. In addition, children who manifest failure to thrive or exhibit
malabsorption or gastrointestinal tract symptoms such as chronic diarrhea should
be treated.
Asymptomatic excreters generally are not treated, except in specific instances
such as outbreak control, prevention of household transmission by toddlers to
pregnant women and patients with hypogammaglobulinemia or cystic fibrosis,
and situations requiring oral antibiotic treatment where Giardia may produce
malabsorption of the antibiotic.
The FDA has approved tinidazole and nitazoxanide for the treatment of
Giardia in the United States. Both medications have been used to treat Giardia
in thousands of patients in other countries and have excellent safety and efficacy
records against Giardia (Table 308.2 ). Tinidazole has the advantage of single-
dose treatment and very high efficacy (>90%), while nitazoxanide has the
advantage of a suspension form, high efficacy (80–90%), and very few adverse
effects. Metronidazole, though never approved by the FDA for treatment of
Giardia, is also highly effective (80–90% cure rate), and the generic form is
considerably less expensive than tinidazole or nitazoxanide. Frequent adverse
effects are seen with metronidazole therapy, and it requires 3-times-a-day dosing
for 5-7 days. Suspension forms of tinidazole and metronidazole must be
compounded by a pharmacy; neither drug is sold in suspension form.

Table 308.2
Drug Treatment for Giardiasis

MEDICATION ADULT DOSAGE (ORAL) PEDIATRIC DOSAGE (ORAL) *

RECOMMENDED
Tinidazole 2 g once >3 yr: 50 mg/kg once
Nitazoxanide 500 mg bid for 3 days 1-3 yr: 100 mg (5 mL) bid for 3 days
4-11 yr: 200 mg (10 mL) bid for 3 days
>12 yr: 500 mg bid for 3 days
Metronidazole 250 mg tid for 5-7 days 15 mg/kg/day in 3 divided doses for 5-7 days
ALTERNATIVE
Albendazole 400 mg once a day for 5 days >6 yr: 400 mg once a day for 5 days
Paromomycin 25-35 mg/kg/day in 3 divided doses for 5-10 Not recommended
days
Quinacrine † 100 mg tid for 5-7 days 6 mg/kg/day in 3 divided doses for 5 days
* All pediatric dosages are up to a maximum of the adult dose.
C H A P T E R 3 11

Leishmaniasis (Leishmania)
Peter C. Melby

The leishmaniases are a diverse group of diseases caused by intracellular

protozoan parasites of the genus Leishmania, which are transmitted by
phlebotomine sandflies. Multiple species of Leishmania are known to cause
human disease involving the skin and mucosal surfaces and the visceral
reticuloendothelial organs (Table 311.1 ). Cutaneous disease is usually localized
and mild but may cause cosmetic disfigurement. Rarely, cutaneous infection can
disseminate or involve the skin diffusely. Mucosal and visceral forms of
leishmaniasis are associated with significant morbidity and mortality.

Table 311.1
Clinical and Epidemiologic Characteristics of Main
Leishmania spp.

MAIN
CLINICAL NATURAL MAIN
SUBGENUS CLINICAL RISK GROUPS
FORM PROGRESSION RESERVOIR
FEATURES

Leishmania Leishmania VL, PKDL Persistent VL is fatal within Predominantly Humans

donovani * fever, 2 yr; PKDL adolescents and
splenomegaly, lesions self-heal young adults for VL;
weight loss, in up to 85% of young children in
and anemia in cases in Africa Sudan and no clearly
VL; multiple but rarely in Asia established risk
painless factors for PKDL
macular,
papular, or
nodular lesions
in PKDL
Leishmania Leishmania CL, LR, Ulcerating dry CL lesions often No well-defined risk Humans, but
tropica * rarely VL lesions, self-heal within 1 groups zoonotic foci
 painless, and yr exist
frequently
multiple

Leishmania Leishmania CL, DCL, Localized Self-healing, Limited evidence; Hyraxes

aethiopica * DsCL, cutaneous except for DCL, adolescents
oronasal CL nodular within 2-5 yr
lesions;
occasionally
oronasal;
rarely ulcerates
Leishmania Leishmania CL Rapid necrosis, Self-healing in No well-defined risk Rodents
major * multiple wet >50% of cases groups
sores, severe within 2-8 mo;
inflammation multiple lesions
slow to heal, and
severe scarring
Leishmania Leishmania VL, CL Persistent fever VL is fatal within Children <5 yr old Dogs, hares,
infantum * and 2 yr; CL lesions and humans
splenomegaly self-heal within 1 immunocompromised
in VL; yr and confers adults for VL; older
typically single individual children and young
nodules and immunity adults for CL
minimal
inflammation
in CL
Leishmania Leishmania CL, DCL, Ulcerating Often self-healing No well-defined risk Rodents,
mexicana † DsCL lesions, single in 3-4 mo groups marsupials
or multiple

Leishmania Leishmania CL, DCL, Ulcerating Not well No well-defined risk Possums,
amazonensis DsCL lesions, single described groups rodents
† or multiple

Leishmania Viannia CL, MCL, Ulcerating Might self-heal in No well-defined risk Dogs,
braziliensis † DCL, LR lesions can 6 mo; 2.5% of groups humans,
progress to cases progress to rodents,
mucocutaneous MCL horses
form; local
lymph nodes
are palpable
before and
early on in the
onset of the
lesions
Leishmania Viannia CL, DsCL, Ulcerating Might self-heal No well-defined risk Possums,
guyanensis † MCL lesions, single within 6 mo groups sloths,
or multiple that anteaters
can progress to
 mucocutaneous
form; palpable
lymph nodes
* Old World leishmaniasis.

† New World leishmaniasis.

‡ Estimates are of all New World leishmaniases, with Leishmania braziliensis comprising the vast

majority of these cases.

CL, Cutaneous leishmaniasis; DCL, diffuse cutaneous leishmaniasis; DsCL, disseminated
cutaneous leishmaniasis; LR, leishmaniasis recidivans; MCL, mucocutaneous leishmaniasis;
PKDL, post–kala-azar dermal leishmaniasis; VL, visceral leishmaniasis.
Adapted from Burza S, Croft SL, Boelaert ML: Leishmaniasis, Lancet 392:951–966, 2018 (Table
1).

Etiology
Leishmania organisms are members of the Trypanosomatidae family and include
2 subgenera, Leishmania (Leishmania) and Leishmania (Viannia) . The parasite
is dimorphic, existing as a flagellate promastigote in the insect vector and as an
aflagellate amastigote that resides and replicates within mononuclear phagocytes
of the vertebrate host. Within the sandfly vector, the promastigote changes from
a noninfective procyclic form to an infective metacyclic stage (Fig. 311.1 ).
Fundamental to this transition are changes that take place in the terminal
polysaccharides of the surface lipophosphoglycan , which allow forward
migration of the infective parasites to be inoculated in the host skin during a
blood meal. Metacyclic lipophosphoglycan also plays an important role in the
entry and survival of Leishmania in the host cells. Once within the macrophage,
the promastigote transforms to an amastigote and resides and replicates within a
phagolysosome. The parasite is resistant to the acidic, hostile environment of the
macrophage and eventually ruptures the cell and goes on to infect other
macrophages. Infected macrophages have a diminished capacity to initiate and
respond to an inflammatory response, thus providing a safe haven for the
intracellular parasite.
 Infection is divided into 2 main phases: acute and chronic (Table 313.1 ).
Acute infection is asymptomatic in up to 95% of infected individuals, but can
manifest as fever, lymphadenopathy, organomegaly, myocarditis, and
meningoencephalitis. Chronic infection in 60–70% of patients is indeterminate,
meaning the patient is asymptomatic but has a positive antibody titer.
Approximately 30% of infected persons proceed to chronic determinate or
symptomatic T. cruzi infection. The T. cruzi genome has been fully sequenced
and contains 12,000 genes, the most widely expanded among trypanosomatids,
and may reflect its ability to invade a wide variety of host tissues. Significant
variability has been also found, along with extensive epigenetic modification of
surface proteins, which may contribute to immune evasion. Six discrete typing
units (DTUs) are recognized, referred to as TcI to TcVI. A newly described 7th
type called Tcbat has recently been identified. DTUs may differ in geographic
distribution, predominant vector, and hosts and may also differ in disease
manifestations and response to treatment.

Table 313.1
Clinical Features and Diagnosis of Chagas Disease

GEOGRAPHIC
CLINICAL SIGNS/SYMPTOMS DIAGNOSIS
DISTRIBUTION
ACUTE FORMS *
Vectorial Endemic Incubation period: 1-2 wk Direct
countries Signs of portal of entry: indurated parasitological
cutaneous lesion (chagoma) or palpebral methods: patent
edema (Romaña sign) parasitemia up to
Most cases are mild disease (95–99%) and 90 days
unrecognized. Microscopic
Persistent fever, fatigue, lymphadenopathy, examination of
hepatomegaly, splenomegaly, morbilliform fresh blood,
rash, edema Giemsa-stained
In rare cases, myocarditis or thin and thick
meningoencephalitis blood films, or
Anemia, lymphocytosis, elevated buffy coat
AST/ALT concentrations Concentration
Risk of mortality: 0.2–0.5% methods:
microhematocrit
and Strout method
PCR techniques
Serology is not
useful.
Congenital Endemic and Incubation period: birth to several weeks Direct
nonendemic Most are asymptomatic or have mild parasitological
countries disease. methods
Prematurity, low birthweight, abortion, Concentration
 neonatal death methods:
Fever, jaundice, edema, hepatomegaly, microhematocrit,
splenomegaly, respiratory distress Strout method
syndrome, myocarditis, Direct microscopy
meningoencephalitis also useful
Anemia and thrombocytopenia PCR: most
Risk of mortality: <2% sensitive technique
Serology: after 9
mo or later
Oral Restricted areas Incubation period: 3-22 days Same as for vectorial.
of endemic Fever, vomiting, periocular edema,
countries dyspnea, fever, myalgia, prostration, cough,
(Amazon basin) splenomegaly, hepatomegaly, chest pain,
and local abdominal pain, digestive hemorrhage
outbreaks Risk of mortality: 1–35%
Transfusion and Endemic and Incubation period: 8-160 days; persistent Same as for
transplant nonendemic fever vectorial.
countries Clinical characteristics similar to those of PCR techniques
vectorial cases (excluding portal of entry usually yield
signs) positive results
Risk of mortality is variable and depends days to weeks
on the severity of baseline disease. before
trypomastigotes
are detectable in
blood.
Tissue samples are
needed in some
circumstances.
Reactivation in Endemic and Behaves as other opportunistic infections Direct
HIV-infected nonendemic Reactivation with <200 CD4 cells per µL parasitological
patients countries (mostly with <100) methods, as in
Affects CNS (75–90%) as single or vectorial cases.
multiple space-occupying lesions or as Parasite can be
severe necrohemorrhagic found in CSF,
meningoencephalitis other body fluids,
Cardiac involvement (10–55%): and tissue samples.
myocarditis, pericardial effusion or PCR: not useful
worsening of previous cardiomyopathy for diagnosis of
Risk of mortality: 20% reactivation
Serology:
indicative of
chronic infection
and helpful in
cases of suspected
disease
Reactivation in Endemic and Reactivation after transplantation or in Direct
other nonendemic patients with hematologic malignancies parasitological
immunosuppressed countries Clinical characteristics similar to those of methods, as in
patients patients who undergo transfusion and those vectorial cases.
with panniculitis and other skin disorders Parasite can be
Risk of mortality is variable and depends found in tissue
on severity of baseline disease and prompt samples.
diagnosis. PCR: increasing
parasite load
detected with real-
 time PCR in serial
specimens could
be indicative of a
high risk of
reactivation.
CHRONIC FORMS
Indeterminate Endemic and Asymptomatic Serology:
nonendemic Normal chest radiograph and 12-lead ECG. detection of IgG
countries PCR: low
sensitivity
Cardiac and Endemic and Cardiac manifestations: fatigue, syncope, Serology:
gastrointestinal nonendemic palpitations, dizziness, stroke; late detection of IgG
countries manifestations: chest pain (atypical), PCR: low
dyspnea, edema, left ventricular sensitivity
dysfunction, congestive heart failure;
alterations in 12-lead ECG,
echocardiography, or other heart function
tests
Gastrointestinal: dysphagia, regurgitation,
severe constipation (dilated esophagus or
colon); alterations in esophageal
manometry, barium swallow, or barium
enema
* Including reactivation in immunosuppressed patients.

ALT, Alanine transaminase; AST, aspartate transaminase; CNS, central nervous system; CSF,
cerebrospinal fluid; ECG, electrocardiogram; PCR, polymerase chain reaction.
From Pérez-Molina J, Molina I: Chagas disease, Lancet 391:82–92, 2018 (Table 2).

T. cruzi infection is primarily a zoonosis, and humans are incidental hosts. T.

cruzi has a large sylvan reservoir and has been isolated from numerous animal
species. The presence of reservoirs and vectors of T. cruzi and the
socioeconomic and educational levels of the population are the most important
risk factors for vector-borne transmission to humans. Insect vectors are found in
rural, wooded areas and acquire infection through ingestion of blood from
humans or animals with circulating trypomastigotes.
Housing conditions are very important in the transmission chain. Incidence
and prevalence of infection depend on the adaptation of the triatomines to human
dwellings, as well as the vector capacity of the species. Animal reservoirs of
reduviid bugs include dogs, cats, rats, opossum, guinea pigs, monkeys, bats, and
raccoons. Humans often become infected when land in enzootic areas is
developed for agricultural or commercial purposes. An estimated 238,000
immigrants from endemic countries living in the United States are likely infected
with T. cruzi . Increasing cases of autochthonous transmission in the United
States have also been reported and confirmed with molecular typing, particularly
from California, Louisiana, Texas, and Georgia, although these numbers remain

FIG. 314.4 Manifestations of severe falciparum malaria by age (A ) and
mortality in children associated with central nervous system involvement,
acidosis, and uremia (B ). Data from 3,228 prospectively studied African
children with severe falciparum malaria. Uremia here is defined as a blood
urea nitrogen >7.14 mmol/L. Surface areas denote the relative prevalence
of the different severity signs, which frequently coexist. The percentages
denote the observed mortality associated with the presenting signs. (From
White NJ, Pukrittayakamee S, Hien TT, et al: Malaria, Lancet 383:723–735,
2014; based on data from von Seidlein L, Olaosebikan R, Hendriksen ICE,
et al: Predicting the clinical outcome of severe falciparum malaria in African
children: findings from a large randomized trial. Clin Infect Dis 54:1080–
1090, 2012.)

Table 314.1
World Health Organization Criteria for Severe Malaria, 2000
• Impaired consciousness
• Prostration
• Respiratory distress
• Multiple seizures
• Jaundice
• Hemoglobinuria
• Abnormal bleeding
• Severe anemia
• Circulatory collapse
• Pulmonary edema

P. vivax malaria has long been considered less severe than P. falciparum
malaria, but recent reports suggest that in some areas it is as frequent a cause of
severe disease and death as P. falciparum . Severe disease and death from P.
vivax are usually caused by severe anemia and sometimes splenic rupture. P.
ovale malaria is the least common type of malaria. It is similar to P. vivax
malaria and usually is found in conjunction with P. falciparum malaria. P.
malariae is the mildest and most chronic of all malaria infections. Nephrotic
syndrome is a rare complication of P. malariae infection that is not observed
with any other human malaria species. Nephrotic syndrome associated with P.
malariae infection is poorly responsive to corticosteroids. Low-level, undetected
P. malariae infection may be present for years and is sometimes unmasked by
immunosuppression or physiologic stress such as splenectomy or corticosteroid
treatment. P. knowlesi malaria is most often uncomplicated but can lead to severe
malaria and death if high-density parasitemia is present.
Recrudescence after a primary attack may occur from the survival of
erythrocyte forms in the bloodstream. Long-term relapse is caused by release of
merozoites from an exoerythrocytic source in the liver, which occurs with P.
vivax and P. ovale , or from persistence within the erythrocyte, which occurs
with P. malariae and rarely with P. falciparum . A history of typical symptoms in
a person >4 wk after return from an endemic area is therefore more likely to be
P. vivax, P. ovale, or P. malariae infection than P. falciparum infection. In the
most recent survey of malaria in the United States (2013) by the CDC, among
individuals in whom a malaria species was identified, 61% of cases were caused
by P. falciparum, 14% by P. vivax, 2% by P. malariae, 4% by P. ovale , and 2%
by mixed-species infection; 94% of P. falciparum infections were diagnosed
within 30 days of arrival in the United States, and 99% within 90 days of arrival.
In contrast, 54% of P. vivax cases occurred >30 days after arrival in the United
States.
for hypotension and cardiac monitoring for widening of the QRS complex or
lengthening of the QTc interval should be performed continuously, and blood
glucose monitoring for hypoglycemia should be performed periodically. Cardiac
adverse events may require temporary discontinuation of the drug or slowing of
the IV infusion. Parenteral therapy should be continued until the parasitemia is
<1%, which usually occurs within 48 hr, and the patient can tolerate oral
medication. Quinidine gluconate (United States) or quinine sulfate (other
countries) is administered for a total of 3 days for malaria acquired in Africa or
South America and for 7 days for malaria acquired in Southeast Asia.
Doxycycline, tetracycline, or clindamycin is then given orally to complete the
therapeutic course (see Tables 314.2 and 314.4 ). Although there are no data to
support the use of quinidine followed by atovaquone-proguanil or artemether-
lumefantrine , the difficulty of maintaining compliance with oral quinine has
led many clinicians to complete oral therapy after IV quinine with a complete
course of atovaquone-proguanil or artemether-lumefantrine.

Table 314.2
CDC Guidelines for Treatment of Malaria in the United
States (Based on Drugs Currently Available for Use in the
United States–Updated July 1, 2013)
(CDC Malaria Hotline: [770] 488-7788 or [855] 856-4713 toll-free Monday-Friday 9 AM to 5 PM EST; [770] 488-
7100 after hours, weekends, and holidays)
CLINICAL REGION RECOMMENDED DRUG AND RECOMMENDED
DIAGNOSIS/ INFECTION ADULT DOSE 1 DRUG AND
PLASMODIUM ACQUIRED PEDIATRIC DOSE 1 ;
spp. PEDIATRIC DOSE
SHOULD NEVER
EXCEED ADULT
DOSE
Uncomplicated Chloroquine- Atovaquone-proguanil (Malarone) 3 Atovaquone-
malaria/P. resistant or Adult tab = 250 mg atovaquone/100 proguanil
falciparum unknown mg proguanil (Malarone) 3
or resistance 2 4 adult tabs PO qd × 3 days Adult tab = 250 mg
Species not (All malarious atovaquone/100 mg
identified regions except proguanil
If “species not those Pediatric (ped) tab
identified” is specified as = 62.5 mg
subsequently “chloroquine- atovaquone/25 mg
diagnosed as P. sensitive,” proguanil
vivax or P. listed below) 5-8 kg: 2 ped tabs
ovale: see P. PO qd × 3 days
vivax and P. 9-10 kg: 3 ped tabs
ovale (below) PO qd × 3 days
regarding 11-20 kg: 1 adult tab
treatment with PO qd × 3 days
primaquine 21-30 kg: 2 adult
tabs PO qd × 3 days
31-40 kg: 3 adult
tabs PO qd × 3 days
>40 kg: 4 adult tabs
PO qd × 3 days
Artemether-lumefantrine (Coartem) 3
1 tablet = 20 mg artemether and 120 mg lumefantrine
A 3-day treatment schedule with a total of 6 oral doses is
recommended for both adult and pediatric patients based on
weight. The patient should receive the initial dose, followed by
2nd dose 8 hr later, then 1 dose PO bid for the following 2 days
5-<15 kg: 1 tablet per dose
15-<25 kg: 2 tablets per dose
25-<35 kg: 3 tablets per dose
≥35 kg: 4 tablets per dose
Quinine sulfate plus 1 of the Quinine sulfate 4
following: doxycycline, tetracycline, plus 1 of the
or clindamycin following:
Quinine sulfate: 542 mg base (=650 doxycycline, 6
4
mg salt) PO tid × 3 or 7 days 5
tetracycline, 6 or
Doxycycline: 100 mg PO bid × 7 days clindamycin
Tetracycline: 250 mg PO qid × 7 days Quinine sulfate: 8.3
Clindamycin: 20 mg base/kg/day PO mg base/kg (=10 mg
divided tid × 7 days salt/kg) PO tid × 3 or
7 days 5
Doxycycline: 2.2
mg/kg PO every 12
hr × 7 days
Tetracycline: 25
mg/kg/day PO
divided qid × 7 days
Clindamycin: 20 mg
base/kg/day PO
divided tid × 7 days
Mefloquine (Lariam and generics) 7 Mefloquine (Lariam
684 mg base (=750 mg salt) PO as and generics) 7
initial dose, followed by 456 mg base 13.7 mg base/kg
(=500 mg salt) PO given 6-12 hr after (=15 mg salt/kg) PO
initial dose as initial dose,
Total dose = 1,250 mg salt followed by 9.1 mg
base/kg (=10 mg
salt/kg) PO given 6-
12 hr after initial
dose. Total dose = 25
mg salt/kg
Uncomplicated Chloroquine- Chloroquine phosphate (Aralen and Chloroquine
malaria/P. sensitive generics) 8 phosphate (Aralen
falciparum (Central 600 mg base (=1,000 mg salt) PO and generics) 8
or America west immediately, followed by 300 mg 10 mg base/kg PO
Species not of Panama base (=500 mg salt) PO at 6, 24, and immediately,
identified Canal; Haiti; 48 hr followed by 5 mg
 the Total dose: 1,500 mg base (=2,500 mg base/kg PO at 6, 24,
Dominican salt) and 48 hr
Republic; and or Total dose: 25 mg
most of the Hydroxychloroquine (Plaquenil and base/kg
Middle East) generics) or
620 mg base (=800 mg salt) PO Hydroxychloroquine
immediately, followed by 310 mg (Plaquenil and
base (=400 mg salt) PO at 6, 24, and generics)
48 hr 10 mg base/kg PO
Total dose: 1,550 mg base (=2,000 mg immediately,
salt) followed by 5 mg
base/kg PO at 6, 24,
and 48 hr
Total dose: 25 mg
base/kg
Uncomplicated All regions Chloroquine phosphate 8 : treatment Chloroquine
malaria/P. malariae as above phosphate: 8
or P. knowlesi or treatment as above
Hydroxychloroquine: treatment as or
above Hydroxychloroquine:
treatment as above

Uncomplicated All regions Chloroquine phosphate 8 plus Chloroquine

malaria/P. vivax or P. NOTE : for
primaquine phosphate 9 phosphate 8 plus
ovale suspected Chloroquine phosphate: treatment as primaquine
chloroquine- above phosphate 9
resistant P. Primaquine phosphate: 30 mg base Chloroquine
vivax, see row PO qd × 14 days phosphate: treatment
below or as above
Hydroxychloroquine plus primaquine Primaquine: 0.5 mg
phosphate 9 base/kg PO qd × 14
Hydroxychloroquine: treatment as days
above or
Primaquine phosphate: 30 mg base Hydroxychloroquine
PO qd × 14 days plus primaquine
phosphate 9
Hydroxychloroquine:
treatment as above
Primaquine
phosphate: 0.5 mg
base/kg PO qd × 14
days
Uncomplicated Chloroquine- Quinine sulfate plus either Quinine sulfate plus
malaria/P. vivax resistant 10 doxycycline or tetracycline plus either doxycycline 6
(Papua New primaquine phosphate 9 or tetracycline 6 plus
Guinea and Quinine sulfate: treatment as above primaquine
Indonesia) Doxycycline or tetracycline: treatment phosphate 9
as above Quinine sulfate:
Primaquine phosphate: treatment as treatment as above
above Doxycycline or
tetracycline:
treatment as above
Primaquine
 phosphate: treatment
as above
Atovaquone-proguanil plus Atovaquone-
primaquine phosphate 9 proguanil plus
Atovaquone-proguanil: treatment as primaquine
above phosphate 9
Primaquine phosphate: treatment as Atovaquone-
above proguanil: treatment
as above
Primaquine
phosphate:
treatment as above
Mefloquine plus primaquine Mefloquine plus
phosphate 9 primaquine
Mefloquine: treatment as above phosphate 9
Primaquine phosphate: treatment as Mefloquine:
above treatment as above
Primaquine
phosphate:
treatment as above
Uncomplicated Chloroquine- Chloroquine phosphate: treatment as Not applicable
malaria: sensitive above
alternatives for (See or
pregnant women 11 - uncomplicated Hydroxychloroquine: treatment as
13 malaria above
sections above
for
chloroquine-
sensitive
species by
region)
Chloroquine- Quinine sulfate plus clindamycin Not applicable
resistant Quinine sulfate: treatment as above
(See sections Clindamycin: treatment as above
above for or
regions with Mefloquine: treatment as above
chloroquine-
resistant P.
falciparum
and P. vivax )

Severe malaria 14 - 16 All regions Quinidine gluconate 14 plus 1 of the Quinidine
following: doxycycline, tetracycline, gluconate 14 plus 1
or clindamycin of the following:
Quinidine gluconate: 6.25 mg doxycycline, 4
base/kg (=10 mg salt/kg) loading dose tetracycline, 4 or
IV over 1-2 hr, then 0.0125 mg clindamycin
base/kg/min (=0.02 mg salt/kg/min) Quinidine
continuous infusion for at least 24 hr. gluconate: same
An alternative regimen is 15 mg mg/kg dosing and
base/kg (=24 mg salt/kg) loading dose recommendations as
IV infused over 4 hr, followed by 7.5 for adults
mg base/kg (=12 mg salt/kg) infused Doxycycline:
over 4 hr every 8 hr, starting 8 hr after treatment as above.
the loading dose (see package insert). If patient not able to
Once parasite density <1% and patient take oral medication,
can take oral medication, complete may give IV. For
treatment with oral quinine, dose as children <45 kg, give
above. Quinidine/quinine course = 7 2.2 mg/kg IV every
days in Southeast Asia; = 3 days in 12 hr and then switch
Africa or South America to oral doxycycline
Doxycycline: treatment as above. If (dose as above) as
patient not able to take oral soon as patient can
medication, give 100 mg IV every 12 take oral medication.
hr and then switch to oral doxycycline For children >45 kg,
(as above) as soon as patient can take use same dosing as
oral medication. For IV use, avoid for adults. For IV
rapid administration. Treatment use, avoid rapid
course = 7 days administration.
Tetracycline: treatment as above Treatment course = 7
Clindamycin: treatment as above. If days
patient not able to take oral Tetracycline:
medication, give 10 mg base/kg treatment as above
loading dose IV followed by 5 mg Clindamycin:
base/kg IV every 8 hr. Switch to oral treatment as above.
clindamycin (oral dose as above) as If patient not able to
soon as patient can take oral take oral medication,
medication. For IV use, avoid rapid give 10 mg base/kg
administration. Treatment course = 7 loading dose IV
days followed by 5 mg
Investigational new drug (contact base/kg IV every 8
CDC for information): hr. Switch to oral
Artesunate followed by 1 of the clindamycin (oral
following: atovaquone-proguanil dose as above) as
(Malarone), doxycycline soon as patient can
(clindamycin in pregnant women), take oral medication.
or mefloquine. Artemether- For IV use, avoid
lumefantrine is not included in rapid administration.
CDC treatment table but may also Treatment course = 7
be given as follow-up drug after days.
artesunate if available. Investigational new
drug (contact CDC
for information):
Artesunate followed
by 1 of the
following:
atovaquone-
proguanil
(Malarone),
clindamycin, or
mefloquine.
Artemether-
lumefantrine is not
included in CDC
treatment table but
may also be given
as follow-up drug
after artesunate if
available.
11 For pregnant women diagnosed with uncomplicated malaria caused by chloroquine-resistant P.

falciparum or chloroquine-resistant P. vivax infection, treatment with doxycycline or tetracycline is

generally not indicated. However, doxycycline or tetracycline may be used in combination with
quinine (as recommended for non-pregnant adults) if other treatment options are not available or
are not being tolerated, and the benefit is judged to outweigh the risks.
12 Atovaquone-proguanil and artemether-lumefantrine are generally not recommended for use in

pregnant women, particularly in the 1st trimester because of a lack of sufficient safety data. For
pregnant women diagnosed with uncomplicated malaria caused by chloroquine-resistant P.
falciparum infection, atovaquone-proguanil or artemether-lumefantrine may be used if other
treatment options are not available or are not being tolerated, and if the potential benefit is judged
to outweigh the potential risks.
13 For P. vivax and P. ovale infections, primaquine phosphate for radical treatment of hypnozoites

should not be given during pregnancy. Pregnant patients with P. vivax and P. ovale infections
should be maintained on chloroquine prophylaxis for the duration of their pregnancy. The
chemoprophylactic dose of chloroquine phosphate is 300 mg base (=500 mg salt) orally once per
week. After delivery, pregnant patients who do not have G6PD deficiency should be treated with
primaquine.
14 Persons with a positive blood smear or history of recent possible exposure and no other
recognized pathology who have 1 or more of the following clinical criteria (impaired
consciousness/coma, severe normocytic anemia, renal failure, pulmonary edema, acute
respiratory distress syndrome, circulatory shock, disseminated intravascular coagulation,
spontaneous bleeding, acidosis, hemoglobinuria, jaundice, repeated generalized convulsions,
and/or parasitemia of >5%) are considered to have manifestations of more severe disease.
Severe malaria is most often caused by P. falciparum.
15 Patients diagnosed with severe malaria should be treated aggressively with parenteral

antimalarial therapy. Treatment with IV quinidine should be initiated as soon as possible after the
diagnosis has been made. Patients with severe malaria should be given an IV loading dose of
quinidine unless they have received >40 mg/kg of quinine in the preceding 48 hr or if they have
received mefloquine within the preceding 12 hr. Consultation with a cardiologist and a physician
with experience treating malaria is advised when treating malaria patients with quinidine. During
administration of quinidine, blood pressure monitoring (for hypotension) and cardiac monitoring
(for widening of the QRS complex and/or lengthening of the QTc interval) should be monitored
continuously and blood glucose (for hypoglycemia) should be monitored periodically. Cardiac
complications, if severe, may warrant temporary discontinuation of the drug or slowing of the
intravenous infusion.
16 Pregnant women diagnosed with severe malaria should be treated aggressively with parenteral

antimalarial therapy.
IV, Intravenous(ly); PO, orally (by mouth); qd, once daily; bid, twice daily; tid, 3 times daily; qid, 4
times daily.
From US Centers for Disease Control and Prevention.
http://www.cdc.gov/malaria/resources/pdf/treatmenttable.pdf .

Table 314.3

Treatment of Uncomplicated Malaria in Malaria Endemic Areas

Treatment of Uncomplicated Malaria in Malaria Endemic Areas
REGIMENS
All Plasmodium falciparum malaria Artemether-lumefantrine, 1.5 mg/kg–9 mg/kg twice
daily for 3 days with food or milk
Artesunate, 4 mg/kg daily for 3 days, and
mefloquine, 25 mg base per kg (8 mg/kg/daily for 3
days* ) †
Dihydroartemisinin-piperaquine, 2.5 mg/kg–20
mg/kg daily for 3 days
Sensitive P. falciparum malaria Artesunate, 4 mg/kg daily for 3 days, and a single
dose of sulfadoxine-pyrimethamine, 25 mg/kg–1.25
mg/kg
Artesunate, 4 mg/kg, and amodiaquine,* 10 mg
base per kg daily for 3 days
Chloroquine-sensitive Plasmodium vivax, ‡ Plasmodium Chloroquine, 10 mg base per kg immediately, followed
malariae, ‡ Plasmodium ovale, ‡ Plasmodium knowlesi ‡ by 10 mg/kg at 24 hr and 5 mg/kg at 48 hr
* World Health Organization prequalified fixed dose formulations are preferable to loose tablets. A

taste masked dispersible pediatric tablet formulation of artemether-lumefantrine is available.

† High failure rates with artesunate-mefloquine have been reported on the Thailand–Myanmar

border.
‡ Any of the artemisinin combination treatments can be given except for artesunate-sulfadoxine-
pyrimethamine where P. vivax is resistant. Patients with P. vivax or P. ovale infections should also
be given a 14-day course of primaquine to eradicate hypnozoites (radical cure). However, severe
glucose-6-phosphate dehydrogenase deficiency is a contraindication because a 14-day course of
primaquine can cause severe hemolytic anemia in this group.
From White NJ, Pukrittayakamee S, Hien TT, et al: Malaria, Lancet 383:723–732, 2014.

Table 314.4
Treatment of Severe Malaria in Adults and Children in
Malaria-Endemic Areas
• Artesunate, 2.4 mg/kg by intravenous or intramuscular* injection, followed by 2.4 mg/kg at 12 hr and 24 hr;
continue injection once daily if necessary †
• Artemether, 3.2 mg/kg by immediate intramuscular* injection, followed by 1.6 mg/kg daily
• Quinine dihydrochloride, 20 mg salt per kg infused during 4 hr, followed by maintenance of 10 mg salt per kg
infused during 2-8 hr every 8 hr (can also be given by intramuscular injection* when diluted to 60-100 mg/mL)
Artesunate is the treatment of choice. Artemether should only be used if artesunate is unavailable. Quinine
dihydrochloride should be given only when artesunate and artemether are unavailable.
* Intramuscular injections should be given to the anterior thigh.

† Young children with severe malaria have lower exposure to artesunate and its main biologically
active metabolite dihydroartemisinin than do older children and adults. Revised dose regimens to
ensure similar drug exposures have been suggested.
From White NJ, Pukrittayakamee S, Hien TT, et al: Malaria, Lancet 383:723–732, 2014.
taste that usually requires that the cut tablet be disguised in another food, such as
chocolate syrup. Mefloquine should not be given to children if they have a
known hypersensitivity to mefloquine, are receiving cardiotropic drugs, have a
history of convulsive or certain psychiatric disorders, or travel to an area where
mefloquine resistance exists (the borders of Thailand with Myanmar and
Cambodia, western provinces of Cambodia, and eastern states of Myanmar).
Atovaquone-proguanil is started 1-2 days before travel, and mefloquine is started
2 wk before travel. It is important that these doses are given, both to allow
therapeutic levels of the drugs to be achieved and to be sure that the drugs are
tolerated. Doxycycline is an alternative for children >8 yr old. It must be given
daily and should be given with food. Side effects of doxycycline include
photosensitivity and vaginal yeast infections. Primaquine is a daily prophylaxis
option for children who cannot tolerate any of the other options, but it should be
provided in consultation with a travel medicine specialist if needed, and all
children should be checked for glucose-6-phosphate dehydrogenase deficiency
before prescribing this medication, because it is contraindicated in children with
G6PD deficiency. Provision of medication can be considered in individuals who
refuse to take prophylaxis or will be in very remote areas without accessible
medical care. Provision of medication for self-treatment of malaria should be
done in consultation with a travel medicine specialist, and the medication
provided should be different than that used for prophylaxis.

Table 314.5
Chemoprophylaxis of Malaria for Children

DOSAGE
AREA DRUG ADVANTAGES DISADVANTAGES BEST USE
(ORAL)
Chloroquine- Mefloquine* † <10 kg: 4.6 mg Once weekly Bitter taste Children
resistant area base (5 mg dosing No pediatric going to
salt)/kg/wk formulation malaria-
10-19 kg: Side effects of endemic
sleep area for ≥4
tab/wk
disturbance, wk
20-30 kg: vivid dreams Children
tab/wk unlikely to
31-45 kg: take daily
medication
tab/wk
>45 kg: 1
tab/wk (228 mg
base)
Doxycycline ‡ 2 mg/kg daily Inexpensive Cannot give to Children going
 (max 100 mg) children <8 yr to area for <4
Daily dosing wk who cannot
Must take with take or cannot
food or causes obtain
stomach upset atovaquone-
Photosensitivity proguanil
Atovaquone/proguanil Pediatric Pediatric Daily dosing Children going
§ (Malarone) tabs: formulation Expensive to malaria-
62.5 mg Generally Can cause endemic area
atovaquone/ well stomach upset for <4 wk
25 mg tolerated
proguanil
Adult tabs:
250 mg
proguanil/
100 mg
proguanil
5-8 kg: pediatric
tab once daily
(off-label)
9-10 kg:
pediatric tab
once daily (off-
label)
11-20 kg: 1
pediatric tab
once daily
21-30 kg: 2
pediatric tabs
once daily
31-40 kg: 3
pediatric tabs
once daily
>40 kg: 1 adult
tab once daily
Chloroquine- Chloroquine 5 mg Once Bitter taste Best
susceptible phosphate base/kg/wk weekly No pediatric medication for
area (max: 300 mg dosing formulation children
base) Inexpensive traveling to
Generally areas with
well Plasmodium
tolerated falciparum or
Plasmodium
vivax that is
chloroquine
susceptible
Drugs used for
chloroquine-resistant
areas can also be used
in chloroquine-
susceptible areas
* Chloroquine and mefloquine should be started 1-2 wk prior to departure and continued for 4 wk

after last exposure.

 R/O, rule out sepsis. Sample size dependent on available birth records/diagnoses at
birth. (Adapted from McLeod R, Boyer KM, Lee D, et al: Prematurity and severity are
associated with Toxoplasma gondii alleles [NCCCTS, 1981–2009], Clin Infect Dis
54:1595–1605, 2012.)

There is also a wide spectrum of symptoms of untreated congenital

toxoplasmosis that presents later in the 1st yr of life (Table 316.1 ). These
children may have IQ scores of <70, and have convulsions and severely
impaired vision.

Table 316.1
Signs and Symptoms Occurring Before Diagnosis or
During the Course of Untreated Acute Congenital
Toxoplasmosis in 152 Infants (A) and in 101 of These Same
Children After They Had Been Followed ≥4 Yr (B)

FREQUENCY OF OCCURRENCE IN PATIENTS WITH

SIGNS AND SYMPTOMS
“Neurologic” Disease* “Generalized” Disease †
A. INFANTS 108 PATIENTS (%) 44 PATIENTS (%)
Chorioretinitis 102 (94) 29 (66)
Abnormal cerebrospinal fluid 59 (55) 37 (84)
Anemia 55 (51) 34 (77)

Convulsions 54 (50) 8 (18)

Intracranial calcification 54 (50) 2 (4)
Jaundice 31 (29) 35 (80)
Hydrocephalus 30 (28) 0 (0)
Fever 27 (25) 34 (77)
Splenomegaly 23 (21) 40 (90)
Lymphadenopathy 18 (17) 30 (68)
Hepatomegaly 18 (17) 34 (77)
Vomiting 17 (16) 21 (48)
Microcephaly 14 (13) 0 (0)
Diarrhea 7 (6) 11 (25)
Cataracts 5 (5) 0 (0)
Eosinophilia 6 (4) 8 (18)
Abnormal bleeding 3 (3) 8 (18)
Hypothermia 2 (2) 9 (20)
Glaucoma 2 (2) 0 (0)
Optic atrophy 2 (2) 0 (0)
Microphthalmia 2 (2) 0 (0)
Rash 1 (1) 11 (25)
Pneumonitis 0 (0) 18 (41)
B. CHILDREN ≥4 YR OLD 70 PATIENTS (%) 31 PATIENTS (%)
Intellectual impairment 62 (89) 25 (81)
Convulsions 58 (83) 24 (77)
Spasticity and palsies 53 (76) 18 (58)
 Severely impaired vision 48 (69) 13 (42)
Hydrocephalus or microcephaly 31 (44) 2 (6)
Deafness 12 (17) 3 (10)
Normal 6 (9) 5 (16)
* Patients with otherwise undiagnosed central nervous system disease in the 1st yr of life.

† Patients with otherwise undiagnosed nonneurologic diseases during the 1st 2 mo of life.

Adapted from Eichenwald H: A study of congenital toxoplasmosis. In Slim JC, editor: Human
toxoplasmosis , Copenhagen, 1960, Munksgaard, pp. 41–49. Study performed in 1947. The most
severely involved institutionalized patients were not included in the later study of 101 children.

Systemic Signs
From 25% to >50% of infants with clinically apparent disease at birth are born
prematurely. Parasite clonal types other than type II are more often associated
with prematurity and more-severe disease. Intrauterine growth restriction, low
Apgar scores, and temperature instability are common. Other manifestations
may include lymphadenopathy, hepatosplenomegaly, myocarditis, pneumonitis,
nephrotic syndrome, vomiting, diarrhea, and feeding problems. Bands of
metaphyseal lucency and irregularity of the line of provisional calcification at
the epiphyseal plate may occur without periosteal reaction in the ribs, femurs,
and vertebrae. Congenital toxoplasmosis may be confused with erythroblastosis
fetalis resulting from isosensitization, although the Coombs test result is usually
negative with congenital T. gondii infection.

Skin
Cutaneous manifestations among newborn infants with congenital toxoplasmosis
include rashes and jaundice and/or petechiae secondary to thrombocytopenia, but
ecchymoses and large hemorrhages secondary to thrombocytopenia also occur.
Rashes may be fine punctate, diffuse maculopapular, lenticular, deep blue-red,
sharply defined macular, or diffuse blue and papular. Macular rashes involving
the entire body including the palms and soles, exfoliative dermatitis, and
cutaneous calcifications have been described. Jaundice with hepatic
involvement and/or hemolysis, cyanosis due to interstitial pneumonitis from
congenital infection, and edema secondary to myocarditis or nephrotic syndrome
may be present. Jaundice and conjugated hyperbilirubinemia may persist for
months.
diagnosis definitively and in immunocompromised patients for diagnosis and
monitoring treatment.

Table 316.2
Generalizations Concerning Clinical Presentations,
Toxoplasma -Specific Diagnostic Tests, and Treatment

CLINICAL TOXOPLASMA -SPECIFIC DIAGNOSTIC TESTS TREATMENT

SAMPLE
SETTING &
SOURCE G M A E Av AC/HS PCR Subinoculation Sp PSL*
MANIFESTATION
PRENATAL
Acute infection in Mother + + + + L Acute AF (17-18 NS + +
pregnant woman ≤18 wk) † No P
wk gestation and no 1st
clinical evidence of trimester
fetal infection
Acute infection in Mother + + + + L Acute AF (may not NS +
pregnant woman ≤18 be necessary) † No P
wk gestation and 1st
signs of fetal trimester
infection
Acute infection in Mother + + + + L Acute AF NS +
pregnant woman at
>21 wk gestation
Congenital infection Infant + + + + L Acute Placenta/buffy Placenta/buffy +
in infant coat coat
POSTNATAL
Acute, Child + + + + L Acute NS NS +
symptomatic
Acute, self-
limited
symptoms
Chronic, Child + − − − H Chronic NS NS
asymptomatic
Acute, severely Child + + + + L Acute § Body +
symptomatic fluids/buffy
coat
Immune Child +/ +/ +/ +/ +/ +/− § Body
compromised ¶ − − − − − fluids/buffy
coat
Laboratory accident Child +/ +/ +/ +/ +/ +/− NS NS +
|| − − − − −
Eye Disease
Quiescent scar** Child + +/ +/ +/ +/ +/− NS NS
− − − −
Active Child + +/ +/ +/ +/ +/− NS NS +
chorioretinitis** − − − −
Active CNVM** Child + +/ +/ +/ +/ +/− NS NS +
− − − −
1-3 yr old; 200 mg twice per day for 3 days for children 4-11 yr; 500 mg twice
per day for 3 days for adolescents and adults) produces cure rates comparable to
single-dose albendazole. Drug resistance has not been reported, but repeated
treatment for ascariasis may be necessary because reinfection is common.

Prevention
Although ascariasis is the most prevalent worm infection in the world, little
attention has been given to its control (Table 317.1 ). Anthelmintic
chemotherapy programs can be implemented in 1 of 3 ways: (1) offering
universal treatment to all individuals in an area of high endemicity; (2) offering
treatment targeted to groups with high frequency of infection, such as children
attending primary school; or (3) offering individual treatment based on intensity
of current or past infection. Improving education about and practices of sanitary
conditions and sewage facilities, discontinuing the practice of using human feces
as fertilizer, and education are the most effective long-term preventive measures.

Table 317.1

Clinical and Public Health Control of Soil-Transmitted Helminthiasis

CLINICAL DIAGNOSIS AND
PUBLIC HEALTH CONTROL
MANAGEMENT
Diagnosis Individual Community level (e.g., in select schools)
Diagnostic criteria Parasitological Residence in an area with soil-transmitted
helminthiasis prevalence >20%
Treatment approach Single dose or multiple dose Single-dose periodic mass treatment
Threshold for Travel history, symptoms and signs, Estimated prevalence of infection in target
treatment positive laboratory test population
Treatment objective Parasitological cure Decreased worm burden; reduction in
transmission
Ancillary treatment Based on clinical signs and symptoms Typically, only if included in mass treatment
(e.g., vitamin A supplementation)
Follow-up Parasitological test of cure; improvement Not usually done
in associated health conditions
Health education Recommended Recommended
(sanitation/hygiene)
From Jourdan PM, Lamberton PHL, Fenwick A, Addiss DG: Soil-transmitted helminth infections,
Lancet 391:252–262, 2018 (Table 1).

Bibliography
headache with elevated Toxocara antibody titers. Eosinophilia may be present in
50–75% of cases. The prevalence of positive Toxocara serology in the general
population supports that most children with T. canis infection are asymptomatic
and will not develop overt clinical sequelae over time. A correlation between
positive Toxocara serology and allergic asthma has also been described.

Table 324.1
Clinical Syndromes of Human Toxocariasis

CLINICAL AVERAGE INFECTIOUS INCUBATION LABORATORY

SYNDROME ELISA
FINDINGS AGE DOSE PERIOD FINDINGS
Visceral larva Fevers, 5 yr Moderate to Weeks to Eosinophilia, High (≥1
migrans hepatomegaly, high months leukocytosis, : 16)
asthma elevated IgE
Ocular larva Visual 12 yr Low Months to Usually none Low
migrans disturbances, years
retinal granulomas,
endophthalmitis,
peripheral
granulomas
Covert Abdominal pain, School-age Low to Weeks to years ± Low to
toxocariasis gastrointestinal to adult moderate Eosinophilia moderate
symptoms, ± Elevated
weakness, IgE
hepatomegaly,
pruritus, rash
ELISA, Enzyme-linked immunosorbent assay; IgE, immunoglobulin E; ±, with or without.
Adapted from Liu LX: Toxocariasis and larva migrans syndrome. In Guerrant RL, Walker DH,
Weller PF, editors: Tropical infectious diseases: principles, pathogens & practice, Philadelphia,
206, Churchill-Livingstone, p 1209.

Diagnosis
A presumptive diagnosis of toxocariasis can be established in a young child with
eosinophilia (>20%), leukocytosis, hepatomegaly, fevers, wheezing, and a
history of geophagia and exposure to puppies or unrestrained dogs. Supportive
laboratory findings include hypergammaglobulinemia and elevated
isohemagglutinin titers to A and B blood group antigens. Most patients with
VLM have an absolute eosinophil count >500/µL. Eosinophilia is less common
in patients with OLM. Biopsy confirms the diagnosis. When biopsies cannot be
obtained, an enzyme-linked immunosorbent assay using excretory-secretory
CHAPTER 328

Adult Tapeworm Infections

Philip R. Fischer, A. Clinton White Jr

Tapeworms are adult forms of cestodes , multicellular helminth parasites, that

live in human intestines and cause non–life-threatening illness. Invasive larval
forms of cestodes are associated with cysts that lead to severe human disease
such as neurocysticercosis (Taenia solium ; see Chapter 329 ) and
echinococcosis (mostly Echinococcus granulosa and E. multilocularis ; Chapter
330 ). The adult worms themselves are flat and multisegmented, varying in
length from 8 mm to 10 meters (m). Table 328.1 summarizes the key features of
tapeworms that affect children.

Table 328.1
Key Features of Common Tapeworms in Children

PARASITE
GEOGRAPHY SOURCE SYMPTOMS TREATMENT
SPECIES
Taenia saginata Asia, Africa, Cysts in beef Abdominal discomfort, motile Praziquantel or
Latin America proglottid migration, passing niclosamide,
segments possibly
nitazoxanide
Taenia solium Asia, Africa, Cysticerci in Minimal, proglottids in stool Praziquantel or
Latin America pork niclosamide,
possibly
nitazoxanide
Taenia asiatica Asia Pigs Minimal Praziquantel or
niclosamide,
possibly
nitazoxanide
Diphyllobothrium Worldwide, Plerocercoid Usually minimal; with prolonged or Praziquantel or
spp. often northern cysts in heavy infection with D. latum , niclosamide
areas freshwater vitamin B12 deficiency
fish
Hymenolepis Worldwide, Infected Mild abdominal discomfort Praziquantel,
often northern humans, niclosamide, or
 areas rodents nitazoxanide
Dipylidium Worldwide Domestic Proglottids in stool, anal pruritus Praziquantel or
caninum dogs and cats confused with pinworm niclosamide

Etiology
The beef tapeworm (Taenia saginata) , the pork tapeworm (T. solium), and the
Asian tapeworm (Taenia asiatica) are long worms (4-10 m) named for their
intermediate hosts (T. saginata , T. solium ) or geographic distribution (T.
asiatica ; larval host is the pig). The adult worms are found only in the human
intestine. As with the adult stage of all tapeworms, their body is a series of 100s
or 1000s of flattened segments (proglottids ) with an anterior attachment organ
(scolex) that anchors the parasite to the bowel wall. New segments arise from the
distal aspect of the scolex with progressively more mature segments attached
distally. The gravid terminal segments contain 50,000-100,000 eggs, and the
eggs or even detached intact proglottids pass out of the child through the anus
(with or separate from defecation). These tapeworms differ most significantly in
that the intermediate stage of the pork tapeworm (cysticercus ) can also infect
humans and cause significant morbidity (see Chapter 329 ), whereas the larval
stage of T. saginata does not cause human disease. T. asiatica is similar to and
often confused with the beef tapeworm.

Epidemiology
The pork and beef tapeworms are distributed worldwide, with the highest risk
for infection in Latin America, Africa, India, Southeast Asia, and China, where
the relevant intermediate host is raised domestically. The prevalence in adults
may not reflect the prevalence in young children, because cultural practices may
dictate how well meat is cooked and how much is served to children.

Pathogenesis
When children ingest raw or undercooked meat containing larval cysts, gastric
acid and bile facilitate release of immature scolices that attach to the lumen of
the small intestine. The parasite grows, adding new segments at the base of the
scolex. The terminal segments mature and after 2-3 mo produce eggs that are
CHAPTER 332

Major Symptoms and Signs of

Digestive Tract Disorders
Asim Maqbool, Chris A. Liacouras

Disorders of organs outside the gastrointestinal (GI) tract can produce symptoms
and signs that mimic digestive tract disorders and should be considered in the
differential diagnosis (Table 332.1 ). In children with normal growth and
development, treatment may be initiated without a formal evaluation based on a
presumptive diagnosis after taking a history and performing a physical
examination. Poor weight gain or weight loss is often associated with a
significant pathologic process and usually necessitates a more formal evaluation.

Table 332.1
Some Nondigestive Tract Causes of Gastrointestinal
Symptoms in Children
ANOREXIA
Systemic disease: inflammatory, neoplastic
Cardiorespiratory compromise
Iatrogenic: drug therapy, unpalatable therapeutic diets
Depression
Anorexia nervosa
VOMITING
Inborn errors of metabolism
Medications: erythromycin, chemotherapy, nonsteroidal antiinflammatory drugs, marijuana
Increased intracranial pressure
Brain tumor
Infection of the urinary tract
Labyrinthitis
Adrenal insufficiency
Pregnancy
Psychogenic
Abdominal migraine
Poisoning/toxins
Renal disease
DIARRHEA
Infection: otitis media, urinary tract infection
Uremia
Medications: antibiotics, cisapride
Tumors: neuroblastoma
Pericarditis
Adrenal insufficiency
CONSTIPATION
Hypothyroidism
Spina bifida
Developmental delay
Dehydration: diabetes insipidus, renal tubular lesions
Medications: narcotics
Lead poisoning
Infant botulism
ABDOMINAL PAIN
Pyelonephritis, hydronephrosis, renal colic
Pneumonia (lower lobe)
Pelvic inflammatory disease
Porphyria
Fabry disease
Angioedema
Endocarditis
Abdominal migraine
Familial Mediterranean fever
Sexual or physical abuse
Systemic lupus erythematosus
School phobia
Sickle cell crisis
Vertebral disk inflammation
Psoas abscess
Pelvic osteomyelitis or myositis
Medications
ABDOMINAL DISTENTION OR MASS
Ascites: nephrotic syndrome, neoplasm, heart failure
Discrete mass: Wilms tumor, hydronephrosis, neuroblastoma, mesenteric cyst, hepatoblastoma, lymphoma
Pregnancy
JAUNDICE
Hemolytic disease
Urinary tract infection
Sepsis
Hypothyroidism
Panhypopituitarism

Dysphagia
Difficulty in swallowing is termed dysphagia. Painful swallowing is termed
odynophagia . Globus is the sensation of something stuck in the throat without
a clear etiology. Swallowing is a complex process that starts in the mouth with
mastication and lubrication of food that is formed into a bolus. The bolus is
pushed into the pharynx by the tongue. The pharyngeal phase of swallowing is
rapid and involves protective mechanisms to prevent food from entering the
airway. The epiglottis is lowered over the larynx while the soft palate is elevated
against the nasopharyngeal wall; respiration is temporarily arrested while the
upper esophageal sphincter opens to allow the bolus to enter the esophagus. In
the esophagus, peristaltic coordinated muscular contractions push the food bolus
toward the stomach. The lower esophageal sphincter relaxes shortly after the
upper esophageal sphincter, so liquids that rapidly clear the esophagus enter the
stomach without resistance.
Dysphagia is classified as oropharyngeal dysphagia and esophageal
dysphagia. Oropharyngeal dysphagia occurs when the transfer of the food
bolus from the mouth to the esophagus is impaired (also termed transfer
dysphagia ). The striated muscles of the mouth, pharynx, and upper esophageal
sphincter are affected in oropharyngeal dysphagia. Neurologic and muscular
disorders can give rise to oropharyngeal dysphagia (Table 332.2 ). Chiari
malformations, Russell-Silver syndrome, and cri du chat may present with upper
esophageal sphincter dysfunction, manifest by dysphagia with solids. The most
serious complication of oropharyngeal dysphagia is life-threatening aspiration.

Table 332.2
Causes of Oropharyngeal Dysphagia
NEUROMUSCULAR DISORDERS
Cerebral palsy
Brain tumors
Cerebrovascular disease/stroke
Chiari malformation
Polio and postpolio syndromes
Multiple sclerosis
Myositis
Dermatomyositis
Myasthenia gravis
Muscular dystrophies
Acquired or inherited dystonia syndrome
Dysautonomia
METABOLIC AND AUTOIMMUNE DISORDERS
Hyperthyroidism
Systemic lupus erythematosus
Sarcoidosis
Amyloidosis
INFECTIOUS DISEASE
Meningitis
 Botulism
Diphtheria
Lyme disease
Neurosyphilis
Viral infection: polio, coxsackievirus, herpes, cytomegalovirus
STRUCTURAL LESIONS
Inflammatory: abscess, pharyngitis
Congenital web
Cricopharyngeal bar
Dental problems
Bullous skin lesions
Plummer-Vinson syndrome
Zenker diverticulum
Extrinsic compression: osteophytes, lymph nodes, thyroid swelling, aberrant
right subclavian artery (dysphagia lusoria)
OTHER
Corrosive injury
Side effects of medications
After surgery
After radiation therapy
Adapted from Gasiorowska A, Faas R: Current approach to dysphagia. Gastroenterol Hepatol
5(4):269–279, 2009.

A complex sequence of neuromuscular events is involved in the transfer of

foods to the upper esophagus. Abnormalities of the muscles involved in the
ingestion process and their innervation, strength, or coordination are associated
with transfer dysphagia in infants and children. In such cases, an oropharyngeal
problem is usually part of a more generalized neurologic or muscular problem
(botulism, diphtheria, neuromuscular disease). Painful oral lesions, such as acute
viral stomatitis or trauma, occasionally interfere with ingestion. If the nasal air
passage is seriously obstructed, the need for respiration causes severe distress
when suckling. Although severe structural, dental, and salivary abnormalities
would be expected to create difficulties, ingestion proceeds relatively well in
most affected children if they are hungry.
Esophageal dysphagia occurs when there is difficulty in transporting the
food bolus down the esophagus. Esophageal dysphagia can result from
neuromuscular disorders or mechanical obstruction (Table 332.3 ). Primary
motility disorders causing impaired peristaltic function and dysphagia are rare in
children. Eosinophilic esophagitis can present with esophageal dysphagia.
Achalasia is an esophageal motility disorder with associated inability of
relaxation of the lower esophageal sphincter, and it rarely occurs in children.
Motility of the distal esophagus is disordered after surgical repair of
tracheoesophageal fistula or achalasia. Abnormal motility can accompany
collagen vascular disorders. Mechanical obstruction can be intrinsic or extrinsic.
Intrinsic structural defects cause a fixed impediment to the passage of food bolus
because of a narrowing within the esophagus, as in a stricture, web, or tumor.
Extrinsic obstruction is caused by compression from vascular rings, mediastinal
lesions, or vertebral abnormalities. Structural defects typically cause more
problems in swallowing solids than liquids. In infants, esophageal web,
tracheobronchial remnant, or vascular ring can cause dysphagia. An esophageal
stricture secondary to esophagitis (chronic gastroesophageal reflux, eosinophilic
esophagitis, chronic infections) occasionally has dysphagia as the first
manifestation. An esophageal foreign body or a stricture secondary to a caustic
ingestion also causes dysphagia. A Schatzki ring, a thin ring of mucosal tissue
near the lower esophageal sphincter, is another mechanical cause of recurrent
dysphagia, and again is rare in children.

Table 332.3
Causes of Esophageal Dysphagia
NEUROMUSCULAR
Eosinophilic esophagitis
Achalasia cardia
Diffuse esophageal spasm
Scleroderma
GERD
INTRINSIC LESIONS
Foreign bodies including pills
Esophagitis: GERD, eosinophilic esophagitis, infections
Stricture: corrosive injury, pill induced, peptic
Esophageal webs
Esophageal rings
Esophageal diverticula
Neoplasm
Chagas disease
EXTRINSIC LESIONS
Vascular compression
Mediastinal lesion
Cervical osteochondritis
Vertebral abnormalities
GERD , Gastroesophageal reflux disease.
Adapted from Gasiorowska A, Faas R: Current approach to dysphagia. Gastroenterol Hepatol
5(4):269–279, 2009.

When dysphagia is associated with a delay in passage through the esophagus,

the patient may be able to point to the level of the chest where the delay occurs,
but esophageal symptoms are usually referred to the suprasternal notch. When a
patient points to the suprasternal notch, the impaction can be found anywhere in
the esophagus.

Regurgitation
Regurgitation is the effortless movement of stomach contents into the esophagus
and mouth. It is not associated with distress, and infants with regurgitation are
often hungry immediately after an episode. The lower esophageal sphincter
prevents reflux of gastric contents into the esophagus. Regurgitation is a result of
gastroesophageal reflux through an incompetent or, in infants, immature lower
esophageal sphincter. This is often a developmental process, and regurgitation or
“spitting” resolves with maturity. Regurgitation should be differentiated from
vomiting, which denotes an active reflex process with an extensive differential
diagnosis (Table 332.4 ).

Table 332.4
Differential Diagnosis of Emesis During Childhood

INFANT CHILD ADOLESCENT

COMMON
Gastroenteritis Gastroenteritis Gastroenteritis
Gastroesophageal reflux Systemic infection GERD
Overfeeding Gastritis Systemic infection
Anatomic obstruction* Toxic ingestion/poisoning Toxic
Systemic infection † Pertussis syndrome ingestion/poisoning/marijuana
Pertussis syndrome Medication Gastritis
Otitis media Reflux (GERD) Sinusitis
Sinusitis Inflammatory bowel disease
Otitis media Appendicitis
Anatomic obstruction* Migraine
Eosinophilic esophagitis Pregnancy
Medications
Ipecac abuse, bulimia
Concussion
RARE
Adrenogenital syndrome Reye syndrome Reye syndrome
Inborn errors of metabolism Hepatitis Hepatitis
Brain tumor (increased intracranial Peptic ulcer Peptic ulcer
pressure) Pancreatitis Pancreatitis
Subdural hemorrhage Brain tumor Cholecystitis
Food poisoning Increased intracranial Brain tumor
Rumination pressure Increased intracranial pressure
Renal tubular acidosis Middle ear Concussion
Ureteropelvic junction obstruction disease/labyrinthitis Middle ear disease/labyrinthitis
Pseudoobstruction Chemotherapy Chemotherapy
Achalasia Cyclic vomiting (migraine)
 Cyclic vomiting Biliary colic
(migraine) Renal colic
Esophageal stricture Porphyria
Duodenal hematoma Diabetic ketoacidosis
Inborn error of Adrenal insufficiency
metabolism Pseudoobstruction
Pseudoobstruction Intestinal tumor
Gastroparesis Gastroparesis
Achalasia
Superior mesentery artery
syndrome
Distal intestinal obstruction
syndrome
* Includes malrotation, pyloric stenosis, intussusception, Hirschsprung disease, adhesions,

hernias.
† Meningitis, sepsis.

GERD , Gastroesophageal reflux disease, inguinal hernia.

Anorexia
Anorexia means prolonged lack of appetite. Hunger and satiety centers are
located in the hypothalamus; it seems likely that afferent nerves from the GI tract
to these brain centers are important determinants of the anorexia that
characterizes many diseases of the stomach and intestine (see Chapter 47 ).
Satiety is stimulated by distention of the stomach or upper small bowel, the
signal being transmitted by sensory afferents, which are especially dense in the
upper gut. Chemoreceptors in the intestine, influenced by the assimilation of
nutrients, also affect afferent flow to the appetite centers. Impulses reach the
hypothalamus from higher centers, possibly influenced by pain or the emotional
disturbance of an intestinal disease. Other regulatory factors include hormones,
ghrelin, leptin, and plasma glucose, which, in turn, reflect intestinal function (see
Chapter 47 ).

Vomiting
Vomiting is a highly coordinated reflex process that may be preceded by
increased salivation and begins with involuntary retching. Violent descent of the
diaphragm and constriction of the abdominal muscles with relaxation of the
gastric cardia actively force gastric contents back up the esophagus. This process
is coordinated in the medullary vomiting center, which is influenced directly by
afferent innervation and indirectly by the chemoreceptor trigger zone and higher
central nervous system (CNS) centers. Many acute or chronic processes can
cause vomiting (see Tables 332.1 and 332.4 ).
Vomiting caused by obstruction of the GI tract is probably mediated by
intestinal visceral afferent nerves stimulating the vomiting center (Table 332.5 ).
If obstruction occurs below the second part of the duodenum, vomitus is usually
bile stained. Emesis can also become bile stained with repeated vomiting in the
absence of obstruction when duodenal contents are refluxed into the stomach.
Nonobstructive lesions of the digestive tract can also cause vomiting; this
includes diseases of the upper bowel, pancreas, liver, or biliary tree. CNS or
metabolic derangements and cyclic vomiting syndrome (Table 332.6 ) can lead
to severe, persistent emesis. Marijuana use among teens has also led to cannabis
hyperemesis syndrome (see Chapter 140.3 ).

Table 332.5
Causes of Gastrointestinal Obstruction
ESOPHAGUS
Congenital
Esophageal atresia
Vascular rings
Schatzki ring
Tracheobronchial remnant
Acquired
Esophageal stricture
Foreign body
Achalasia
Chagas disease
Collagen vascular disease
STOMACH
Congenital
Antral webs
Pyloric stenosis
Acquired
Bezoar, foreign body
Pyloric stricture (ulcer)
Chronic granulomatous disease of childhood
Eosinophilic gastroenteritis
Crohn disease
Epidermolysis bullosa
SMALL INTESTINE
Congenital
Duodenal atresia
Annular pancreas
Malrotation/volvulus
Malrotation/Ladd bands
 Ileal atresia
Meconium ileus
Meckel diverticulum with volvulus or intussusception
Inguinal hernia
Internal hernia
Intestinal duplication
Pseudoobstruction
Acquired
Postsurgical adhesions
Crohn disease
Intussusception
Distal ileal obstruction syndrome (cystic fibrosis)
Duodenal hematoma
Superior mesenteric artery syndrome
COLON
Congenital
Meconium plug
Hirschsprung disease
Colonic atresia, stenosis
Imperforate anus
Rectal stenosis
Pseudoobstruction
Volvulus
Colonic duplication
Acquired
Ulcerative colitis (toxic megacolon)
Chagas disease
Crohn disease
Fibrosing colonopathy (cystic fibrosis)

Table 332.6
Criteria for Cyclic Vomiting Syndrome
All of the criteria must be met for the consensus definition of cyclic vomiting syndrome:
• At least 5 attacks in any interval, or a minimum of 3 episodes during a 6-mo period
• Recurrent episodes of intense vomiting and nausea lasting 1 hr to 10 days and occurring at least 1 wk apart
• Stereotypical pattern and symptoms in the individual patient
• Vomiting during episodes occurs ≥4 times/hr for ≥1 hr
• Return to baseline health between episodes
• Not attributed to another disorder
From Li, B UK, Lefevre F, Chelimsky GG, et al: North American Society for Pediatric
Gastroenterology, Hepatology, and Nutrition consensus statement on the diagnosis and
management of cyclic vomiting syndrome. J Pediatr Gastroenterol Nutr 47:379–393, 2008.

Potential complications of emesis are noted in Table 332.7 . Broad

management strategies for vomiting in general and specific causes of emesis are
noted in Tables 332.8 and 332.9 .

Table 332.7
Complications of Vomiting

HISTORY, PHYSICAL EXAMINATION,

COMPLICATION PATHOPHYSIOLOGY
AND LABORATORY STUDIES
Metabolic Fluid loss in emesis Dehydration
HCl loss in emesis Alkalosis; hypochloremia
Na, K loss in emesis Hyponatremia; hypokalemia
Acidosis Dehydration
Nutritional Emesis of calories and nutrients Malnutrition; “failure to thrive”
Anorexia for calories and
nutrients
Mallory-Weiss tear Retching → tear at lesser curve of Forceful emesis → hematemesis
gastroesophageal junction
Esophagitis Chronic vomiting → esophageal acid Heartburn; Hemoccult + stool
exposure
Aspiration Aspiration of vomitus, especially in Pneumonia; neurologic dysfunction
context of obtundation
Shock Severe fluid loss in emesis or in Dehydration (accompanying diarrhea can explain
accompanying diarrhea acidosis?)
Severe blood loss in hematemesis Blood volume depletion
Pneumomediastinum, Increased intrathoracic pressure Chest x-ray
pneumothorax
Petechiae, retinal Increased intrathoracic pressure Normal platelet count
hemorrhages
From Kliegman RM, Greenbaum LA, Lye PS, editors: Practical strategies in pediatric diagnosis
and therapy, ed 2, Philadelphia, 2004, Elsevier, p 318.

Table 332.8
Pharmacologic Therapies for Vomiting Episodes

DISORDER/THERAPEUTIC
DRUG DOSAGE
DRUG CLASS
REFLUX
Dopamine antagonist Metoclopramide 0.1-0.2 mg/kg PO or IV qid
(Reglan)
GASTROPARESIS
Dopamine antagonist Metoclopramide 0.1-0.2 mg/kg PO or IV qid
(Reglan)
Motilin agonist Erythromycin 3-5 mg/kg PO or IV tid-qid
INTESTINAL PSEUDOOBSTRUCTION
Stimulation of intestinal migratory Octreotide 1 µg/kg SC bid-tid
myoelectric complexes (Sandostatin)
CHEMOTHERAPY
Dopamine antagonist Metoclopramide 0.5-1.0 mg/kg IV qid, with antihistamine
prophylaxis of extrapyramidal side effects
Serotoninergic 5-HT3 antagonist Ondansetron (Zofran) 0.15-0.3 mg/kg IV or PO tid
Phenothiazines (extrapyramidal, Prochlorperazine ≈0.3 mg/kg PO bid-tid
hematologic side effects) (Compazine)
 Chlorpromazine >6 mo of age: 0.5 mg/kg PO or IV tid-qid
(Thorazine)
Steroids Dexamethasone 0.1 mg/kg PO tid
(Decadron)
Cannabinoids Tetrahydrocannabinol 0.05-0.1 mg/kg PO bid-tid
(Nabilone)
POSTOPERATIVE
Ondansetron, See under chemotherapy
phenothiazines
MOTION SICKNESS, VESTIBULAR DISORDERS
Antihistamine Dimenhydrinate 1 mg/kg PO tid-qid
(Dramamine)
Anticholinergic Scopolamine Adults: 1 patch/3 days
(Transderm Scop)
ADRENAL CRISIS
Steroids Cortisol 2 mg/kg IV bolus followed by 0.2-0.4 mg/kg/hr IV
(±1 mg/kg IM)
ECG , Electrocardiogram; GI , gastrointestinal.
From Kliegman RM, Greenbaum LA, Lye PS, editors: Practical strategies in pediatric diagnosis
and therapy, ed 2, Philadelphia, 2004, Elsevier, p 317.

Table 332.9
Supportive and Nonpharmacologic Therapies for Vomiting
Episodes

DISEASE THERAPY
All Treat cause
• Obstruction: operate
• Allergy: change diet (±steroids)
• Metabolic error: Rx defect
• Acid peptic disease: H2RAs, PPIs, etc.
COMPLICATIONS
Dehydration IV fluids, electrolytes
Hematemesis Transfuse, correct coagulopathy
Esophagitis H2 RAs, PPIs
Malnutrition NG or NJ drip feeding useful for many chronic conditions
Meconium Gastrografin enema
ileus
DIOS Gastrografin enema; balanced colonic lavage solution (e.g., GoLYTELY)
Intussusception Barium enema; air reduction enema
Hematemesis Endoscopic: injection sclerotherapy or banding of esophageal varices; injection therapy, fibrin
sealant application, or heater probe electrocautery for selected upper GI tract lesions
Sigmoid Colonoscopic decompression
volvulus
Reflux Positioning; dietary measures (infants: rice cereal, 1 tbs/oz of formula)
Psychogenic Psychotherapy; tricyclic antidepressants; anxiolytics (e.g., diazepam: 0.1 mg/kg PO tid-qid)
components
DIOS , Distal intestinal obstruction syndrome; GI , gastrointestinal; H2 RA , H2 -receptor
antagonist; NG , nasogastric; NJ , nasojejunal; PPIs , proton pump inhibitors; tbs , tablespoon.
From Kliegman RM, Greenbaum LA, Lye PS, editors: Practical strategies in pediatric diagnosis
and therapy , ed 2, Philadelphia, 2004, Elsevier, p 319.

Diarrhea
Diarrhea is best defined as excessive loss of fluid and electrolyte in the stool.
Acute diarrhea is defined as sudden onset of excessively loose stools of >10
mL/kg/day in infants and >200 g/24 hr in older children, which lasts <14 days.
When the episode lasts longer than 14 days, it is called chronic or persistent
diarrhea.
Normally, a young infant has approximately 5 mL/kg/day of stool output; the
volume increases to 200 g/24 hr in an adult. The greatest volume of intestinal
water is absorbed in the small bowel; the colon concentrates intestinal contents
against a high osmotic gradient. The small intestine of an adult can absorb 10-11
L/day of a combination of ingested and secreted fluid, whereas the colon absorbs
approximately 0.5 L. Disorders that interfere with absorption in the small bowel
tend to produce voluminous diarrhea, whereas disorders compromising colonic
absorption produce lower-volume diarrhea. Dysentery (small-volume, frequent
bloody stools with mucus, tenesmus, and urgency) is the predominant symptom
of colitis.
The basis of all diarrheas is disturbed intestinal solute transport and water
absorption. Water movement across intestinal membranes is passive and is
determined by both active and passive fluxes of solutes, particularly sodium,
chloride, and glucose. The pathogenesis of most episodes of diarrhea can be
explained by secretory, osmotic, or motility abnormalities or a combination of
these (Table 332.10 ).

Table 332.10
Mechanisms of Diarrhea

PRIMARY STOOL
DEFECT EXAMPLES COMMENT
MECHANISM EXAMINATION
Secretory Decreased Watery, normal Cholera, toxigenic Escherichia Persists during fasting;
absorption, osmolality with ion coli ; carcinoid, VIP, bile salt malabsorption
increased gap <100 mOsm/kg neuroblastoma, congenital can also increase
secretion, chloride diarrhea, Clostridium intestinal water
electrolyte difficile , cryptosporidiosis secretion; no stool
transport (AIDS) leukocytes
 Osmotic Maldigestion, Watery, acidic, and Lactase deficiency, glucose- Stops with fasting;
transport reducing galactose malabsorption, increased breath
defects substances; lactulose, laxative abuse hydrogen with
ingestion of increased carbohydrate
unabsorbable osmolality with ion malabsorption; no stool
substances gap >100 mOsm/kg leukocytes
Increased Decreased Loose to normal- Irritable bowel syndrome, Infection can also
motility transit time appearing stool, thyrotoxicosis, postvagotomy contribute to increased
stimulated by dumping syndrome motility
gastrocolic reflex
Decreased Defect in Loose to normal- Pseudoobstruction, blind loop Possible bacterial
motility neuromuscular appearing stool overgrowth
unit(s) stasis
(bacterial
overgrowth)
Decreased Decreased Watery Short bowel syndrome, celiac Might require elemental
surface area functional disease, rotavirus enteritis diet plus parenteral
(osmotic, capacity alimentation
motility)
Mucosal Inflammation, Blood and Salmonella, Shigella infection; Dysentery evident in
invasion decreased increased WBCs in amebiasis; Yersinia, blood, mucus, and
colonic stool Campylobacter infection WBCs
reabsorption,
increased
motility
VIP , Vasoactive intestinal peptide; WBC , white blood cell.
From Kliegman RM, Greenbaum LA, Lye PS, editors: Practical strategies in pediatric diagnosis
and therapy, ed 2, Philadelphia, 2004, Elsevier, p 274.

Secretory diarrhea occurs when the intestinal epithelial cell solute transport
system is in an active state of secretion. It is often caused by a secretagogue,
such as cholera toxin, binding to a receptor on the surface epithelium of the
bowel and thereby stimulating intracellular accumulation of cyclic adenosine
monophosphate or cyclic guanosine monophosphate. Some intraluminal fatty
acids and bile salts cause the colonic mucosa to secrete through this mechanism.
Diarrhea not associated with an exogenous secretagogue can also have a
secretory component (congenital microvillus inclusion disease). Secretory
diarrhea is usually of large volume and persists even with fasting. The stool
osmolality is predominantly indicated by the electrolytes and the ion gap is 100
mOsm/kg or less. The ion gap is calculated by subtracting the concentration of
electrolytes from total osmolality:

Osmotic diarrhea occurs after ingestion of a poorly absorbed solute. The

solute may be one that is normally not well absorbed (magnesium, phosphate,
lactulose, or sorbitol) or one that is not well absorbed because of a disorder of
the small bowel (lactose with lactase deficiency or glucose with rotavirus
diarrhea). Malabsorbed carbohydrate is fermented in the colon, and short-chain
fatty acids are produced. Although short-chain fatty acids can be absorbed in the
colon and used as an energy source, the net effect is increase in the osmotic
solute load. This form of diarrhea is usually of lesser volume than a secretory
diarrhea and stops with fasting. The osmolality of the stool will not be explained
by the electrolyte content, because another osmotic component is present and so
the anion gap is >100 mOsm.
Motility disorders can be associated with rapid or delayed transit and are not
generally associated with large-volume diarrhea. Slow motility can be associated
with bacterial overgrowth leading to diarrhea. The differential diagnosis of
common causes of acute and chronic diarrhea is noted in Table 332.11 .

Table 332.11
Differential Diagnosis of Diarrhea

INFANT CHILD ADOLESCENT

ACUTE
Common
Gastroenteritis (viral > bacterial > Gastroenteritis (viral > Gastroenteritis (viral >
protozoal) bacterial > protozoal) bacterial > protozoal)
Systemic infection Food poisoning Food poisoning
Antibiotic associated Systemic infection Antibiotic associated
Overfeeding Antibiotic associated
Rare
Primary disaccharidase deficiency Toxic ingestion Hyperthyroidism
Hirschsprung toxic colitis Hemolytic uremic syndrome Appendicitis
Adrenogenital syndrome Intussusception
Neonatal opiate withdrawal
CHRONIC
Common
Postinfectious secondary lactase Postinfectious secondary Irritable bowel syndrome
deficiency lactase deficiency Inflammatory bowel disease
Cow's milk or soy protein Irritable bowel syndrome Lactose intolerance
intolerance (allergy) Celiac disease Giardiasis
Chronic nonspecific diarrhea of Cystic fibrosis Laxative abuse (anorexia
infancy Lactose intolerance nervosa)
Excessive fruit juice (sorbitol) Excessive fruit juice (sorbitol) Constipation with encopresis
ingestion ingestion
Celiac disease Giardiasis
Cystic fibrosis Inflammatory bowel disease
AIDS enteropathy AIDS enteropathy
Rare
 Primary immune defects Primary and acquired immune Secretory tumor
Autoimmune enteropathy defects Primary bowel tumor
IPEX and IPEX-like syndromes Secretory tumors Parasitic infections and
Glucose-galactose malabsorption Pseudoobstruction venereal diseases
Microvillus inclusion disease Sucrase-isomaltase deficiency Appendiceal abscess
(microvillus atrophy) Eosinophilic gastroenteritis Addison disease
Congenital transport defects Secretory tumors
(chloride, sodium)
Primary bile acid malabsorption
Factitious syndrome by proxy
Hirschsprung disease
Shwachman syndrome
Secretory tumors
Acrodermatitis enteropathica
Lymphangiectasia
Abetalipoproteinemia
Eosinophilic gastroenteritis
Short bowel syndrome
IPEX, Immunodysregulation polyendocrinopathy enteropathy X-linked.
From Kliegman RM, Greenbaum LA, Lye PS, editors: Practical strategies in pediatric diagnosis
and therapy, ed 2, Philadelphia, 2004, Elsevier, p 272.

Constipation
Any definition of constipation is relative and depends on stool consistency, stool
frequency, and difficulty in passing the stool. A normal child might have a soft
stool only every second or third day without difficulty; this is not constipation. A
hard stool passed with difficulty every third day should be treated as
constipation. Constipation can arise from defects either in filling or emptying the
rectum (Table 332.12 ).

Table 332.12
Causes of Constipation
NONORGANIC (FUNCTIONAL)—RETENTIVE
Anatomic
Anal stenosis, atresia with fistula
Imperforate anus
Anteriorly displaced anus
Intestinal stricture (postnecrotizing enterocolitis)
Anal stricture
Abnormal Musculature
Prune-belly syndrome
Gastroschisis
Down syndrome
Muscular dystrophy
 Intestinal Nerve or Muscle Abnormalities
Hirschsprung disease
Pseudoobstruction (visceral myopathy or neuropathy)
Intestinal neuronal dysplasia
Spinal cord lesions
Tethered cord
Autonomic neuropathy
Spinal cord trauma
Spina bifida
Chagas disease
Drugs
Anticholinergics
Narcotics
Methylphenidate
Phenytoin
Antidepressants
Chemotherapeutic agents (vincristine)
Pancreatic enzymes (fibrosing colonopathy)
Lead, arsenic, mercury
Vitamin D intoxication
Calcium channel blocking agents
Metabolic Disorders
Hypokalemia
Hypercalcemia
Hypothyroidism
Diabetes mellitus, diabetes insipidus
Porphyria
Intestinal Disorders
Celiac disease
Cow's milk protein intolerance
Cystic fibrosis (meconium ileus equivalent)
Inflammatory bowel disease (stricture)
Tumor
Connective tissue disorders
Systemic lupus erythematosus
Scleroderma
Psychiatric Diagnosis
Anorexia nervosa

A nursing infant might have very infrequent stools of normal consistency; this
is usually a normal pattern. True constipation in the neonatal period is most
likely secondary to Hirschsprung disease, intestinal pseudoobstruction, or
hypothyroidism.
Defective rectal filling occurs when colonic peristalsis is ineffective (in cases
of hypothyroidism or opiate use and when bowel obstruction is caused either by
a structural anomaly or by Hirschsprung disease). The resultant colonic stasis
leads to excessive drying of stool and a failure to initiate reflexes from the
rectum that normally trigger evacuation. Emptying the rectum by spontaneous
evacuation depends on a defecation reflex initiated by pressure receptors in the
rectal muscle. Therefore stool retention can also result from lesions involving
nerve endings probably account for the pain caused by ischemia. Perception of
these painful stimuli can be modulated by input from both cerebral and
peripheral sources. Psychologic factors are particularly important. Tables 332.13
and 332.14 list features of abdominal pain. Pain that suggests a potentially
serious organic etiology is associated with age younger than 5 yr; fever; weight
loss; bile- or blood-stained emesis; jaundice; hepatosplenomegaly; back or flank
pain or pain in a location other than the umbilicus; awakening from sleep in
pain; referred pain to shoulder, groin or back; elevated erythrocyte sedimentation
rate, white blood cell count, or C-reactive protein; anemia; edema;
hematochezia; or a strong family history of inflammatory bowel disease or celiac
disease.

Table 332.13
Chronic Abdominal Pain in Children

DISORDER CHARACTERISTICS KEY EVALUATIONS

NONORGANIC
Functional abdominal Nonspecific pain, often periumbilical Hx and PE; tests as indicated
pain
Irritable bowel Intermittent cramps, diarrhea, and Hx and PE
syndrome constipation
Nonulcer dyspepsia Peptic ulcer–like symptoms without Hx; esophagogastroduodenoscopy
abnormalities on evaluation of the upper
GI tract
GASTROINTESTINAL TRACT
Chronic constipation Hx of stool retention, evidence of Hx and PE; plain x-ray of abdomen
constipation on examination
Lactose intolerance Symptoms may be associated with lactose Trial of lactose-free diet; lactose breath
ingestion; bloating, gas, cramps, and hydrogen test
diarrhea
Parasite infection Bloating, gas, cramps, and diarrhea Stool evaluation for O&P; specific
(especially Giardia ) immunoassays for Giardia
Excess fructose or Nonspecific abdominal pain, bloating, Large intake of apples, fruit juice, or candy or
sorbitol ingestion gas, and diarrhea chewing gum sweetened with sorbitol
Crohn disease See Chapter 362
Peptic ulcer Burning or gnawing epigastric pain; Esophagogastroduodenoscopy, upper GI
worse on awakening or before meals; contrast x-rays, or MRI enteroscopy
relieved with antacids
Esophagitis Epigastric pain with substernal burning Esophagogastroduodenoscopy
Meckel diverticulum Periumbilical or lower abdominal pain; Meckel scan or enteroclysis
may have blood in stool (usually painless)
Recurrent Paroxysmal severe cramping abdominal Identify intussusception during episode or
intussusception pain; blood may be present in stool with lead point in intestine between episodes with
episode contrast studies of GI tract
Internal, inguinal, or Dull abdomen or abdominal wall pain PE, CT of abdominal wall
abdominal wall hernia
 Chronic appendicitis Recurrent RLQ pain; often incorrectly Barium enema, CT
or appendiceal diagnosed, may be rare cause of
mucocele abdominal pain
GALLBLADDER AND PANCREAS
Cholelithiasis RUQ pain, might worsen with meals Ultrasound of gallbladder
Choledochal cyst RUQ pain, mass ± elevated bilirubin Ultrasound or CT of RUQ
Recurrent pancreatitis Persistent boring pain, might radiate to Serum amylase and lipase ± serum
back, vomiting trypsinogen; ultrasound, CT, or MRI-ERCP
of pancreas
GENITOURINARY TRACT
Urinary tract infection Dull suprapubic pain, flank pain Urinalysis and urine culture; renal scan
Hydronephrosis Unilateral abdominal or flank pain Ultrasound of kidneys
Urolithiasis Progressive, severe pain; flank to inguinal Urinalysis, ultrasound, IVP, CT
region to testicle
Other genitourinary Suprapubic or lower abdominal pain; Ultrasound of kidneys and pelvis;
disorders genitourinary symptoms gynecologic evaluation
MISCELLANEOUS CAUSES
Abdominal migraine See text; nausea, family Hx migraine Hx
Abdominal epilepsy Might have seizure prodrome EEG (can require >1 study, including sleep-
deprived EEG)
Gilbert syndrome Mild abdominal pain (causal or Serum bilirubin
coincidental?); slightly elevated
unconjugated bilirubin
Familial Paroxysmal episodes of fever, severe Hx and PE during an episode, DNA diagnosis
Mediterranean fever abdominal pain, and tenderness with other
evidence of polyserositis
Sickle cell crisis Anemia Hematologic evaluation
Lead poisoning Vague abdominal pain ± constipation Serum lead level
Henoch-Schönlein Recurrent, severe crampy abdominal pain, Hx, PE, urinalysis
purpura occult blood in stool, characteristic rash,
arthritis
Angioneurotic edema Swelling of face or airway, crampy pain Hx, PE, upper GI contrast x-rays, serum C1
esterase inhibitor
Acute intermittent Severe pain precipitated by drugs, fasting, Spot urine for porphyrins
porphyria or infections
Anterior cutaneous Exquisite localized (~2 × 2 cm) Pain relief within 15 min of abdominal wall
nerve entrapment tenderness that is replicable, most often injection of local anesthetic; may need
syndrome (ACNES) right lower quadrant surgery
ERCP, Endoscopic retrograde cholangiopancreatography.EEG , Electroencephalogram; GI ,
gastrointestinal; Hx , history; IVP , intravenous pyelography; O&P , ova and parasites; PE ,
physical exam; RLQ , right lower quadrant; RUQ , right upper quadrant.

Table 332.14
Distinguishing Features of Acute Abdominal Pain in
Children

DISEASE ONSET LOCATION REFERRAL QUALITY COMMENTS

Pancreatitis Acute Epigastric, left upper Back Constant, sharp, Nausea, emesis,
quadrant boring tenderness
 Intestinal Acute or Periumbilical-lower abdomen Back Alternating Distention,
obstruction gradual cramping obstipation, emesis,
(colic) and increased bowel
painless periods sounds
Appendicitis Acute Periumbilical, then localized Back or Sharp, steady Anorexia, nausea,
(1-3 to lower right quadrant; pelvis if emesis, local
days) generalized with peritonitis retrocecal tenderness, fever with
peritonitis
Intussusception Acute Periumbilical-lower abdomen None Cramping, with Hematochezia, knees
painless periods in pulled-up position
Urolithiasis Acute, Back (unilateral) Groin Sharp, Hematuria
sudden intermittent,
cramping
Urinary tract Acute Back Bladder Dull to sharp Fever, costovertebral
infection angle tenderness,
dysuria, urinary
frequency
Pelvic Acute Pelvis, lower quadrant Upper thigh Aching, Vaginal discharge,
inflammatory peritoneal signs fever
disease
Small bowel Acute to Periumbilical None Cramping Emesis and
obstruction subacute diffuse obstipation
Ruptured Acute Pelvis, lower quadrant None Sharp, intense, Vaginal bleeding,
ectopic sudden localized shock
pregnancy

Visceral pain tends to be dull and aching and is experienced in the

dermatome from which the affected organ receives innervations. So, most often,
the pain and tenderness are not felt over the site of the disease process. Painful
stimuli originating in the liver, pancreas, biliary tree, stomach, or upper bowel
are felt in the epigastrium; pain from the distal small bowel, cecum, appendix, or
proximal colon is felt at the umbilicus; and pain from the distal large bowel,
urinary tract, or pelvic organs is usually suprapubic. The pain from the cecum,
ascending colon, and descending colon sometimes is felt at the site of the lesion
because of the short mesocecum and corresponding mesocolon. The pain caused
by appendicitis is initially felt in the periumbilical region, and pain from the
transverse colon is usually felt in the supra pubic region. The shifting
(localization) of pain is a pointer toward diagnosis; for example, periumbilical
pain of a few hours localizing to the right lower quadrant suggests appendicitis.
Radiation of pain can be helpful in diagnosis; for example, in biliary colic the
radiation of pain is toward the inferior angle of the right scapula, pancreatic pain
radiated to the back, and the renal colic pain is radiated to the inguinal region on
the same side.
Somatic pain is intense and usually well localized. When the inflamed viscus
comes in contact with a somatic organ such as the parietal peritoneum or the
abdominal wall, pain is localized to that site. Peritonitis gives rise to generalized
abdominal pain with rigidity, involuntary guarding, rebound tenderness, and
cutaneous hyperesthesia on physical examination.
Referred pain from extraintestinal locations, from shared central projections
with the sensory pathway from the abdominal wall, can give rise to abdominal
pain, as in pneumonia when the parietal pleural pain is referred to the abdomen.

Gastrointestinal Hemorrhage
Bleeding can occur anywhere along the GI tract, and identification of the site
may be challenging (Table 332.15 ). Bleeding that originates in the esophagus,
stomach, or duodenum can cause hematemesis. When exposed to gastric or
intestinal juices, blood quickly darkens to resemble coffee grounds; massive
bleeding is likely to be red. Red or maroon blood in stools, hematochezia,
signifies either a distal bleeding site or massive hemorrhage above the distal
ileum. Moderate to mild bleeding from sites above the distal ileum tends to
cause blackened stools of tarry consistency (melena); major hemorrhages in the
duodenum or above can also cause melena.

Table 332.15
Differential Diagnosis of Gastrointestinal Bleeding in
Childhood

INFANT CHILD ADOLESCENT

COMMON
Bacterial enteritis Bacterial enteritis Bacterial enteritis
Milk protein allergy intolerance Anal fissure Inflammatory bowel disease
Intussusception Colonic polyps Peptic ulcer/gastritis
Swallowed maternal blood Intussusception Prolapse (traumatic)
Anal fissure Peptic ulcer/gastritis gastropathy secondary to
Lymphonodular hyperplasia Swallowed epistaxis emesis
Prolapse (traumatic) Mallory-Weiss syndrome
gastropathy secondary to Colonic polyps
emesis Anal fissure
Mallory-Weiss syndrome
RARE
Volvulus Esophageal varices Hemorrhoids
Necrotizing enterocolitis Esophagitis Esophageal varices
Meckel diverticulum Meckel diverticulum Esophagitis
Stress ulcer, gastritis Lymphonodular hyperplasia Pill ulcer
Coagulation disorder Henoch-Schönlein purpura Telangiectasia-angiodysplasia
(hemorrhagic disease of Foreign body Graft versus host disease
newborn) Hemangioma, arteriovenous Duplication cyst
Esophagitis malformation • Angiodysplasia
 Sexual abuse • Angiodysplasia with von
Hemolytic-uremic syndrome Willebrand disease
Inflammatory bowel disease • Blue rubber bleb nevus syndrome
Coagulopathy
Duplication cyst
• Angiodysplasia
• Angiodysplasia with von
Willebrand disease
• Blue rubber bleb nevus syndrome

Erosive damage to the mucosa of the GI tract is the most common cause of
bleeding, although variceal bleeding secondary to portal hypertension occurs
often enough to require consideration. Prolapse gastropathy producing
subepithelial hemorrhage and Mallory-Weiss lesions secondary to mucosal tears
associated with emesis are causes of upper intestinal bleeds. Vascular
malformations are a rare cause in children; they are difficult to identify (Figs.
332.1 and 332.2 ). Upper intestinal bleeding is evaluated with
esophagogastroduodenoscopy. Evaluation of the small intestine is facilitated by
capsule endoscopy. The capsule-sized imaging device is swallowed in older
children or placed endoscopically in younger children. Lower GI bleeding is
investigated with a colonoscopy. In brisk intestinal bleeding of unknown
location, a tagged red blood cell scan is helpful in locating the site of the
bleeding, although CT angiography is usually diagnostic. Occult blood in stool is
usually detected by using commercially available fecal occult blood testing
cards, which are based on a chemical reaction between the chemical guaiac and
oxidizing action of a substrate (hemoglobin), giving a blue color. The guaiac test
is very sensitive, but random testing can miss chronic blood loss, which can lead
to iron-deficiency anemia. GI hemorrhage can produce hypotension and
tachycardia but rarely causes GI symptoms; brisk duodenal or gastric bleeding
can lead to nausea, vomiting, or diarrhea. The breakdown products of
intraluminal blood might tip patients into hepatic coma if liver function is
already compromised and can lead to elevation of serum bilirubin.
premolars. On the other hand, the permanent first, second, and third molars arise
from extension of the dental laminae distal to the second primary molars; buds
for these teeth develop at approximately 4 mo of gestation, 1 yr of age, and 4-5
yr of age, respectively.

Histodifferentiation–Morphodifferentiation
As the epithelial bud proliferates, the deeper surface invaginates and a mass of
mesenchyme becomes partially enclosed. The epithelial cells differentiate into
the ameloblasts that lay down an organic matrix that forms enamel; the
mesenchyme forms the dentin and dental pulp.

Calcification
After the organic matrix has been laid down, the deposition of the inorganic
mineral crystals takes place from several sites of calcification that later coalesce.
The characteristics of the inorganic portions of a tooth can be altered by
disturbances in formation of the matrix, decreased availability of minerals, or the
incorporation of foreign materials. Such disturbances can affect the color,
texture, or thickness of the tooth surface. Calcification of primary teeth begins at
3-4 mo in utero and concludes postnatally at approximately 12 mo, with
mineralization of the second primary molars (Table 333.1 ).

Table 333.1
Calcification, Crown Completion, and Eruption

TOOTH FIRST EVIDENCE OF CALCIFICATION CROWN COMPLETED ERUPTION

PRIMARY DENTITION
Maxillary
Central incisor 3-4 mo in utero 4 mo 7.5 mo
Lateral incisor 4.5 mo in utero 5 mo 8 mo
Canine 5.5 mo in utero 9 mo 16-20 mo
First molar 5 mo in utero 6 mo 12-16 mo
Second molar 6 mo in utero 10-12 mo 20-30 mo
Mandibular
Central incisor 4.5 mo in utero 4 mo 6.5 mo
Lateral incisor 4.5 mo in utero mo 7 mo
Canine 5 mo in utero 9 mo 16-20 mo
First molar 5 mo in utero 6 mo 12-16 mo
Second molar 6 mo in utero 10-12 mo 20-30 mo
PERMANENT DENTITION
 Maxillary
Central incisor 3-4 mo 4-5 yr 7-8 yr
Lateral incisor 10 mo 4-5 yr 8-9 yr
Canine 4-5 mo 6-7 yr 11-12 yr
First premolar 1.5- yr 5-6 yr 10-11 yr
Second premolar 2- yr 6-7 yr 10-12 yr
First molar At birth 2.5-3 yr 6-7 yr
Second molar 2.5-3 yr 7-8 yr 12-13 yr
Third molar 7-9 yr 12-16 yr 17-21 yr
Mandibular
Central incisor 3-4 mo 4-5 yr 6-7 yr
Lateral incisor 3-4 mo 4-5 yr 7-8 yr
Canine 4-5 mo 6-7 yr 9-10 yr
First premolar -2 yr 5-6 yr 10-12 yr
Second premolar -2.5 yr 6-7 yr 11-12 yr
First molar At birth 2.5-3 yr 6-7 yr
Second molar 2.5-3 yr 7-8 yr 11-13 yr
Third molar 8-10 yr 12-16 yr 17-21 yr
Modified from Logan WHG, Kronfeld R: Development of the human jaws and surrounding
structures from birth to age 15 years. J Am Dent Assoc 20:379, 1993.

Eruption
At the time of tooth bud formation, each tooth begins a continuous movement
toward the oral cavity. Table 333.1 lists the times of eruption of the primary and
permanent teeth.
Anomalies Associated With Eruption Pattern: Delayed eruption of the 20
primary teeth can be familial or indicate systemic or nutritional disturbances
such as hypopituitarism, hypothyroidism, cleidocranial dysplasia, trisomy 21,
and multiple other syndromes. Failure of eruption of single or small groups of
teeth can arise from local causes such as malpositioned teeth, supernumerary
teeth, cysts, or retained primary teeth. Premature loss of primary teeth is most
commonly caused by premature eruption of the permanent teeth. If the entire
dentition is advanced for age and sex, precocious puberty or hyperthyroidism
should be considered.
Natal teeth are observed in approximately 1 in 2,000 newborn infants, usually
in the position of the mandibular central incisors. Natal teeth are present at birth,
whereas neonatal teeth erupt in the first mo of life. Attachment of natal and
neonatal teeth is generally limited to the gingival margin, with little root
formation or bony support. They may be a supernumerary or a prematurely
erupted primary tooth. A radiograph can easily differentiate between the 2
CHAPTER 334

Disorders of the Oral Cavity

Associated With Other Conditions
Vineet Dhar

Disorders of the teeth and surrounding structures can occur in isolation or in

combination with other systemic conditions (Table 334.1 ). Most commonly,
medical conditions that occur during tooth development can affect tooth
formation or appearance. Damage to teeth during their development is
permanent.

Table 334.1

Dental Problems Associated With Selected Medical Conditions

MEDICAL CONDITION COMMON ASSOCIATED DENTAL OR ORAL FINDINGS
Cleft lip and palate Missing teeth, extra (supernumerary) teeth, shifting of arch segments,
feeding difficulties, speech problems
Kidney failure Mottled enamel (permanent teeth), facial dysmorphology
Cystic fibrosis Stained teeth with extensive medication, mottled enamel
Immunosuppression Oral candidiasis with potential for systemic candidiasis, cyclosporine-
induced gingival hyperplasia
Low birthweight Palatal groove, narrow arch with prolonged oral intubation; enamel
defects of primary teeth
Heart defects with susceptibility to Bacteremia from dental procedures or trauma
bacterial endocarditis
Neutrophil chemotactic deficiency Aggressive periodontitis (loss of supporting bone around teeth)
Diabetes mellitus type I (uncontrolled) Aggressive periodontitis
Neuromotor dysfunction Oral trauma from falling; malocclusion (open bite); gingivitis from lack
of hygiene
Prolonged illness (generalized) during Enamel hypoplasia of crown portions forming during illness
tooth formation
Seizures Gingival enlargement if phenytoin is used
Maternal infections Syphilis: abnormally shaped teeth
Vitamin D–dependent rickets Enamel hypoplasia

FIG. 338.6 Facial swelling from an abscessed primary molar. Resolution of the
inflammation can be achieved by a course of antibiotics, followed by either extraction
or root canal of the offending tooth.

Table 338.1
Red Flags Suggestive of a Spreading Dental Infection
• Pyrexia
• Tachycardia or tachypnea
• Trismus; may be relative due to pain or absolute due to a collection within the muscle causing muscle spasm in
cases of masticator space involvement
• Raised tongue and floor of mouth, drooling
• Periorbital cellulitis
• Difficulty with speaking, swallowing, and breathing
• Hypotension
• Increased white blood cell count
• Lymphadenopathy
• Dehydration
From Robertson DP, Keys W, Rautemaa-Richardson R, et al: Management of severe acute dental
mg fluoride per liter (ppm F) was introduced in the United States in the 1940s.
Because fluoride from water supplies is now one of several sources of fluoride,
the Department of Health and Human Services proposes to not have a fluoride
range, but instead to limit the recommendation to the lower limit of 0.7 ppm F.
The rationale is to balance the benefits of preventing dental caries with reducing
the chance of fluorosis. Children who reside in areas with fluoride-deficient
water supplies or who consume primarily bottled water, and are at risk for caries,
benefit from dietary fluoride supplements (Table 338.2 ). If the patient uses a
private water supply, it is necessary to get the water tested for fluoride levels
before prescribing fluoride supplements. To avoid potential overdoses, no
fluoride prescription should be written for more than a total of 120 mg of
fluoride. However, because of confusion regarding fluoride supplements among
practitioners and parents, association of supplements with fluorosis, and lack of
parent compliance with the daily administration, supplements may no longer be
the first-line approach for preventing caries in preschool-aged children.

Table 338.2
Supplemental Fluoride Dosage Schedule

FLUORIDE IN HOME WATER

AGE
<0.3 (PPM) 0.3-0.6 (PPM) >0.6 (PPM)
6 mo-3 yr 0.25* 0 0
3-6 yr 0.50 0.25 0
6-16 yr 1.00 0.50 0
* Milligrams of fluoride per day.

Topical fluoride on a daily basis can be achieved by using fluoridated

toothpaste. Supervised use of less than a pea-sized amount of toothpaste
(approximately 0.25 g) on the toothbrush in children between 3 and 6 yr of age
reduces the risk of fluorosis. Children younger than 3 yr of age should brush
with less than a smear or grain-sized amount of fluoridated toothpaste.
Professional topical fluoride applications performed semiannually reportedly
reduce caries by approximately 30%. Fluoride varnish is ideal for professional
applications in preschool children because of ease of use, even with non–dental
health providers, and its safety because of single-dose dispensers. Products that
are available come in containers of 0.25, 0.4, or 0.6 mL of varnish,
corresponding to 5.6, 9.0, and 13.6 mg fluoride, respectively. Fluoride varnish
should be administered twice a year for preschool children at moderate caries

FIG. 340.1 Tooth fractures can involve enamel, dentin, or pulp and can
occur in the crown or root of a tooth. PDL, periodontal ligament. (From
Pinkham JR: Pediatric dentistry: infancy through adolescence,
Philadelphia, 1988, WB Saunders, p. 172.)

Table 340.1

Injuries to Crowns of Teeth

TYPE OF
DESCRIPTION TREATMENT AND REFERRAL
TRAUMA
Enamel Incomplete fracture of enamel Initially might not require therapy but should be assessed
infraction without loss of tooth structure periodically by dentist
(crazing)
Enamel Fracture of only the tooth enamel Tooth may be smoothed or treated to replace fragment
fractures
Enamel Fracture of enamel and dentinal Refer as soon as possible. Area should be treated to preserve the
and dentin layer of the tooth. Tooth may be integrity of the underlying pulp
fracture sensitive to cold or air. Pulp may
become necrotic, leading to
periapical abscess
Enamel, Bacterial contamination can lead Refer immediately. The dental therapy of choice depends on the
dentin to pulpal necrosis and periapical extent of injury, the condition of the pulp, the development of the
fracture abscess. The tooth might have tooth, time elapsed from injury, and any other injuries to the
involving the appearance of bleeding or supporting structures. Therapy is directed toward minimizing
the pulp might display a small red spot contamination in an effort to improve the prognosis
The aphthous ulcer (canker sore) is a distinct oral lesion (Fig. 341.1 ), prone to
recurrence; Table 341.1 notes the differential diagnosis. Aphthous ulcers are
reported to develop in 20% of the population. Their etiology is unclear, but
allergic or immunologic reactions, emotional stress, genetics, and injury to the
soft tissues in the mouth have been implicated. Aphthous-like lesions may be
associated with inflammatory bowel disease, Behçet disease, gluten-sensitive
enteropathy, periodic fever-aphthae-pharyngitis-adenitis syndrome, Sweet
syndrome, HIV infection (especially if ulcers are large and slow to heal), and
cyclic neutropenia. Clinically, these ulcers are characterized by well-
circumscribed, ulcerative lesions with a white necrotic base surrounded by a red
halo. The lesions generally last 10-14 days and heal without scarring.
Nonprescription palliative therapies, such as benzocaine and topical lidocaine,
are effective, as are topical steroids. Tetracycline has benefit with severe
outbreaks, but caution is necessary in pregnant women, since it is classified as
FDA pregnancy category D. In younger children (≤8 yr), tetracycline can affect
developing teeth and cause permanent staining of the teeth.

FIG. 341.1 Major aphthous in a child. (From Gürkan A, Özlü SG, Altiaylik-Özer P, et al:
Recurrent aphthous stomatitis in childhood and adolescence: a single-center
experience. Pediatr Dermatol 32(4):476–480, 2015. Fig. 1.)

Table 341.1
Differential Diagnosis of Oral Ulceration
CONDITION COMMENT
Common
Aphthous ulcers (canker sores) Painful circumscribed lesions; recurrences
Traumatic ulcers Accidents, chronic cheek biter, after dental local anesthesia
Hand, foot, and mouth disease Painful; lesions on tongue, anterior oral cavity, hands, and feet
Herpangina Painful; lesions confined to soft palate and oropharynx
Herpetic gingivostomatitis Vesicles on mucocutaneous borders; painful, febrile
Recurrent herpes labialis Vesicles on lips; painful
Chemical burns Alkali, acid, aspirin; painful
Heat burns Hot food, electrical
Uncommon
Neutrophil defects Agranulocytosis, leukemia, cyclic neutropenia; painful
Systemic lupus erythematosus Recurrent; may be painless
Behçet syndrome Resembles aphthous lesions; associated with genital ulcers, uveitis
Necrotizing ulcerative gingivostomatitis Vincent stomatitis; painful
Syphilis Chancre or gumma; painless
Oral Crohn disease Aphthous-like; painful
Histoplasmosis Lingual
Pemphigus May be isolated to the oral cavity
Stevens-Johnson syndrome May be isolated to or appear initially in the oral cavity

Herpetic Gingivostomatitis
After an initial incubation period of approximately 1 wk, the primary infection
with herpes simplex virus manifests as fever and malaise, usually in a child
younger than 5 yr (see Chapter 279 ). The oral cavity can show various
expressions, including the gingiva becoming erythematous, mucosal
hemorrhages, and clusters of small vesicles erupting throughout the mouth.
There is often involvement of the mucocutaneous margin and perioral skin (Fig.
341.2 ). The oral symptoms generally are accompanied by fever,
lymphadenopathy, and difficulty eating and drinking. The symptoms usually
regress within 2 wk without scarring. Fluids should be encouraged because the
child may become dehydrated. Analgesics and anesthetic rinses can make the
child more comfortable. Oral acyclovir, if taken within the first 3 days of
symptoms in immunocompetent patients, is beneficial in shortening the duration
of symptoms. Caution should be exercised to prevent autoinoculation, especially
of the eyes.

FIG. 344.1 A continuous tracing of esophageal motility showing 2
swallows, as indicated by the pharyngeal contraction associated with
relaxation of the upper esophageal sphincter (UES) and followed by
peristalsis in the body of the esophagus. The lower esophageal sphincter
(LES) also displays a transient relaxation (arrow) unassociated with a
swallow. There is an episode of gastroesophageal reflux (*) recorded by a
pH probe at the time of the transient LES relaxation. (Courtesy John Dent,
FRACP, PhD and Geoffrey Davidson, MD.)

Table 344.1

Mechanical Events of the Oropharyngeal Swallow and Evidence of Dysfunction

MECHANICAL EVENT EVIDENCE OF DYSFUNCTION
Nasopharyngeal closure Nasopharyngeal regurgitation
Nasal voice
Laryngeal closure Aspiration during bolus transit
Upper esophageal sphincter opening Dysphagia
Post-swallow residue/aspiration
Diverticulum formation
 Tongue loading and bolus propulsion Sluggish misdirected bolus
Pharyngeal clearance Post-swallow residue in hypopharynx/aspiration
Modified from Pandolfino JE, Kahrilas PJ: Esophageal neuromuscular function and motility
disorders. In Feldman M, Friedman LS, Brandt LJ, editors: Sleisenger and Fordtran's
gastrointestinal and liver disease , ed 10, New York, 2016, Elsevier (Table 43.1).

In addition to relaxing to move swallowed material past the GEJ into the
stomach, the LES normally relaxes to vent swallowed air or to allow retrograde
expulsion of material from the stomach. Perhaps as an extension of these
functions, the normal LES also permits physiologic reflux episodes, brief events
that occur approximately 5 times in the first postprandial hour, particularly in the
awake state, but are otherwise uncommon. Transient LES relaxation, not
associated with swallowing, is the major mechanism underlying pathologic
reflux (see Fig. 344.1 ).
The close linkage of the anatomy of the upper digestive and respiratory tracts
has mandated intricate functional protections of the respiratory tract during
retrograde movement of gastric contents as well as during swallowing. The
protective functions include the LES tone, the bolstering of the LES by the
surrounding diaphragmatic crura, and the backup protection of the UES tone.
Secondary peristalsis, akin to primary peristalsis but without an oral component,
originates in the upper esophagus, triggered mainly by GER, and thereby also
clears refluxed gastric contents from the esophagus. Another protective reflex is
the pharyngeal swallow (initiated above the esophagus, but without lingual
participation). Multiple levels of protection against aspiration include the
rhythmic coordination of swallowing and breathing and a series of protective
reflexes with esophagopharyngeal afferents and efferents that close the UES or
larynx. These reflexes include the esophago-UES contractile reflex, the
pharyngo-UES contractile reflex, the esophagoglottal closure reflex, and 2
pharyngoglottal adduction reflexes. The last 2 reflexes have chemoreceptors on
the laryngeal surface of the epiglottis and mechanoreceptors on the aryepiglottic
folds as their sites of stimulus. It is likely that interactions between the
esophagus and the respiratory tract, which cause extraesophageal manifestations
of gastroesophageal reflux disease (GERD), will be explained by subtle
abnormalities in these protective reflexes.

344.1

FIG. 345.3 H-type fistula (arrow) demonstrated in an infant after barium
swallow on frontal-oblique chest x-ray. The tracheal aspect of the fistula is
characteristically superior to the esophageal aspect. Barium is seen to
outline the tracheobronchial tree. (From Wyllie R, Hyams JS, editors:
Pediatric gastrointestinal and liver disease, ed 3, Philadelphia, 2006,
Saunders Elsevier, p. 299.)

Table 345.1
Clinical Aspects of Esophageal Developmental Anomalies

AGE AT PREDOMINANT
ANOMALY DIAGNOSIS TREATMENT
PRESENTATION SYMPTOMS
Isolated Newborns Regurgitation of Esophagogram* Surgery
atresia feedings Plain film: gasless
Aspiration abdomen
Atresia + Newborns Regurgitation of Esophagogram* Surgery
distal TEF feedings Plain film: gas-filled
Aspiration abdomen
H-type TEF Infants to adults Recurrent pneumonia Esophagogram* Surgery
 Bronchiectasis Bronchoscopy †
Esophageal Infants to adults Dysphagia Esophagogram* Dilation ‡
stenosis Food impaction Endoscopy † Surgery §
Duplication Infants to adults Dyspnea, stridor, EUS* Surgery
cyst cough (infants) MRI/CT †
Dysphagia, chest pain
(adults)
Vascular Infants to adults Dyspnea, stridor, Esophagogram* Dietary
anomaly cough (infants) Angiography † modification ‡
Dysphagia (adults) MRI/CT/EUS Surgery §
Esophageal Children to adults Dysphagia Esophagogram* Dilation ‡
ring Endoscopy † Endoscopic
incision §
Esophageal Children to adults Dysphagia Esophagogram* Bougienage
web Endoscopy †
* Diagnostic test of choice.

†
Confirmatory test.
‡ Primary therapeutic approach.

§ Secondary therapeutic approach.

TEF, tracheoesophageal fistula.

From Madanick R, Orlando RC: Anatomy, histology, embryology, and developmental anomalies of
the esophagus. In Feldman M, Friedman LS, Brandt LJ, editors: Sleisenger and Fordtran's
gastrointestinal and liver disease , ed 10, New York, 2016, Elsevier, Table 42.2.

Management
Initially, maintaining a patent airway, pre-operative proximal pouch
decompression to prevent aspiration of secretions, and use of antibiotics to
prevent consequent pneumonia are paramount. Prone positioning minimizes
movement of gastric secretions into a distal fistula, and esophageal suctioning
minimizes aspiration from a blind pouch. Endotracheal intubation with
mechanical ventilation is to be avoided if possible because it can worsen
distention of the stomach. Surgical ligation of the TEF and primary end-to-end
anastomosis of the esophagus via right-sided thoracotomy constitute the current
standard surgical approach. In the premature or otherwise complicated infant, a
primary closure may be delayed by temporizing with fistula ligation and
gastrostomy tube placement. If the gap between the atretic ends of the esophagus
is >3 to 4 cm (>3 vertebral bodies), primary repair cannot be done; options
include using gastric, jejunal, or colonic segments interposed as a neoesophagus.
Careful search must be undertaken for the common associated cardiac and other
locus is termed GERD1.

Table 349.1
Symptoms According to Age

MANIFESTATIONS INFANTS CHILDREN ADOLESCENTS AND ADULTS

Impaired quality of life +++ +++ +++
Regurgitation ++++ + +
Excessive crying/irritability +++ + –
Vomiting ++ ++ +
Food refusal/feeding disturbances/anorexia ++ + +
Persisting hiccups ++ + +
Failure to thrive ++ + –
Abnormal posturing/Sandifer syndrome ++ + –
Esophagitis + ++ +++
Persistent cough/aspiration pneumonia + ++ +
Wheezing/laryngitis/ear problems + ++ +
Laryngomalacia/stridor/croup + ++ –
Sleeping disturbances + + +
Anemia/melena/hematemesis + + +
Apnea/BRUE/desaturation + – –
Bradycardia + ? ?
Heartburn/pyrosis ? ++ +++
Epigastric pain ? + ++
Chest pain ? + ++
Dysphagia ? + ++
Dental erosions/water brush ? + +
Hoarseness/globus pharyngeus ? + +
Chronic asthma/sinusitis – ++ +
Laryngostenosis/vocal nodule problems – + +
Stenosis – (+) +
Barrett/esophageal adenocarcinoma – (+) +
+++ , Very common; ++ common; + possible; (+) rare; − absent; ? unknown; BRUE , brief resolved

unexplained event; previously called as ALTE , apparent life-threatening event.

From Wyllie R, Hyams JS, Kay M, editors: Pediatric gastrointestinal and liver disease, ed 4,
Philadelphia, 2011, WB Saunders, Table 22.3, p. 235.

Clinical Manifestations
Most of the common clinical manifestations of esophageal disease can signify
the presence of GERD and are generally thought to be mediated by the
pathogenesis involving acid GER (Table 349.2 ). Although less noxious for the
esophageal mucosa, nonacid reflux events are recognized to play an important
role in extraesophageal disease manifestations. Infantile reflux manifests more
often with regurgitation (especially postprandially), signs of esophagitis
(irritability, arching, choking, gagging, feeding aversion), and resulting failure to
thrive; symptoms resolve spontaneously in the majority of infants by 12-24 mo.
Older children can have regurgitation during the preschool years; this complaint
diminishes somewhat as children age, and complaints of abdominal and chest
pain supervene in later childhood and adolescence. Occasional children present
with food refusal or neck contortions (arching, turning of head) designated
Sandifer syndrome. The respiratory presentations are also age dependent:
GERD in infants may manifest as obstructive apnea or as stridor or lower airway
disease in which reflux complicates primary airway disease such as
laryngomalacia or bronchopulmonary dysplasia. Otitis media, sinusitis,
lymphoid hyperplasia, hoarseness, vocal cord nodules, and laryngeal edema have
all been associated with GERD. Airway manifestations in older children are
more commonly related to asthma or to otolaryngologic disease such as
laryngitis or sinusitis. Despite the high prevalence of GERD symptoms in
asthmatic children, data showing direction of causality are conflicting.

Table 349.2
Symptoms and Signs That May Be Associated With
Gastroesophageal Reflux
SYMPTOMS
Recurrent regurgitation with or without vomiting
Weight loss or poor weight gain
Irritability in infants
Ruminative behavior
Heartburn or chest pain
Hematemesis
Dysphagia, odynophagia
Wheezing
Stridor
Cough
Hoarseness
SIGNS
Esophagitis
Esophageal stricture
Barrett esophagus
Laryngeal/pharyngeal inflammation
Recurrent pneumonia
Anemia
Dental erosion
Feeding refusal
Dystonic neck posturing (Sandifer syndrome)
 Apnea spells
Apparent life-threatening events
From Wyllie R, Hyams JS, Kay M, editors: Pediatric gastrointestinal and liver disease, ed 4,
Philadelphia, 2011, WB Saunders, Table 22.1, p. 235.

Neurologically challenged children are one group that is recognized to be at

an increased risk for GERD. It is not well established if the greater risk is
conferred due to inadequate defensive mechanisms and/or inability to express
symptoms. A low clinical threshold is important in the early identification and
prompt treatment of GERD symptoms in these individuals.

Diagnosis
For most of the typical GERD presentations, particularly in older children, a
thorough history and physical examination suffice initially to reach the
diagnosis. This initial evaluation aims to identify the pertinent positives in
support of GERD and its complications and the negatives that make other
diagnoses unlikely. The history may be facilitated and standardized by
questionnaires (e.g., the Infant Gastroesophageal Reflux Questionnaire, the I-
GERQ, and its derivative, the I-GERQ-R), which also permit quantitative scores
to be evaluated for their diagnostic discrimination and for evaluative assessment
of improvement or worsening of symptoms. The clinician should be alerted to
the possibility of other important diagnoses in the presence of any alarm or
warning signs : bilious emesis, frequent projectile emesis, gastrointestinal
bleeding, lethargy, organomegaly, abdominal distention, micro- or macrocephaly,
hepatosplenomegaly, failure to thrive, diarrhea, fever, bulging fontanelle, and
seizures. The important differential diagnoses to consider in the evaluation of an
infant or a child with chronic vomiting are milk and other food allergies,
eosinophilic esophagitis, pyloric stenosis, intestinal obstruction (especially
malrotation with intermittent volvulus), nonesophageal inflammatory diseases,
infections, inborn errors of metabolism, hydronephrosis, increased intracranial
pressure, rumination, and bulimia. Focused diagnostic testing, depending on the
presentation and the differential diagnosis, can then supplement the initial
examination.
Most of the esophageal tests are of some use in particular patients with
suspected GERD. Contrast (usually barium) radiographic study of the
esophagus and upper gastrointestinal tract is performed in children with
vomiting and dysphagia to evaluate for achalasia, esophageal strictures and
patients. It may also be an incidental finding in asymptomatic patients, notably
in those with EoE receiving topical swallowed corticosteroids. Esophageal viral
infections can also manifest in immunocompetent hosts as an acute febrile
illness. Infectious esophagitis, like other forms of esophageal inflammation,
occasionally progresses to esophageal stricture. Diagnosis of infectious
esophagitis is made by endoscopy, usually notable for white plaques in candida,
multiple superficial ulcers or volcano ulcers in herpes simplex virus, and single
deep ulcer in cytomegalovirus. Histopathologic examination solidifies the
diagnosis with the detection of yeast and pseudohyphae in Candida; tissue
invasion distinguishes esophagitis from mere colonization. Multinucleated giant
cells with intranuclear Cowdry type A (eosinophilic) and type B (ground glass
appearance) inclusions in HSV, and both intranuclear and intracytoplasmic
inclusions producing an owl's eye appearance in CMV are typically described.
Adding polymerase chain reaction, tissue-viral culture, and
immunocytochemistry enhances the diagnostic sensitivity and precision.
Treatment is with appropriate antimicrobial agents; azole therapy, particularly
oral fluconazole for Candida; oral acyclovir for HSV, and oral valganciclovir for
CMV, or alternatively intravenous ganciclovir in severe CMV disease.

Pill Esophagitis
This acute injury is produced by contact with a damaging agent. Medications
implicated in pill esophagitis include tetracycline, doxycycline, potassium
chloride, ferrous sulfate, nonsteroidal antiinflammatory medications, cloxacillin,
and alendronate (Table 350.1 ). Most often the offending tablet is ingested at
bedtime with inadequate water. This practice often produces acute discomfort
followed by progressive retrosternal pain, odynophagia, and dysphagia.
Endoscopy shows a focal lesion often localized to one of the anatomic narrowed
regions of the esophagus or to an unsuspected pathologic narrowing (Fig. 350.4
). Treatment is supportive; lacking much evidence, sucralfate, antacids, topical
anesthetics, and bland or liquid diets are often used. The offending pill may be
restarted after complete resolution of symptoms, if deemed necessary, though
with clear emphasis on ingestion with adequate volume of water, usually at least
4 oz.

Table 350.1
Medications Commonly Associated With Esophagitis or
Esophageal Injury
ANTIBIOTICS
Clindamycin
Doxycycline
Penicillin
Rifampin
Tetracycline
ANTIVIRAL AGENTS
Nelfinavir
Zalcitabine
Zidovudine
BISPHOSPHONATES
Alendronate
Etidronate
Pamidronate
CHEMOTHERAPEUTIC AGENTS
Bleomycin
Cytarabine
Dactinomycin
Daunorubicin
5-Fluorouracil
Methotrexate
Vincristine
NSAIDs
Aspirin
Ibuprofen
Naproxen
OTHER MEDICATIONS
Ascorbic acid
Ferrous sulfate
Lansoprazole
Multivitamins
Potassium chloride
Quinidine
Theophylline
From Katzka DA: Esophageal disorders caused by medications, trauma, and infection. In
Feldman M, Friedman LS, Brandt LJ, editors: Sleisenger and Fordtran's gastrointestinal and liver
disease , ed 10, 2016, Box 46.1.
coagulation necrosis and a somewhat protective thick eschar. They can produce
severe gastritis, and volatile acids can result in respiratory symptoms. Children
younger than 5 yr of age account for half of the cases of caustic ingestions, and
boys are far more often involved than girls.

Table 353.1
Ingestible Caustic Materials Around the House

OTHER
CATEGORY MOST DAMAGING AGENTS
AGENTS
Alkaline drain cleaners, milking machine Sodium or potassium hydroxide Ammonia
pipe cleaners Sodium
hypochlorite
Aluminum
particles
Acidic drain openers Hydrochloric acid
Sulfuric acid
Toilet cleaners Hydrochloric acid Ammonium
Sulfuric acid chloride
Phosphoric acid Sodium
Other acids hypochlorite
Oven and grill cleaners Sodium hydroxide
Perborate (borax)
Denture cleaners Persulfate (sulfur)
Hypochlorite (bleach)
Dishwasher detergent Sodium hydroxide
• Liquid Sodium hypochlorite
• Powdered Sodium carbonate
• Packaged
Bleach Sodium hypochlorite Ammonia salt
Swimming pool chemicals Acids, alkalis, chlorine
Battery acid (liquid) Sulfuric acid
Disk batteries Electric current Zinc or other
metal salts
Rust remover Hydrofluoric, phosphoric, oxalic, and other acids
Household delimers Phosphoric acid
Hydroxyacetic acid
Hydrochloric acid
Barbeque cleaners Sodium and potassium hydroxide
Glyphosate surfactant (RoundUp) acid Glyphosate herbicide Surfactants
Hair relaxer Sodium hydroxide
Weed killer Dichlorophenoxyacetate, ammonium phosphate,
propionic acid
From Wylie R, Hyams JS, Kay M, editors: Pediatric gastrointestinal and liver disease , ed 4,
Philadelphia, 2011, WB Saunders, Table 19.1, p. 198.
Source: National Library of Medicine: Health and safety information on household products
(website). http://householdproducts.nlm.nih.gov/
 Caustic ingestions produce signs and symptoms such as vomiting, drooling,
refusal to drink, oral burns, dysphagia, dyspnea, abdominal pain, hematemesis,
and stridor. Twenty percent of patients develop esophageal strictures. Absence of
oropharyngeal lesions does not exclude the possibility of significant
esophagogastric injury, which can lead to perforation or stricture. The absence of
symptoms is usually associated with no or minimal lesions; hematemesis,
respiratory distress, or presence of at least 3 symptoms predicts severe lesions.
An upper endoscopy is recommended as the most efficient means of rapid
identification of tissue damage and must be undertaken in all symptomatic
children.
Dilution by water or milk is recommended as acute treatment, but
neutralization, induced emesis, and gastric lavage are contraindicated. Treatment
depends on the severity and extent of damage (Table 353.2 , Fig. 353.5 ).
Stricture risk is increased by circumferential ulcerations, white plaques, and
sloughing of the mucosa and is reported to occur in 70–100% of grade IIB and
grade III caustic esophagitis. Strictures can require treatment with dilation, and
in some severe cases, surgical resection and colon or small bowel interposition
are needed. Silicone stents (self-expanding) placed endoscopically after a
dilation procedure can be an alternative and conservative approach to the
management of strictures. Rare late cases of superimposed esophageal
carcinoma are reported. The role of corticosteroids is controversial; they are not
recommended in grade 1 burns, but they can reduce the risk of strictures in
more-advanced caustic esophagitis. Many centers also use proton pump
inhibitors as well as antibiotics in the initial treatment of caustic esophagitis on
the premise that reducing superinfection in the necrotic tissue bed will, in turn,
lower the risk of stricture formation. Studies examining the role of antibiotics in
caustic esophagitis have not reported a clinically significant benefit even in those
with grade 2 or greater severity of esophagitis.

Table 353.2

Classification of Caustic Injury

GRADE VISIBLE APPEARANCE CLINICAL SIGNIFICANCE
Grade 0 History of ingestion but no visible damage or symptoms Able to take fluids immediately
Grade 1 Edema, loss of normal vascular pattern, hyperemia, no Temporary dysphagia, able to swallow
transmucosal injury within 0-2 days, no long-term sequelae
Grade 2a Transmucosal injury with friability, hemorrhage, Scarring, no circumferential damage (no
blistering, exudate, scattered superficial ulceration stenosis), no long-term sequelae
Grade 2b Grade 2a plus discrete ulceration and/or circumferential Small risk of perforation, scarring that may
 ulceration result in later stenosis
Grade 3a Scattered deep ulceration with necrosis of the tissue Risk of perforation, high risk of later
stenosis
Grade 3b Extensive necrotic tissue High risk of perforation and death, high risk
of stenosis
From Wylie R, Hyams JS, Kay M, editors: Pediatric gastrointestinal and liver disease , ed 4,
Philadelphia, 2011, WB Saunders, Table 19.2, p. 199.

FIG. 353.5 Computed Tomography (CT) Grading of Corrosive Injuries of
the Esophagus and the Stomach. Grade 1, normal appearance; grade 2,
wall and soft tissue edema, increased wall enhancement (arrow) ; grade 3,
transmural necrosis with absent wall enhancement (arrow) . (From Chirica
M, Bonavina L, Kelly MD, et al: Caustic ingestion, Lancet 389:2041–2050,
2017, Fig. 1.)

There may be an increase of esophageal (not gastric) carcinoma following a

caustic ingestion.

Bibliography
Chirica M, Bonavina L, Kelly MD, et al. Caustic ingestion.
Lancet . 2017;389:2041–2050.
Contini S, Garatti M, Swarray-Deen A, et al. Corrosive
esophageal strictures in children: outcomes after timely or
 pyloric canal is typical of congenital hypertrophic pyloric stenosis.

Differential Diagnosis
Gastric waves are occasionally visible in small, emaciated infants who do not
have pyloric stenosis. Infrequently, gastroesophageal reflux, with or without a
hiatal hernia, may be confused with pyloric stenosis. Gastroesophageal reflux
disease can be differentiated from pyloric stenosis by radiographic studies.
Adrenal insufficiency from the adrenogenital syndrome can simulate pyloric
stenosis, but the absence of a metabolic acidosis and elevated serum potassium
and urinary sodium concentrations of adrenal insufficiency aid in differentiation
(see Chapter 594 ). Inborn errors of metabolism can produce recurrent emesis
with alkalosis (urea cycle) or acidosis (organic acidemia) and lethargy, coma, or
seizures. Vomiting with diarrhea suggests gastroenteritis, but patients with
pyloric stenosis occasionally have diarrhea. Rarely, a pyloric membrane or
pyloric duplication results in projectile vomiting, visible peristalsis, and, in the
case of a duplication, a palpable mass (Table 355.1 ). Duodenal stenosis
proximal to the ampulla of Vater results in the clinical features of pyloric
stenosis but can be differentiated by the presence of a pyloric mass on physical
examination or ultrasonography.

Table 355.1
Anomalies of the Stomach
AGE AT SYMPTOMS
ANOMALY INCIDENCE TREATMENT
PRESENTATION AND SIGNS
Stomach
Gastric, antral, or 3/100,000, when combined Infancy Nonbilious emesis Gastroduodenostomy,
pyloric atresia with webs gastrojejunostomy
Pyloric or antral As above Any age Failure to thrive, Incision or excision,
membrane (web) emesis pyloroplasty
Microgastria Rare Infancy Emesis, Continuous-drip
malnutrition feedings or jejunal
reservoir pouch
Gastric Rare Any age Usually Usually unnecessary
diverticulum asymptomatic
Gastric duplication Rare; male:female, 1 : 2 Any age Abdominal mass, Excision or partial
emesis, gastrectomy
hematemesis;
peritonitis if
ruptured
 Gastric teratoma Rare Any age Upper abdominal Resection
mass
Gastric volvulus Rare Any age Emesis, refusal to Reduction of
feed volvulus, anterior
gastropexy
Pyloric stenosis United States, 3/1,000 Infancy Non-bilious Pyloromyotomy
(infantile (range, 1-8/1,000 in various emesis
hypertrophic and regions); male:female, 4 : 1
adult forms)
Congenital absence Rare Childhood, Dyspepsia, if Usually unnecessary
of the pylorus adulthood symptomatic
Modified from Semrin MG, Russo MA: Anatomy, histology, and developmental anomalies of the
stomach and duodenum. In Feldman M, Friedman LS, Brandt LJ, editors: Sleisenger and
Fordtran's gastrointestinal and liver disease , ed 10, Philadelphia, Saunders, 2015, Table 48.1.

Treatment
The preoperative treatment is directed toward correcting the fluid, acid–base,
and electrolyte losses. Correction of the alkalosis is essential to prevent
postoperative apnea, which may be associated with anesthesia. Most infants can
be successfully rehydrated within 24 hr. Vomiting usually stops when the
stomach is empty, and only an occasional infant requires nasogastric suction.
The surgical procedure of choice is pyloromyotomy. The traditional Ramstedt
procedure is performed through a short transverse skin incision. The underlying
pyloric mass is cut longitudinally to the layer of the submucosa, and the incision
is closed. Laparoscopic technique is equally successful and in one study resulted
in a shorter time to full feedings and discharge from the hospital as well as
greater parental satisfaction. The success of laparoscopy depends on the skill of
the surgeon. Postoperative vomiting occurs in half the infants and is thought to
be secondary to edema of the pylorus at the incision site. In most infants,
feedings can be initiated within 12-24 hr after surgery and advanced to
maintenance oral feedings within 36-48 hr after surgery. Persistent vomiting
suggests an incomplete pyloromyotomy, gastritis, gastroesophageal reflux
disease, or another cause of the obstruction. The surgical treatment of pyloric
stenosis is curative, with an operative mortality of 0–0.5%. Endoscopic balloon
dilation has been successful in infants with persistent vomiting secondary to
incomplete pyloromyotomy.
Conservative management with nasoduodenal feedings is advisable in patients
who are not good surgical candidates. Oral and intravenous atropine sulfate
(pyloric muscle relaxant) has also been described when surgical expertise is not
CHAPTER 358

Motility Disorders and Hirschsprung

Disease

358.1
Chronic Intestinal Pseudoobstruction
Asim Maqbool, Kristin N. Fiorino, Chris A. Liacouras

Chronic intestinal pseudoobstruction (CIPO) comprises a group of primary and

secondary disorders characterized as a motility disorder with the dominant defect
of impaired peristalsis; symptoms are consistent with intestinal obstruction in the
absence of mechanical obstruction (Table 358.1 ). The natural history of primary
pseudoobstruction is that of a progressive disorder, although there are occasional
cases of secondary pseudoobstruction caused by conditions that can transiently
or permanently alter bowel motility. The most common cause of acute
pseudoobstruction is Ogilvie syndrome (acute pseudoobstruction of the colon).
Pseudoobstruction represents a wide spectrum of pathologic disorders from
abnormal myoelectric activity to abnormalities of the nerves (intestinal
neuropathy) or musculature (intestinal myopathy) of the gut. The organs
involved can include the entire gastrointestinal tract or be limited to certain
components, although almost always include the small bowel. The distinctive
pathologic abnormalities are considered together because of their clinical
similarities. For these reasons, CIPO may be thought of more as a clinical
syndrome at times.

Table 358.1
Causes of Secondary Chronic Intestinal
Pseudoobstruction in Children
Autoimmune
Autoimmune myositis
Autoimmune ganglionitis
Scleroderma
Endocrine
Diabetes mellitus
Hypoparathyroidism
Hypothyroidism
Gastrointestinal
Celiac disease
Eosinophilic gastroenteritis
Inflammatory bowel disease
Hematology/oncology
Multiple myeloma
Paraneoplastic syndromes
Pheochromocytoma
Sickle cell disease
Infection
Chagas disease
Cytomegalovirus
Epstein-Barr virus
Herpes zoster
JC virus
Kawasaki disease
Postviral neuropathy
Medications and toxins
Chemotherapy
Cyclopentolate and phenylephrine eye drops
Diltiazem and nifedipine
Fetal alcohol syndrome
Jellyfish envenomation
Opioid medications
Postanesthesia
Radiation injury
Mitochondrial disorders
Mitochondrial neurogastrointestinal encephalomyopathy
Musculoskeletal disorders
Ehlers-Danlos syndrome
Myotonic dystrophy
Duchenne muscular dystrophy
Rheumatology
Amyloidosis
Dermatomyositis
Polymyositis
Systemic lupus erythematous
From Bitton S, Markowitz JF: Ulcerative colitis in children and adolescents. In Wyllie R, Hyams
JS, Kay M, editors: Pediatric gastrointestinal and liver disease, 5th ed, Elsevier, 2016,
Philadelphia, Box. 44.3, p. 548.

Most congenital forms of primary pseudoobstruction occur sporadically,

neuropathic disease. Symptoms can manifest as recurrent urinary tract infection,
megacystis, or obstructive symptoms. Megacystis-microcolon–intestinal
hypoperistalsis syndrome is a prenatal or neonatal manifestation of CIPO.

Table 358.2

Main Similarities and Differences in Chronic Intestinal Pseudoobstruction in

Children, Adolescents, and Young Adults
CHILDREN ADOLESCENTS—YOUNG ADULTS
Etiology Mainly idiopathic Half of cases are secondary to acquired diseases
Histopathology Myopathies and neuropathies Mainly neuropathies
Symptom In utero, from birth or early infancy Median age of onset at 17 yr
onset with 65–80% of patients symptomatic
by 12 mo of age
Clinical Occlusive symptoms at birth Chronic abdominal pain and distension with
features and/or chronic symptoms without superimposed acute episodes of pseudoobstruction
free intervals Urinary bladder involvement not so often reported
Urologic involvement is commonly
encountered ranging from 36% to
100% pediatric case series
High risk of colonic and small
bowel volvulus secondary to
severe gut dilation, dysmotility,
congenital bridles, or concurrent
malrotation
Natural history Myopathic CIPO, urinary involvement The ability to restore oral feeding and the presence of
and concurrent intestinal malrotation symptoms <20 yr of age is associated with a low
are poor prognostic factors mortality; while, systemic sclerosis and severe/diffuse
esophageal and intestinal dysmotility are associated
with a high mortality
Diagnostic Specialized tests (e.g., intestinal Various methodologic approaches usually starting from
approach manometry) often difficult to perform; endoscopy and radiological tests up to more
noninvasive, radiation-free imaging sophisticated functional exams
tests are warranted
Nutritional To ensure normal growth extensively To improve nutritional status and prevent malnutrition
therapy hydrolyzed and elemental formulas are
often empirically used to facilitate
intestinal absorption
Pharmacologic Small number/sample size-controlled Small number/sample-size controlled trials; few
therapy trials conclusions can be drawn for most drugs
Surgical Venting ostomies (although Venting ostomies can be helpful; resective surgery may
therapy characterized by high complication be indicated in accurately selected patients (i.e., cases
rates) possibly helpful; surgery as a with proven segmental gut dysfunction)
“bridge” to transplantation may be
indicated in highly selected cases
From Di Nardo G, Di Lorenzo C, Lauro A, et al: Chronic intestinal pseudo-obstruction in children
and adults: diagnosis and therapeutic options, Neurogastroenterol Motil 29:e12945, 2017, Table
2.
 like) symptoms. Note the evident air-fluid levels detectable in upright position in
anteroposterior (F) and laterolateral (G) plain abdominal radiographs. (A, From Shen O,
Schimmel MS, Eitan R, et al: Prenatal diagnosis of intestinal pseudo-obstruction,
Ultrasound Obstet Gynecol 29:229–231, 2007. B–G, From Di Nardo G, Di Lorenzo C,
Lauro A, et al: Chronic intestinal pseudo-obstruction in children and adults: diagnosis
and therapeutic options, Neurogastroenterol Motil 29:e12945, 2017.)

Table 358.3
Findings in Pseudoobstruction

GI
FINDINGS*
SEGMENT
Esophageal Abnormalities in approximately half of CIPO, although in some series up to 85% demonstrate
motility abnormalities
Decreased LES pressure
Failure of LES relaxation
Esophageal body: low-amplitude waves, poor propagation, tertiary waves, retrograde peristalsis,
occasionally aperistalsis
Gastric May be delayed
emptying
EGG Tachygastria or bradygastria may be seen
ADM Postprandial antral hypomotility is seen and correlates with delayed gastric emptying
Myopathic subtype: low-amplitude contractions, <10-20 mm Hg
Neuropathic subtype: contractions are uncoordinated, disorganized
Absence of fed response
Fasting MMC is absent, or MMC is abnormally propagated
Colonic Absence of gastrocolic reflex because there is no increased motility in response to a meal
ARM Normal rectoanal inhibitory reflex
* Findings can vary according to the segment(s) of the GI tract that are involved.

ADM, antroduodenal manometry; ARM, anorectal manometry; CIPO, chronic intestinal

pseudoobstruction; EGG, electrogastrography; GI, gastrointestinal; LES, lower esophageal
sphincter; MMC, migrating motor complex.
From Steffen R: Gastrointestinal motility. In Wyllie R, Hyams JS, Kay M, editors: Pediatric
gastrointestinal and liver disease, ed 3, Philadelphia, 2006, WB Saunders, p. 66.

The initial focus is to rule out anatomic obstruction and to assess for bladder
involvement, because that is a frequent and significant extraintestinal
manifestation of concern. Manometric evidence of a normal migrating motor
complex and postprandial activity should redirect the diagnostic evaluation.
CIPO due to an intestinal myopathy may demonstrate manometry evidence of
low-amplitude contractions, whereas CIPO due to enteric neuropathy
demonstrates normal amplitude but poorly organized contractions (nonperistaltic
or tonic). Anorectal motility is normal and differentiates pseudoobstruction from
Hirschsprung disease. Full-thickness intestinal biopsy might show involvement
withholding of stool. An acute episode usually precedes the chronic course. This
acute event could include a social stressor such as initiation of toilet training,
birth of a sibling, starting daycare, or abuse. The acute episode may be a dietary
change from human milk to cow's milk, secondary to the change in the protein
and carbohydrate ratio or an allergy to cow's milk. Although iron has been
suspected of causing issues with cow's milk–related constipation, this has not
been consistently demonstrated or substantiated. The stool becomes firm,
smaller, and difficult to pass, resulting in anal irritation and often an anal fissure.
In toddlers, coercive or inappropriately early toilet training is a factor that can
initiate a pattern of stool retention. In older children, retentive constipation can
develop after entering a situation that makes stooling inconvenient such as
school. Because the passage of bowel movements is painful, voluntary
withholding of feces to avoid the painful stimulus develops.

Table 358.4
Rome IV Diagnostic Criteria for Defecatory Disorders in
Neonates and Toddlers

AGE
FGID CRITERIA REQUIREMENTS CRITERIA ELEMENTS
RANGE
Functional All pediatric Must include 1 month of ≥2 of the • 2 or fewer defections weekly
constipation age groups following in infants up to 4 months of • History of excessive stool retention
age: • History of hard/painful bowel
In toilet trained children, the following movements
additional criteria may be used: • History of large-diameter stools
• Presence of a large fecal mass in the
rectum
• At least 1 weekly episode of
incontinence after being toilet
trained
• History of large-diameter stools that
may clog the toilet
FGID, Functional gastrointestinal disorders.
Modified from Benninga MA, Faure C, Hyman PE, et al. Childhood functional gastrointestinal
disorders: neonate/toddler, Gastroenterology 150:1443–1455, 2016.

Table 358.5
Rome IV Diagnostic Criteria for Defecatory Disorders in
Children and Adolescents
 AGE RANGE CRITERIA REQUIREMENTS CRITERIA ELEMENTS
Functional Developmental Must include ≥2 of the following ≥1/wk for • ≤ 2 defecations in the toilet per
Constipation age ≥4 yr 1 ≥1 mo with insufficient criteria to week
diagnose irritable bowel syndrome • ≥1 episode of fecal incontinence
per week
• History of retentive posturing or
excessive volitional stool retention
• History of painful or hard bowel
movements
• Presence of a large fecal mass in
the rectum
• History of large diameter stools that
can obstruct the toilet
• After appropriate evaluation,
symptoms cannot be fully
explained by another medical
condition
Nonretentive developmental ≥1-mo history of the following symptoms: • Defecation into places
Fecal age ≥4 yr inappropriate to the sociocultural
Incontinence context
• No evidence of fecal retention
• After appropriate evaluation,
symptoms cannot be fully
explained by another medical
condition
Modified from Hyams JS, Di Lorenzo C, Saps M, et al. Childhood functional gastrointestinal
disorders: child/adolescent, Gastroenterology 150:1456–1468, 2016.

Clinical Manifestations
When children have the urge to defecate, typical behaviors include contracting
the gluteal muscles by stiffening the legs while lying down, holding onto
furniture while standing, or squatting quietly in corners, waiting for the call to
stool to pass. The urge to defecate passes as the rectum accommodates to its
contents. A vicious cycle of retention develops, as increasingly larger volumes of
stool need to be expelled. Caregivers may misinterpret these activities as
straining, but it is withholding behavior. There is often a history of blood in the
stool noted with the passage of a large bowel movement. Findings suggestive of
underlying pathology include failure to thrive, weight loss, abdominal pain,
vomiting, or persistent anal fissure or fistula.
In functional constipation, daytime encopresis is common. Encopresis is
defined as voluntary or involuntary passage of feces into inappropriate places at
least once a mo for 3 consecutive months once a chronologic or developmental
age of 4 yr has been reached. Encopresis is not diagnosed when the behavior is
exclusively the result of the direct effects of a substance (e.g., laxatives) or a
reflexes. Spinal cord lesions can occur with overlying skin anomalies. Urinary
tract symptoms include recurrent urinary tract infection and enuresis. Children
with no evidence of abnormalities on physical examination rarely require
radiologic evaluation.
In refractory patients (intractable constipation), specialized testing should be
considered to rule out conditions such as hypothyroidism, hypocalcemia, lead
toxicity, celiac disease, and disorders of neuromuscular gastrointestinal
pathology (Table 358.6 ). Colonic transit studies using radiopaque markers or
scintigraphy techniques may be useful. Selected children can benefit from MRI
of the spine to identify an intraspinal process, motility studies to identify
underlying myopathic or neuropathic bowel abnormalities, or a contrast enema
to identify structural abnormalities. In patients with severe functional
constipation, water-soluble contrast enema reveals the presence of a mega
rectosigmoid (Fig. 358.3 ). Anorectal motility studies can demonstrate a pattern
of paradoxical contraction of the external anal sphincter during defecation,
which can be treated by behavior modification and biofeedback. Colonic
motility can guide therapy in refractory cases, demonstrating segmental
problems that might require surgical intervention.

Table 358.6
London Classification of Gastrointestinal Neuromuscular
Pathology
1. Neuropathies
1.1 Absent neurons
1.1.1 Aganglionosis*
1.2 Decreased numbers of neurons
1.2.1 Hypoganglionosis
1.3 Increased numbers of neurons
1.3.1 Ganglioneuromatosis †
1.3.2 IND, type B ‡
1.4 Degenerative neuropathy §
1.5 Inflammatory neuropathies
1.5.1 Lymphocytic ganglionitis ¶
1.5.2 Eosinophilic ganglionitis
1.6 Abnormal content in neurons
1.6.1 Intraneuronal nuclear inclusions
1.6.2 Megamitochondria
1.7 Abnormal neurochemical coding**
1.8 Relative immaturity of neurons
1.9 Abnormal enteric glia
1.9.1 Increased numbers of enteric glia
 2. Myopathies
2.1 Muscularis propria malformations ††
2.2 Muscle cell degeneration
2.2.1 Degenerative leiomyopathy/ ‡‡
2.2.2 Inflammatory leiomyopathy
2.2.2.1 Lymphocytic leiomyositis
2.2.2.2 Eosinophilic leiomyositis
2.3 Muscle hyperplasia/hypertrophy
2.3.1 Muscularis mucosae hyperplasia
2.4 Abnormal content in myocytes
2.4.1 Filament protein abnormalities
2.4.1.1 Alpha-actin myopathy §§
2.4.1.2 Desmin myopathy
2.4.2 Inclusion bodies
2.4.2.1 Polyglucosan bodies
2.4.2.2 Amphophilic
2.4.2.3 Megamitochondria ¶¶
2.5 Abnormal supportive tissue
2.5.1 Atrophic desmosis***
3. ICC abnormalities (enteric mesenchymopathy)
3.1 Abnormal ICC networks †††
* Can include rare cases of non-Hirschsprung disease severe hypoplastic hypoganglionosis with

long interganglionic intervals (zonal aganglionosis).

† Although neurons have not been formally quantified, gross increases of disorganized neurons
are evident.
‡ Can include retarded neuronal maturation.

§ May occur with or without neuronal loss but is best regarded as a separate entity.

¶ May occur with neuronal degeneration and/or loss; lymphocytic epithelioganglionitis is a variant.

**
Includes neurotransmitter loss (e.g., reduced or absent expression) or loss of a neurochemically
defined functional subset of nerves (see text).
††
Includes absence, fusion, or additional muscle coats.
‡‡ Hollow visceral myopathy may be diagnosed in familial cases with other characteristic
phenotypic features; myopathy with autophagic activity and pink blush myopathy with nuclear
crowding are rare variants in which degenerative findings are less overt.
§§ Smooth muscle alpha-actin deficiency is best described, although deficiencies of other proteins

related to the contractile apparatus of myocytes have been reported.

¶¶ Mitochondrial neurogastrointestinal encephalomyopathy causes a degenerative appearance
predominantly in the longitudinal muscle.
*** Absent connective tissue scaffold has been almost exclusively described in the colon.

††† Generally reduced or absent ICC, although abnormal morphology also reported.

ICC, interstitial cells of Cajal; IND, intestinal neuronal dysplasia.

From Knowles CH, De Giorgio R, Kapur RP, et al: The London classification of gastrointestinal
neuromuscular pathology: report on behalf of the Gastro 2009 International Working Group, Gut
regular postprandial toilet sitting and adoption of a balanced diet. In addition,
caregivers should be instructed not to respond to soiling with retaliatory or
punitive measures, because children are likely to become angry, ashamed, and
resistant to intervention. From the outset, parents should be actively encouraged
to reward the child for adherence to a healthy bowel regimen and to avoid power
struggles.
If an impaction is present on the initial physical examination, an enema is
usually required to clear the impaction while stool softeners are started as
maintenance medications. Typical regimens include the use of polyethylene
glycol preparations, lactulose, or mineral oil (Tables 358.7 and 358.8 ).
Prolonged use of stimulants such as senna or bisacodyl should be avoided.

Table 358.7
Suggested Medications and Dosages for Disimpaction

MEDICATION AGE DOSAGE

RAPID RECTAL DISIMPACTION
Glycerin suppositories Infants and
toddlers
Phosphate enema <1 yr 60 mL
>1 yr 6 mL/kg body weight, up to 135 mL twice
SLOW ORAL DISIMPACTION IN OLDER CHILDREN
Over 2-3 Days
Polyethylene glycol with 25 mL/kg body weight/hr, up to 1,000 mL/hr until clear fluid
electrolytes comes from the anus
Over 5-7 Days
Polyethylene without 1.5 g/kg body weight/day for 3 days
electrolytes
Milk of magnesia 2 mL/kg body weight twice/day for 7 days
Mineral oil 3 mL/kg body weight twice/day for 7 days
Lactulose or sorbitol 2 mL/kg body weight twice/day for 7 days
From Loening-Baucke V: Functional constipation with encopresis. In Wyllie R, Hyams JS, Kay M,
editors: Pediatric gastrointestinal and liver disease , ed 3, Philadelphia, 2006, WB Saunders, p.
183.

Table 358.8
Suggested Medications and Dosages for Maintenance
Therapy of Constipation

MEDICATION AGE DOSE

TYPICAL DOSES FOR LONG-TERM TREATMENT (YEARS)
 Milk of magnesia >1 mo 1-3 mL/kg body weight/day, divided into 1-2 doses
Mineral oil >12 mo 1-3 mL/kg body weight/day, divided into 1-2 doses
Lactulose or sorbitol >1 mo 1-3 mL/kg body weight/day, divided into 1-2 doses
Polyethylene glycol 3350 (MiraLAX) >1 yr 0.7 g/kg body weight/day (max 17.5 g/day)
FOR SHORT-TERM TREATMENT (MONTHS)
Senna (Senokot) syrup, tablets 1-5 yr 5 mL (1 tablet) with breakfast, max 15 mL daily
5-15 yr 2 tablets with breakfast, maximum 3 tablets daily
Glycerin enemas >10 yr 20-30 mL/day ( glycerin and normal saline)
Bisacodyl suppositories >10 yr 10 mg daily
From Loening-Baucke V: Functional constipation with encopresis. In Wyllie R, Hyams JS, Kay M,
editors: Pediatric gastrointestinal and liver disease , ed 3, Philadelphia, 2006, WB Saunders, p.
185.

Compliance can wane, and failure of this standard treatment approach

sometimes requires more intensive intervention. In cases where behavioral or
psychiatric problems are evident, involvement of a psychologist or behavioral
management (e.g., behavior programs and/or biofeedback) is recommended.
Maintenance therapy is generally continued until a regular bowel pattern has
been established and the association of pain with the passage of stool is
abolished.
For children with chronic diarrhea and/or irritable bowel syndrome where
stress and anxiety play a major role, stress reduction and learning effective
coping strategies can play an important role in responding to the encopresis.
Relaxation training, stress inoculation, assertiveness training, and/or general
stress management procedures can be helpful, and the participation of behavioral
health specialists is valuable.
Neurostimulation (transcutaneous or sacral implantation) and pelvic
physiotherapy are novel approaches used in patients with medication refractory
constipation. Children with spinal problems can be successfully managed with
low volumes of fluid through a cecostomy or sigmoid tube.

Bibliography
Auth MKH, Vora R, Farrelly P, et al. Childhood constipation.
BMJ . 2012;345:38–43.
Bar-Maor JA, Eitan A. Determination of the normal position of
the anus (with reference to idiopathic constipation). J Pediatr
Gastroenterol Nutr . 1987;6:559–561.
Bekkali NLH, van den Berg MM, Dijkgraaf MGW, et al. Rectal
of stool. Some neonates pass meconium normally but subsequently present with
a history of chronic constipation. Failure to thrive with hypoproteinemia from
protein-losing enteropathy is a less common presentation because Hirschsprung
disease is usually recognized early in the course of the illness but has been
known to occur. Breastfed infants might not present as severely as formula-fed
infants.
Failure to pass stool leads to dilation of the proximal bowel and abdominal
distention. As the bowel dilates, intraluminal pressure increases, resulting in
decreased blood flow and deterioration of the mucosal barrier. Stasis allows
proliferation of bacteria, which can lead to enterocolitis (Clostridium difficile,
Staphylococcus aureus, anaerobes, coliforms) with associated diarrhea,
abdominal tenderness, sepsis, and signs of bowel obstruction. Red flags in the
neonatal period then include neonatal intestinal obstruction, bowel perforation,
delayed passage of meconium, abdominal distention relieved by digital rectal
stimulation or enemas, chronic severe constipation, and enterocolitis. Early
recognition of Hirschsprung disease before the onset of enterocolitis is essential
in reducing morbidity and mortality.
Hirschsprung disease in older patients must be distinguished from other
causes of abdominal distention and chronic constipation (see Tables 358.6 and
358.9 and Figs. 358.4 and 358.5 ). The history often reveals constipation starting
in infancy that has responded poorly to medical management. Failure to thrive is
not uncommon. Fecal incontinence, fecal urgency, and stool-withholding
behaviors are usually not present. Significant abdominal distention is unusual in
non-Hirschsprung related constipation, as is emesis. The abdomen is tympanitic
and distended, with a large fecal mass palpable in the left lower abdomen. Rectal
examination demonstrates a normally placed anus that easily allows entry of the
finger but feels snug. The rectum is usually empty of feces, and when the finger
is removed, there may be an explosive discharge of foul-smelling feces and gas.
The stools, when passed, can consist of small pellets, be ribbon-like, or have a
fluid consistency, unlike the large stools seen in patients with functional
constipation. Intermittent attacks of intestinal obstruction from retained feces
may be associated with pain and fever. Urinary retention with enlarged bladder
or hydronephrosis can occur secondary to urinary compression.

Table 358.9
Distinguishing Features of Hirschsprung Disease and
Functional Constipation
VARIABLE FUNCTIONAL HIRSCHSPRUNG DISEASE
HISTORY
Onset of After 2 yr of age At birth
constipation
Encopresis Common Very rare
Failure to thrive Uncommon Possible
Enterocolitis None Possible
Forced bowel Usual None
training
EXAMINATION
Abdominal Uncommon Common
distention
Poor weight gain Rare Common
Rectum Filled with stool Empty
Rectal examination Stool in rectum Explosive passage of stool
Malnutrition None Possible
INVESTIGATIONS
Anorectal Relaxation of internal anal sphincter Failure of internal anal sphincter relaxation
manometry
Rectal biopsy Normal No ganglion cells, increased acetylcholinesterase
staining
Barium enema Massive amounts of stool, no transition Transition zone, delayed evacuation (>24 hr)
zone
From Imseis E, Gariepy C: Hirschsprung disease. In Walker WA, Goulet OJ, Kleinman RE, et al,
editors: Pediatric gastrointestinal disease , ed 4, Hamilton, ON, 2004, BC Decker, p. 1035.
Table 361.1
Etiologic Classification of Peptic Ulcers
• Positive for Helicobacter pylori infection
• Drug (NSAID)-induced
• Helicobacter pylori and NSAID-positive
• H. pylori and NSAID-negative*
• Acid hypersecretory state (Zollinger-Ellison syndrome)
• Anastomosis ulcer after subtotal gastric resection
• Tumors (cancer, lymphoma)
• Rare specific causes
• Crohn disease of the stomach or duodenum
• Eosinophilic gastroduodenitis
• Systemic mastocytosis
• Radiation damage
• Viral infections (cytomegalovirus or herpes simplex infection, particularly in immunocompromised patients)
• Colonization of stomach with Helicobacter heilmannii
• Severe systemic disease
• Cameron ulcer (gastric ulcer where a hiatal hernia passes through the diaphragmatic hiatus)
• True idiopathic ulcer
* Requires search for other specific causes. NSAID, nonsteroidal antiinflammatory drug. (From
Vakil N, Megraud F: Eradication therapy for Helicobacter pylori, Gastroenterology 133:985–1001,
2007.)

Pathogenesis
Acid Secretion
By 3-4 yr of age, gastric acid secretion approximates adult values. Acid initially
secreted by the oxyntic cells of the stomach has a pH of approximately 0.8,
whereas the pH of the stomach contents is 1-2. Excessive acid secretion is
associated with a large parietal cell mass, hypersecretion by antral G cells, and
increased vagal tone, resulting in increased or sustained acid secretion in
response to meals and increased secretion during the night. The secretagogues
that promote gastric acid production include acetylcholine released by the vagus
nerve, histamine secreted by enterochromaffin cells, and gastrin released by the
G cells of the antrum. Mediators that decrease gastric acid secretion and enhance
protective mucin production include prostaglandins.

Mucosal Defense
A continuous layer of mucous gel that serves as a diffusion barrier to hydrogen
Table 361.2
Recommended Eradication Therapies for Helicobacter
pylori –Associated Disease in Children

MEDICATIONS DOSE DURATION OF TREATMENT

Proton pump inhibitor 1 mg/kg/dose twice a day 1 mo
ANTIBIOTICS WEIGHT DOSE DURATION OF TREATMENT
Amoxicillin 15-24 kg 500 mg twice a day 14 days
25-34 kg 750 mg twice a day
>35 kg 1,000 mg twice a day
Clarithromycin 15-24 kg 250 mg twice a day 14 days
25-34 kg 500 mg in AM , 250 mg in PM
>35 kg 500 mg twice a day
Metronidazole 15-24 kg 250 mg twice a day 14 days
25-34 kg 500 mg in AM , 250 mg in PM
>35 kg 500 mg twice a day
Depending on previous antibiotic use history, recommended combinations are Amoxicillin +
Clarithromycin + PPI OR Amoxicillin + Metronidazole + PPI OR Clarithromycin + Metronidazole +
PPI. (Modified from Jones NL, Koletzko S, Goodman K, et al: Joint ESPGHAN/NASPGHAN
Guidelines for the Management of Helicobacter pylori in Children and Adolescents, J Pediatr
Gastroenterol Nutr 64(6):991–1003, 2017.)

Table 361.3
Antisecretory Therapy With Pediatric Dosages

MEDICATION PEDIATRIC DOSE HOW SUPPLIED

H2 RECEPTOR ANTAGONISTS
Ranitidine 4-10 mg/kg/day Syrup: 75 mg/5 mL
Divided 2 or 3 × a day Tablets: 75, 150, 300 mg
Famotidine 1-2 mg/kg/day Syrup: 40 mg/5 mL
Divided twice a day Tablets: 20, 40 mg
Nizatidine 5-10 mg/kg/day divided twice a day Solution: 15 mg/mL
Older than 12 yr: 150 mg twice a day Capsule 150, 300
Tablet: 75 mg
PROTON PUMP INHIBITORS
Omeprazole 1.0-3.3 mg/kg/day weigh < 20 kg: 10 mg/day Capsules: 10, 20, 40 mg
weigh > 20 kg: 20 mg/day
Approved for use in those older than 2 yr
Lansoprazole 0.8-4 mg/kg/day weigh < 30 kg: 15 mg/day Capsules: 15, 30 mg
weigh > 30 kg: 30 mg/day Powder packet: 15, 30 mg
Approved for use in those older than 1 yr SoluTab: 15, 30 mg
Rabeprazole 1-11 yr (weigh < 15 kg): 5 mg/day Delayed release capsule: 5, 10
1-11 yr (weigh > 15 kg): 10 mg/day mg
>12 yr: 20 mg tablet Delayed release tablet: 20 mg
Pantoprazole 1-5 yr: 0.3-1.2 mg/kg/day (limited data) Tablet: 20, 40 mg
>5 yr of age: Powder pack: 40 mg
 weigh > 15 kg to < 40 kg: 20 mg/day
weigh > 40 kg: 40 mg/day
Esomeprazole 1 mo - < 1 yr old Capsules: 20, 40
weigh 3 kg to 5 kg: 2.5 mg Delayed release single dose
weigh > 5 kg to 7.5 kg: 5 mg packs: 2.5, 5, 10, 20 mg
weigh > 7.5 kg to 12 kg: 10 mg
1-11 yr old
weigh < 20 kg: 10 mg
weigh > 20 kg: 20 mg
Approved for use 1 mo and older
Dexlansoprazole 12-17 yr: 30-60 mg Capsules: 30, 60
Approved for use in 12-17 yr
Omeprazole sodium Not approved for use < 18 yr at time of publication Capsules: 20, 40
bicarbonate Powder for oral suspension: 20
mg, 40 mg
CYTOPROTECTIVE AGENTS
Sucralfate 40-80 mg/kg/day Suspension: 1,000 mg/5 mL
Tablet: 1,000 mg

FIG. 361.3 Rescue therapy for failed eradication of H. pylori . *Bismuth-
based therapy with tetracycline instead of amoxicillin if patients >8 yr.
Bismuth dose is 262 mg four times a day for patients 8–10 yr and 524 mg
four times a day for those >10 yr. (See Tables 361.2 and 361.3 .) In
adolescents, levofloxacin or tetracycline can be considered. High-dose
amoxicillin ranges from 750 mg twice a day for body weight 15–24 kg, 1000
mg twice a day for 25–34 kg, and 1500 mg twice a day for >35 kg. (Adapted
from Jones NL, Koletzko S, Goodman K, et al: Joint
ESPGHAN/NASPGHAN guidelines for the management of Helicobacter
pylori in children and adolescents, J Pediatr Gastroenterol Nutr 64:991–
1003, 2017.)
than dizygotic. The concordance rate in twins is higher in Crohn disease (36%)
than in ulcerative colitis (16%). Genetic disorders that have been associated with
IBD include Turner syndrome, the Hermansky-Pudlak syndrome, glycogen
storage disease type Ib, and various immunodeficiency disorders. In 2001, the
first IBD gene, NOD2, was identified through association mapping. A few
months later, the IBD 5 risk haplotype was identified. These early successes
were followed by a long period without notable risk factor discovery. Since
2006, the year of the first published genome-wide array study on IBD, there has
been an exponential growth in the set of validated genetic risk factors for IBD
(Table 362.1 ).

Table 362.1
Selection of Most Important Genes Associated With
Inflammatory Bowel Disease and the Most Commonly
Associated Physiological Functions and Pathways

ASSOCIATED GENE FUNCTION AND PHYSIOLOGICAL

GENE NAME
DISEASE ASSOCIATED PATHWAYS FUNCTION
NOD2 Nucleotide-binding Crohn disease Bacterial recognition and Innate mucosal
oligomerization domain- response, NFκB activation and defense
containing protein 2 autophagy and apoptosis
IL10 Interleukin 10 Crohn disease Antiinflammatory cytokine, NFκB Immune tolerance
inhibition, JAK-STAT regulation
IL10RA Interleukin 10 receptor A Crohn disease Antiinflammatory cytokine Immune tolerance
receptor, NFκB inhibition, JAK-
STAT regulation
IL10RB Interleukin 10 receptor B Crohn disease Antiinflammatory cytokine Immune tolerance
receptor, NFκB inhibition, JAK-
STAT regulation
IL23R Interleukin 23 receptor Crohn disease Immune regulation, Interleukin 23/T
and ulcerative proinflammatory pathways—JAK- helper 17
colitis STAT regulation
TKY2 Tyrosine kinase 2 Crohn disease Inflammatory pathway signaling Interleukin 23/T
and ulcerative (interleukin 10 and 6 etc) through helper 17
colitis intracellular activity
IRGM Immunity related GTPase Crohn disease Autophagy and apoptosis in cells Autophagy
M infected with bacteria
ATG16L1 Autophagy related 16 like Crohn disease Autophagy and apoptotic Autophagy
1 pathways
SLC22A4 Solute carrier family 22 Crohn disease Cellular antioxidant transporter Solute transporters
member 4
CCL2 C-C motif chemokine Crohn disease Cytokine involved in chemotaxis Immune cell
ligand 2 for monocytes recruitment
CARD9 Caspase recruitment Crohn disease Apoptosis regulation and NFκB Oxidative stress
domain family member 9 and ulcerative pathway activation
colitis
 IL2 Interleukin 2 Ulcerative Cytokine involved in immune cell T-cell regulation
colitis activation
MUC19 Mucin 19 Crohn disease Gel-forming mucin protein Epithelial barrier
and ulcerative
colitis
JAK-STAT, Janus kinase-signal transducers and activators of transcription; NFκB, nuclear factor
κ-light chain enhancer of activated B cells.
From Ashton JJ, Ennis S, Beattie RM: Early-onset paediatric inflammatory bowel disease, Lancet
1:147–158, 2017, Table 1, p 148.

A perinuclear antineutrophil cytoplasmic antibody is found in approximately

70% of patients with ulcerative colitis compared with <20% of those with Crohn
disease and is believed to represent a marker of genetically controlled
immunoregulatory disturbance. Approximately 55% of those with Crohn disease
are positive for anti–Saccharomyces cerevisiae antibody. Since the importance of
these were first described, multiple other serologic and immune markers of
Crohn disease and ulcerative colitis have been recognized.
IBD is caused by dysregulated or inappropriate immune response to
environmental factors in a genetically susceptible host. An abnormality in
intestinal mucosal immunoregulation may be of primary importance in the
pathogenesis of IBD, involving activation of cytokines, triggering a cascade of
reactions that results in bowel inflammation. These cytokines are recognized as
known or potential targets for IBD therapies.
Multiple environmental factors are recognized to be involved in the
pathogenesis of IBD, none more critical than the gut microbiota. The increasing
incidence of IBD over time is likely in part attributable to alterations in the
microbiome. Evidence includes association between IBD and residence in or
immigration to industrialized nations, a Western diet , increased use of
antibiotics at a younger age, high rates of vaccination, and less exposure to
microbes at a young age. While gut microbes likely play an important role in the
pathogenesis of IBD, the exact mechanism needs to be elucidated further. Some
environmental factors are disease specific; for example, cigarette smoking is a
risk factor for Crohn disease but paradoxically protects against ulcerative colitis.
It is usually possible to distinguish between ulcerative colitis and Crohn
disease by the clinical presentation and radiologic, endoscopic, and
histopathologic findings (Table 362.2 ). It is not possible to make a definitive
diagnosis in approximately 10% of patients with chronic colitis; this disorder is
called indeterminate colitis. Occasionally, a child initially believed to have
ulcerative colitis on the basis of clinical findings is subsequently found to have
Crohn colitis. This is particularly true for the youngest patients, because Crohn
disease in this patient population can more often manifest as exclusively colonic
inflammation, mimicking ulcerative colitis. The medical treatments of Crohn
disease and ulcerative colitis overlap.

Table 362.2

Comparison of Crohn Disease and Ulcerative Colitis

FEATURE CROHN DISEASE ULCERATIVE COLITIS
Rectal bleeding Sometimes Common
Diarrhea, mucus, pus Variable Common
Abdominal pain Common Variable
Abdominal mass Common Not present
Growth failure Common Variable
Perianal disease Common Rare
Rectal involvement Occasional Universal
Pyoderma gangrenosum Rare Present
Erythema nodosum Common Less common
Mouth ulceration Common Rare
Thrombosis Less common Present
Colonic disease 50–75% 100%
Ileal disease Common None except backwash ileitis
Stomach–esophageal disease More common Chronic gastritis can be seen
Strictures Common Rare
Fissures Common Rare
Fistulas Common Rare
Toxic megacolon None Present
Sclerosing cholangitis Less common Present
Risk for intestinal cancers Increased Greatly increased
Discontinuous (skip) lesions Common Not present
Transmural involvement Common Unusual
Crypt abscesses Less common Common
Granulomas Common None
Linear ulcerations Uncommon Common
Perinuclear antineutrophil cytoplasmic antibody–positive <20% 70%

Extraintestinal manifestations occur slightly more commonly with Crohn

disease than with ulcerative colitis (Table 362.3 ). Growth retardation is seen in
15–40% of children with Crohn disease at diagnosis. Decrease in height velocity
occurs in nearly 90% of patients with Crohn disease diagnosed in childhood or
adolescence. Of the extraintestinal manifestations that occur with IBD, joint,
skin, eye, mouth, and hepatobiliary involvement tend to be associated with
colitis, whether ulcerative or Crohn. The presence of some manifestations, such
as peripheral arthritis, erythema nodosum, and anemia, correlates with activity of
the bowel disease. Activity of pyoderma gangrenosum correlates less well with
activity of the bowel disease, whereas sclerosing cholangitis, ankylosing
spondylitis, and sacroiliitis do not correlate with intestinal disease. Arthritis
occurs in 3 patterns: migratory peripheral arthritis involving primarily large
joints, ankylosing spondylitis, and sacroiliitis. The peripheral arthritis of IBD
tends to be nondestructive. Ankylosing spondylitis begins in the 3rd decade and
occurs most commonly in patients with ulcerative colitis who have the human
leukocyte antigen B27 phenotype. Symptoms include low back pain and
morning stiffness; back, hips, shoulders, and sacroiliac joints are typically
affected. Isolated sacroiliitis is usually asymptomatic but is common when a
careful search is performed. Among the skin manifestations, erythema nodosum
is most common. Patients with erythema nodosum or pyoderma gangrenosum
have a high likelihood of having arthritis as well. Glomerulonephritis, uveitis,
and a hypercoagulable state are other rare manifestations that occur in childhood.
Cerebral thromboembolic disease has been described in children with IBD.

Table 362.3
Extraintestinal Complications of Inflammatory Bowel
Disease
MUSCULOSKELETAL
Peripheral arthritis
Granulomatous monoarthritis
Granulomatous synovitis
Rheumatoid arthritis
Sacroiliitis
Ankylosing spondylitis
Digital clubbing and hypertrophic osteoarthropathy
Periostitis
Osteoporosis, osteomalacia
Rhabdomyolysis
Pelvic osteomyelitis
Recurrent multifocal osteomyelitis
Relapsing polychondritis
SKIN AND MUCOUS MEMBRANES
Oral lesions
Cheilitis
Aphthous stomatitis, glossitis
Granulomatous oral Crohn disease
Inflammatory hyperplasia fissures and cobblestone mucosa
Peristomatitis vegetans
DERMATOLOGIC
Erythema nodosum
Pyoderma gangrenosum
Sweet syndrome
Metastatic Crohn disease
Psoriasis
Epidermolysis bullosa acquisita
Perianal skin tags
Polyarteritis nodosa
Melanoma and nonmelanoma skin cancers
OCULAR
Conjunctivitis
Uveitis, iritis
Episcleritis
Scleritis
Retrobulbar neuritis
Chorioretinitis with retinal detachment
Crohn keratopathy
Posterior segment abnormalities
Retinal vascular disease
BRONCHOPULMONARY
Chronic bronchitis with bronchiectasis
Chronic bronchitis with neutrophilic infiltrates
Fibrosing alveolitis
Pulmonary vasculitis
Small airway disease and bronchiolitis obliterans
Eosinophilic lung disease
Granulomatous lung disease
Tracheal obstruction
CARDIAC
Pleuropericarditis
Cardiomyopathy
Endocarditis
Myocarditis
MALNUTRITION
Decreased intake of food
• Inflammatory bowel disease
• Dietary restriction
Malabsorption
• Inflammatory bowel disease
• Bowel resection
• Bile salt depletion
• Bacterial overgrowth
Intestinal losses
• Electrolytes
• Minerals
• Nutrients
Increased caloric needs
• Inflammation
• Fever
HEMATOLOGIC/ONCOLOGIC
Anemia: iron deficiency (blood loss)
Vitamin B12 (ileal disease or resection, bacterial overgrowth, folate deficiency)
Anemia of chronic inflammation
Anaphylactoid purpura (Crohn disease)
Hyposplenism
Autoimmune hemolytic anemia
Coagulation abnormalities
Increased activation of coagulation factors
Activated fibrinolysis
Anticardiolipin antibody
 Increased risk of arterial and venous thrombosis with cerebrovascular stroke, myocardial infarction, peripheral
arterial, and venous occlusions
Systemic lymphoma (nonenteric)
RENAL AND GENITOURINARY
Metabolic
• Urinary crystal formation (nephrolithiasis, uric acid, oxylate)
Hypokalemic nephropathy
Inflammation
• Retroperitoneal abscess
• Fibrosis with ureteral obstruction
• Fistula formation
Glomerulitis
Membrane nephritis
Renal amyloidosis, nephrotic syndrome
PANCREATITIS
Secondary to medications (sulfasalazine, 6-mercaptopurine, azathioprine, parenteral nutrition)
Ampullary Crohn disease
Granulomatous pancreatitis
Decreased pancreatic exocrine function
Sclerosing cholangitis with pancreatitis
HEPATOBILIARY
Primary sclerosing cholangitis
Small duct primary sclerosing cholangitis (pericholangitis)
Carcinoma of the bile ducts
Fatty infiltration of the liver
Cholelithiasis
Autoimmune hepatitis
ENDOCRINE AND METABOLIC
Growth failure, delayed sexual maturation
Thyroiditis
Osteoporosis, osteomalacia
NEUROLOGIC
Peripheral neuropathy
Meningitis
Vestibular dysfunction
Pseudotumor cerebri
Cerebral vasculitis
Migraine
Modified from Kugathasan S: Diarrhea. In Kliegman RM, Greenbaum LA, Lye PS, editors:
Practical strategies in pediatric diagnosis and therapy, ed 2, Philadelphia, 2004, WB Saunders, p
285.

362.1
Chronic Ulcerative Colitis
Clinical Manifestations
Blood, mucus, and pus in the stool as well as diarrhea are the typical
presentation of ulcerative colitis. Constipation may be observed in those with
proctitis. Symptoms such as tenesmus, urgency, cramping abdominal pain
(especially with bowel movements), and nocturnal bowel movements are
common. The mode of onset ranges from insidious with gradual progression of
symptoms to acute and fulminant (Table 362.4 and Figs. 362.1 and 362.2 ).
Fever, severe anemia, hypoalbuminemia, leukocytosis, and more than 5 bloody
stools per day for 5 days define fulminant colitis . Chronicity is an important
part of the diagnosis; it is difficult to know if a patient has a subacute, transient
infectious colitis or ulcerative colitis when a child has had 1-2 wk of symptoms.
Symptoms beyond this duration often prove to be secondary to IBD. Anorexia,
weight loss, and growth failure may be present, although these complications are
more typical of Crohn disease.

Table 362.4
Montreal Classification of Extent and Severity of Ulcerative
Colitis
• E1 (proctitis): inflammation limited to the rectum
• E2 (left-sided; distal): inflammation limited to the splenic flexure
• E3 (pancolitis): inflammation extends to the proximal splenic flexure
• S0 (remission): no symptoms
• S1 (mild): 4 or less stools per day (with or without blood), absence of systemic symptoms, normal inflammatory
markers
• S2 (moderate): 4 stools per day, minimum signs of systemic symptoms
• S3 (severe): 6 or more bloody stools per day, pulse rate of ≥90 beats/min, temperature ≥37.5°C (99.5°F),
hemoglobin concentration <105 g/L, erythrocyte sedimentation rate ≥30 mm/hr
E, extent; S, severity.
From Ordàs I, Eckmann L, Talamini M, et al: Ulcerative colitis, Lancet 380:1606–1616, 2012,
Panel 2, p 1610.
younger children. The gross appearance of the colitis or development of small
bowel disease eventually leads to the correct diagnosis; this can occur years after
the initial presentation.

Table 362.5
Infectious Agents Mimicking Inflammatory Bowel Disease

AGENT MANIFESTATIONS DIAGNOSIS COMMENTS

BACTERIAL
Campylobacter Acute diarrhea, fever, fecal blood, and Culture Common in adolescents,
jejuni leukocytes may relapse
Yersinia Acute → chronic diarrhea, right lower Culture Common in adolescents as
enterocolitica quadrant pain, mesenteric adenitis– fever of unknown origin,
pseudoappendicitis, fecal blood, and weight loss, abdominal
leukocytes pain
Extraintestinal manifestations,
mimics Crohn disease
Clostridium Postantibiotic onset, watery → bloody Cytotoxin assay May be nosocomial
difficile diarrhea, pseudomembrane on Toxic megacolon
sigmoidoscopy possible
Escherichia coli Colitis, fecal blood, abdominal pain Culture and typing Hemolytic uremic
O157:H7 syndrome
Salmonella Watery → bloody diarrhea, foodborne, Culture Usually acute
fecal leukocytes, fever, pain, cramps
Shigella Watery → bloody diarrhea, fecal Culture Dysentery symptoms
leukocytes, fever, pain, cramps
Edwardsiella Bloody diarrhea, cramps Culture Ulceration on endoscopy
tarda
Aeromonas Cramps, diarrhea, fecal blood Culture May be chronic
hydrophila Contaminated
drinking water
Plesiomonas Diarrhea, cramps Culture Shellfish source
shigelloides
Tuberculosis Rarely bovine, now Mycobacterium Culture, purified Can mimic Crohn disease
tuberculosis protein derivative,
Ileocecal area, fistula formation biopsy
PARASITES
Entamoeba Acute bloody diarrhea and liver abscess, Trophozoite in stool, Travel to endemic area
histolytica colic colonic mucosal flask
ulceration, serologic
tests

Giardia lamblia Foul-smelling, watery diarrhea, cramps, “Owl”-like May be chronic

flatulence, weight loss; no colonic trophozoite and cysts
involvement in stool; rarely
duodenal intubation
AIDS-ASSOCIATED ENTEROPATHY
Cryptosporidium Chronic diarrhea, weight loss Stool microscopy Mucosal findings not like
inflammatory bowel
disease
 Isospora belli As in Cryptosporidium Tropical location
Cytomegalovirus Colonic ulceration, pain, bloody diarrhea Culture, biopsy More common when on
immunosuppressive
medications

At the onset, the colitis of hemolytic uremic syndrome may be identical to that
of early ulcerative colitis. Ultimately, signs of microangiopathic hemolysis (the
presence of schistocytes on blood smear), thrombocytopenia, and subsequent
renal failure should confirm the diagnosis of hemolytic-uremic syndrome.
Although Henoch-Schönlein purpura can manifest as abdominal pain and bloody
stools, it is not usually associated with colitis. Behçet disease can be
distinguished by its typical features (see Chapter 186 ). Other considerations are
radiation proctitis, viral colitis in immunocompromised patients, and ischemic
colitis (Table 362.6 ). In infancy, dietary protein intolerance can be confused
with ulcerative colitis, although the former is a transient problem that resolves
on removal of the offending protein, and ulcerative colitis is extremely rare in
this age group. Hirschsprung disease can produce an enterocolitis before or
within months after surgical correction; this is unlikely to be confused with
ulcerative colitis.

Table 362.6
Chronic Inflammatory Bowel-Like Intestinal Disorders
Including Monogenetic Diseases
INFECTION (see Table 362.5 )
AIDS-Associated
Toxin
Immune–Inflammatory
Severe combined immunodeficiency diseases
Agammaglobulinemia
Chronic granulomatous disease
Wiskott-Aldrich syndrome
Common variable immunodeficiency diseases
Acquired immunodeficiency states
Dietary protein enterocolitis
Autoimmune polyendocrine syndrome type 1
Behçet disease
Lymphoid nodular hyperplasia
Eosinophilic gastroenteritis
Omenn syndrome
Graft-versus-host disease
IPEX (immune dysfunction, polyendocrinopathy, enteropathy, X-linked) syndromes
Interleukin-10 signaling defects
Autoimmune enteropathy*
Microscopic colitis
 Hyperimmunoglobulin M syndrome
Hyperimmunoglobulin E syndromes
Mevalonate kinase deficiency
Familial Mediterranean fever
Phospholipase Cγ2 defects
IL10RA mutation
Familial hemophagocytic lymphohistiocytosis type 5
X-linked lymphoproliferative syndromes types 1, 2 (XIAP gene)
Congenital neutropenias
TRIM22 mutation
Leukocyte adhesion deficiency 1
VASCULAR–ISCHEMIC DISORDERS
Systemic vasculitis (systemic lupus erythematosus, dermatomyositis)
Henoch-Schönlein purpura
Hemolytic uremic syndrome
Granulomatosis with angiitis
OTHER
Glycogen storage disease type 1b
Dystrophic epidermolysis bullosa
X-linked ectodermal dysplasia and immunodeficiency
Dyskeratosis congenita
ADAM-17 deficiency
Prestenotic colitis
Diversion colitis
Kindler syndrome
Radiation colitis
Neonatal necrotizing enterocolitis
Typhlitis
Sarcoidosis
Hirschsprung colitis
Intestinal lymphoma
Laxative abuse
Endometriosis
Hermansky-Pudlak syndrome
Trichohepatoenteric syndrome
Phosphatase and tensin homolog (PTEN) hamartoma tumor syndrome
* May be the same as IPEX.

Diagnosis
The diagnosis of ulcerative colitis or ulcerative proctitis requires a typical
presentation in the absence of an identifiable specific cause (see Tables 362.5
and 362.6 ) and typical endoscopic and histologic findings (see Tables 362.2 and
362.4 ). One should be hesitant to make a diagnosis of ulcerative colitis in a
child who has experienced symptoms for <2-3 wk until infection has been
excluded. When the diagnosis is suspected in a child with subacute symptoms,
the physician should make a firm diagnosis only when there is evidence of
chronicity on colonic biopsy. Laboratory studies can demonstrate evidence of
ulcerative colitis and prevent recurrence. It is recommended that the medication
be continued even when the disorder is in remission. These medications might
also modestly decrease the lifetime risk of colon cancer.
Approximately 5% of patients have an allergic reaction to 5-ASA,
manifesting as rash, fever, and bloody diarrhea, which can be difficult to
distinguish from symptoms of a flare of ulcerative colitis. 5-ASA can also be
given in enema or suppository form and is especially useful for proctitis.
Hydrocortisone enemas are used to treat proctitis as well, but they are probably
not as effective. A combination of oral and rectal 5-ASA as well as monotherapy
with rectal preparation has been shown to be more effective than just oral 5-ASA
for distal colitis. Extended release budesonide may also induce remission in
patients with mild-to-moderate ulcerative colitis.
Probiotics are effective in adults for maintenance of remission for ulcerative
colitis, although they do not induce remission during an active flare. The most
promising role for probiotics has been to prevent pouchitis, a common
complication following colectomy and ileal–pouch anal anastomosis surgery.
Children with moderate to severe pancolitis or colitis that is unresponsive to
5-ASA therapy should be treated with corticosteroids, most commonly
prednisone. The usual starting dose of prednisone is 1-2 mg/kg/24 hr (40-60 mg
maximum dose). This medication can be given once daily. With severe colitis,
the dose can be divided twice daily and can be given intravenously. Steroids are
considered an effective medication for acute flares, but they are not appropriate
maintenance medications because of loss of effect and side effects, including
growth retardation, adrenal suppression, cataracts, osteopenia, aseptic necrosis of
the head of the femur, glucose intolerance, risk of infection, mood disturbance,
and cosmetic effects.
For a hospitalized patient with persistence of symptoms despite intravenous
steroid treatment for 3-5 days, escalation of therapy or surgical options should be
considered. The validated pediatric ulcerative colitis activity index can be used
to help determine current disease severity based on clinical factors and help
determine who is more likely to respond to steroids and those who will likely
require escalation of therapy (Table 362.7 ).

Table 362.7
Pediatric Ulcerative Colitis Activity Index

ITEM POINTS
 (1) Abdominal Pain
No pain 0
Pain can be ignored 5
Pain cannot be ignored 10
(2) Rectal Bleeding
None 0
Small amount only, in <50% of stools 10
Small amount with most stools 20
Large amount (>50% of the stool content) 30
(3) Stool Consistency of Most Stools
Formed 0
Partially formed 5
Completely unformed 10
(4) Number of Stools Per 24 hr
0-2 0
3-5 5
6-8 10
>8 15
(5) Nocturnal Stools (Any Episode Causing Wakening)
No 0
Yes 10
(6) Activity Level
No limitation of activity 0
Occasional limitation of activity 5
Severe restricted activity 10
Sum of Index (0-85)

With medical management, most children are in remission within 3 mo;

however, 5–10% continue to have symptoms unresponsive to treatment beyond 6
mo. Many children with disease requiring frequent corticosteroid therapy are
started on immunomodulators such as azathioprine (2.0-2.5 mg/kg/day) or 6-
mercaptopurine (1-1.5 mg/kg/day). Uncontrolled data suggest a corticosteroid-
sparing effect in many treated patients. This is not an appropriate choice in a
steroid nonresponsive patient with acute severe colitis because of longer onset of
action. Lymphoproliferative disorders are associated with thiopurine use.
Cyclosporine, which is associated with improvement in some children with
severe or fulminant colitis, is rarely used owing to its high side-effect profile, its
inability to change the natural history of disease, and the increasing use of
infliximab, a chimeric monoclonal antibody to tumor necrosis factor (TNF)-α,
which is also effective in cases of fulminant colitis. Infliximab is effective for
induction and maintenance therapy in children and adults with moderate to
severe disease. TNF blocking agents are associated with an increased risk of
infection (particularly tuberculosis) and malignancies (lymphoma, leukemia).
Adalimumab is also approved for treatment of moderate to severe ulcerative
colitis in adults. Vedolizumab, a humanized monoclonal antibody that inhibits
(a normal finding) may be mistaken for Crohn ileitis. Right lower quadrant pain
or mass with fever can be the result of periappendiceal abscess. This entity is
occasionally associated with diarrhea as well.

Table 362.8

Differential Diagnosis of Presenting Symptoms of Crohn Disease

PRIMARY PRESENTING
DIAGNOSTIC CONSIDERATIONS
SYMPTOM
Right lower quadrant abdominal Appendicitis, infection (e.g., Campylobacter, Yersinia spp.), lymphoma,
pain, with or without mass intussusception, mesenteric adenitis, Meckel diverticulum, ovarian cyst
Chronic periumbilical or Irritable bowel syndrome, constipation, lactose intolerance, peptic disease
epigastric abdominal pain
Rectal bleeding, no diarrhea Fissure, polyp, Meckel diverticulum, rectal ulcer syndrome
Bloody diarrhea Infection, hemolytic-uremic syndrome, Henoch-Schönlein purpura, ischemic
bowel, radiation colitis
Watery diarrhea Irritable bowel syndrome, lactose intolerance, giardiasis, Cryptosporidium
infection, sorbitol, laxatives
Perirectal disease Fissure, hemorrhoid (rare), streptococcal infection, condyloma (rare)
Growth delay Endocrinopathy
Anorexia, weight loss Anorexia nervosa
Arthritis Collagen vascular disease, infection
Liver abnormalities Chronic hepatitis
From Kugathasan S: Diarrhea. In Kliegman RM, Greenbaum LA, Lye PS, editors: Practical
strategies in pediatric diagnosis and therapy , ed 2, Philadelphia, 2004, WB Saunders, p 287.

Growth failure may be the only manifestation of Crohn disease; other

disorders such as growth hormone deficiency, gluten-sensitive enteropathy
(celiac disease), Turner syndrome, or anorexia nervosa must be considered. If
arthritis precedes the bowel manifestations, an initial diagnosis of juvenile
idiopathic arthritis may be made. Refractory anemia may be the presenting
feature and may be mistaken for a primary hematologic disorder. Chronic
granulomatous disease of childhood can cause inflammatory changes in the
bowel as well as perianal disease. Antral narrowing in this disorder may be
mistaken for a stricture secondary to Crohn disease. Other immunodeficiencies
or autoinflammatory conditions and monogenetic disorders may present with GI
symptoms suggestive of IBD, particularly in very early or infant/toddler onset of
disease (see Table 362.6 ).

Diagnosis
Crohn disease can manifest as a variety of symptom combinations (see Fig.
CHAPTER 364

Disorders of Malabsorption
Raanan Shamir

All disorders of malabsorption are associated with diminished intestinal

absorption of one or more dietary nutrients. Malabsorption can result from a
defect in the nutrient digestion in the intestinal lumen or from defective mucosal
absorption. Malabsorption disorders can be categorized into generalized
mucosal abnormalities usually resulting in malabsorption of multiple nutrients
(Table 364.1 ) or malabsorption of specific nutrients (carbohydrate, fat, protein,
vitamins, minerals, and trace elements) (Table 364.2 ). Almost all the
malabsorption disorders are accompanied by chronic diarrhea, which further
worsens the malabsorption (Chapter 367 ).

Table 364.1
Malabsorption Disorders and Chronic Diarrhea Associated
With Generalized Mucosal Defect
MUCOSAL DISORDERS
Gluten-sensitive enteropathy (celiac disease)
Cow's milk and other protein-sensitive enteropathies
Eosinophilic enteropathy
PROTEIN-LOSING ENTEROPATHY
Lymphangiectasia (congenital and acquired)
Disorders causing bowel mucosal inflammation, Crohn disease
CONGENITAL BOWEL MUCOSAL DEFECTS
Microvillous inclusion disease
Tufting enteropathy
Carbohydrate-deficient glycoprotein syndrome
Enterocyte heparan sulfate deficiency
Enteric anendocrinosis (NEUROG 3, PCSK1 mutations)
Tricho-hepatic-enteric syndrome
IMMUNODEFICIENCY DISORDERS
Congenital immunodeficiency disorders
Selective immunoglobulin A deficiency (can be associated with celiac disease)
 Severe combined immunodeficiency
Agammaglobulinemia
X-linked hypogammaglobulinemia
Wiskott-Aldrich syndrome
Common variable immunodeficiency disease
Chronic granulomatous disease
ACQUIRED IMMUNE DEFICIENCY
HIV infection
Immunosuppressive therapy and post–bone marrow transplantation
AUTOIMMUNE ENTEROPATHY
IPEX (i mmune dysregulation, p olyendocrinopathy, e nteropathy, X -linked inheritance)
IPEX-like syndromes
Autoimmune polyglandular syndrome type 1
MISCELLANEOUS
Immunoproliferative small intestinal disease
Short bowel syndrome
Blind loop syndrome
Radiation enteritis
Protein–calorie malnutrition
Crohn disease
Pseudoobstruction

Table 364.2
Classification of Malabsorption Disorders and Chronic
Diarrhea Based on the Predominant Nutrient Malabsorbed
CARBOHYDRATE MALABSORPTION
Lactose malabsorption
Congenital lactase deficiency
Hypolactasia (adult type)
Secondary lactase deficiency
Congenital sucrase isomaltase deficiency
Glucose galactose malabsorption
FAT MALABSORPTION
Exocrine pancreatic insufficiency
Cystic fibrosis
Shwachman-Diamond syndrome
Johanson-Blizzard syndrome
Pearson syndrome
Secondary exocrine pancreatic insufficiency
Chronic pancreatitis
Protein–calorie malnutrition
Decreased pancreozymin/cholecystokinin secretion
Isolated enzyme deficiency
Enterokinase deficiency
Trypsinogen deficiency
Lipase/colipase deficiency
Disrupted enterohepatic circulation of bile salts
Cholestatic liver disease
Bile acid synthetic defects
Deconjugation of bile acids (bacterial overgrowth)
 Bile acid malabsorption (terminal ileal disease)
Intestinal brush border disorders
Allergic enteropathy
Autoimmune enteropathy
Disorders in formation and transport of chylomicrons by enterocytes to the lymphatics
Abetalipoproteinemia
Homozygous hypobetalipoproteinemia
Chylomicron retention disease (Anderson disease)
Disorders of lymph flow
Lymphangiectasia primary/secondary
PROTEIN/AMINO ACID MALABSORPTION
Lysinuric protein intolerance (defect in dibasic amino acid transport)
Hartnup disease (defect in free neutral amino acids)
Blue diaper syndrome (isolated tryptophan malabsorption)
Oasthouse urine disease (defect in methionine absorption)
Lowe syndrome (lysine and arginine malabsorption)
Enterokinase deficiency
Protein-losing enteropathy
DGAT1 mutation
Congenital disorders of glycosylation
CD55 deficiency
MINERAL AND VITAMIN MALABSORPTION
Congenital chloride diarrhea
Congenital sodium absorption defect
Acrodermatitis enteropathica (zinc malabsorption)
Menkes disease (copper malabsorption)
Vitamin D–dependent rickets
Folate malabsorption
Congenital
Secondary to mucosal damage (celiac disease)
Vitamin B12 malabsorption
Autoimmune pernicious anemia
Decreased gastric acid (H2 blockers or proton pump inhibitors)
Terminal ileal disease (e.g., Crohn disease) or resection
Inborn errors of vitamin B12 transport and metabolism
Primary hypomagnesemia
DRUG INDUCED
Sulfasalazine: folic acid malabsorption
Cholestyramine: calcium and fat malabsorption
Anticonvulsant drugs such as phenytoin (causing vitamin D deficiency and folic acid and calcium malabsorption)
Gastric acid suppression: vitamin B12
Methotrexate: mucosal injury

Clinical Approach
The clinical features depend on the extent and type of the malabsorbed nutrient.
The common presenting features, especially in toddlers with malabsorption, are
diarrhea, abdominal distention, and failure to gain weight, with a fall in growth
chart percentiles. Physical findings include abdominal distention, muscle
wasting, and the disappearance of the subcutaneous fat, with subsequent loose
Severe PLE is often associated with malabsorption syndromes (CD, congenital
disorders of glycosylation, intestinal lymphangiectasia) and causes
hypoalbuminemia and edema. Other nutrient deficiencies include iron
malabsorption causing microcytic anemia and low reticulocyte count, low serum
folate levels in conditions associated with mucosal atrophy, especially in the
proximal part of the small intestinal tract and low serum vitamin A and vitamin
E concentrations in fat malabsorption.
The evaluation of a child with malabsorption should be proceed in a stepwise
manner. Clinical history alone might not be sufficient to make a specific
diagnosis, but it can direct the pediatrician toward a more structured and rational
investigative approach. Diarrhea is the main clinical expression of
malabsorption. The onset of diarrhea in early infancy suggests a congenital
defect (Table 364.3 ). In secretory diarrhea caused by disorders such as
congenital chloride diarrhea (CCD) and microvillus inclusion disease (MVID),
the stool is watery and voluminous and can be mistaken for urine (see Chapter
367 ). The onset of symptoms after the introduction of a particular food into a
child's diet can provide diagnostic clues, such as with sucrose in sucrase-
isomaltase deficiency. The nature of the diarrhea may be helpful: explosive
watery diarrhea suggests carbohydrate malabsorption; loose, bulky stools are
associated with CD; and pasty and yellowish offensive stools suggest an
exocrine pancreatic insufficiency. Stool color is usually not helpful; green stool
with undigested “peas and carrots” can suggest rapid intestinal transit in toddler's
diarrhea, which by itself is a self-limiting condition unassociated with failure to
thrive.

Table 364.3

Diarrheal Diseases Appearing in the Neonatal Period

CONDITION CLINICAL FEATURES
Congenital enteropathy
Microvillus inclusion disease Secretory diarrhea
Tufting enteropathy Secretory diarrhea
Congenital intestinal transport defect
Congenital glucose–galactose malabsorption Acidic diarrhea
Congenital bile acid malabsorption Steatorrhea
Congenital chloride diarrhea Secretory diarrhea, metabolic alkalosis
Congenital sodium diarrhea (GUCY2C mutation) Hydramnion, secretory diarrhea
Congenital isolated enzyme deficiency
Congenital lactase deficiency Acidic diarrhea
Congenital enterokinase deficiency Failure to thrive, edema
Congenital trypsinogen deficiency Failure to thrive, edema
 Congenital lipase and/or colipase deficiency Failure to thrive, oily stool
Enteric anendocrinosis (NEUROG 3 mutation) Hyperchloremic acidosis, failure to thrive
Immunodeficiency and autoinflammatory diseases (see Table Failure to thrive, opportunistic infections,
362.6 ) eczema

Following medical history, physical examination and laboratory testing (see

next Chapter 364.1 ), intestinal biopsies may assist in the diagnosis. This is
usually done for chronic rather than acute diseases (that can be self-limited).
Generalized mucosal villous atrophy (flat mucosa) may be associated with
malabsorption of multiple macronutrients and micronutrients and has a wide
range of differential diagnoses (see Chapter 364.2 ).

364.1
Evaluation of Children With
Suspected Intestinal Malabsorption
Firas Rinawi, Raanan Shamir

Keywords
Steatorrhea
protein-losing enteropathy
carbohydrate malabsorption

The investigation is guided by the history and physical examination. In a child

presenting with chronic or recurrent diarrhea, the initial work-up should include
stool cultures and antibody tests for parasites; stool microscopy for ova and
parasites such as Giardia ; and fecal leukocytes and calprotectin or lactoferrin to
exclude inflammatory disorders. Stool pH and reducing substances for
carbohydrate malabsorption, stool osmolality to differentiate between osmotic
and secretory diarrhea and quantitative stool fat examination and α1 -antitrypsin
Table 364.4
Extraintestinal Manifestations of Celiac Disease

MANIFESTATION PROBABLE CAUSE(S)

CUTANEOUS
Ecchymoses and petechiae Vitamin K deficiency; rarely, thrombocytopenia
Edema Hypoproteinemia
Dermatitis herpetiformis Epidermal (type 3) tTG autoimmunity
Follicular hyperkeratosis and Vitamin A malabsorption, vitamin B complex malabsorption
dermatitis
ENDOCRINOLOGIC
Amenorrhea, infertility, impotence, Malnutrition, hypothalamic-pituitary dysfunction, immune dysfunction
delayed puberty
Secondary hyperparathyroidism Calcium and/or vitamin D malabsorption with hypocalcemia
HEMATOLOGIC
Anemia Iron, folate, vitamin B12 , or pyridoxine deficiency
Hemorrhage Vitamin K deficiency; rarely, thrombocytopenia due to folate deficiency
Thrombocytosis, Howell-Jolly bodies Hyposplenism
HEPATIC
Elevated liver biochemical test Lymphocytic hepatitis
levels Autoimmunity
Autoimmune hepatitis
MUSCULAR
Atrophy Malnutrition due to malabsorption
Tetany Calcium, vitamin D, and/or magnesium malabsorption
Weakness Generalized muscle atrophy, hypokalemia
NEUROLOGIC
Peripheral neuropathy Deficiencies of vitamin B12 and thiamine; immune-based neurologic
dysfunction
Ataxia Cerebellar and posterior column damage
Demyelinating central nervous system Immune-based neurologic dysfunction
lesions
Seizures Unknown
SKELETAL
Osteopenia, osteomalacia, and Malabsorption of calcium and vitamin D, secondary
osteoporosis hyperparathyroidism, chronic inflammation
Osteoarthropathy Unknown
Pathologic fractures Osteopenia and osteoporosis
OTHER
Enamel hypoplasia Vitamin D, calcium malabsorption
Anxiety, schizophrenia Unknown, uncertain
Pulmonary hemosiderosis Unknown, uncertain
Aphthous stomatitis Unknown
tTG , tissue transglutaminase.
Modified from Kelly CP: Celiac disease. In Feldman M, Friedman LS, Brandt LJ, editors:
Sleisenger and Fordtran's gastrointestinal and liver disease , ed 10, Philadelphia, 2016, Elsevier.
Table 107.1.
Table 364.5
National Institute for Health and Care Excellence
Guidelines on the Indications That Should Prompt Testing
for Celiac Disease
CELIAC TESTING RECOMMENDED
• Persistent unexplained abdominal or gastrointestinal symptoms
• Faltering growth
• Prolonged fatigue
• Unexpected weight loss
• Severe or persistent mouth ulcers
• Unexplained iron, vitamin B12, or folate deficiency
• Type 1 diabetes
• Autoimmune thyroid disease
• Irritable bowel syndrome
• First degree relatives of people with coeliac disease
• Dermatitis herpetiformis
CELIAC TESTING SHOULD BE CONSIDERED
• Metabolic bone disorders (reduced bone mineral density or osteomalacia)
• Unexplained neurological symptoms (particularly peripheral neuropathy or ataxia)
• Unexplained subfertility or recurrent miscarriage
• Persistently increased concentrations of liver enzymes with unknown cause
• Dental enamel defects
• Down syndrome
• Turner syndrome
• William syndrome
• Selective IgA deficiency
IgA , immunoglobulin-A.
From Downey L, Houten R, Murch S, Longson D for the Guideline Development Group:
Recognition, assessment, and management of coeliac disease: summary of updated NICE
guidance, BMJ 351: h4513, 2015.

Table 364.6
Clinical Spectrum of Celiac Disease
SYMPTOMATIC
Frank malabsorption symptoms and signs (e.g., chronic diarrhea, failure to thrive, weight loss)
Extraintestinal symptoms and signs (e.g., anemia, fatigue, hypertransaminasemia, neurologic disorders, short
stature, dental enamel defects, arthralgia, aphthous stomatitis)
SILENT
No apparent symptoms in spite of histologic evidence of villous atrophy
In most cases identified by serologic screening in at-risk groups (see Table 364.1 )
LATENT
Subjects who have a normal intestinal histology, but at some other time have shown a gluten-dependent
enteropathy
POTENTIAL
 Subjects with positive celiac disease serology but without evidence of altered intestinal histology. Patients may or
may not have symptoms and signs of disease and may or may not develop a gluten-dependent enteropathy later

Some diseases—many with an autoimmune pathogenesis—are found with a

higher-than-normal incidence in CD patients. Among these are type 1 diabetes,
autoimmune thyroid disease, Addison disease, Sjögren syndrome, rheumatoid
arthritis, autoimmune cholangitis, autoimmune hepatitis, and primary biliary
cholangitis. Such associations have been interpreted as a consequence of the
sharing of identical HLA haplotypes, but a direct role of gluten in promoting
autoimmunity cannot be excluded. The relation between CD and other
autoimmune diseases is poorly defined; once those diseases are established, they
are not influenced by a gluten-free diet. Other associated conditions include
selective IgA deficiency and Down, Turner, and Williams syndromes.

Diagnosis
The diagnosis of CD is based on a combination of symptoms, antibodies, HLA
status, and duodenal histology. The initial approach to symptomatic patients is to
test for anti-TG2 IgA antibodies and for total IgA in serum to exclude IgA
deficiency. If IgA anti-TG2 antibodies are negative, and serum total IgA is
normal for age, CD is unlikely to be the cause of the symptoms. If anti-TG2
antibody testing is positive the patients should be referred to a pediatric
gastroenterologist for further diagnostic workup, which depends on the serum
antibody levels.
IgA anti-TG2 decline if the patient is on a gluten free diet. In patients with
selective IgA deficiency, testing is recommended with IgG antibodies to TG2.
Patients with positive anti-TG2 antibody levels <10 times the upper limit of
normal should undergo upper endoscopy with multiple biopsies. In patients with
positive anti-TG2 antibody levels at or >10 times the upper limit of normal,
blood should be drawn for HLA and EMA testing. If the patient is positive for
EMA antibodies and positive for DQ2 or DQ8 HLA testing, the diagnosis of CD
is confirmed, a life-long gluten-free diet is started and the patient is followed for
the improvement of symptoms and the decline of antibodies. HLA testing is
almost always positive; thus, it is possible that HLA testing will not be necessary
in the future to establish diagnosis. In the rare case of negative results for HLA
and/or anti-EMA in a child with TG2 antibody titers >10 times the upper limits
of normal, the diagnostic workup should be extended, including repeated testing
and duodenal biopsies (Fig. 364.4 ). In asymptomatic persons belonging to high-
 FIG. 364.5 Diagnostic algorithm for celiac disease (CD) in asymptomatic
children/adolescents belonging to at-risk groups, according to ESPGHAN.
EGD, Esophagogastroduodenoscopy; EMA , endomysial antibodies; Ig ,
immunoglobulin; HLA , human leukocyte antigen; TG2 , transglutaminase.
(Modified from Husby S, Koletzko S, Korponay-Szabò IR, et al: European
Society for Pediatric Gastroenterology, Hepatology and Nutrition Guidelines
for the diagnosis of celiac disease, J Pediatr Gastroenterol Nutr 54[1]:136–
160, 2012. Fig. 2.)

Table 364.7
Other Causes of Flat Mucosa
Autoimmune enteropathy
Tropical sprue
Giardiasis
HIV enteropathy
Bacterial overgrowth
Crohn disease
Eosinophilic gastroenteritis
Cow's milk enteropathy
Food allergy
Primary immunodeficiency
 Graft-versus-host disease
Chemotherapy and radiation
Protein energy malnutrition

Treatment
The only treatment for CD is lifelong strict adherence to a gluten-free diet. This
requires a wheat-, barley-, and rye-free diet (Tables 364.8 and 364.9 ). Despite
evidence that oats are safe for most patients with CD, there is concern regarding
the possibility of contamination of oats with gluten during harvesting, milling,
and shipping. Nevertheless, it seems wise to add oats to the gluten-free diet only
when the latter is well established, so that possible adverse reactions can be
readily identified. There is a consensus that all CD patients should be treated
with a gluten-free diet regardless of the presence of symptoms. However,
whereas it is relatively easy to assess the health improvement after treatment of
CD in patients with clinical symptoms of the disease, it proves difficult in
persons with asymptomatic CD. The nutritional risks, particularly osteopenia
and increased risk for other autoimmune disorders, are those mainly feared for
subjects who have silent CD and continue on a gluten-containing diet. Little is
known about the health risks in untreated patients with potential CD.

Table 364.8
Principles of Initial Dietary Therapy for Patients With Celiac
Disease
Avoid all foods containing wheat, rye, and barley gluten (pure oats usually safe).
Avoid malt unless clearly labeled as derived from corn.
Use only rice, corn, maize, buckwheat, millet, amaranth, quinoa, sorghum, potato or potato starch, soybean,
tapioca, and teff, bean, and nut flours.
Wheat starch and products containing wheat starch should only be used if they contain <20 ppm gluten and are
marked “gluten free.”
Read all labels and study ingredients of processed foods.
Beware of gluten in medications, supplements, food additives, emulsifiers, or stabilizers.
Limit milk and milk products initially if there is evidence of lactose intolerance.
Avoid all beers, lagers, ales, and stouts (unless labeled gluten free).
Wine, most liqueurs, ciders, and spirits, including whiskey and brandy, are allowed.

ppm , Parts per million.

Table 364.9
Some Potential Sources of Hidden Gluten
Beers, ales, other fermented beverages (distilled beverages acceptable)
Bouillon and soups
Candy
Communion wafers
Drink mixes
Gravy and sauces
Herbal tea
Imitation meat and seafood
Nutritional supplements
Play-Doh
Salad dressings and marinades
Self-basting turkeys
Soy sauce
From Kelly CP. Celiac disease. In Feldman M, Friedman LS, Brandt LJ, editors: Sleisenger and
Fordtran's gastrointestinal and liver disease , ed 10, Philadelphia, Elsevier, 2016. Box 107.3.

Some patients do not respond to a gluten free diet; refractory or

nonresponsive CD requires a systematic approach to determine the correct
diagnosis, compliance, and therapeutic options (Fig. 364.6 ).
Table 364.10
Causes of Protein-Losing Enteropathy

PROTEIN-LOSING ENTEROPATHY AGENT, DISEASES (GENE )

Gastrointestinal Viral infections CMV, rotavirus
infections Bacterial and parasitic Salmonella, Shigella, Campylobacter,
diseases Clostridium difficile, Helicobacter pylori,
Gastrointestinal Whipple disease
infestations Small bowel bacterial overgrowth
Giardiasis
Strongyloides stercoralis
Gastrointestinal Gastric diseases Menetrier disease
inflammatory disorders Gastrointestinal disorders Eosinophilic gastroenteropathy
Food induced enteropathy
Celiac disease, Crohn disease,
Ulcerative colitis, Tropical sprue
Radiation enteritis
GVHD, NEC
Gastrointestinal Adenocarcinomas Esophageal, gastric, colonic
malignancies Lymphomas
Kaposi sarcoma
Vasculitic disorders Henoch Schönlein purpura
Systemic lupus
erythematosus
Drugs NSAIDs
Metabolic/genetic Congenital disorders of CDG-Ib (MPI)
glycosylation (CDG) Congenital enterocyte heparan sulphate
Mutations in DGAT1 gene deficiency (ALG6)
Mutations in CD55
Intestinal Congenital/ Primary IL Turner, Noonan, Klippel–Trenaunay–Weber
lymphangiectasia • Syndromal/genetic/ metabolic Hennekam syndrome (CCBE1, FAT4)
PLE with skeletal dysplasia (FGFR3 )
Generalized lymphatic dysplasia (PIEZO1)
Secondary Abdominal tuberculosis
• Infection Crohn disease, sarcoidosis
• Inflammation Retroperitoneal fibrosis
• Radiotherapy Retroperitoneal malignancies, lymphoma
• Neoplastic disorders Constrictive pericarditis, after Fontan operation,
• Cardiac disorders congestive heart failure
CDG , Carbohydrate deficient glycoprotein; CMV , cytomegalovirus; GVHD , graft versus host
disease; IL , intestinal lymphangiectasia; NEC , NSAIDs , nonsteroidal anti-inflammatory drugs;
PLE , protein-losing enteropathy.

IL is characterized by diffuse or local dilatation of the enteric lymphatics and

is located in the mucosa, submucosa, or subserosa. Lymph rich in proteins,
lipids, and lymphocytes leak into the bowel lumen, resulting in PLE, steatorrhea,
and lymphocyte depletion. Hypoalbuminemia, hypogammaglobulinemia, edema,
lymphopenia, malabsorption of fat and fat-soluble vitamins, and chylous ascites
often occur. IL can also manifest with ascites, peripheral edema, and a low serum
 enteral autonomy
complications
central line infection
intestinal failure associated liver disease
small bowel bacterial overgrowth
lengthening procedure
intestinal transplantation

Short bowel (or short gut) syndrome results from congenital malformations or
resection of the small bowel (Table 364.11 ). Its incidence increases with low
birth weight and earlier gestational age and is estimated at 7/1,000 live births in
U.S. infants with birth weight <1,500 mg. Loss of >50% of the small bowel,
with or without a portion of the large intestine, can result in symptoms of
generalized malabsorptive disorder or in specific nutrient deficiencies,
depending on the region of the bowel resected. At birth, the length of small
bowel is 200-250 cm; by adulthood, it grows to 300-800 cm. Bowel resection in
an infant has a better prognosis than in an adult because of the potential for
intestinal growth and adaptation. An infant with as little as 15 cm of bowel with
an ileocecal valve, or 20 cm without, has the potential to survive and be
eventually weaned from parenteral nutrition.

Table 364.11
Causes of Short Bowel Syndrome
CONGENITAL
Congenital short bowel syndrome
Intestinal atresia
Gastroschisis
BOWEL RESECTION
Necrotizing enterocolitis
Volvulus with or without malrotation
Long segment Hirschsprung disease
Meconium peritonitis
Crohn disease
Trauma

In addition to the length of the bowel, the anatomic location of the resection is
also important. The proximal 100-200 cm of jejunum is the main site for
carbohydrate, protein, iron, and water-soluble vitamin absorption, whereas fat
absorption occurs over a longer length of the small bowel. Depending on the
The complications of intestinal failure include loss of venous access, life-
threatening infections, and TPN-induced cholestatic liver disease.

Table 365.1
Causes of Intestinal Failure in Children Requiring
Transplantation
SHORT BOWEL
• Congenital disorders
• Volvulus
• Gastroschisis
• Necrotizing enterocolitis
• Intestinal atresia
• Trauma
INTESTINAL DYSMOTILITY
• Intestinal pseudoobstruction
• Intestinal aganglionosis (Hirschsprung disease)
ENTEROCYTE DYSFUNCTION
• Microvillus inclusion disease
• Tufting enteropathy
• Autoimmune disorders
• Crohn disease
TUMORS
• Familial polyposis
• Inflammatory pseudotumor

Paucity of Venous Access

Administration of TPN requires the insertion of a centrally placed venous
catheter, there being only 6 readily accessible sites (bilateral internal jugulars,
subclavians, iliac veins). The loss of venous access generally occurs in the
setting of recurrent catheter sepsis and thrombosis; clinical convention suggests
that loss of 50% of these venous access sites places the patient at risk of not
being able to be treated with TPN.

Life-Threatening Infections
Life-threatening infections are usually catheter-related; the absence of significant
lengths of intestine may be associated with abnormal motility of the residual
bowel (producing both delayed or rapid emptying), with varying degrees of
bacterial overgrowth and possible bacterial or fungal translocation as a
consequence of loss of intestinal barrier function and/or loss of gut immunity.
CHAPTER 366

Acute Gastroenteritis in Children

Karen L. Kotloff

The term gastroenteritis denotes inflammation of the gastrointestinal tract, most

commonly the result of infections with bacterial, viral, or parasitic pathogens
(Tables 366.1 to 366.3 ). Many of these infections are foodborne illnesses (Table
366.4 ). Several clinical syndromes are often described because they have
different (albeit overlapping) etiologies, outcomes, and treatments. Acute
gastroenteritis (AGE) captures the bulk of infectious cases of diarrhea. The
most common manifestations are diarrhea and vomiting, which can also be
associated with systemic features such as abdominal pain and fever. Dysentery
refers to a syndrome characterized by frequent small stools containing visible
blood, often accompanied by fever, tenesmus, and abdominal pain. This should
be distinguished from bloody diarrhea (larger volume bloody stools with less
systemic illness) because the etiologies may differ. Prolonged (lasting 7-13
days) and persistent diarrhea (lasting 14 days or longer) are important because
of their impact on growth and nutrition.

Table 366.1
Etiologies of Viral Gastroenteritis

COMMERCIALLY
ACUTE DURATION PRINCIPAL
INCUBATION RISK AVAILABLE
ETIOLOGY SIGNS AND OF VEHICLE AND
PERIOD FACTORS DIAGNOSTIC
SYMPTOMS ILLNESS TRANSMISSION
TEST
Caliciviruses 12-48 hr Nausea, 1-3 days Person-to-person Very No. Testing of
(including vomiting, (fecal-oral and contagious stool or vomitus
noroviruses abdominal aerosolized vomit), (chlorine using real time
and cramping, and food, water, and heat reverse
sapoviruses) diarrhea, and fomites resistant); transcriptase
fever, contaminated with produces (RT)-
myalgia, and human feces. large quantitative
some outbreaks in PCR is the
 headache closed preferred
settings such method,
as cruise available in
ships, and public health
restaurants. laboratories.
Immunoassays
for norovirus
have poor
sensitivity.
FDA-cleared
multiplex PCR
assays are
available to
detect these
organisms.
Norovirus
genotyping (GI
and GII) is
performed by
CDC.
Rotavirus 2-4 days Often begins 3-8 days Person-to-person Nearly all Yes. Rotavirus:
(groups A- with (fecal-oral), infants and immunoassay
C), vomiting, fomites. Aerosol children (preferred), latex
astrovirus, followed by transmission of worldwide agglutination, and
and enteric watery rotavirus may be were immune-
adenovirus diarrhea, low- possible. infected by chromatography of
(serotypes 40 grade fever 2 yr of age stool. Enteric
and 41) before adenovirus:
vaccine immunoassay. FDA-
introduction. cleared multiplex
PCR assays are
available to detect
these organisms.
CDC, Centers for Disease Control and Prevention.
Modified from Centers for Disease Control and Prevention: Diagnosis and management of
foodborne illnesses, MMWR 53(RR-4):1–33, 2004.

Table 366.2
Etiologies of Bacterial Gastroenteritis

DURATION PRINCIPAL
INCUBATION ACUTE SIGNS
ETIOLOGY OF VEHICLE AND RISK FACTORS
PERIOD AND SYMPTOMS
ILLNESS TRANSMISSION
Bacillus cereus 1-6 hr Sudden onset of 24 hr Soil and water Improperly
(preformed emetic severe nausea and refrigerated cooked
toxin) vomiting; diarrhea or fried rice, meats
may be present
Bacillus cereus 8-16 hr Abdominal cramps, 1-2 days Soil and water Meats, stews,
(enterotoxins watery diarrhea; gravies, vanilla
formed in vivo) nausea and vomiting sauce
 may be present
Campylobacter 1-5 days Diarrhea, (10–20% of 5-7 days Wild and domestic Raw and
jejuni episodes are (sometimes animals and animal undercooked
prolonged), cramps, >10 days) products, including poultry,
fever, and vomiting; usually self- pets unpasteurized milk,
bloody diarrhea, limiting untreated surface
bacteremia, water
extraintestinal
infections, severe
disease in
immunocompromised
Clostridium Unknown—can Mild to moderate Variable Person-person Immunosuppression,
difficile toxin appear weeks watery diarrhea that (fecal-oral), mostly intestinal disease or
after antibiotic can progress to within healthcare surgery, prolonged
cessation severe, facilities hospitalization,
pseudomembranous antibiotics
colitis with systemic
toxicity.
Clostridium 8-16 hr Watery diarrhea, 1-2 days Environment, Meats, poultry,
perfringens toxin nausea, abdominal human and animal gravy, dried or
cramps; fever is rare intestines precooked foods
with poor
temperature control
Enterohemorrhagic 1-9 days Watery diarrhea 4-7 days Food and water Undercooked beef
Escherichia coli (usually 3-4 that becomes contaminated with especially
(EHEC) including days) bloody in 1-4 feces from hamburger,
E. coli O157:H7 days in ~40% of ruminants; infected unpasteurized milk
and other Shiga infections; in people and animals and juice, raw fruits
toxin–producing contrast to (fecal-oral); and petting zoos,
E. coli (STEC) dysentery, bloody predominantly recreational
stools are large high-resource swimming, daycare.
volume and countries Antimotility agents
fever/toxicity are and antibiotics
minimal. increase risk of
More common in hemolytic uremic
children <4 yr syndrome
old.
Enterotoxigenic E. 1-5 days Watery diarrhea, 3-7 days Water or food Infants and young
coli (ETEC) abdominal cramps, contaminated with children in LMIC
some vomiting human feces and travelers
Salmonella , 1-5 days Diarrhea, (10–20% 5-7 days Domestic poultry, Ingestion of raw or
nontyphoidal prolonged), cramps, (sometimes cattle, reptiles, undercooked food,
fever, and vomiting; >10 days) amphibians, birds improper food
bloody diarrhea, usually self- handling, travelers,
bacteremia, limiting immunosuppression,
extraintestinal hemolytic anemia,
infections, severe achlorhydria,
disease in contact with
immunocompromised infected animal
Shigella spp. 1-5 days (up to Abdominal 5-7 days Infected people or Poor hygiene and
10 days for S. cramps, fever, fecally sanitation,
dysenteriae diarrhea contaminated crowding, travelers,
type 1) Begins with surfaces (fecal- daycare, MSM,
watery stools that oral) prisoners
can be the only
 manifestation or
proceed to
dysentery.
Staphylococcus 1-6 hr Sudden onset of 1-3 days Birds, mammals, Unrefrigerated or
aureus (preformed severe nausea and dairy, and improperly
enterotoxin) vomiting environment refrigerated meats,
Abdominal potato and egg
cramps salads, cream
Diarrhea and pastries
fever may be
present
Vibrio cholerae O1 1-5 days Watery diarrhea and 3-7 days Food and water Contaminated water,
and O139 vomiting, that can be contaminated with fish, shellfish,
profuse and lead to human feces street-vended food
severe dehydration from endemic or
and death within epidemic settings;
hours. blood group O,
vitamin A
deficiency

Vibrio 2-48 hr Watery diarrhea, 2-5 days Estuaries and Undercooked or raw
parahaemolyticus abdominal cramps, marine seafood, such as
nausea, vomiting. environments; fish, shellfish
Bacteremia and currently
wound infections undergoing
occur uncommonly, pandemic spread
especially in high-risk
patients, e.g., with
liver disease and
diabetes.
Vibrio vulnificus 1-7 days Vomiting, diarrhea, 2-8 days Estuaries and Undercooked or raw
abdominal pain. marine shellfish, especially
Bacteremia and environments oysters, other
wound infections, contaminated
particularly in patients seafood, and open
with chronic liver wounds exposed to
disease (presents with seawater
septic shock and
hemorrhagic bullous
skin lesions)
Yersinia 1-5 days Diarrhea, (10–20% 5-7 days Swine products, Undercooked pork,
enterocolitica and prolonged), cramps, (sometimes occasionally improper food
Yersinia fever, and vomiting; >10 days) person-to-person handling,
pseudotuberculosis bloody diarrhea, usually self- and animal-to- unpasteurized milk,
bacteremia, limiting humans, water- tofu, contaminated
extraintestinal borne, bloodborne water, transfusion
infections, severe (can multiply from a bacteremic
disease in during person, cirrhosis,
immunocompromised; refrigeration) chelation therapy.
pseudoappendicitis
occurs primarily in
older children.
† FDA-cleared multiplex PCR assays are available but generally not recommended for diagnosis

in individual patients because of inability to determine antimicrobial susceptibility to guide

treatment or speciate the organism for outbreak investigation.
FDA, Food and Drug Administration; LMIC, low and middle-income countries; MSM, men who
have sex with men; PCR, polymerase chain reaction; TCBS, thiosulfate-citrate-bile salts-sucrose.
Modified from Centers for Disease Control and Prevention: Diagnosis and management of
foodborne illnesses, MMWR 53(RR-4):1–33, 2004.

Table 366.3
Etiologies of Parasitic Gastroenteritis

COMMERCIALLY
ACUTE SIGNS PRINCIPAL
INCUBATION DURATION RISK AVAILABLE
ETIOLOGY AND VEHICLE AND
PERIOD OF ILLNESS FACTORS DIAGNOSTIC
SYMPTOMS TRANSMISSION
TEST
Cryptosporidium 1-11 days Diarrhea 1-2 wk; may be Person-to-person Infants 6-18 mo Request specific
(usually watery), remitting and (fecal-oral), of age living in microscopic
bloating, relapsing over Contaminated food endemic examination of stool
flatulence, weeks to months and water settings in with special stains
cramps, (including LMIC, patients (direct fluorescent
malabsorption, municipal and with AIDS, antibody staining is
weight loss, and recreational water childcare preferable to
fatigue may wax contaminated with settings, modified acid fast)
and wane. human feces. drinking for Cryptosporidium.
Persons with unfiltered Immunoassays and
AIDS or surface water, PCR
malnutrition MSM, IgA sensitive than
have more deficiency microscopy.
severe disease.
Cyclospora 1-11 days Same as Same as Fresh produce Travelers,
cayetanensis Cryptosporidium Cryptosporidium (imported berries, consumption of
lettuce) fresh produce
imported from
the tropics.

Entamoeba 2-4 wk Gradual onset of Variable; may be Fecal-oral Persons living

histolytica cramps, watery protracted transmission in or traveling
diarrhea and (several weeks Any uncooked to LMIC,
often dysentery to several food or food institutionalized
with cramps but months) contaminated persons, MSM.
rarely fever. Can by an ill food
wax and wane handler after
with weight loss. cooking;
 Dissemination to drinking water
live and other
organs can
occur.
Giardia 1-4 wk Diarrhea, 2-4 wk Any uncooked Hikers drinking Microscopic
intestinalis stomach cramps, food or food unfiltered examination of stool
gas, weight loss; contaminated by surface water, for ova and parasites
symptoms may an ill food handler persons living may need at least 3
wax and wane. after cooking; in or traveling samples;
drinking water to LMIC, immunoassay is
MSM, IgA more sensitive.
deficiency Multiplex PCR.
† FDA-cleared multiplex PCR assays are available.

IgA, Immunoglobulin A; LMID, low- and middle-income countries; MSM, men who have sex with
men; PCR, polymerase chain reaction.
Modified from Centers for Disease Control and Prevention: Diagnosis and management of
foodborne illnesses, MMWR 53(RR-4):1–33, 2004.

Table 366.4
Incidence of Bacterial and Parasitic Food-Borne Infections
in 2017 and Percentage Change Compared With 2014-2016
Average Annual Incidence by Pathogen FoodNet Sites,*
2014-2017 †

2017 2017 VERSUS 2014-2016

PATHOGEN
NO. OF CASES INCIDENCE RATE § % CHANGE ¶ (95% CI)
Bacteria
Campylobacter 9,421 19.1 10 (2 to 18)
Salmonella 7,895 16.0 −5 (−11 to 1)
Shigella 2,132 4.3 −3 (−25 to 25)
Shiga toxin–producing E. coli ** 2,050 4.2 28 (9 to 50)
Yersinia 489 1.0 166 (113 to 234)
Vibrio 340 0.7 54 (26 to 87)
Listeria 158 0.3 26 (2 to 55)
Parasites
Cryptosporidium 1,836 3.7 10 (−16 to 42)
Cyclospora 163 0.3 489 (253 to 883)
* Connecticut, Georgia, Maryland, Minnesota, New Mexico, Oregon, Tennessee, and selected
counties in California, Colorado, and New York.
† Data for 2017 are preliminary.

§ Per 100,000 population.

¶ Percentage change reported as increase or decrease.

ability to mass-produce and widely distribute food has led to large multistate
outbreaks of AGE due to NTS, STEC, and other agents. Globalization has
cultivated a taste for tropical fruits and vegetables, creating a mechanism for
importation of novel pathogens. The increasing frequency of antimicrobial
resistance among bacteria that causes AGE has been linked to the use of
antibiotics as growth-promotors for animals bred for food. Recreational
swimming facilities and water treatment systems have provided a vehicle for
massive outbreaks of Cryptosporidium , a chlorine-resistant organism. Venues
serving catered food to large groups of people, such as hotels and cruise ships,
are conducive to outbreaks, as are institutions where hygiene is compromised,
such as daycare centers, prisons, and nursing homes. Hospitalization and modern
medical therapy have created a niche for nosocomial C. difficile toxin infection
(Table 366.5 ).

Table 366.5
Exposure or Condition Associated With Pathogens
Causing Diarrhea

EXPOSURE OR
PATHOGEN(S)
CONDITION
FoodBorne
Foodborne outbreaks in Norovirus, nontyphoidal Salmonella , Clostridium perfringens , Bacillus cereus ,
hotels, cruise ships, resorts, Staphylococcus aureus , Campylobacter spp., ETEC, STEC, Listeria , Shigella ,
restaurants, catered events Cyclospora cayetanensis , Cryptosporidium spp.
Consumption of Salmonella , Campylobacter , Yersinia enterocolitica , S. aureus toxin,
unpasteurized milk or dairy Cryptosporidium , and STEC. Listeria is infrequently associated with diarrhea,
products Brucella (goat milk cheese), Mycobacterium bovis , Coxiella burnetii
Consumption of raw or STEC (beef), C. perfringens (beef, poultry), Salmonella (poultry), Campylobacter
undercooked meat or poultry (poultry), Yersinia (pork, chitterlings), S. aureus (poultry), and Trichinella spp.
(pork, wild game meat)
Consumption of fruits or STEC, nontyphoidal Salmonella , Cyclospora , Cryptosporidium , norovirus,
unpasteurized fruit juices, hepatitis A, and Listeria monocytogenes
vegetables, leafy greens, and
sprouts
Consumption of Salmonella , Shigella (egg salad)
undercooked eggs
Consumption of raw Vibrio species, norovirus, hepatitis A, Plesiomonas
shellfish
Exposure or Contact
Swimming in or drinking Campylobacter , Cryptosporidium , Giardia , Shigella , Salmonella , STEC,
untreated fresh water Plesiomonas shigelloides
Swimming in recreational Cryptosporidium and other potentially waterborne pathogens when disinfectant
water facility with treated concentrations are inadequately maintained
water
Healthcare, long-term care, Norovirus, Clostridium difficile , Shigella , Cryptosporidium , Giardia , STEC,
 prison exposure, or rotavirus
employment
Childcare center attendance Rotavirus, Cryptosporidium , Giardia , Shigella , STEC
or employment
Recent antimicrobial therapy C. difficile , multidrug-resistant Salmonella
Travel to resource- Escherichia coli (enteroaggregative, enterotoxigenic, enteroinvasive), Shigella ,
challenged countries typhi and nontyphoidal Salmonella , Campylobacter , Vibrio cholerae , Entamoeba
histolytica , Giardia , Blastocystis , Cyclospora , Cystoisospora , Cryptosporidium
Exposure to house pets with Campylobacter , Yersinia
diarrhea
Exposure to pig feces in Balantidium coli
certain parts of the world
Contact with young poultry Nontyphoidal Salmonella
or reptiles
Visiting a farm or petting STEC, Cryptosporidium , Campylobacter
zoo
Exposure or Condition
Age group Rotavirus (6-18 mo of age), nontyphoidal Salmonella (infants from birth to 3 mo of
age and adults >50 yr with a history of atherosclerosis), Shigella (1-7 yr of age),
Campylobacter (young adults)
Underlying Nontyphoidal Salmonella , Cryptosporidium , Campylobacter , Shigella , Yersinia
immunocompromising
condition
Hemochromatosis or Y. enterocolitica , Salmonella
hemoglobinopathy
AIDS, immunosuppressive Cryptosporidium , Cyclospora , Cystoisospora , microsporidia, Mycobacterium
therapies avium –intercellulare complex, cytomegalovirus
Anal-genital, oral-anal, or Shigella , Salmonella , Campylobacter , E. histolytica , Giardia lamblia ,
digital-anal contact Cryptosporidium
ETEC, enterotoxigenic Escherichia coli ; STEC, Shiga toxin–producing Escherichia coli .
From Shane AL, Mody RK, Crump JA, et al: 2017 Infectious Diseases Society for America clinical
practice guidelines for the diagnosis and management of infectious diarrhea, Clin Infect Dis
65(12):e45–80, 2017 (Table 2, p. e48).

Endemic Diarrhea. In the United States, rotavirus was the most common
cause of medically attended AGE among children younger than 5 yr until the
introduction of rotavirus vaccine for routine immunization of infants. Annual
epidemics swept across the country beginning in the southwest in November and
reaching the northeast by May, affecting nearly every child by the age of 2 yr.
Since vaccine introduction, healthcare utilization for AGE has decreased
markedly. Norovirus is the leading cause of AGE among children in the United
States seeking healthcare, followed by sapovirus, adenovirus 40 and 41, and
astrovirus (see Table 366.1 ).
Foodborne Transmission. The most comprehensive resource for describing
the burden of bacterial and protozoal diarrhea in the United States is the
Foodborne Diseases Active Surveillance Network (FoodNet) maintained by the
Centers for Disease Control and Prevention (CDC) (see Table 366.4 ). FoodNet
performs active laboratory-based surveillance of 9 bacterial and protozoal
enteric infections commonly transmitted by food. Among children 0-19 yr of age
in 2015, NTS was most common, followed by Campylobacter and Shigella ,
then STEC and Cryptosporidium . Vibrio, Yersinia, and Cyclospora were the
least common (see Table 366.5 ). Children younger than 5 yr have the highest
incidence of disease, and the elderly have the highest frequency of
hospitalization and death. Only 5% of these infections are associated with
recognized outbreaks.
Noninfectious agents may also cause foodborne gastrointestinal symptoms
due to a direct toxic effect of the food (mushrooms) or contamination (heavy
metals) (Table 366.6 ).

Table 366.6
Foodborne Noninfectious Illnesses

DURATION
INCUBATION SIGNS AND ASSOCIATED LABORATORY
ETIOLOGY OF TREATMENT
PERIOD SYMPTOMS FOODS TESTING
ILLNESS
Antimony 5 min-8 hr Vomiting, Usually self- Metallic Identification of Supportive care
usually <1 hr metallic taste limited container metal in
beverage or food
Arsenic Few hours Vomiting, colic, Several days Contaminated Urine Gastric lavage,
diarrhea food Can cause BAL
eosinophilia (dimercaprol)
Cadmium 5 min-8 hr Nausea, Usually self- Seafood, Identification of Supportive care
usually <1 hr vomiting, limited oysters, clams, metal in food
myalgia, lobster, grains,
increase in peanuts
salivation,
stomach pain
Ciguatera fish 2-6 hr GI: abdominal Days to A variety of Radioassay for Supportive
poisoning pain, nausea, weeks to large reef fish: toxin in fish or a care, IV
(ciguatera toxin) vomiting, months grouper, red consistent mannitol
diarrhea snapper, history Children
amberjack, and more
barracuda vulnerable
(most common)
3 hr Neurologic:
paresthesias,
reversal of hot
or cold, pain,
weakness
2-5 days Cardiovascular:
bradycardia,
hypotension,
increase in T-
wave
 abnormalities
Copper 5 min-8 hr Nausea, Usually self- Metallic Identification of Supportive care
usually <1 hr vomiting, blue limited container metal in
or green beverage or food
vomitus
Mercury 1 wk or longer Numbness, May be Fish exposed to Analysis of Supportive care
weakness protracted organic blood, hair
of legs, mercury, grains
spastic treated with
paralysis, mercury
impaired fungicides
vision,
blindness,
coma
Pregnant
women and
the
developing
fetus are
especially
vulnerable
Mushroom toxins, <2 hr Vomiting, Self-limited Wild Typical Supportive care
short-acting diarrhea, mushrooms syndrome and
(muscimol, confusion, (cooking might mushroom
muscarine, visual not destroy identified or
psilocybin, disturbance, these toxins) demonstration of
Coprinus salivation, the toxin
atramentaria , diaphoresis,
ibotenic acid) hallucinations,
disulfiram-like
reaction,
confusion,
visual
disturbance
Mushroom toxins, 4-8 hr diarrhea; Diarrhea, Often fatal Mushrooms Typical Supportive
long-acting 24-48 hr liver abdominal syndrome and care, life-
(amanitin) failure cramps, leading mushroom threatening,
to hepatic and identified and/or may need life
renal failure demonstration of support
the toxin
Nitrite poisoning 1-2 hr Nausea, Usually self- Cured meats, Analysis of the Supportive
vomiting, limited any food, blood care, methylene
cyanosis, contaminated blue
headache, foods, spinach
dizziness, exposed to
weakness, loss excessive
of nitrification
consciousness,
chocolate-
brown blood
Pesticides Few minutes to Nausea, Usually self- Any Analysis of the Atropine; 2-
(organophosphates few hours vomiting, limited contaminated food, blood PAM
or carbamates) abdominal food (pralidoxime) is
cramps, used when
diarrhea, atropine is not
 headache, able to control
nervousness, symptoms;
blurred vision, rarely
twitching, necessary in
convulsions, carbamate
salivation, poisoning
meiosis
Puffer fish <30 min Paresthesias, Death Puffer fish Detection of Life-
(tetrodotoxin) vomiting, usually in 4- tetrodotoxin in threatening,
diarrhea, 6 hr fish may need
abdominal pain, respiratory
ascending support
paralysis,
respiratory
failure
Scombroid 1 min-3 hr Flushing, rash, 3-6 hr Fish: bluefin, Demonstration Supportive
(histamine) burning tuna, skipjack, of histamine in care,
sensation of mackerel, food or clinical antihistamines
skin, mouth and marlin, escolar, diagnosis
throat, and mahi
dizziness,
urticaria,
paresthesias
Shellfish toxins Diarrheic Nausea, Hours to 2-3 A variety of Detection of the Supportive
(diarrheic, shellfish vomiting, days shellfish, toxin in shellfish; care, generally
neurotoxic, poisoning: 30 diarrhea, and primarily high-pressure self-limiting
amnesic) min-2 hr abdominal pain mussels, liquid
accompanied oysters, chromatography
by chills, scallops, and
headache, and shellfish from
fever the Florida
coast and the
Gulf of Mexico
Neurotoxic Tingling and
shellfish numbness of
poisoning: few lips, tongue,
minutes to and throat,
hours muscular aches,
dizziness,
reversal of the
sensations of
hot and cold,
diarrhea, and
vomiting
Amnesic Vomiting, Elderly are
shellfish diarrhea, especially
poisoning: 24- abdominal pain sensitive to
48 hr and neurologic amnesic
problems such shellfish
as confusion, poisoning
memory loss,
disorientation,
seizure, coma
Shellfish toxins 30 min-3 hr Diarrhea, Days Scallops, Detection of Life-
(paralytic shellfish nausea, mussels, clams, toxin in food or threatening,
 poisoning) vomiting cockles water where fish may need
leading to are located; high- respiratory
paresthesias of pressure liquid support
mouth and lips, chromatography
weakness,
dysphasia,
dysphonia,
respiratory
paralysis
Sodium fluoride Few minutes to Salty or soapy Usually self- Dry foods (e.g., Testing of Supportive care
2 hr taste, numbness limited dry milk, flour, vomitus or
of mouth, baking powder, gastric
vomiting, cake mixes) washings
diarrhea, dilated contaminated Analysis of
pupils, spasms, with NaF- the food
pallor, shock, containing
collapse insecticides and
rodenticides
Thallium Few hours Nausea, Several days Contaminated Urine, hair Supportive care
vomiting, food
diarrhea,
painful
paresthesias,
motor
polyneuropathy,
hair loss
Tin 5 min-8 hr Nausea, Usually self- Metallic Analysis of the Supportive care
usually <1 hr vomiting, limited container food
diarrhea
Vomitoxin Few minutes to Nausea, Usually self- Grains such as Analysis of the Supportive care
3 hr headache, limited wheat, corn, food
abdominal pain, barley
vomiting
Zinc Few hours Stomach Usually self- Metallic Analysis of the Supportive care
cramps, nausea, limited container food, blood and
vomiting, feces, saliva or
diarrhea, urine
myalgias
BAL, bronchoalveolar lavage; GI, gastrointestinal.
From Centers for Disease Control and Prevention: Diagnosis and management of foodborne
illnesses, MMWR 53(RR-4):1–33, 2004.

Diarrhea Outbreaks. The U.S. Foodborne Disease Outbreak Surveillance

System quantifies enteric infections associated with foodborne outbreaks. In
2015, among all age groups, norovirus was the most common agent (46%),
followed by NTS (23%). Less common are C . perfringens (6%), STEC (5%),
Campylobacter (5%), and S . aureus (2%), followed much less often (each 1%)
by B . cereus , Clostridium botulinum, Shigella, Cryptosporidium, Yersinia,
Listeria, Vibrio parahaemolyticus, and Shigella . Outbreaks of enteric pathogens
propagated by direct person-to-person contact are most often caused by
Campylobacter, Yersinia , and Cryptosporidium ) are more frequent and more
severe when the host is immunocompromised or malnourished.
Additional risks factors for AGE include immunodeficiency, measles,
malnutrition, and lack of exclusive or predominant breastfeeding. Malnutrition
increases the risk of diarrhea and associated mortality, and moderate to severe
stunting increases the odds of diarrhea-associated mortality. The fraction of such
infectious diarrhea deaths that are attributable to nutritional deficiencies varies
with the prevalence of deficiencies; the highest attributable fractions are in sub-
Saharan Africa, South Asia, and Andean Latin America. The risks are
particularly high with malnutrition, particularly when associated with
micronutrient deficiency. Vitamin A deficiency accounts for 157,000 deaths from
diarrhea, measles, and malaria. Zinc deficiency is estimated to cause 116,000
deaths from diarrhea and pneumonia. Table 366.7 summarizes some of the key
risk factors associated with childhood diarrhea globally, especially in the
presence of micronutrient deficiency.

Table 366.7
Proven Risk Factors With Direct Biologic Links to Diarrhea:
Relative Risks or Odds Ratios and 95% Confidence
Intervals

DIARRHEAL MORBIDITY DIARRHEAL MORTALITY

No breastfeeding (0-5 mo) RR = 2.7 (1.7-4.1) compared with RR = 10.5 (2.8-39.6) compared with
exclusive breastfeeding exclusive breastfeeding
No breastfeeding (6-23 mo) RR = 1.3 (1.1-1.6) compared with any RR = 2.2 (1.1-4.2) compared with any
breastfeeding breastfeeding
Underweight (compared with ≥2 WAZ) (compared with ≥1 WAZ)
−2 to ≤1 WAZ OR = 2.1 (1.6-2.7)
−3 to ≤2 WAZ RR = 1.2 (1.1-1.4) OR = 3.4 (2.7-4.4)
≤3 WAZ OR = 9.5 (5.5-16.5)
Stunted

−2 to ≤1 HAZ OR = 1.2 (0.9-1.7)

−3 to ≤2 HAZ OR = 1.6 (1.1-2.5)
<−3 HAZ OR = 4.6 (2.7-14.7)
Wasted
−2 to ≤1 WHZ OR = 1.2 (0.7-1.9)
−3 to ≤2 WHZ OR = 2.9 (1.8-4.5)
≤3 WHZ OR = 6.3 (2.7-14.7)
Vitamin A deficiency (vs. RR = 1.5 (1.3-1.8)
not deficient)
 Zinc deficiency (vs. not RR = 1.2 (1.1-1.2) RR = 1.2 (1.0-1.6)
deficient)
HAZ, height-for-age Z-score; OR, odds ratio; RR, relative risk; WAZ, weight-for-age Z score;
WHZ, weight-for-height Z-score.
Modified from Walker CL, Rudan I, Liu L, et al: Global burden of childhood pneumonia and
diarrhoea, Lancet 381:1405–1416, 2013.

Pathogenesis of Infectious Diarrhea

Intrinsic properties of the organism help to define the mode of transmission and
incubation period (Table 366.8 ). Enteropathogens that are infectious in small
inocula (Shigella, STEC, norovirus, rotavirus, G. intestinalis, Cryptosporidium
spp., C. difficile, E. histolytica ) are readily transmitted by person-to-person
contact via the fecal-oral route. Pathogens with larger infectious doses, such as
cholera, NTS, ETEC, and Campylobacter , generally require food or water
vehicles (see Tables 366.1 to 366.3 ). Pathogens that produce preformed toxins
(S. aureus, B. cereus emetic toxin) have shorter incubation periods (1-6 hr)
compared with 8-16 hr for those that must elaborate enterotoxins in situ (e.g., C.
perfringens and B. cereus enterotoxin ). Incubation periods of 1-5 days are seen
with pathogens that attach to the epithelium and elaborate enterotoxins (e.g., V.
cholerae , ETEC) or cytotoxins (e.g., S . dysenteriae type 1 and STEC) or those
that invade and disrupt the intestinal epithelium (Shigella , NTS, Campylobacter
, and Yersinia ). The requirement for protozoa to progress through a life cycle to
trigger pathogenic processes results in a more extended incubation period. Other
properties affecting transmissibility are bioavailability as conferred by a copious
and/or prolonged fecal shedding, extended infectivity in the environment, and
resistance to disinfection (all exhibited by norovirus and Cryptosporidium ), or a
large environmental or animal reservoir (e.g., Campylobacter ). The ability to
circumvent immune surveillance by frequent antigenic changes resulting from
recombinational events (e.g., norovirus) or a large serotype diversity (e.g.,
Shigella ) maintains a susceptible host population.

Table 366.8
Comparison of 3 General Pathogenic Mechanisms of
Enteric Infection

TYPE OF INFECTION
 PARAMETER
I II III
Mechanism Noninflammatory Inflammatory, epithelial Penetrating
(enterotoxin or destruction (invasion,
adherence/superficial cytotoxin)
invasion)
Location Proximal small bowel Colon Distal small bowel
Illness Watery diarrhea Dysentery Enteric fever
Stool No fecal leukocytes Fecal Fecal mononuclear leukocytes
examination Mild or no ↑ lactoferrin polymorphonuclear
leukocytes
↑↑ Lactoferrin
Examples Vibrio cholerae Shigella Yersinia enterocolitica
ETEC EIEC Salmonella Typhi, S. Paratyhpi,
Clostridium perfringens STEC and occasionally NTS,
Bacillus cereus NTS Campylobacter, and Yersinia
Staphylococcus aureus Vibrio
Also † : parahaemolyticus
Giardia intestinalis Clostridium difficile
Rotavirus Campylobacter
Noroviruses jejuni
Cryptosporidium spp. Entamoeba
EPEC, EAEC histolytica *
Cyclospora
cayetanensis
* Although amebic dysentery involves tissue inflammation, the leukocytes are characteristically

pyknotic or absent, having been destroyed by the virulent amebae.

† Although not typically enterotoxic, these pathogens alter bowel physiology via adherence,
superficial cell entry, cytokine induction, or toxins that inhibit cell function.
EAEC, enteroaggregative E. coli; EIEC, enteroinvasive E. coli; EPEC, enteropathogenic
Escherichia coli; ETEC, enterotoxigenic Escherichia coli ; NTS, nontyphoidal Salmonella; STEC,
Shiga toxin–producing Escherichia coli .
Modified from Mandell GL, Bennett JE, Dolin R, editors: Principles and practices of infectious
diseases , ed 7, Philadelphia, 2010, Churchill Livingstone.

Viral AGE causes a cytolytic infection of the small intestinal villus tips
resulting in decreased absorption of water, disaccharide malabsorption,
inflammation, and cytokine activation. The rotavirus protein NSP4 acts as a viral
enterotoxin that produces secretory diarrhea. In addition, rotavirus activates the
enteric nervous system causing decreased gastric emptying and increased
intestinal mobility. There is a genetic susceptibility to both rotavirus and
norovirus infection that is mediated by histo-blood group antigens on the
epithelial cell surface and in mucus secretions (Fig. 366.2 ).
 FIG. 366.5 Pathogenesis of shigella infection and diarrhea. IL-8, interleukin-8. (Modified
from Opal SM, Keusch GT: Host responses to infection. In Cohen J, Powderly WG, Opal
SM, et al, editors: Infectious diseases, ed 2, London, 2004, Mosby, pp. 31–52.)

Cryptosporidia sporozoites released from ingested cysts penetrate intestinal

epithelial cells and develop into trophozoites within the intracellular, but
extracytoplasmic, environment. After undergoing asexual multiplication and
sexual development, they are released in the colon as infectious oocysts capable
of causing autoinfection. Host factors, in particular T-cell function, play a critical
role in disease severity. Cyclospora cysts are not infectious in freshly passed
stools but must sporulate in the environment for 1-2 wk to become infectious;
they are usually transmitted in contaminated produce and water (see Table 366.4
).

Clinical Manifestation of Diarrhea

General Findings. Diarrhea is usually defined as the passage of 3 or more
abnormally loose or liquid stools per day. Frequent passage of formed stools is
not diarrhea, nor is the passing of loose, pasty stools by breastfed babies.
Clinical clues to the possible etiology of gastroenteritis are noted in Table 366.9 .

Table 366.9
Clinical Presentations Suggestive of Infectious Diarrhea Etiologies
FINDING LIKELY PATHOGENS
Persistent or chronic diarrhea Cryptosporidium spp., Giardia lamblia , Cyclospora cayetanensis , Entamoeba
histolytica , non-typhoidal Salmonella, Yersinia, and Campylobacter spp.
Visible blood in stool STEC, Shigella , Salmonella , Campylobacter , Entamoeba histolytica ,
noncholera Vibrio parahaemolyticus , Yersinia , Balantidium coli , and
Aeromonas
Fever Not highly discriminatory—viral, bacterial, and parasitic infections can cause
fever. In general, higher temperatures are suggestive of bacterial etiology or E.
histolytica . Patients infected with STEC usually are not febrile at time of
presentation
Abdominal pain STEC, Salmonella , Shigella , Campylobacter , Yersinia , noncholera Vibrio
species, Clostridium difficile
Severe abdominal pain, often STEC, Salmonella , Shigella , Campylobacter , and Yersinia enterocolitica
grossly bloody stools
(occasionally nonbloody), and
minimal or no fever
Persistent abdominal pain and Y. enterocolitica and Y. pseudotuberculosis ; may mimic appendicitis
fever
Nausea and vomiting lasting ≤24 Ingestion of Staphylococcus aureus enterotoxin or Bacillus cereus (short-
hr incubation emetic syndrome)
Diarrhea and abdominal Ingestion of Clostridium perfringens or Bacillus cereus (long-incubation emetic
cramping lasting 1-2 days syndrome)
Vomiting and nonbloody Norovirus (low-grade fever usually present during the first 24 hr in 40% of
diarrhea infections); diarrhea usually lasts 2-3 days or less; other viral diarrheas (e.g.,
rotavirus, enteric adenovirus, sapovirus, astrovirus) usually last 3-8 days.
Chronic watery diarrhea, often Brainerd diarrhea (epidemic secretory diarrhea, etiologic agent has not been
lasting a year or more identified); postinfectious irritable bowel syndrome
STEC, Shiga toxin–producing Escherichia coli .
From Shane AL, Mody RK, Crump JA, et al: 2017 Infectious Diseases Society for America clinical
practice guidelines for the diagnosis and management of infectious diarrhea, Clin Infect Dis
65(12):e45–80, 2017 (Table 3, p. e54).

In the past, many guidelines divided patients into subgroups for mild (3–5%),
moderate (6–9%), and severe (≥10%) dehydration. However, it is difficult to
distinguish between mild and moderate dehydration based on clinical signs
alone. Therefore most guidelines now combine mild and moderate dehydration
and simply use none, some, and severe dehydration. The individual signs that
best predict dehydration are prolonged capillary refill time >2 sec, abnormal skin
turgor, hyperpnea (deep, rapid breathing suggesting acidosis), dry mucous
membranes, absent tears, and general appearance (including activity level and
thirst). As the number of signs increases, so does the likelihood of dehydration.
Tachycardia, altered level of consciousness, and cold extremities with or without
hypotension suggest severe dehydration.
Viral Diarrhea. Symptoms of rotavirus AGE usually begin with vomiting
followed by frequent passage of watery nonbloody stools, associated with fever
 A and B primarily affect preschool and school-age children in endemic
countries, other bacterial enteropathogens most often cause disease in
infants (particularly <3 mo), the immunocompromised, and children
with malnutrition. Additional risk factors include hemolytic anemia and
intravascular lesions for NTS, and iron overload, cirrhosis, and chelation
therapy for Yersinia sepsis. The distinct clones of NTS that have arisen
in sub-Saharan Africa described earlier are causing enteric fever–type
illnesses often in the absence of AGE. Shigella sepsis is rare and is seen
most often in malnourished and immunocompromised hosts.
4. Extraintestinal invasive infections can result from either local invasion or
bacteremic spread (Table 366.10 ). Examples of local invasion include
mesenteric adenitis, appendicitis, and rarely cholecystitis, mesenteric
venous thrombosis, pancreatitis, hepatic, or splenic abscess. Bacteremic
spread may result in pneumonia, osteomyelitis, meningitis (3 conditions
seen most commonly with NTS), abscesses, cellulitis, septic arthritis,
and endocarditis. Shigella can cause noninvasive contiguous infections
such as vaginitis and urinary tract infections.

Table 366.10
Intestinal and Extraintestinal Complications of Enteric Infections

ASSOCIATED ENTERIC
COMPLICATION
PATHOGEN(S)
Intestinal Complications
Persistent diarrhea All causes
Recurrent diarrhea (usually immunocompromised Salmonella, Shigella , Yersinia
persons) , Campylobacter, Clostridium
Toxic megacolon difficile , Entamoeba
Intestinal perforation histolytica , Cryptosporidium,
Rectal prolapse Giardia
Enteritis necroticans–jejunal hemorrhagic necrosis Shigella , C. difficile , E.
histolytica
Shigella , Yersinia, C. difficile
, E. histolytica
Shigella , STEC, C. difficile
Clostridium perfringens type
C beta toxin

Extraintestinal Complications
Dehydration, metabolic abnormalities, malnutrition, All causes
micronutrient deficiency Nontyphoidal Salmonella,
Bacteremia with systemic spread of bacterial Shigella, Yersinia,
pathogens, including endocarditis, osteomyelitis, Campylobacter
meningitis, pneumonia, hepatitis, peritonitis,
 chorioamnionitis, soft tissue infection, and septic
thrombophlebitis
Local spread (e.g., vulvovaginitis and urinary tract Shigella
infection) Yersinia, Campylobacter
Pseudoappendicitis (occasionally)
Exudative pharyngitis, cervical adenopathy Yersinia
Rhabdomyolysis and hepatic necrosis Bacillus cereus emetic toxin
Postinfectious Complications
Reactive arthritis Salmonella, Shigella, Yersinia,
Campylobacter, Cryptosporidium,
C. difficile
Guillain-Barré syndrome Campylobacter
Hemolytic uremic syndrome STEC, Shigella dysenteriae 1
Glomerulonephritis, myocarditis, pericarditis Shigella, Campylobacter, Yersinia
Immunoglobulin A (IgA) nephropathy Campylobacter
Erythema nodosum Yersinia, Campylobacter,
Salmonella
Hemolytic anemia Campylobacter, Yersinia
Intestinal perforation Salmonella, Shigella,
Campylobacter, Yersinia,
Entamoeba histolytica
Osteomyelitis, meningitis, aortitis Salmonella, Yersinia, Listeria
STEC, Shiga toxin–producing Escherichia coli.
From Centers for Disease Control and Prevention: Managing acute gastroenteritis
among children, MMWR Recomm Rep 53:1–33, 2004.

5. Vertical transmission of Shigella , NTS, and Campylobacter can produce

perinatal infection resulting in a spectrum of illness from isolated
diarrhea or hematochezia to fulminant neonatal sepsis. One species of
Campylobacter, C. fetus, is particularly virulent in pregnant women and
can result in chorioamnionitis, abortion, and neonatal sepsis and
meningitis.

Crampy abdominal pain and nonbloody diarrhea are the first symptoms of
STEC infection, sometimes with vomiting. Within several days, diarrhea
becomes bloody and abdominal pain worsens. Bloody diarrhea lasts between 1
and 22 days (median 4 days). In contrast to dysentery, the stools associated with
STEC hemorrhagic colitis are large volume and rarely accompanied by high
fever. ETEC produce a secretory watery diarrhea that affects infants and young
children in developing countries and is the major causative agents of travelers’
diarrhea, accounting for about half of all episodes in some studies. EPEC
remains a leading cause of persistent diarrhea associated with malnutrition
among infants from developing countries. EIEC, which are genetically,
vitamin deficiencies. Infection with Entamoeba can cause severe ulcerating
colitis, colonic dilation, and perforation. The parasite may spread systemically,
most commonly causing liver abscesses. In high-risk settings, it is critical to
exclude Entamoeba infection and tuberculosis before initiating corticosteroids
for presumed ulcerative colitis.

Differential Diagnosis
The physician should also consider noninfectious diseases that can present with
bright red blood per rectum or hematochezia (Table 366.11 ). In an infant or
young child without systemic symptoms, these may include anal fissures,
intermittent intussusception, juvenile polyps, and Meckel diverticulum.
Necrotizing enterocolitis can cause lower gastrointestinal bleeding in infants,
especially premature neonates. Inflammatory bowel disease should be
considered in older children. Examples of noninfectious causes of nonbloody
diarrhea include congenital secretory diarrheas, endocrine disorders
(hyperthyroidism), neoplasms, food intolerance, and medications (particularly
antibiotics). Noninfectious causes of chronic or relapsing diarrhea include cystic
fibrosis, celiac disease, milk protein intolerance, and congenital or acquired
disaccharidase deficiency. Significant abdominal pain should raise suspicion of
other infectious processes in the abdomen such as appendicitis and pelvic
inflammatory disease. Prominent vomiting with or without abdominal pain can
be a manifestation of pyloric stenosis, intestinal obstruction, pancreatitis,
appendicitis, and cholecystitis.

Table 366.11
Differential Diagnosis of Acute Dysentery and
Inflammatory Enterocolitis
Specific Infectious Processes
• Bacillary dysentery (Shigella dysenteriae, Shigella flexneri, Shigella sonnei, Shigella boydii; invasive
Escherichia coli)
• Campylobacteriosis (Campylobacter jejuni)
• Amebic dysentery (Entamoeba histolytica)
• Ciliary dysentery (Balantidium coli)
• Bilharzial dysentery (Schistosoma japonicum, Schistosoma mansoni)
• Other parasitic infections (Trichinella spiralis)
• Vibriosis (Vibrio parahaemolyticus)
• Salmonellosis (Salmonella typhimurium)
 • Typhoid fever (Salmonella typhi)
• Enteric fever (Salmonella choleraesuis, Salmonella paratyphi)
• Yersiniosis (Yersinia enterocolitica)
• Spirillar dysentery (Spirillum spp.)
Proctitis
• Gonococcal (Neisseria gonorrhoeae)
• Herpetic (herpes simplex virus)
• Chlamydial (Chlamydia trachomatis)
• Syphilitic (Treponema pallidum)
Other Syndromes
• Necrotizing enterocolitis of the newborn
• Enteritis necroticans
• Pseudomembranous enterocolitis (Clostridium difficile)
• Typhlitis
Chronic Inflammatory Processes
• Enteropathogenic and enteroaggregative E. coli
• Gastrointestinal tuberculosis
• Gastrointestinal mycosis
• Parasitic enteritis
Syndromes Without Known Infectious Cause
• Idiopathic ulcerative colitis
• Celiac disease
• Crohn disease
• Radiation enteritis
• Ischemic colitis
• Immune deficiency including HIV infection
• Allergic enteritis
From Mandell GL, Bennett JE, Dolin R, editors: Principles and practices of infectious diseases ,
ed 7, Philadelphia, 2010, Churchill Livingstone.

Clinical Evaluation of Diarrhea

In the initial evaluation of all patients with AGE, the physician should focus on
the patient's hydration status and electrolyte balance, as well as evidence of
sepsis or invasive bacterial infection, which could complicate bacterial AGE
(Fig. 366.6 ). Once the patient is stabilized, the history and physical examination
can focus on detecting risk factors and exposures, as well as the clinical features
that may suggest specific etiologic agents (see Tables 366.5 and 366.6 ).
 FIG. 366.6 Integrated Management of Childhood Illnesses protocol for the
recognition and management of diarrhea in developing countries. ORS,
oral rehydration solution.

Important elements of the medical history include the duration of diarrhea and
a description of stools (frequency, amount, presence of blood or mucus), fever
(duration, magnitude), vomiting (onset, amount and frequency), and the amount
and type of solid and liquid oral intake. Clinical signs of dehydration should be
evaluated (Table 366.12 ): urine output (number of wet diapers per day and time
since the last urination), whether eyes appear sunken, whether the child is active,
whether the child drinks vigorously, and the date and value of the most recent
weight measurement. A documented weight loss can be used to calculate the
fluid deficit. The past medical history should identify comorbidities that might
increase the risk or severity of AGE.

Table 366.12
Clinical Signs Associated With Dehydration

MINIMAL OR NO
SYMPTOM SOME DEHYDRATION SEVERE DEHYDRATION
DEHYDRATION
Mental status Well; alert Normal, fatigued or Apathetic, lethargic, unconscious
restless, irritable
Thirst Drinks normally; might Thirsty; eager to drink Drinks poorly; unable to drink
refuse liquids
Heart rate Normal Normal to increased Tachycardia, with bradycardia in most
 severe cases
Quality of Normal Normal to decreased Weak, thready, or impalpable
pulses
Breathing Normal Normal; fast Deep
Eyes Normal Slightly sunken Deeply sunken
Tears Present Decreased Absent
Mouth and Moist Dry Parched
tongue
Skinfold Instant recoil Recoil in <2 sec Recoil in >2 sec
Capillary Normal Prolonged Prolonged; minimal
refill
Extremities Warm Cool Cold; mottled; cyanotic
Urine output Normal to decreased Decreased Minimal
Modified from Duggan C, Santosham M, Glass RI: The management of acute diarrhea in children:
oral rehydration, maintenance, and nutritional therapy, MMWR Recomm Rep 41(RR-16):1–20,
1992; and World Health Organization: The treatment of diarrhoea: a manual for physicians and
other senior health workers, Geneva, 1995, World Health Organization; and Centers for Disease
Control and Prevention: Diagnosis and management of foodborne illnesses, MMWR 53(RR-4):1–
33, 2004.

Certain physical signs are best assessed before approaching the child directly,
so he/she remains calm, including general appearance (activity, response to
stimulation) and respiratory patterns. Skin turgor is assessed by pinching a small
skin fold on the lateral abdominal wall at the level of the umbilicus. If the fold
does not promptly return to normal after release, the recoil time is quantified as
delayed slightly or ≥2 sec. Excess subcutaneous tissue and hypernatremia may
produce a false negative test and malnutrition can prolong the recoil time. To
measure capillary refill time, the palmar surface of the child's distal fingertip is
pressed until blanching occurs, with the child's arm at heart level. The time
elapsed until restoration of normal color after release usually exceeds 2 sec in
the presence of dehydration. Mucous membrane moisture level, presence of
tears, and extremity temperature should be assessed.

Laboratory Diagnosis
Most cases of AGE do not require diagnostic laboratory testing. Stool specimens
could be examined for mucus, blood, neutrophils or fecal lactoferrin, a
neutrophil product. The finding of more than 5 leukocytes per high-power field
or a positive lactoferrin assay in an infant not breastfeeding suggests an infection
with a classical bacterial enteropathogen; patients infected with STEC and E.
histolytica usually have negative tests.
Laboratory diagnosis of viral AGE may be helpful when an outbreak is
suspected, cases are linked to a suspected outbreak, or when cohorting of
immunocompromised, or have hemolytic anemia or other risk factors. If diarrhea
persists with no cause identified, endoscopic evaluation may be indicated.
Biopsy specimens help in diagnosing inflammatory bowel disease or identifying
infecting agents that may mimic it. A sweat test is warranted if cystic fibrosis is
suspected.

Treatment
The broad principles of management of AGE in children include rehydration and
maintenance ORS plus replacement of continued losses in diarrheal stools and
vomitus after rehydration, continued breastfeeding, and refeeding with an age-
appropriate, unrestricted diet as soon as dehydration is corrected. Zinc
supplementation is recommended for children in developing countries.

Hydration
Children, especially infants, are more susceptible than adults to dehydration
because of the greater basal fluid and electrolyte requirements per kilogram and
because they are dependent on others to meet these demands (Table 366.13 ).
Dehydration must be evaluated rapidly and corrected in 4-6 hr according to the
degree of dehydration and estimated daily requirements. When there is emesis,
small volumes of ORS can be given initially by a dropper, teaspoon, or syringe,
beginning with as little as 5 mL at a time. The volume is increased as tolerated.
The low-osmolality World Health Organization (WHO) ORS containing 75 mEq
of sodium, 64 mEq of chloride, 20 mEq of potassium, and 75 mmol of glucose
per liter, with total osmolarity of 245 mOsm/L, is now the global standard of
care and more effective than home fluids. Soda beverages, fruit juices, tea, and
other home fluids are not suitable for rehydration or maintenance therapy
because they have inappropriately high glucose concentration and osmolalities
and low sodium concentrations. Tables 366.12 and 366.13 outline a clinical
evaluation plan and management strategy for children with moderate to severe
diarrhea. Replacement for emesis or stool losses is noted in Table 366.13 . Oral
rehydration can also be given by a nasogastric tube if needed; this is not the
usual route.

Table 366.13

Fluid and Nutritional Management of Diarrhea

Fluid and Nutritional Management of Diarrhea
REPLACEMENT
OF LOSSES
DEGREE OF
REHYDRATION THERAPY DURING
DEHYDRATION*
MAINTENANCE
†
Some dehydration Infants ‡ and children: ORS, 50-100 mL/kg over 3-4 hr. Continue Infants and
breast feeding. After 4 hr, give food every 3-4 hr for children who children:
normally receive solid foods. <10 kg body
weight: 50-
100 mL ORS
for each
diarrheal stool
or vomiting
episode, up to
~500 mL/day
>10 kg body
weight: 100-
200 mL ORS
for each
diarrheal stool
or vomiting
episode; up to
~1 L/day
Replace losses
as above as
long as
diarrhea or
vomiting
continues
Severe dehydration Malnourished infants may benefit from smaller-volume, frequent Infants and
boluses of 10 mL/kg body weight due to reduced capacity to children:
increase cardiac output with larger volume resuscitation. <10 kg body
Infants (<12 months) and children (12 mo to 5 yr) without weight: 50-
malnutrition: Give 20-30 mL/kg boluses of intravenous isotonic 100 mL ORS
crystalloid solution (e.g., normal saline solution) over 30-60 min. for each
Repeat boluses as necessary to restore adequate perfusion. Then diarrheal stool
give 70 mL/kg over 2.5-5 hr. (Note the slower infusion times are or vomiting
for infants.) Reassess the infant or child frequently and adjust episode, up to
infusion rate if needed. Switch to ORS, breast milk, and feed as ~500 mL/day
described for some dehydration, when the child can drink, >10 kg body
perfusion is adequate, and mental status is normal. Adjust weight: 100-
electrolytes and administer dextrose based on chemistry values. 200 mL ORS
for each
diarrheal stool
or vomiting
episode; up to
~1 L/day
Adolescents
and adults:
Ad libitum, up
to ~2 L/day
Replace losses
as above as
long as
 diarrhea or
vomiting
continue.
If unable to
drink,
administer
either through
a nasogastric
tube or give
5% dextrose
0.25 normal
saline solution
with 20
mEq/L
potassium
chloride
intravenously.
* A variety of scales are available to grade the severity of dehydration in young children, but no
single, standard, validated method exists. Note that signs of dehydration may be masked when a
child is hypernatremic. The World Health Organization defines some dehydration as the presence
of two or more of the following signs: restlessness/irritability, sunken eyes, drinks eagerly, thirsty,
and skin pinch goes back slowly. Severe dehydration is defined as two or more of the following
signs: lethargy/unconsciousness, sunken eyes, unable to drink/drinks poorly, and skin pinch goes
back very slowly (>2 sec).
† After rehydration is complete, maintenance fluids should be resumed along with an age-
appropriate normal diet offered every 3-4 hr. Children previously receiving a lactose-containing
formula can tolerate the same product in most instances. Diluted formula does not appear to
confer any benefit.
‡ Breastfed infants should continue nursing throughout the illness.

Low-osmolarity ORS can be given to all age groups, with any cause of diarrhea. It is safe in the
presence of hypernatremia, as well as hyponatremia (except when edema is present). Some
commercially available formulations that can be used as ORS include Pedialyte Liters (Abbott
Nutrition), CeraLyte (Cero Products), and Enfalac Lytren (Mead Johnson). Popular beverages that
should not be used for rehydration include apple juice, Gatorade, and commercial soft drinks.
ORS, oral rehydration solution.
Modified from Centers for Disease Control and Prevention: Managing acute gastroenteritis among
children: oral rehydration, maintenance, and nutritional therapy. MMWR Recomm Rep 52(RR-
16):1–16, 2003; and World Health Organization. Pocket book of hospital care for children:
Guidelines for the management of common childhood illnesses, ed 2
(http://www.who.int/maternal_child_adolescent/documents/child_hospital_care/en/ ).

A small minority of children, including those with severe dehydration or

unable to tolerate oral fluids, require initial intravenous rehydration, but oral
rehydration is the preferred mode of rehydration and replacement of ongoing
losses. Signs of severe dehydration that might necessitate intravenous
resuscitation are shown in Table 366.13 . Limitations to ORS include shock,
decreased level of consciousness, an ileus, intussusception, carbohydrate
malignant hyperpyrexia).

Antibiotic Therapy
Judicious antibiotic therapy for suspected or proven bacterial infections can
reduce the duration and severity of illness and prevent complications (Table
366.14 ). Several factors justify limited use. First, most episodes of AGE are
self-limited among otherwise healthy children. Second, the increasing
prevalence of antibiotic resistance has prompted restricted use of these drugs.
Third, antibiotics may worsen outcome, because some studies have shown that
antibiotic therapy of STEC infection increases the risk of HUS and prolongs
excretion of NTS without improving clinical outcome. Therefore antibiotics are
used primarily to treat severe infections, prevent complications in high-risk
hosts, or to limit the spread of infection. Microbiologic (culture) confirmation of
the etiology and susceptibility testing should be sought prior to treatment if
possible.

Table 366.14
Antibiotic Therapy for Infectious Diarrhea

DOSAGE AND DURATION

ORGANISM INDICATION FOR THERAPY
OF TREATMENT
Shigella spp. In high-income countries, judicious treatment is First line:
recommended to curtail growing antibiotic resistance • Ciprofloxacin* 15 mg/kg/day
because most shigellosis is self-limited. Treatment should PO bid × 3 days; OR
be reserved for moderate to severe disease (require • Ceftriaxone 50-100 mg/kg/day
hospitalization, have systemic disease or complications), IV or IM, qd × 3 days for
immunocompromised, or to prevent or mitigate outbreaks in severe illness requiring
certain settings (e.g., childcare or food handling). Also parenteral therapy; OR
consider treating patients with significant discomfort, • Azithromycin* 12 mg/kg once
intestinal comorbidities, institutional settings, or household on 1st day, then 6 mg/kg once
exposure to high-risk individuals. WHO recommends daily on days 2 through 4 (total
empiric antibiotics for all children in developing countries course: 4 days)
with dysentery assuming that most cases are caused by Second line:
Shigella. • Cefixime 8 mg/kg once daily
for 3 days; OR
• Trimethoprim-sulfamethoxazole
4 mg/kg/day of TMP and 20
mg/kg/day SMX twice a day for
5 days (if susceptibility known
or likely based on local data)
ETEC Watery diarrhea in a traveler returning from an endemic First line:
area that interferes with planned activities or is persistent. • Azithromycin* 12 mg/kg once
on first day, then 6 mg/kg once
 daily on days 2 and 3 (total
course: 3 days)
Second line:
• Ciprofloxacin* 15 mg/kg/day
PO bid × 3 days
STEC Avoid antimicrobials and anti-motility drugs
Salmonella , Antibiotics for uncomplicated gastroenteritis in normal See treatment of Shigella.
non-typhoidal host are ineffective and may prolong excretion and are Patients without bacteremia can
not recommended be treated orally for 5-7 days.
Treatment should be reserved for infection in infants Patients with bacteremia (proven
younger than 3 mo, and patients with or until blood culture results are
immunocompromise, malignancy, chronic GI disease, available in a high-risk host)
severe colitis hemolytic anemia, or HIV infection. should be treated parenterally for
Most strains are resistant to multiple antibiotics 10-14 days. Focal or
disseminated invasive infections
(e.g., osteomyelitis, meningitis)
and bacteremic patients with
HIV/AIDS should be treated
parenterally for 4-6 wk.
Yersinia spp. Antibiotics are not usually required for diarrhea, which For bacteremia or focal invasive
is usually self-limited and clinical benefits of infections, use third generation
antibiotics are not established. cephalosporins. Can also consider
Bacteremia and focal invasive infections should be carbapenem, doxycycline (for
treated. children ≥8 yr) plus
Deferoxamine therapy should be withheld for severe aminoglycoside, TMP-SMX, or
infections or associated bacteremia fluoroquinolone at doses
recommended for sepsis. Begin
IV then switch to oral when
clinically stable, for a total course
of 2-6 wk.
Campylobacter Dysentery, moderate and severe gastroenteritis or at risk for For gastroenteritis or
spp. severe disease (e.g., elderly, pregnant, or dysentery:
immunocompromised), and bacteremia or focal invasive • Erythromycin PO 40 mg/kg/day
infection should be treated. Treatment of gastroenteritis divided qid × 5 days; OR
appears effective if given within 3 days of onset of illness. • Azithromycin PO 10 mg/kg/day
× 3 days
For bacteremia or focal
invasive infection:
• Consider parenteral macrolides
or carbapenems pending
susceptibility results.
Fluoroquinolone resistance is
>50% in some areas of the
world.
Clostridium Colitis First line (mild-moderate
difficile • Discontinue inciting antibiotics if possible; colitis):
• Infectious disease consult suggested if disease is persistent • Metronidazole PO 30
or recurrent. mg/kg/day divided tid or qid ×
10 days; max 500 mg/dose; OR
• Vancomycin PO 40 mg/kg/day
divided qid × 10 days, max 125
mg/dose
Second line (severe colitis):
• Vancomycin PO 40 mg/kg/day
divided qid × 10 days, max 500
 mg/dose; OR
• If ileus, give same dose PR as
500 mg/100 mL normal saline
by retention enema with or
without plus metronidazole IV
30 mg/kg/day divided tid × 10
days; max 500 mg/dose
• Fidaxomicin not yet approved
for children; see text
Entamoeba Treat the following conditions: Asymptomatic cyst excretors:
histolytica • Asymptomatic cyst excretors • Iodoquinol PO 30-40
• Mild to moderate intestinal disease mg/kg/day, max 2 g, divided tid
• Severe intestinal or extraintestinal disease (including liver × 20 days; OR
abscess) • Paromomycin PO 25-35
mg/kg/d divided tid × 7 days;
Mild to moderate intestinal
disease and severe intestinal
or extra-intestinal disease:
• Metronidazole PO 30-40
mg/kg/day divided tid × 7-10
days; OR
• Tinidazole PO 50 mg/kg, single
dose, max 2 g (for children ≥ 3
yr old) × 3 days, OR 5 days for
severe disease
EITHER FOLLOWED BY
(to prevent relapse)
• Iodoquinol PO 30-40 mg/kg/day
tid × 20 days;
OR
• Paromomycin PO 25-35
mg/kg/day tid × 7 days
Giardia Persistent symptoms • Tinidazole PO 50 mg/kg, single
intestinalis dose, max 2 g (for children ≥ 3
yr old); OR
• Nitazoxanide PO; OR
– Age 1-3 yr: 100 mg bid × 3
days
– Age 4-11 yr: 200 mg bid × 3
days
– Age over 11 yr: 500 mg bid × 3
days
• Metronidazole PO 30-40
mg/kg/day divided tid × 7 days
(max 250 mg per dose)
Cryptosporidium Treat immunocompromised and HIV-infected hosts, Immunocompetent children:
spp. although efficacy is equivocal • Nitazoxanide, as for Giardia
Treatment may not be needed in normal hosts Solid organ transplants:
• Nitazoxanide, as for Giardia , ×
≥14 days; reduce
immunosuppression if possible
and consider paromomycin
combined with azithromycin for
severe symptoms or treatment
failure
 HIV-infected children:
• Combined antiretroviral therapy
is the primary treatment
• Nitazoxanide, as for Giardia ,
generally for 3-14 days while
awaiting CD4 cell recovery; OR
• Consider paromomycin alone or
combined with azithromycin in
severe disease or treatment
failure
Cyclospora spp All symptomatic children TMP 5 mg/kg/day and SMX 25
Isospora belli mg/kg/day PO bid × 7-10 days
(now designated (HIV-infected children may need
Cystoisospora longer courses)
belli ).
Blastocystis The significance of B. hominis as a cause of disease is • Metronidazole PO 30-40
hominis controversial, so treatment should be reserved for those mg/kg/day divided tid × 7-10
with suggestive symptoms and no other pathogen that could days; OR
be the cause. • Nitazoxanide, as for Giardia ;
OR
TMP-SMX as for Cyclospora ;
OR
Tinidazole, as for Giardia
* Azithromycin and fluoroquinolones should be avoided in patients taking the antimalarial

artemether. These drugs can prolong the QT interval on the electrocardiogram and trigger
arrhythmias.
EIEC, enteroinvasive Escherichia coli ; EPEC, enteropathogenic E. coli ; ETEC, enterotoxigenic
E. coli ; GI, gastrointestinal; IV, intravenous; IM , intramuscular; max, maximum; SMX,
sulfamethoxazole; TMP, trimethoprim; WHO , World Health Organization.

Treatment of C. difficile infection warrants special consideration. Removal of

the offending antibiotic, if possible, is the first step. Antibiotic therapy directed
against C. difficile should be instituted if the symptoms are severe or persistent.
Testing for C. difficile is discouraged for children with diarrhea who are <2 yr
unless there is strong evidence to implicate C. difficile as the etiologic agent.
This recommendation is based on the high rates of asymptomatic infection with
toxigenic and nontoxigenic strains and the rarity of characteristic clinical
manifestations not attributed to other pathogens in this age group. Oral
vancomycin and metronidazole for 7-14 days (first line agents) displayed
equivalent efficacy in a prospective randomized trial; however, metronidazole is
preferred because of lower cost and decreased potential for inducing
vancomycin-resistant enterococci. Twenty percent of adults treated for C.
difficile diarrhea have a relapse, but the frequency in children is not known. The
first relapse should be treated with another course of antibiotics based on
severity of illness. For recurrent disease, tapering and/or pulsed regimen of oral
vancomycin over a 4- to 6-wk period has been proposed. In the absence of
 Osmotic diarrhea is caused by nonabsorbed nutrients in the intestinal lumen
as a result of one or more of the following mechanisms: (1) intestinal damage
(e.g., enteric infection); (2) reduced absorptive surface area (e.g., active celiac
disease); (3) defective digestive enzyme or nutrient carrier (e.g., lactase
deficiency); (4) decreased intestinal transit time (e.g., functional diarrhea); and
(5) nutrient overload, exceeding the digestive capacity (e.g., overfeeding,
sorbitol in fruit juice). Whatever the mechanism, the osmotic force generated by
nonabsorbed solutes drives water into the intestinal lumen. A very common
example of osmotic diarrhea is lactose intolerance. Lactose, if not absorbed in
the small intestine, reaches the colon, where it is fermented to short-chain
organic acids, releasing hydrogen that is detected in the lactose breath test, and
generating an osmotic overload. Another risk for chronic osmotic diarrhea often
noted in patients with diarrhea-associated irritable bowel syndrome are foods
containing FODMAPs (fermentable oligo-di-monosaccharides and polyols).
In many children chronic diarrhea may be caused by the combination of
multiple mechanisms.

Etiology
Table 367.1 summarizes the main etiologies of chronic diarrhea in infants and
children.

Table 367.1

Main Etiologies of Chronic Diarrhea in Children Older and Younger Than 2 Yr of Age
YOUNGER OLDER
ETIOLOGY
THAN 2 YR THAN 2 YR
Infections +++ +++
Postenteritis syndrome +++ +++
Immune deficiency ++ Rare
Celiac disease +++ (after gluten +++
introduction)
Food allergy +++ +
Inflammatory bowel disease + (rare) +++
Pancreatic insufficiency ++ ++
Cholestasis and insufficient bile acids ++ ++
Cystic fibrosis ++ +
Lactose intolerance ++ (mostly +++
postinfectious)
Intestinal lymphangiectasia + +
Motility disorders ++ Rare
Short bowel syndrome +++ +
 Short bowel syndrome +++ +
Toddler's and functional diarrhea ++ ++
Excessive intake of fruit juices and fluids ++ ++
Congenital diarrheal disorders, including structural enterocyte defects and ++ Unlikely
enzymatic or transport malabsorption syndromes

Infectious
Enteric infections are by far the most frequent cause of persistent or chronic
diarrhea, both in developing and industrialized countries, however outcomes are
often very different. In the former, comorbid conditions, such as HIV/AIDS,
malaria, or tuberculosis, result in malnutrition that impairs the child's immune
response, thereby potentiating the likelihood of prolonging diarrhea or acquiring
another enteric infection. In children with HIV/AIDS, the viral infection itself
impairs immune function and may trigger a vicious circle with malnutrition.
Sequential infections with the same or different pathogens may also be
responsible for chronic diarrhea. In developing countries, enteroadherent
Escherichia coli and Giardia lamblia have been implicated in chronic diarrhea,
whereas, in developed countries, chronic infectious diarrhea usually runs a more
benign course and the etiology is often viral, with a major role of rotavirus and
norovirus (Table 367.2 ).

Table 367.2
A Comparative List of Prevalent Agents and Conditions in
Children With Persistent Infectious Diarrhea in
Industrialized and Developing Countries

AGENT/DISEASE
INDUSTRIALIZED COUNTRIES DEVELOPING COUNTRIES
Clostridium difficile Enteroaggregative E. coli
Enteroaggregative Escherichia coli Atypical E. coli
Shigella
Heat stable/heat labile enterotoxin-producing E. coli
Astrovirus Rotavirus*
Norovirus Cryptosporidium
Rotavirus* Giardia lamblia
Small intestinal bacterial overgrowth (SIBO) Tropical sprue
Postenteritis diarrhea syndrome
* More frequent in industrialized than in developing countries as agent of chronic diarrhea.

Chronic diarrhea in travelers to or expatriates from developing countries may

digestion, absorption and transport of nutrients and electrolytes; defects of
enterocyte differentiation and polarization; defects of enteroendocrine cell
differentiation; and defects of modulation of intestinal immune response.

Table 367.3
Classification of Congenital Diarrheal Disorders Based on
Their Molecular Defect and Their Inheritance

DEFECTS OF DIGESTION, ABSORPTION, AND TRANSPORT OF NUTRIENTS AND

ELECTROLYTES
GENE GENE TRANSMISSION AND
DISEASE MECHANISM
NAME LOCATION INCIDENCE
GENES ENCODING BRUSH-BORDER ENZYMES
Congenital lactase LCT 2q21.3 AR, 1 in 60,000 in Finland; lower in Osmotic
deficiency (LD) other ethnic groups
Congenital sucrase- SI 3q26.1 AR, 1 in 5,000; higher incidence in Osmotic
isomaltase deficiency Greenland, Alaska, and Canada
(SID)
Congenital maltase- Not defined — Few cases described Osmotic
glucoamylase deficiency
(MGD)
GENES ENCODING MEMBRANE CARRIERS
Glucose-galactose SLC5A1 22q13.1 AR, few hundred cases described Osmotic
malabsorption (GGM)
Fructose malabsorption Not defined — Up to 40% Osmotic
(FM)
Fanconi-Bickel SLC2A2 3q26.2 AR, rare, higher frequency in Osmotic
syndrome (FBS) consanguineous
Acrodermatitis SLC39A4 8q24.3 AR, 1 in 500,000 Osmotic
enteropathica (ADE)
Congenital chloride SLC26A3 7q31.1 AR, sporadic; frequent in some Osmotic
diarrhea (CCD, DIAR 1) ethnicities
Lysinuric protein SLC7A7 14q11.2 AR, about 1 in 60,000 in Finland and Osmotic
intolerance (LPI) Japan; rare in other ethnic groups
Primary bile acid SLC10A2 13q33.1 AR Secretory
malabsorption (PBAM)
Cystic fibrosis (CF) CFTR 7q31.2 AR, 1 in 2,500 Osmotic
GENES ENCODING PANCREATIC ENZYMES
Enterokinase deficiency PRSS7 21q21 AR Osmotic
(EKD)
Hereditary pancreatitis PRSS1 7q34 AD, cases with compound mutations Osmotic
(HP) PRSS2 7q34 in different genes; SPINK1 mutations
SPINK1 5q32 may also cause tropical pancreatitis
CTRC 1p36.21
Congenital absence of PNLIP 10q25.3 AR Osmotic
pancreatic lipase (APL)
GENES ENCODING PROTEINS OF LIPOPROTEIN METABOLISM
Abetalipoproteinemia MTP 4q27 AR, about 100 cases described; Osmotic
(ALP) higher frequency among Ashkenazi
 Jews
Hypobetalipoproteinemia APOB 2p24.1 Autosomal codominant Osmotic
(HLP)
Chylomicron retention SAR1B 5q31.1 AR, about 40 cases described Osmotic
disease (CRD)
GENES ENCODING OTHER TYPES OF PROTEINS
Congenital sodium SPINT2 19q13.2 AR Osmotic
diarrhea (CSD) (only 5p15.33
syndromic
CSD)
SLC9A3
Shwachman-Diamond SBDS 7q11 AR Osmotic
syndrome (SDS)
Activating guanylate GUCY2C 12p12.3 AD Secretory
cyclase-C mutation
GENES ENCODING FOR OTHER ENZYMES
Defect in triglyceride DGAT1 8q24.3 AR Protein-losing
synthesis enteropathy
DEFECTS OF ENTEROCYTE DIFFERENTIATION AND POLARIZATION
Microvillous inclusion MYO5B 18q21.1 AR; rare; higher frequency among Secretory
disease (MVID, DIAR 2) Navajo
Congenital tufting EPCAM 2p21 AR; 1 in 50,000-100,000; higher Secretory
enteropathy (CTE, DIAR among Arabians
5)
Trichohepatoenteric TTC37 5q15 AR; 1 in 400,000 Secretory
syndrome (THE) SKIV2L 6p21.33
DEFECTS OF ENTEROENDOCRINE CELL DIFFERENTIATION
Congenital NEUROG3 10q22.1 AR; few cases described Osmotic
malabsorptive diarrhea
(CMD, DIAR 4)
Proprotein convertase PCSK1 5q15 AR Osmotic
1/3 deficiency (PCD)
DEFECTS OF MODULATION OF INTESTINAL IMMUNE RESPONSE
Autoimmune AIRE 21q22.3 AR; AD (1 family) Secretory
polyglandular syndrome
type 1 (APS1)
Immune dysfunction, FOXP3 Xp11.23 X-linked (autosomal cases described), Secretory
polyendocrinopathy, X- very rare
linked (IPEX)
IPEX-like syndrome Not defined — Not X-linked Secretory
AD , autosomal dominant; AR , autosomal recessive.

Although CDDs are rare diseases, in most specific disorders the genetic defect
and transmission are known. The incidence of genetic disorders associated with
CDD can range from 1 in 2,500 for cystic fibrosis, 1 in 5,000 for sucrose-
isomaltase deficiency, 1 in 60,000 for congenital lactase deficiency, to 1 in
400,000 for trichohepatoenteric syndrome. For most CDDs, such as IPEX
syndrome or autoimmune polyglandular syndrome type 1, the clinical
application of exome sequencing is likely to increase identification of more
patients with these rare causes of chronic diarrhea. Selected CDDs are more
manifestations (arthritis, diabetes, thrombocytopenia, etc.) may suggest an
autoimmune disease. Specific skin lesions may be suggestive of acrodermatitis
enteropathica that might respond to zinc supplementation. Typical facial
abnormalities and woolly hair are associated with phenotypic diarrhea.

Investigations
Microbiologic investigation should include a thorough list of intestinal bacterial,
viral, and protozoan pathogens. Proximal intestinal bacterial overgrowth may be
determined using the lactulose hydrogen breath test, but false-positive tests are
common (see Chapter 364.4 ).
Initial investigations of a child with chronic diarrhea should always include an
assessment of intestinal inflammation using fecal calprotectin or lactoferrin, and
serology for celiac disease (see Chapter 364.2 ). The role of a mucosal biopsy is
determined by the noninvasive diagnostic evaluation in consultation with a
pediatric gastroenterologist.
Noninvasive assessment of digestive-absorptive function and of intestinal
inflammation plays a key role in the diagnostic workup (Table 367.4 ).
Abnormalities in the digestive-absorptive function tests suggest small bowel
involvement, whereas intestinal inflammation, as demonstrated by increased
fecal calprotectin or lactoferrin, supports colitis.

Table 367.4

Noninvasive Tests for Intestinal Digestive–Absorptive Function and Inflammation

TEST NORMAL VALUES IMPLICATION
α1 -Antitripsin concentration <0.9 mg/g Increased intestinal
permeability/protein loss
Steatocrit <2.5% (older than 2 yr) fold increase over age- Fat malabsorption
related values (younger than 2 yr)
Fecal-reducing substances Absent Carbohydrate malabsorption
Elastase concentration >200 µg/g Pancreatic function
Chymotrypsin concentration >7.5 units/g Pancreatic function
>375 units/24 hr
Fecal occult blood Absent Blood loss in the
stools/inflammation
Fecal calprotectin <100 µg/g (in children to 4 yr of age) Intestinal inflammation
concentration <50 µg/g (older than 4 yr)
Fecal leukocytes <5/microscopic field Colonic inflammation
Fecal lactoferrin Absent Inflammation
Nitric oxide in rectal dialysate <5 µM of NO2 − /NO3 − Rectal inflammation
 Dual sugar Urine excretion ratio: 0.010 ± 0.018 Increased intestinal
(cellobiose/mannitol) permeability
absorption test
Xylose oral load 25 mg/dL Reduced intestinal surface

Determining the osmotic versus secretory nature of the diarrhea in neonates

and infants with protracted diarrhea is especially important. The stool osmolar
gap , sometimes called stool ion gap, is calculated as 290 mOsm/kg (or
measured stool osmolality) minus [2 × (stool Na + stool K)]. If the osmolar gap
is above 100 mOsm/kg, fecal osmolality is derived from ingested or
nonabsorbed osmotically active solutes or nonmeasured ions. In contrast, a low
gap (<50 mOsm/kg) is typically observed in secretory diarrhea. It is also
important to measure Cl− concentration in the stool to rule out CCD, which is
characterized by low osmolar gap due to high Cl− fecal loss (>90 mmol/L).
Whereas most etiologies of chronic diarrhea can be exaggerated by feeding
and have osmotic or mixed nature to the stool, secretory diarrhea necessitates
investigation for congenital defects in enterocytes, defects in the intestinal
immune response (IPEX and autoimmune enteropathy), and disorders of bile
acid malabsorption. Because of the overlap between secretory and osmotic
features of the diarrhea in many diseases, a classification based on the response
to bowel rest was also introduced. Severe diarrhea that persists at bowel rest is
characteristic of congenital enteropathies (microvillous inclusion disease,
tufting enteropathy, syndromic diarrhea). Diarrhea that disappears at bowel rest
can imply carbohydrate or fat malabsorptive syndromes, as well as defects in
enteroendocrine cells. In most other etiologies the diarrhea can decrease
significantly, but not disappear, in response to bowel rest, including some
congenital diseases as well as acquired inflammatory and other enteropathies.
Histology is important in establishing mucosal involvement, noting changes in
the epithelial cells, or in identifying specific intracellular inclusion bodies caused
by pathogens, such as cytomegalovirus, or the presence of parasites. Electron
microscopy is essential to detect subcellular structural abnormalities such as
microvillous inclusion disease. Immunohistochemistry allows the study of
mucosal immunity as well as of other cell types (smooth muscle cells and enteric
neuronal cells).
Imaging has a major role in the diagnostic approach. Abdominal ultrasound
may help in detecting liver and pancreatic abnormalities or an increase in distal
ileal wall thickness that suggests inflammatory bowel disease. A preliminary
plain abdominal x-ray is useful for detection of abdominal distention, suggestive
of intestinal obstruction, or increased retention of colonic feces. Intramural or
portal gas may be seen in necrotizing enterocolitis or intussusception. Structural
abnormalities such as diverticula, malrotation, stenosis, blind loop, and
congenital short bowel, as well as motility disorders, may be investigated
through a barium meal and a small bowel follow-through. Capsule endoscopy
can be done when the patient weighs more than 10 kg and allows the exploration
of the entire intestinal tract searching for structural changes, inflammation, or
bleeding; the new SmartPill measures pressure, pH, and temperature as it moves
through the GI tract, assessing motility.
Specific investigations should be carried out for specific diagnostic
indications. Prick and patch test may support a diagnosis of food allergy.
However, an elimination diet with withdrawal of the suspected harmful food
from the diet and subsequent challenge is the most reliable strategy by which to
establish a diagnosis. Bile malabsorption may be explored by the retention of the
bile acid analog 75 Se-homocholic acid-taurine (75 SeHCAT) in the enterohepatic
circulation. A scintigraphic examination, with radio-labeled octreotide is
indicated in suspected APUD cell neoplastic proliferation. In other diseases,
specific imaging techniques such as computed tomography, or nuclear magnetic
resonance endoscopic retrograde cholangiopancreatography and magnetic
resonance cholangiopancreatography, may have important diagnostic value.
Once infectious agents have been excluded and nutritional assessment
performed, a stepwise approach to the child with chronic diarrhea may be
applied. The main causes of chronic diarrhea should be investigated, based on
the features of the diarrhea and the specific nutrient(s) that is (are) affected. The
use of whole-exome sequencing or specific molecular analysis may be especially
essential in children suspected of having CDD. A step-by-step diagnostic
approach is important to minimize the unnecessary use of invasive procedures as
well as the cost, while optimizing the yield of the diagnostic evaluation (Table
367.5 ).

Table 367.5
Stepwise Diagnostic Approach to Children and Infants With
Chronic Diarrhea
INITIAL EVALUATION
• Personal and family history: Prenatal sonography; feeding • Infectious workup: Stool cultures; parasites;
history; family history of protracted diarrhea; viruses
consanguinity • Allergic workup: Elimination diet trial
 • Physical examination: Dysmorphism; skeletal
abnormalities; organomegaly; dermatitis
⇩
LABORATORY TESTS
• Stool analysis: Stool volume following fasting; stool • Blood and serum analysis: Serum electrolytes;
electrolytes and ion gap; pH and reducing substances; lipid profile; albumin and pre-albumin; amylase
steatocrit; fecal leukocytes and calprotectin; fecal and lipase; inflammatory markers; ammonia;
elastase; α 1 -antitrypsin celiac serology
⇩
IMAGING
• Abdominal ultrasound: Bowel wall thickening; liver and • X-ray and contrast studies: Congenital
bile disorders malformation; signs of motility disorders
⇩
ENDOSCOPIES AND INTESTINAL HISTOLOGY
Endoscopy and standard jejunal/colonic histology* ; morphometry; PAS staining; intestinal
immunohistochemistry; electron microscopy
⇩
GENETIC INVESTIGATION
• Specific molecular analysis • Whole-exome sequencing
⇩
OTHER SPECIAL INVESTIGATIONS
Sweat test; specific carbohydrates breath tests; 75 SeHCAT measurement; antienterocyte antibodies; metabolic
diseases workup; motility studies; neuroendocrine tumor markers
*
The decision to perform an upper or a lower endoscopy may be supported by noninvasive tests.
PAS , Periodic acid–Schiff; 75 SeHCAT , 75 Se-homocholic acid-taurine.

Treatment
Chronic diarrhea associated with impaired nutritional status should always be
considered a serious disease, and therapy should be started promptly. Treatment
includes general supportive measures, nutritional rehabilitation, elimination diet,
and medications. The latter include therapies for specific etiologies as well as
interventions aimed at counteracting fluid secretion and/or promoting restoration
of disrupted intestinal epithelium. Because death in most instances is caused by
dehydration, replacement of fluid and electrolyte losses is the most important
early intervention.
Nutritional rehabilitation is often essential and is based on clinical and
biochemical assessment. In moderate to severe malnutrition, caloric intake
should be carefully advanced to avoid the development of refeeding syndrome
and may be progressively increased to 50% or more above the recommended
dietary allowances. The intestinal absorptive capacity should be monitored by
digestive function tests. In children with steatorrhea, medium-chain triglycerides
may be the main source of lipids. A lactose-free diet should be started in all
Table 367.6
Antimicrobial Treatment for Persistent Diarrhea

DRUG INDICATIONS DOSAGE DURATION

Antibiotics Trimethoprim- Salmonella spp., Shigella spp. 6-12 mg/kg/day (of 5-7 days
sulfamethoxazole Trimethoprim) in 2 divided
doses–daily os
Azithromycin Shigella spp., Campylobacter 1 day: 12 mg/kg/day once– 5 days
daily os
2-5 days: 6 mg/kg/day once–
daily os
*alternative: 10 mg/kg/day
once–daily os, for 3 days
Ciprofloxacin Shigella spp. 20-30 mg/kg/day in 2 divided 3 days
doses–os or IV
Ceftriaxone Shigella spp. 50-100 mg/kg/day once–IM or 2-5 days
IV
Metronidazole Giardia, Amebiasis , 15-35 mg/kg/day in 2-3 divided 7-10 days
Blastocystis , Clostridium doses–os
difficile
Paromomycin Amebiasis 25-35 mg/kg/day in 3 divided 7 days
doses–os
Vancomycin Clostridium difficile 40 mg/kg/day in 4 divided 10 days
doses–os
Antiparasitic Nitazoxanide Amebiasis , Giardiasis , 100 mg every 12 hr for 3 days
Blastocystis, children ages 12-47 mo
Cryptosporidiosis 200 mg every 12 hr for
children ages 4-11 yr
500 mg every 12 hr for
children older than 11 yr
Albendazole Ascaris, Hookworm, and 400 mg Once
Pinworm infection
Depends on local susceptibility profile. IM , intramuscular; IV , intravenous; os , by mouth.

Treatment may be also directed at modifying specific pathophysiologic

processes. Secretion of ions may be reduced by antisecretory agents, such as the
enkephalinase inhibitor racecadotril. Some benefit from absorbents, such as
diosmectite, has been described, with reduction of diarrhea duration in infectious
diarrhea. In diarrhea caused by neuroendocrine tumors (NETs), microvillus
inclusion disease and enterotoxin-induced severe diarrhea, a trial of somatostatin
analog octreotide may be considered. Zinc promotes both enterocyte growth and
ion absorption and may be effective when intestinal atrophy and ion secretion
are associated. However, when therapeutic attempts and other nutritional support
have failed, the only option to treat children with intestinal failure, while
maintaining adequate growth and development, may be long-term parenteral
nutrition or eventually intestinal transplantation.
by radioimmunologic methods (in the plasma or as their urinary metabolites).
These peptides therefore also act as tumor markers. In clinically functioning
tumors, the secreted peptides cause a recognizable syndrome that can include
watery diarrhea. Compared to carcinoid, vasoactive intestinal polypeptide
(VIP)omas are much less frequent. Because it secretes VIP, a more potent
vasoactive peptide, it induces more profuse diarrhea, with up to 70% of patients
having volumes greater than 3 L/day. Though rare as a cause of watery diarrhea,
a NET should be considered in the differential diagnosis when diarrhea is
unusually severe or takes a chronic course (resulting in electrolyte and fluid
depletion). GI-NETs may be associated with flushing, palpitations, or
bronchospasm. Furthermore, patients may have a positive family history of
multiple endocrine neoplasia MEN 1 or 2 syndromes. (Table 367.7 ).

Table 367.7
Diarrhea Caused by Neuroendocrine Tumors

SIGNS OF
TUMOR AND
SITE MARKERS HORMONE THERAPY
CELL TYPE
HYPERSECRETION
Carcinoid Intestinal Serotonin (5- Secretory diarrhea, Resection
argentaffin cells, HT), urine 5- crampy abdominal Somatostatin
typically midgut, HIAA * pain, flushing, analog,
also foregut and (diagnostic) wheezing (and cardiac (palliative)
hindgut, ectopic Also produce valve damage if Genetic MEN-1
bronchial tree substance P, foregut site)
neuropeptide K,
somatostatin,
VIP
Chromogranin
A
Gastrinoma, Pancreas, small Gastrin Multiple peptic ulcers, H2 -blockers,
Zollinger-Ellison bowel, liver, and secretory diarrhea PPI, tumor
syndrome spleen resection,
(gastrectomy)
Genetic MEN-1
Mastocytoma Cutaneous, Histamine , VIP Pruritus, flushing, H1 - and H2 -
intestine, liver, apnea blockers, steroids,
spleen If VIP, diarrhea resection if solitary
Medullary carcinoma Thyroid C-cells Calcitonin , VIP , Secretory diarrhea Radical
prostaglandins thyroidectomy ±
lymphadenectomy
(genetic MEN-
2A/B, familial
MTC)
Ganglioneuroma, Chromaffin cells; Metanephrines Hypertension, Perioperative α-
pheochromocytoma, abdominal > other and tachycardia, adrenergic (BP)
 ganglioneuroblastoma, sites; extraadrenal catecholamines paroxysmal and β-
neuroblastoma or adrenal , VIP palpitations, sweating, adrenergic
VMA, HMA in anxiety, watery blockade with
neuroblastoma diarrhea † volume support
tumor resection
Genetic MEN-2
(RET gene),
VHL, NF-1,
SDH
Somatostatinoma Pancreas Somatostatin Secretory diarrhea, Resection
steatorrhea, Genetic MEN-1
cholelithiasis, diabetes
VIPoma Pancreas VIP , Secretory diarrhea, Somatostatin
prostaglandins achlorhydria, analogs,
hypokalemia resection
Genetic MEN-1
* Bold indicates major markers.

† Diarrhea has been reported only in adult patients with pheochromocytoma.

BP , blood pressure; H1 , histamine receptor type 1; H2 , histamine receptor type 2; HMA ,

homovanillic acid; MEN-1 , multiple endocrine neoplasia type 1; MTC , medullary thyroid
carcinoma; NF-1 , neurofibromatosis type 1; PPI , proton pump inhibitor; SDH , succinate
dehydrogenase; VHL , von Hippel-Lindau disease; VIP , vasoactive intestinal polypeptide; VMA ,
vanillylmandelic acid.
(Modified from Spoudeas HA, editor: Paediatric endocrine tumors. A multidisciplinary consensus
statement of best practice from a working group convened under the auspices of the British
Society of Paediatric Endocrinology and Diabetes (BSPED) and the United Kingdom Children's
Cancer Study Group (UKCCSG) , Crawley, West Sussex, 2005, Novo Nordisk.)

Baseline tests should include plasma chromogranin A and urinary 5-

hydroxyindoloacetic acid (metabolite of serotonin) and other specific
biochemistry being guided by the suspected syndrome (see Table 367.7 ).
Localization of any NET is best achieved using a multimodality approach.
Whole-body CT, MRI, and somatostatin receptor scintigraphy may be required
(because nearly all NETs express membrane receptors for small peptides, e.g.,
somatostatin), with gallium-68 positron emission tomography. Therapeutic
interventions to be considered include surgical, pharmacological, and
radioisotope therapy. Details to be considered when making therapeutic
decisions include disease extent and location, tumor grade, pace of disease
progression, symptoms, and co-morbidities.
Tumor resection is the treatment of choice when the tumor is small and
localized. However, resection is potentially hazardous as it can precipitate life-
threatening adrenergic crises. When arising in the appendix, carcinoid tumors
less than 2 cm in size can be managed by simple appendectomy. When greater
than 2 cm in size or arising from the base of the appendix, a right hemicolectomy
CHAPTER 368

Functional Gastrointestinal Disorders

Asim Maqbool, Chris A. Liacouras

Functional gastrointestinal disorders (FGIDs) comprise a group of conditions

that relate to the gastrointestinal (GI) tract. These disorders cannot be completely
explained by anatomical or biochemical abnormalities (infectious,
inflammatory). FGIDs commonly afflict children across a broad range of
manifestations and are defined primarily by symptoms. The symptom-based
criteria employed to classify FGIDs have been developed by expert consensus
and opinion under the auspices of the Rome Foundation, and are referred to as
Rome IV Criteria. FGIDs pose diagnostic challenges as there is no anatomical or
laboratory-based testing that is used to define them. FGID defining criteria strive
not to be entirely based on diagnoses of exclusion, but rather aim to be based on
objective, unambiguous, and accurate criteria derived from the presentation as
elicited during obtaining the medical history and performing a clinical
examination. These criteria strive to be uniform, reliable, reproducible, and to
minimize unnecessary evaluations/testing with low diagnostic yield or relevance.
FGIDs often coexist across the spectrum of GI disorders, such as inflammatory
bowel disease, celiac disease, or irritable bowel syndrome (IBS). FGIDs may be
influenced by psychosocial stressors, or a result of an otherwise benign episode
of abdominal pain. The brain–gut axis likely plays a prominent role in the
pathophysiology of many FGIDs. Some FGID manifestations may relate to
dysbiosis and the intestinal microbiota. There may be a genetic basis to some of
these disorders as well. Early life physical or psychologic stressors may manifest
later as FGID. Maladaptive responses or lack of adequate coping skills may
complicate the treatment of FGIDs but may also allow for a valuable approach to
management using behavioral therapies.
FGIDs encompass 2 age groups: infants and toddlers or children and
adolescents. Aerophagia, functional constipation, and cyclical vomiting span
both age groups (Fig. 368.1 ).

FIG. 368.1 Age distribution of functional gastrointestinal disorders in
infants, toddlers, children, and adolescents. *History may not be reliable
below this age. FAP-NOS , Functional abdominal pain—not otherwise
specified. (Modified from Benninga MA, Nurko S, Faure C, et al: Childhood
functional gastrointestinal disorders: neonate/toddler, Gastroenterology
150[6]:1443–1455.e2, 2016.)

Infant regurgitation implies effortless retrograde and involuntary passage of

gastric contents from the stomach cephalad and is more commonly referred to as
gastroesophageal reflux (Table 368.1 ). When refluxate reaches the oropharynx
and is visible, it is labelled as regurgitation. This phenomenon is normal for
healthy infants, unless there are complications associated with the process, such
as esophageal inflammation, dysphagia, feeding difficulties, inadequate oral
intake to meet needs leading to failure to thrive, or the inability to protect the
airway with risk for aspiration; in this setting gastroesophageal reflux disease is
the correct designation (Chapter 349 ). Unlike vomiting, regurgitation does not
include the forceful expulsion of gastric contents via the mouth. Rumination is a
different phenomenon, in that previously ingested and swallowed food is brought
back up to the oral cavity, remasticated and subsequently reswallowed.

Table 368.1
Diagnostic Criteria for Infant Regurgitation
 Must include both of the following in otherwise healthy infants 3 wk to 12 mo of age:
1. Regurgitation 2 or more times per day for 3 or more wk
2. No retching, hematemesis, aspiration, apnea, failure to thrive, feeding or swallowing difficulties, or abnormal
posturing
From Benninga MA, Nurko S, Faure C, et al: Childhood functional gastrointestinal disorders:
neonate/toddler, Gastroenterology 150(6):1443–1455.e2, 2016.

Infant rumination is defined as a habitual regurgitation of gastric contents

into the oropharynx to allow for remastication and reswallowing (Table 368.2 ).
It is thought to be a form of self-stimulation and may occur in the setting of
emotional or sensory deprivation. The regurgitation of gastric contents is
effortless and can be remasticated and reswallowed versus expulsion from the
oropharynx. Infant rumination occurs between 3 and 8 mo of age and does not
respond to measures used to manage regurgitation. This phenomenon does not
occur during socialization/interaction with individuals, does not occur during
sleep, and is not associated with distress. Empathy and nurturing lay the
foundation for management. Behavior management is important to achieve
resolution of this phenomenon.

Table 368.2
Diagnostic Criteria for Infant Rumination Syndrome
Must include all of the following for at least 2 mo:
1. Repetitive contractions of the abdominal muscles, diaphragm, and tongue
2. Effortless regurgitation of gastric contents, which are either expelled from the mouth or rechewed and
reswallowed
3. Three or more of the following:
a. Onset between 3 and 8 mo
b. Does not respond to management for gastroesophageal reflux disease and regurgitation
c. Unaccompanied by signs of distress
d. Does not occur during sleep and when the infant is interacting with individuals in the environment
From Benninga MA, Nurko S, Faure C, et al: Childhood functional gastrointestinal disorders:
neonate/toddler, Gastroenterology 150(6):1443–1455.e2, 2016.

Infant colic (Chapter 22.1 ) is a normal developmental process associated

with fussiness, irritability, and difficultly consoling the infant (Table 368.3 ). A
trigger is not identifiable. This phenomenon usually occurs between 1 and 4 mo
of age. The typical behavior usually leads to consultation with a pediatrician or a
pediatric gastroenterologist out of suspicion for abdominal pain. Patients are
often unnecessarily treated for gastroesophageal reflux, gas, or suspected cow-
milk protein or soy allergy leading to dietary changes and the use of medications
for the management of acidity or gas. Probiotics have been investigated as a
possible treatment. Probiotics may be more beneficial for breast versus cow-
milk-fed infants. Soothing in a quiet, tranquil space may also be effective.
Providing reassurance, education, support, and ensuring adequate coping skills
and support for family members are key. This is a self-limited phenomenon that
resolves on its own.

Table 368.3
Diagnostic Criteria for Infant Colic
For clinical purposes, must include all of the following:
1. An infant who is < 5 mo of age when the symptoms start and stop
2. Recurrent and prolonged periods of infant crying, fussing, or irritability reported by caregivers that occur
without obvious cause and cannot be prevented or resolved by caregivers
3. No evidence of infant failure to thrive, fever, or illness
“Fussing” refers to intermittent distressed vocalization and has been defined as “[behavior] that is not quite crying
but not awake and content either.” Infants often fluctuate between crying and fussing, so that the 2 symptoms are
difficult to distinguish in practice.
For clinical research purposes, a diagnosis of infant colic must meet the preceding diagnostic criteria and also
include both of the following:
1. Caregiver reports infant has cried or fussed for 3 or more hr per day during 3 or more days in 7 days in a
telephone or face-to-face screening interview with a researcher or clinician
2. Total 24-hr crying plus fussing in the selected group of infants is confirmed to be 3 hr or more when measured
by at least 1 prospectively kept, 24-hr behavior diary
From Benninga MA, Nurko S, Faure C, et al: Childhood functional gastrointestinal disorders:
neonate/toddler, Gastroenterology 150(6):1443–1455.e2, 2016.

Functional diarrhea is often also referred to as toddler's diarrhea (Table

368.4 ). This condition excludes steatorrhea. Excessive fruit juice with
nonabsorbable carbohydrates (i.e., sorbitol) intake coupled with a low-fat diet
drive this osmotic process. An evaluation of the diet for possible other etiologies
as well as assessment for infections, inflammation, antibiotic, and laxative use is
important. In addition, assessments of growth as well as ruling out fecal
impaction and encopresis via digital rectal examination are important. The
diarrhea is usually stool colored, painless, liquid-watery, and may contain
undigested foods. Growth is usually not affected. Dietary changes such as
reducing fruit juice intake as well as fructose are helpful in resolving symptoms.

Table 368.4
Diagnostic Criteria for Functional Diarrhea
Must include all of the following:
1. Daily painless, recurrent passage of 4 or more large, unformed stools
 2. Symptoms last more than 4 wk
3. Onset between 6 and 60 mo of age
4. No failure to thrive if caloric intake is adequate
From Benninga MA, Nurko S, Faure C, et al: Childhood functional gastrointestinal disorders:
neonate/toddler, Gastroenterology 150(6):1443–1455.e2, 2016.

Infant dyschezia is manifested by infants straining prior to defecation

associated with visible distress, crying, a red/purple facial discoloration, with
symptoms persisting for 10-20 min alleviated by the passage in stools, limited to
infants < 9 mo of age. There is no associated obstruction or anal anomaly; stools
are passed several times daily and are not associated with other health problems.
Dyschezia is thought to represent discoordinated intraabdominal musculature
contraction with pelvic floor relaxation. A good medical history and neurological
and digital rectal examinations to rule out anatomical or neuromuscular
abnormalities are key. Normal growth is to be expected. Reassurance provides
the basis of management. Laxative, suppository, or digital manipulation is not
required and may be counterproductive.
Functional constipation (Chapter 358.3 ) is associated with withholding
behaviors, which in turn may relate to social stressors or changes in social
situations (Table 368.5 ). These often occur at the time of diet changes in infants
and at the initiation of toilet training for toddlers. Painful passage of hard, large
caliber stools < 2 times/wk in the setting of withholding behaviors is noted. For
those children who have previously been toilet trained, fecal incontinence or
encopresis is often observed. Large-caliber stools that obstruct the toilet are also
noted frequently. Abdominal examination may reveal a palpable mass, and
digital rectal examination may reveal a large rectal stool mass. The differential
diagnosis for constipation is extensive, with functional constipation and slow
transit constipation common. Dietary factors may play a role. Anorectal
malformations, neuromuscular and motility issues may also present as such.
Hirschsprung disease is on the differential diagnosis. The evaluation and
management are based on a detailed history and thorough physical examination.
A defecation history extending to the first 1-2 days of life is particularly
important, as almost all children pass their first bowel movement within the first
48 hr of life. Assessment for associated signs and symptoms and growth trends
are important. Red flags are noted in Table 368.6 . Imaging plays a role, and
rectal suction biopsy or even full thickness rectal biopsy may be required to rule
out Hirschsprung disease in cases with high index of suspicion. Management
encompasses dietary and lifestyle changes, and medications to soften stool with
osmotic laxatives over stimulant laxatives. The goal is to achieve painless
defection and resolve fear and withholding revolving around defecation.
Behavior modification including reassurance and positive incentive reward
systems are useful. Avoidance of toilet training until symptoms resolve and the
child shows interest or willingness to proceed are generally advocated.

Table 368.5
Diagnostic Criteria for Functional Constipation
Must include 1 mo of at least 2 of the following in infants up to 4 yr of age:
1. Two or fewer defecations per week
2. History of excessive stool retention
3. History of painful or hard bowel movements
4. History of large-diameter stools
5. Presence of a large fecal mass in the rectum
In toilet-trained children, the following additional criteria may be used:
6. At least 1 episode/wk of incontinence after the acquisition of toileting skills
7. History of large-diameter stools that may obstruct the toilet
From Benninga MA, Nurko S, Faure C, et al: Childhood functional gastrointestinal disorders:
neonate/toddler, Gastroenterology 150(6):1443–1455.e2, 2016.

Table 368.6
Potential Alarm Features in Constipation
Passage of meconium >48 hr in a term newborn
Constipation starting in the 1st mo of life
Family history of Hirschsprung disease
Ribbon stools
Blood in the stools in the absence of anal fissures
Failure to thrive
Bilious vomiting
Severe abdominal distension
Abnormal thyroid gland
Abnormal position of the anus
Absent anal or cremasteric reflex
Decreased lower extremity strength/tone/reflex
Sacral dimple
Tuft of hair on spine
Gluteal cleft deviation
Anal scars
From Hyams JS, Di Lorenzo C, Saps M, et al: Childhood functional gastrointestinal disorders:
child/adolescent, Gastroenterology 150(6):1456–1468.e2, 2016 (Table 3, p. 1465).
Functional Gastrointestinal Disorders in
Children and Adolescents
Functional nausea and functional vomiting may coexist or may occur
independently of one another (Table 368.7 ). These conditions occur without
coincident abdominal pain. The presentation may accompany autonomic
symptoms such as diaphoresis, pallor, tachycardia, and dizziness. The differential
diagnosis includes anatomical, inflammatory, infectious, and motility etiologies.
Anxiety and other behavioral conditions can be present with these FGIDs and
should be evaluated for and managed accordingly. Cyproheptadine may be
effective in the management of nausea.

Table 368.7
Diagnostic Criteria* for Functional Nausea and Functional
Vomiting
FUNCTIONAL NAUSEA
Must include all of the following fulfilled for the last 2 mo:
1. Bothersome nausea as the predominant symptom, occurring at least twice per week, and generally not related to
meals
2. Not consistently associated with vomiting
3. After appropriate evaluation, the nausea cannot be fully explained by another medical condition
FUNCTIONAL VOMITING
Must include all of the following:
1. On average, 1 or more episodes of vomiting per week
2. Absence of self-induced vomiting or criteria for an eating disorder or rumination
3. After appropriate evaluation, the vomiting cannot be fully explained by another medical condition
* Criteria fulfilled for at least 2 mo before diagnosis.

From Hyams JS, Di Lorenzo C, Saps M, et al: Childhood functional gastrointestinal disorders:
child/adolescent, Gastroenterology 150(6):1456–1468, 2016 (p. 1457).

Rumination in older children and adolescents may be associated with an

unpleasant sensation or discomfort such as abdominal pressure or burning (Table
368.8 ). Repeated regurgitation and remastication or oral repulsion of
regurgitated gastric contents occurs soon after ingesting foodstuffs and does not
occur during sleep. It is not preceded by active expulsion of gastric
contents/retching and cannot be explained by any other medical condition.
Eating disorders may also present and must be considered. There is no
expectation that older children and adolescents need to be treated for or fail to
respond to treatment for gastroesophageal reflux for this diagnosis to be made. A
triggering event can be identified prior to symptoms, which may occur following
resolution of an infectious illness or with psychosocial stress. Other GI issues to
be considered include anatomical, infectious, inflammatory, and motility
disorders. An important distinction between rumination and other GI etiologies
of emesis includes effortless versus forceful regurgitation, and the time course,
which is usually immediately following ingestion of foodstuffs. Given the
significant behavioral component in this behavior, psychologic-behavioral
therapy is key in management.

Table 368.8
Diagnostic Criteria* for Rumination Syndrome in Children
Must include all of the following:
1. Repeated regurgitation and rechewing or expulsion of food that:
a. Begins soon after ingestion of a meal
b. Does not occur during sleep
2. Not preceded by retching
3. After appropriate evaluation, the symptoms cannot be fully explained by another medical condition. An eating
disorder must be ruled out
* Criteria fulfilled for at least 2 mo before diagnosis.

From Hyams JS, Di Lorenzo C, Saps M, et al: Childhood functional gastrointestinal disorders:
child/adolescent, Gastroenterology 150(6):1456–1468, 2016 (p. 1458).)

Aerophagia is often seen in patients with impairments in neurocognition. Air

swallowing is described as excessive, occurring throughout the day with
progressive abdominal distention and with repetitive passage of gas via belching
and/or flatus. Symptoms may be more severe in those children who cannot
belch. Chewing gum and gulping down liquids may be risk factors in cognitively
normal children. Symptoms are not attributable to any other causes such as
partial obstructions, small bowel bacterial overgrowth, GI dysmotility
(pseudoobstruction), or to malabsorptive disorders. Abdominal pain, nausea, and
early satiety are reported associated GI symptoms; sleeping difficulty,
headaches, and dizziness are also reported. Anxiety is a frequent comorbidity
and may contribute to the behavior. Treatment is multidisciplinary and may
include behavioral therapy and medications to relieve anxiety.

Functional Abdominal Pain Disorders

Functional Dyspepsia
Functional dyspepsia includes postprandial fullness and early satiety as well as
epigastric pain or burning that is exclusive of defecation and not fully
explainable by another or an underlying medical condition (Table 368.9 ).
Subtypes may include postprandial distress syndrome (symptoms may preclude
finishing a meal or be manifest by bloating, nausea, and excessive belching
following a meal) as well as epigastric pain syndrome (epigastric pain/burning
sufficient to preclude or disrupt normal activities, with pain not generalizable or
localizable to other abdominal or chest regions, and not relieved by defecation or
passage of flatus). An impaired gastric accommodation reflex, food allergy,
delayed gastric emptying, or post viral gastroparesis has been implicated.
Increased visceral hypersensitivity has also been suspected. The differential
diagnosis includes GI etiologies of epigastric pain. Causes for concern can be
guided by the family history and by the nature of symptoms including abdominal
pain and other alarm features (Tables 368.10 and 368.11 ). Evaluation is based
on symptoms. Initial treatment measures include a trial of diet (avoiding spicy
foods, coffee, NSAID) and lifestyle changes if food triggers can be identified,
and gastric acid reduction therapy. Assessment by a pediatric gastroenterologist
and upper endoscopy/esophagogastroduodenoscopy are often performed. Further
treatment with cyproheptadine to improve gastric accommodation or to decrease
visceral hypersensitivity can be attempted. Use of amitriptyline or prokinetic
medications can be considered. Electrical stimulation of the stomach (or
percutaneous) is a potential option for patients refractory to standard therapy.

Table 368.9
Diagnostic Criteria* for Functional Dyspepsia
Must include 1 or more of the following bothersome symptoms at least 4 days/mo:
1. Postprandial fullness
2. Early satiation
3. Epigastric pain or burning not associated with defecation
4. After appropriate evaluation, the symptoms cannot be fully explained by another medical condition.
Within FD, the following subtypes are now adopted:
1. Postprandial distress syndrome includes bothersome postprandial fullness or early satiation that prevents
finishing a regular meal. Supportive features include upper abdominal bloating, postprandial nausea, or
excessive belching.
2. Epigastric pain syndrome, which includes all of the following: bothersome (severe enough to interfere with
normal activities) pain or burning localized to the epigastrium. The pain is not generalized or localized to other
abdominal or chest regions and is not relieved by defecation or passage of flatus. Supportive criteria can
include (a) burning quality of the pain but without a retrosternal component and (b) the pain commonly induced
or relieved by ingestion of a meal but may occur while fasting.
* Criteria fulfilled for at least 2 mo before diagnosis.
From Hyams JS, Di Lorenzo C, Saps M, et al: Childhood functional gastrointestinal disorders:
child/adolescent, Gastroenterology 150(6):1456–1468, 2016 (p. 1460).

Table 368.10
Alarm Symptoms Usually Needing Further Investigations in
Children With Chronic Abdominal Pain
• Pain that wakes up the child from sleep
• Persistent right upper or right lower quadrant pain
• Significant vomiting (bilious vomiting, protracted vomiting, cyclical vomiting, or worrisome pattern to the
physician)
• Unexplained fever
• Genitourinary tract symptoms
• Dysphagia
• Odynophagia
• Chronic severe diarrhea or nocturnal diarrhea
• Gastrointestinal blood loss
• Involuntary weight loss
• Deceleration of linear growth
• Delayed puberty
• Family history of inflammatory bowel disease, celiac disease, and peptic ulcer disease

Table 368.11
Alarm Signs Usually Needing Further Investigations in
Children With Chronic Abdominal Pain
• Localized tenderness in the right upper quadrant
• Localized tenderness in the right lower quadrant
• Localized fullness or mass
• Hepatomegaly
• Splenomegaly
• Jaundice
• Costovertebral angle tenderness
• Arthritis
• Spinal tenderness
• Perianal disease
• Abnormal or unexplained physical findings
• Hematochezia
• Anemia

Pediatric IBS
Pediatric IBS can be classified into 4 groups: IBS with predominant
constipation (IBS-C), IBS with predominant diarrhea (IBS-D), IBS with
constipation and diarrhea, and unspecified IBS. IBS includes findings of
abdominal pain ≥ 4 days/mo associated with defecation and/or a change in
frequency of stool from baseline and/or a change in form/appearance of stool
(Table 368.12 ). It is noteworthy that pain does not resolve following resolution
of constipation; if it does, it is then reclassified as functional constipation. In
fact, IBS-C is often confused with functional constipation. IBS cannot be
explained by another or underlying medical condition. The pathophysiology of
IBS is thought to involve the brain-gut axis and includes a psychosocial stressor
component. Visceral hypersensitivity may be attenuated or amplified by
psychosocial stressors. Abdominal or rectal pain may occur. A postinfectious
IBS phenomenon is known to occur in children, adolescents, and adults and may
be driven by inflammatory cytokines. Perturbations in the intestinal microbiota
or by dysbiosis may be coincident, with causality or consequence not yet
established. The GI differential diagnosis includes anatomical, infectious,
inflammatory, and motility disorders as well as conditions associated with
malabsorption. Differentiation between those GI disorders and IBS is guided by
the history and physical, and markers of inflammation particularly in the stool
such as fecal calprotectin are clinically useful (see Tables 368.10 and 368.11 ).
Management of symptoms can include dietary modification to reduce or restrict
foods that may provoke symptoms or cause gas (see fiber section and
FODMAPS [fermentable oligo-di-monosaccharides and polyols] discussion
Chapter 57 ). Altering microbiota by use of probiotics has been effective; drug
therapy for IBS is noted in Table 368.13 . Peppermint oil has been shown to
reduce pain in children with IBS. Cognitive behavioral therapy is important to
identify possible psychosocial stressors and to help identify coping mechanisms.
Preliminary data suggests that transcutaneous neurostimulation may also be of
value.

Table 368.12
Diagnostic Criteria* for Irritable Bowel Syndrome
Must include all of the following:
1. Abdominal pain at least 4 days/mo associated with one or more of the following:
a. Related to defecation
b. A change in frequency of stool
c. A change in form (appearance) of stool
2. In children with constipation, the pain does not resolve with resolution of the constipation (children in whom
the pain resolves have functional constipation, not irritable bowel syndrome)
3. After appropriate evaluation, the symptoms cannot be fully explained by another medical condition
* Criteria fulfilled for at least 2 mo before diagnosis.

From Hyams JS, Di Lorenzo C, Saps M, et al: Childhood functional gastrointestinal disorders:
child/adolescent, Gastroenterology 150(6):1456–1468, 2016 (p. 1461).

Table 368.13
Recommendations for Treatment of Irritable Bowel
Syndrome
RECOMMENDATIONS FOR TREATMENT OF IBS
• Mild symptoms often respond to dietary changes.
• Antispasmodics can be used as needed for abdominal pain or postprandial symptoms.
• Antidepressants can improve abdominal pain and global symptoms. They may be considered for patients with
moderate to severe symptoms.
IBS WITH CONSTIPATION (IBS-C)
• Fiber may relieve constipation in patients with mild symptoms.
• Polyethylene glycol can increase the frequency of bowel movements, but may not improve overall symptoms or
abdominal pain.
• Lubiprostone or linaclotide can be tried in patients whose symptoms have not responded to polyethylene glycol.
IBS WITH DIARRHEA (IBS-D)
• Taken as needed, loperamide can reduce postprandial urgency and stool frequency, but it does not improve
global symptoms.
• Rifaximin and eluxadoline have been modestly more effective than placebo in relieving symptoms.
• Alosetron should be reserved for women with severe, chronic IBS-D that is unresponsive to other drugs.
IBS , Irritable bowel syndrome.
From Drugs for irritable bowel syndrome, The Medical Letter 58(1504):121–126, 2016 (p. 121).

Abdominal Migraine
Abdominal migraine shares some features with cyclic vomiting syndrome.
Stereotypical patterns and symptoms afflict the patient, and are typically of acute
onset, intense, lasting for at least an hour, being either periumbilical or
generalized, and usually debilitating during a bout (Table 368.14 ). Episodes can
include anorexia, nausea, emesis, headaches, photophobia, and pallor. Episodes
are separated by weeks to months, with bouts occurring over at least a 6-mo
period. Between bouts, patients return to baseline functioning and are symptom
free. Triggers include sleep hygiene disruption, fatigue, travel, and are usually
alleviated by sleep. The differential diagnosis includes anatomical, infectious, or
inflammatory conditions, as well as hepatobiliary and pancreatic disorders,
neurological and metabolic conditions, and psychiatric disorders. Anatomical
obstruction of the GI or urological tract should be included in the differential
diagnosis. Preventing exposure to known triggers once identified is important.
Similar to prophylaxis for cyclic vomiting syndrome, cyproheptadine,
propranolol, and amitriptyline may be effective. Oral pizotifen (antiserotonin,
antihistamine) is an effective prophylactic agent. Anti-migraine therapies such as
triptans may be effective in aborting bouts. This disorder shares many features
with both cyclic vomiting syndrome and migraine headaches and may evolve
into migraine headaches in adulthood.

Table 368.14
Diagnostic Criteria* for Abdominal Migraine
Must include all of the following occurring at least twice:
1. Paroxysmal episodes of intense, acute periumbilical, midline, or diffuse abdominal pain lasting 1 hr or more
(should be the most severe and distressing symptom)
2. Episodes are separated by weeks to months.
3. The pain is incapacitating and interferes with normal activities
4. Stereotypical pattern and symptoms in the individual patient
5. The pain is associated with 2 or more of the following:
a. Anorexia
b. Nausea
c. Vomiting
d. Headache
e. Photophobia
f. Pallor
6. After appropriate evaluation, the symptoms cannot be fully explained by another medical condition.
* Criteria fulfilled for at least 6 mo before diagnosis.

From Hyams JS, Di Lorenzo C, Saps M, et al: Childhood functional gastrointestinal disorders:
child/adolescent, Gastroenterology 150(6):1456–1468, 2016 (p. 1462).

Functional Abdominal Pain Not Otherwise

Specified
Functional abdominal pain not otherwise specified occurs at least 4 times/mo
with either intermittent or continuous abdominal pain not associated with a
particular activity or coincident to another physiologic event such as menses or
eating, cannot be explained by any other or underlying medical condition, and is
of ≥2 mo duration. In many ways, it is a FGID of exclusion, as it does not meet
criteria for IBS, functional dyspepsia, or abdominal migraine. Psychosocial
stressors may play a role. There may be increased coincidence with postural
orthostatic hypotension. Behavioral approaches may be helpful to identify and
manage stressors and exacerbators.
Functional Defecation Disorders
Functional Constipation
Functional constipation in children and adolescents may have onset revolving
around a social stressor, change in social situation, and peaks at the time of toilet
training, when withholding behaviors emerge (Table 368.15 ). Encopresis may
occur without sensation if the rectum is chronically distended sufficiently.
Anorexia, abdominal distention, and pain are often coincident. The diagnosis is
based on medical history and physical examination, including digital rectal
examination. An abdominal x-ray is not required to make the diagnosis if a
digital rectal examination can be performed to appreciate the fecal mass. The
differential diagnosis for constipation in children and adolescents is similar to
that as for infants and toddlers and is the approach to the evaluation and
management of constipation (see Table 368.6 ). Management includes
disimpaction followed by dietary and lifestyle approaches, osmotic laxatives to
soften stools, and behavioral approaches similar to those employed for younger
children discussed previously (Chapter 358.3 ).

Table 368.15
Diagnostic Criteria for Functional Constipation in Children
With Chronic Abdominal Pain
Must include 2 or more of the following occurring at least once per week for a minimum of 1 mo with insufficient
criteria for a diagnosis of irritable bowel syndrome:
1. Two or fewer defecations in the toilet per week in a child of a developmental age of at least 4 yr
2. At least 1 episode of fecal incontinence per week
3. History of retentive posturing or excessive volitional stool retention
4. History of painful or hard bowel movements
5. Presence of a large fecal mass in the rectum
6. History of large diameter stools that can obstruct the toilet
After appropriate evaluation, the symptoms cannot be fully explained by another medical condition.
From Hyams JS, Di Lorenzo C, Saps M, et al: Childhood functional gastrointestinal disorders:
child/adolescent, Gastroenterology 150(6):1456–1468, 2016 (p. 1464).

Nonretentive Fecal Incontinence

Nonretentive fecal incontinence occurs in the setting of not having fecal
retention, occurring in inappropriate settings for a specific society and culture,
CHAPTER 369

Cyclic Vomiting Syndrome

Asim Maqbool, B U.K. Li, Chris A. Liacouras

Cyclic vomiting syndrome (CVS) is an idiopathic disorder manifested as

episodic vomiting, usually of sudden onset and high intensity/frequency
(4/hr:12-15 episodes/day) of vomiting, with eventual resolution and return to a
normal baseline between attacks. Typical bouts last for 24-48 hr, and usually
respond promptly to hydration. To meet the criteria for CVS, identifiable organic
disorders are excluded following an appropriate workup (Table 369.1 ).

Table 369.1
Consensus Definition for Diagnostic Criteria and Red Flags
for Cyclic Vomiting Syndrome
DIAGNOSTIC CRITERIA
• Episodic (≥2 or more) attacks of intense nausea and paroxysmal vomiting lasting hours to days within a 6-mo
period
• Stereotypical pattern and symptoms in the individual patient
• Episodes are separated by weeks to months
• Return to baseline between episodes
• Not attributable to another disorder
RED FLAGS
• Bilious emesis, abdominal tenderness, and/or severe abdominal pain
• Attacks precipitated by an intercurrent illness, fasting, and/or a high protein meal
• Neurological abnormalities (mental status changes, ophthalmic abnormalities asymmetry/focal changes, ataxia)
• Atypical pattern or progression/deterioration from a typical presentation for the individual patient to a more
continuous or chronic pattern
Modified from the Rome IV Criteria: Li BU, Lefevre F, Chelimsky GG, et al: North American
Society for Pediatric Gastroenterology, Hepatology and Nutrition consensus statement on the
diagnosis and management of cyclic vomiting syndrome, J Pediatr Gastroenterol Nutr 47(3):379–
393, 2008.

The prevalence of CVS in children is estimated at ~2% in predominantly

Caucasian populations, although it does occur in those of African or Asian
hypoglycemia, and renal dysfunction during episodes, and an UGI radiograph to
exclude malrotation. Presenting with gastrointestinal (bilious emesis, abdominal
tenderness), metabolic (fasting or meal-induced), and neurological (papilledema,
altered mental status) red flags warrants further evaluation (see Table 369.1 ).
In the management of acute episodes, early and aggressive hydration
(especially with dextrose) may shorten episodes in addition to correcting fluid
losses. Reducing extraneous sensory stimulation, similar to the management
approach for migraines, may also be beneficial (Table 369.2 ). Regardless of
intervention, episodes will eventually spontaneously resolve with return to a
normal baseline. Triptans can be used as an abortive medication in patients with
a family history of migraines, at the onset of symptoms. Ondansetron may
reduce nausea and emesis. Sedation may reduce severity or stop a CVS episode;
drugs include antihistamines such as diphenhydramine and promethazine.
Lorazepam or rectal diazepam can be also used. These measures are empiric; a
lack of evidence base limits our understanding of efficacy. For rare but severe
refractory cases, general anesthetics have been used. A dramatic change in
presentation of attacks suggests a red flag such as acute hydronephrosis or small
bowel obstruction from volvulus.

Table 369.2
Supportive Care and Abortive Treatment Approaches in
Cyclic Vomiting Syndrome
SUPPORTIVE CARE
Fluid and electrolyte management Dextrose containing fluid (D10) and normal saline as a single infusion or as a
Y infusion
Nutrition • Resume enteral nutrition as soon as possible.
• If unable to tolerate enteral nutrition and meets criteria, start parenteral
nutrition after 3-4 days.
Medications Antiemetics Ondansetron
• 0.3-0.4 mg/kg/dose IV every 4-6 hr (maximum 16 mg/dose)
• Side effect: constipation, QTc prolongation
Alternative: Granisetron
Sedatives Diphenhydramine
• 1-1.25 mg/kg/dose IV every 6 hr
Lorazepam 0.05-0.1 mg/kg/dose IV every 6 hr
• Side effects: respiratory depression, hallucinations
Chlorpromazine 0.5-1 mg/kg/dose every 6-8 hr +
diphenhydramine IV
Analgesics Ketorolac 0.5 mg/kg/dose IV every 6 hr (maximum dose 30 mg)
Treatment of specific signs and Epigastric pain
symptoms • Acid reduction therapy with an H2 RA or a PPI
Diarrhea
 • Antidiarrheals
Hypertension
• Short-acting ACE inhibitors such as captopril
Treatment of specific • Dehydration and electrolyte deficits: replace calculated deficits
complications • Metabolic acidosis: determine etiology and rectify
• SIADH: restrict free water intake
• Hyperemesis: IV acid reduction
• Weight loss: enteral or parenteral nutrition
ABORTIVE CARE
Antimigraine (triptans) Sumatriptan
• 20 mg intranasally at episode onset
• Side effects: neck pain/burning, coronary vasospasm
• Contraindications: basilar artery migraine
RECOVERY AND REFEEDING
• Feed ad libitum when the child declares that the episode is over
Medications listed above are for off-label use.
Modified from Li BU, Lefevre F, Chelimsky GG, et al: North American Society for Pediatric
Gastroenterology, Hepatology and Nutrition consensus statement on the diagnosis and
management of cyclic vomiting syndrome, J Pediatr Gastroenterol Nutr 47(3):379–393, 2008.

Prophylactic management begins with lifestyle measures (maintenance fluid

intake, adequate calories, sleep hygiene, and exercise), including avoidance of
known triggering foods (allergens, chocolate, aged cheese, monosodium
glutamate; Table 369.3 ). Recommendations for prophylactic regimens include
cyproheptadine in patients less than 5 yr of age and amitriptyline in patients ≥5
yr; propranolol serves as a secondary agent in both age groups. Supplements
such as coenzyme Q10 and L-carnitine have occasionally been reported to be
useful adjuncts. When standard care fails, the addition of anticonvulsants such as
topiramate has been implemented. For those with catamenial CVS, low-dose
estrogen oral contraceptives or Depo-Provera may prevent episodes. Treatment
of comorbid disorders , especially anxiety (cognitive behavioral therapy,
antianxiety agents) and postural orthostatic tachycardia syndrome (fluids, salt,
fludrocortisone), may be needed for effective management of CVS.

Table 369.3
Prophylactic Lifestyle Changes and Pharmacological
Options for Cyclic Vomiting Syndrome
LIFESTYLE MEASURES
Reassurance and • Episodes are not intentional.
anticipatory Guidance • The natural history of CVS is that it will resolve with time.
Avoidance of triggers • Identify dietary triggers (“vomit diary”) and avoid precipitating factors.
• Triggering foods may include chocolate, cheese, monosodium glutamate.
• Fasting a common trigger
 • Excitement a potential trigger
• Excessive activity/exhaustion
• Avoid sleep deprivation and practice good sleep hygiene
Managing triggers • Provide supplemental energy as carbohydrates for fasting induced episodes.
• Provision of snacks between meals, before sleep and before exertion
Migraine headache • Aerobic exercise and avoidance of overexertion
type lifestyle • Regular mealtime schedule—avoid skipping meals
interventions • Avoid/moderate caffeine intake
PROPHYLACTIC PHARMACOLOGICAL APPROACHES
Age <5 yr Age ≥5 yr
Antihistamines: Tricyclic antidepressants:
• Cyproheptadine • Amitriptyline
• 0.25-0.5 mg/kg/day in 2 daily • Begin at 0.25-0.5 mg/kg qhs and increase weekly
divided doses or as a single by 5-10 mg until achieve 1-1.5 mg/kg
dose qhs • Monitor EKG for prolonged QTc interval at
• Side effects of increased baseline before initiation and 10 days after peak
appetite, weight gain, and dose achieved
sedation • Side effects: constipation, sedation, arrhythmias,
• Pizotifen behavioral changes
β-blockers: (2nd choice) Alternatives: nortriptyline
• Propranolol β-blockers: (2nd choice):
• 0.25-1 mg/kg/day, most often • Propranolol
10 mg 2-3×/day. Other agents:
• Side effects include lethargy Anticonvulsants:
and reduced exercise • Phenobarbital 2 mg/kg qhs
tolerance. • Side effects: sedation, cognitive impairment
• Contraindicated in asthma, Alternatives:
diabetes, heart disease, • Topiramate, valproic acid, gabapentin, levetiracetam
depression
• Taper over 1-2 wk to
discontinue
DIETARY SUPPLEMENTS
• L-Carnitine 50-100 mg/kg/day divided 2-3×/day, maximum dose of 2 g 2×/day
• Coenzyme Q10 200 mg 2×/day divided 2-3×/day, maximum dose 100 mg 3×/day
Medications listed above are for off-label use. CVS , cyclic vomiting syndrome.
Modified from Li BU, Lefevre F, Chelimsky GG, et al: North American Society for Pediatric
Gastroenterology, Hepatology and Nutrition consensus statement on the diagnosis and
management of cyclic vomiting syndrome, J Pediatr Gastroenterol Nutr 47(3):379–393, 2008.

Bibliography
Bhandari S, Venkatesan T. Clinical characteristics,
Comorbidities and hospital outcomes in hospitalizations with
cyclic vomiting syndrome: a nationwide analysis. Dig Dis Sci
. 2017;62(8):2035–2044.
Bhandari S, Venkatesan T. Novel treatments for cyclic vomiting
syndrome: beyond ondansetron and amitriptyline. Curr Treat
include that it is well-tolerated, non-invasive, and lacks ionizing radiation
exposure. CT is reserved for cases of nonvisualization of the appendix on
ultrasound, or when the ultrasound findings are inconclusive.

Table 370.1

Pediatric Appendicitis Scores

FEATURE SCORE
Fever > 38°C (100.4°F) 1
Anorexia 1
Nausea/vomiting 1
Cough/percussion/hopping tenderness 2
Right lower quadrant tenderness 2
Migration of pain 1
Leukocytosis > 10,000 (109 /L) 1
Polymorphonuclear-neutrophilia > 7,500 (109 /L) 1
Total 10
From Acheson J, Banerjee J: Management of suspected appendicitis in children, Arch Dis Child
Educ Pract Ed. 95:9–13, 2010.

The use of appendicitis risk scoring systems, in conjunction with clinical

judgment, have demonstrated high sensitivity and specificity for acute
appendicitis (80–90%) and their application has reduced practice variability,
improved diagnostic accuracy, decreased preoperative radiation exposure, and
enabled efficient resource utilization—all important elements of current quality
improvement and safety initiatives. Their greatest value to date appears to be in
predicting patients that have a low likelihood of the diagnosis of appendicitis
(negative predictive value) and can avoid imaging studies, and particularly
ionizing radiation exposure.

Laboratory Findings
A variety of laboratory tests have been used in the evaluation of children with
suspected appendicitis. Individually, none are very sensitive or specific for
appendicitis, but collectively they can affect the clinician's level of suspicion and
decision-making to proceed with pediatric surgery consultation, discharge, or
imaging studies.
A complete blood count with differential and urinalysis are obtained. The
leukocyte count in early appendicitis may be normal, and typically is only mildly
elevated (11,000-16,000/mm3 ) with a left shift as the illness progresses in the
radial aspect of the upper extremity and are termed the VACTERL (v ertebral, a
nal, c ardiac, t racheal, e sophageal, r enal, l imb) anomalad.

Table 371.1
Associated Malformations
GENITOURINARY
• Vesicoureteric reflux
• Renal agenesis
• Renal dysplasia
• Ureteral duplication
• Cryptorchidism
• Hypospadias
• Bicornuate uterus
• Vaginal septa
VERTEBRAL
• Spinal dysraphism
• Tethered chord
• Presacral masses
• Meningocele
• Lipoma
• Dermoid
• Teratoma
CARDIOVASCULAR
• Tetralogy of Fallot
• Ventricular septal defect
• Transposition of the great vessels
• Hypoplastic left-heart syndrome
GASTROINTESTINAL
• Tracheoesophageal fistula
• Duodenal atresia
• Malrotation
• Hirschsprung disease
CENTRAL NERVOUS SYSTEM
• Spina bifida
• Tethered cord

Anorectal malformations, particularly anal stenosis and rectal atresia, can also
present as Currarino triad, which includes sacral agenesis, presacral mass, and
anorectal stenosis. These patients present with a funnel appearing anus, have
sacral bony defects on plain x-ray, and have a presacral mass (teratoma,
meningocele, dermoid cyst, enteric cyst) on exam or imaging. It is an autosomal
dominant disorder due in most patients to a mutation in the MNX1 gene.
A good correlation exists between the degree of sacral development and future
function. Patients with an absent sacrum usually have permanent fecal and
urinary incontinence. Spinal abnormalities and different degrees of dysraphism
are often associated with these defects. Tethered cord occurs in approximately
division of the fistula without injury to the urinary tract. The rectum is then
dissected proximally until enough length is gained to suture it to an appropriate
perineal position. The muscles of the sphincter complex are then sutured around
(and especially behind) the rectum.
Other operative approaches (such as an anterior approach) are used, but the
most popular procedure is by laparoscopy. This operation allows division of the
fistula under direct visualization and identification of the sphincter complex by
transillumination of perineum. Other imaging techniques in the management of
anorectal malformations include 3D endorectal ultrasound, intraoperative MRI,
and colonoscopy-assisted PSARPs, which may help perform a technically better
operation. None of these other procedures or innovations has demonstrated
improved outcomes.
A similar procedure can be done for female high anomalies with variations to
deal with separating the vagina and rectum from within the cloacal stem. When
the stem is longer than 3 cm, this is an especially difficult and complex
procedure.
Usually the colostomy can be closed 6 wk or more after the PSARP. Two
weeks after any anal procedure, twice-daily dilatations are performed by the
family. By doing frequent dilatations, each one is not so painful and there is less
tissue trauma, inflammation, and scarring.

Outcome
The ability to achieve rectal continence depends on both motor and sensory
elements. There must be adequate muscle in the sphincter complex and proper
positioning of the rectum within the complex. There must also be intact
innervation of the complex and of sensory elements, as well as the presence of
these sensory elements in the anorectum. Patients with low lesions are more
likely to achieve true continence. They are also, however, more prone to
constipation, which leads to overflow incontinence. It is very important that all
these patients are followed closely, and that the constipation and anal dilation are
well managed until toilet training is successful. Tables 371.2 and 371.3 outline
the results of continence and constipation in relation to the malformation
encountered.

Table 371.2
Types of Anorectal Malformation by Sex
MALE (PERCENTAGE CHANCE OF BOWEL CONTROL * )
• Rectoperineal fistula (100%)
• Rectourethral bulbar fistula (85%)
• Imperforate anus without fistula (90%)
• Rectourethral prostatic fistula (65%)
• Rectobladder neck fistula (15%)
FEMALE (PERCENTAGE CHANCE OF BOWEL CONTROL * )
• Rectoperineal fistula (100%)
• Rectovestibular fistula (95%)
• Imperforate anus without fistula (90%)
• Rectovaginal fistula (rare anomaly) †
• Cloaca (70%) ‡
* Provided patients have a normal sacrum, no tethered cord, and they receive a technically correct

operation without complications.

† Rectovaginal anomalies are extremely unusual; usually their prognosis is like rectovestibular
fistula.
‡ Cloaca represents a spectrum; those with a common channel length <3 cm have the best
functional prognosis.
From Bischoff A, Bealer J, Pená A: Controversies in anorectal malformations, Lancet
Child/Adolesc 1:323–330, 2017 (Panel p. 323).

Table 371.3

Constipation and Type of Anogenital Malformation

TYPE PERCENTAGE
Vestibular fistula 61
Bulbar urethral fistula 64
Rectal atresia/stenosis 50
Imperforate with no fistula 55
Perineal fistula 57
Long cloaca 35
Prostatic fistula 45
Short cloaca 40
Bladder neck fistula 16
Modified from Levitt MA, Peña A: Outcomes from the correction of anorectal malformations, Curr
Opin Pediatr 17:394–401, 2005.

Children with high lesions, especially males with rectoprostatic urethral

fistulas and females with cloacal anomalies, have a poorer chance of being
continent, but they can usually achieve a socially acceptable defecation (without
a colostomy) pattern with a bowel management program. Often, the bowel
CHAPTER 372

Tumors of the Digestive Tract

Danielle Wendel, Karen F. Murray

Tumors of the digestive tract in children are mostly polypoid. They are also
commonly syndromic tumors and tumors with known genetic identification
(Table 372.1 ). They usually manifest as painless rectal bleeding, but when large
they can cause obstruction or serve as lead points for intussusception. Most
intestinal tumors can be generally classified into 2 groups: hamartomatous or
adenomatous.

Table 372.1
General Features of the Inherited Colorectal Cancer
Syndromes

AGE RISK OF
POLYP GENETIC CLINICAL ASSOCIATED
SYNDROME OF COLON
DISTRIBUTION LESION MANIFESTATIONS LESIONS
ONSET CANCER
HAMARTOMATOUS POLYPS
Juvenile Large and small 1st ~10–50% PTEN, Possible rectal bleeding, Congenital
polyposis intestine, gastric decade SMAD4, abdominal pain, abnormalities in
polyps BMPR1A intussusception 20% of the
Autosomal nonfamilial
dominant type, clubbing,
AV
malformations
Peutz-Jeghers Small and large 1st Increased LKB1/STK11 Possible rectal bleeding, Orocutaneous
syndrome intestine decade Autosomal abdominal pain, melanin
dominant intussusception pigment spots
Cowden Colon 2nd Not PTEN gene Macrocephaly,
syndrome decade increased breast/thyroid/endometrial
cancers, developmental
delay
Bannayan- Colon 2nd Not PTEN gene Macrocephaly, speckled
Riley- decade increased penis, thyroid/breast
Ruvalcaba cancers, hemangiomas,
syndrome lipomas
 ADENOMATOUS POLYPS
Familial Large intestine, 16 yr 100% 5q (APC gene), Rectal bleeding, Desmoids,
adenomatous often >100 (range: autosomal abdominal pain, bowel CHRPE, upper
polyposis 8-34 yr) dominant obstruction GI polyps,
(FAP) osteoma,
hepatoblastoma,
thyroid cancer
Attenuated Colon (fewer in >18 yr Increased APC gene Same as FAP Fewer
familial number) associated
adenomatous lesions
polyposis
(AFAP)
MYH- Colon >20 yr High risk MYH autosomal Same as FAP May be
associated recessive confused with
polyposis sporadic FAP or
AFAP; few
extraintestinal
findings
Gardner Large and small 16 yr 100% 5q (APC gene) Rectal bleeding, Desmoid
syndrome intestine (range: abdominal pain, bowel tumors,
8-34 yr) obstruction multiple
osteomas,
fibromas,
epidermoid
cysts
Hereditary Large intestine 40 yr 30% DNA Rectal bleeding, Other tumors
nonpolyposis mismatch abdominal pain, bowel (e.g., ovary,
colon cancer, repair genes obstruction ureter, pancreas,
(Lynch (MMR) stomach)
syndrome) Autosomal
dominant
APC, adenomatous polyposis coli; AV , arteriovenous; CHRPE , congenital hypertrophy of the
retinal pigment epithelium; GI, gastrointestinal; PTEN , phosphatase and tensin homolog.

Hamartomatous Tumors
Hamartomas are benign tumors composed of tissues that are normally found in
an organ but that are not organized normally. Juvenile, retention, or
inflammatory polyps are hamartomatous polyps, which represent the most
common intestinal tumors of childhood, occurring in 1–2% of children. Patients
generally present in the 1st decade, most often at ages 2-5 yr, and rarely at
younger than 1 yr. Polyps may be found anywhere in the gastrointestinal (GI)
tract, most commonly in the rectosigmoid colon; they are often solitary but may
be multiple.
Histologically, juvenile polyps are composed of hamartomatous collections of
mucus-filled glandular and stromal elements with inflammatory infiltrate,
confined to the inguinal region or pass down into the scrotum. Complete failure
of obliteration of the PV, mostly seen in infants, predisposes to a complete
inguinal hernia characterized by a protrusion of abdominal contents into the
inguinal canal and extending into the scrotum. Obliteration of the PV distally
(around the testis) with patency proximally results in the classic indirect inguinal
hernia with a bulge in the inguinal canal.
A hydrocele occurs when only fluid enters the patent PV; the swelling may
exist only in the scrotum (scrotal hydrocele), only along the spermatic cord in
the inguinal region (hydrocele of the spermatic cord), or extend from the
scrotum through the inguinal canal and even into the abdomen (abdominal–
scrotal hydrocele). A hydrocele is termed a communicating hydrocele if it
demonstrates fluctuation in size, often increasing in size after activity and, at
other times, being smaller when the fluid decompresses into the peritoneal cavity
often after laying recumbent. Occasionally, hydroceles develop in older children
following trauma, inflammation, torsion of the appendix testes, or in association
with tumors affecting the testis.
Although reasons for failure of closure of the PV are unknown, it is more
common in cases of testicular nondescent (cryptorchidism) and prematurity. In
addition, persistent patency of the PV is twice as common on the right side,
presumably related to later descent of the right testis and interference with
obliteration of the PV from the developing inferior vena cava and external iliac
vein. Table 373.1 lists the risk factors identified as contributing to failure of
closure of the PV and to the development of clinical inguinal hernia. The
incidence of inguinal hernia in patients with cystic fibrosis is approximately
15%, believed to be related to an altered embryogenesis of the wolffian duct
structures, which leads to an absent vas deferens and infertility in males with this
condition. There is also an increased incidence of inguinal hernia in patients with
testicular feminization syndrome and other disorders of sexual development.
The rate of recurrence after repair of an inguinal hernia in patients with a
connective tissue disorder approaches 50%, and often the diagnosis of
connective tissue disorders in children results from investigation following
development of a recurrent inguinal hernia.

Table 373.1
Predisposing Factors for Hernias
• Prematurity
 • Urogenital
• Cryptorchidism
• Exstrophy of the bladder or cloaca
• Ambiguous genitalia
• Hypospadias/epispadias
• Increased peritoneal fluid
• Ascites
• Ventriculoperitoneal shunt
• Peritoneal dialysis catheter
• Increased intraabdominal pressure
• Repair of abdominal wall defects
• Severe ascites (chylous)
• Meconium peritonitis
• Chronic respiratory disease
• Cystic fibrosis
• Connective tissue disorders
• Ehlers-Danlos syndrome
• Hunter-Hurler syndrome
• Marfan syndrome
• Mucopolysaccharidosis

Clinical Presentation and Diagnosis

An inguinal hernia typically appears as an intermittent, asymptomatic bulge or
mass in the inguinal region or scrotum, most often noted on routine physical
examination or by a parent; after bathing or urination are classic presentations.
In females, the mass typically occurs in the upper portion of the labia majora.
The bulge or mass is most visible at times of irritability or increased
intraabdominal pressure (crying, straining, coughing). Most inguinal hernias
present clinically in young children, approximately 50% in the 1st yr, and most
are asymptomatic or minimally symptomatic. The classic history from the
parents is of intermittent groin, labial, or scrotal swelling that spontaneously
reduces but that is gradually enlarging or is more persistent and is becoming
more difficult to reduce. The hallmark signs of an inguinal hernia on physical
examination are a smooth, firm mass that emerges through the external inguinal
ring lateral to the pubic tubercle and enlarges with increased intraabdominal
pressure. When the child relaxes, the hernia typically reduces spontaneously or
can be reduced by gentle pressure, 1st posteriorly to free it from the external ring
and then upward toward the peritoneal cavity. In males, the hernia sac contains
intestines; female infants often have an ovary and fallopian tube in the hernia
sac.
The diagnosis of inguinal hernia is clinical and generally is made by history
and physical examination. Methods used to demonstrate the hernia on
examination vary depending on the age of the child. A quiet infant can be made
CHAPTER 377

Treatment of Pancreatic Insufficiency

Michael Wilschanski, Steven L. Werlin

The most important treatment of pancreatic insufficiency (PI) is pancreatic

enzyme replacement therapy (PERT). In modern enzyme capsules the enzymes
are enterically coated to protect the enzymes from degradation by gastric acid
and from autodigestion in the small intestine. It is common for patients to change
from one product to another using a 1 : 1 lipase ratio and then titrating for
maximum efficacy (Table 377.1 ).

Table 377.1
FDA-Approved Pancreatic Enzyme Replacement Products
for Exocrine Pancreatic Insufficiency*

DRUG AVAILABLE STRENGTHS COST ($)

†
IMMEDIATE-RELEASE–
Viokace (Allergan) ‡ , § , || 10,440 or 20,880 units of lipase ¶ 8.80
DELAYED-RELEASE–
Creon (Abbvie) 3,000, 6,000, 12,000, 24,000, or 36,000 USP units of lipase ¶ , ** 8.20
Pancreaze (Janssen) 2,600, 4,200, 10,500, 16,800, or 21,000 units of lipase ¶ , ** 8.80
Pertzye (Digestive Care) 4,000, 8,000, 16,000, or 24,000 units of lipase ¶ , ** 8.40
Zenpep (Allergan) 3,000, 5,000, 10,000, 15,000, 20,000, 25,000, or 40,000 units of lipase ¶ , 9.60
**
* Pancrelipase products are not interchangeable. All of these products contain a combination of
porcine-derived lipases, proteases, and amylases.
† Approximate WAC for one dose (as close as possible to 35,000 USP units of lipase using

available formulations) for a 70-kg patient. WAC is wholesaler acquisition cost, or manufacturer's
published price to wholesalers; WAC represents published catalogue or list prices and may not
represent an actual transactional price.
‡ Viokace is only approved for use in adults.
§ Should be used in combination with a proton pump inhibitor to maximize absorption in the

duodenum.
|| FDA-approved only for treatment of adults with EPI due to chronic pancreatitis or

pancreatectomy.
¶ Should not be crushed or chewed.

** Capsules can be opened and contents sprinkled on soft acidic food (pH ≤ 4.5) such as

applesauce.
From The Medical Letter: Pancreatic enzyme replacement products, Med Lett 59(1531):170,
2017.
Source: AnalySource Monthly. September 5, 2017. Reprinted from First Databank, Inc. All rights
reserved. ©2017. www.fdbhealth.com/policies/drug-pricing-policy/ .

The North American CF Foundation has published dosing guidelines based on

age and fat ingestion (Table 377.2 ). Because these products contain excess
protease compared with lipase, the dosage is estimated from the lipase
requirement. The final dosage of PERT for children is often established by trial
and error. An adequate dose is one that is followed by resumption of normal
growth and the return of stools to normal fat content, which, when desired, can
be verified by a 72-hr fecal fat collection and normalization of stool consistency
and color. Because there is no elastase in enzyme preparations, fecal elastase
cannot be used to monitor appropriateness of PERT dosage. Enzyme
replacement should be divided and given at the beginning of and during the
meal. Enzymes should not be chewed, crushed, or dissolved in food, which
would allow gastric acid to penetrate the enteric coating and destroy the
enzymes. Enzymes must also be given with snacks which contain fat. Increasing
enzyme supplements beyond the recommended dose does not improve
absorption, might retard growth, and can cause fibrosing colonopathy (see
below).

Table 377.2

Pancreatic Enzyme Replacement Therapy: North American CF Foundation

Consensus Statement
Infants (up to 12 2,000-4,000 U lipase/120 mL breast milk or formula
mo)
12 mo to 4 yr 1,000 U lipase/kg/meal initially, then titrate per response
Children >4 yr 500 U lipase/kg/meal initially, up to maximum of 2,500 U lipase/kg/meal or 10,000 U
and adults lipase/kg/day or 4,000 U lipase/g fat ingested per day
PLUS: one half the standard meal dose to be given with snacks.
are caused by infections, metabolic disorders, or mutations in susceptibility
genes (see Chapter 378.1 ). Only 10–20% of cases are idiopathic (Table 378.1 ).

Table 378.1
Etiology of Acute and Recurrent Pancreatitis in Children
DRUGS AND TOXINS
• Acetaminophen overdose
• Alcohol
• L -Asparaginase
• Azathioprine
• Cannabis
• Carbamazepine
• Cimetidine
• Corticosteroids
• Cytosine arabinoside
• Dapsone
• Didanosine
• Enalapril
• Erythromycin
• Estrogen
• Furosemide
• Glucagon-like peptide-1 agents
• Interferon α
• Isoniazid
• Lamivudine
• Lisinopril
• 6-Mercaptopurine
• Methyldopa
• Mesalamine
• Metronidazole
• Octreotide
• Organophosphate poisoning
• Pentamidine
• Procainamide
• Retrovirals: DDC (dideoxycytidine), DDI (dideoxyinosine), tenofovir
• Rifampin
• Sulfonamides: mesalamine, 5-aminosalicytates, sulfasalazine, trimethoprim-sulfamethoxazole
• Sulindac
• Tetracycline
• Thiazides
• Valproic acid
• Venom (spider, scorpion, Gila monster lizard)
• Vincristine
• Volatile hydrocarbons
GENETIC
• Cationic trypsinogen gene (PRSS1)
• Chymotrypsin C gene (CTRC)
• Cystic fibrosis gene (CFTR)
• Trypsin inhibitor gene (SPINK1)
INFECTIOUS
• Ascariasis
• Coxsackie B virus
• Echovirus
• Enterovirus
• Epstein-Barr virus
• Hepatitides A, B
• Herpes viruses
• Influenzae A, B
• Leptospirosis
• Malaria
• Measles
• Mumps
• Mycoplasma
• Rabies
• Rubella
• Reye syndrome: varicella, influenza B
• Septic shock
• Thyroid fever
OBSTRUCTIVE
• Ampullary disease
• Ascariasis
• Biliary tract malformations
• Choledochal cyst
• Choledochocele
• Cholelithiasis, microlithiasis, and choledocholithiasis (stones or sludge)
• Duplication cyst
• Endoscopic retrograde cholangiopancreatography (ERCP) complication
• Pancreas divisum
• Pancreatic ductal abnormalities
• Postoperative
• Sphincter of Oddi dysfunction
• Tumor
SYSTEMIC DISEASE
• Autoimmune pancreatitis (IgG4 -related systemic disease)
• Brain tumor
• Collagen vascular diseases
• Congenital partial lipodystrophy
• Crohn disease
• Diabetes mellitus (ketoacidosis)
• Head trauma
• Henoch-Schönlein purpura
• Hemochromatosis
• Hemolytic uremic syndrome
• Hyperlipidemia: types I, IV, V
• Hyperparathyroidism/hypercalcemia
• Kawasaki disease
• Malnutrition
• Organic acidemia
• Peptic ulcer
• Periarteritis nodosa
• Renal failure
• Scorpion venom
• Systemic lupus erythematosus
• Transplantation: bone marrow, heart, liver, kidney, pancreas
• Vasculitis
TRAUMATIC
 • Blunt injury
• Burns
• Child abuse
• Hypothermia
• Surgical trauma
• Total-body cast

After an initial insult, such as ductal disruption or obstruction, there is

premature activation of trypsinogen to trypsin within the acinar cell. Trypsin
then activates other pancreatic proenzymes, leading to autodigestion, further
enzyme activation, and release of active proteases. Lysosomal hydrolases
colocalize with pancreatic proenzymes within the acinar cell. Pancreastasis
(similar in concept to cholestasis) with continued synthesis of enzymes occurs.
Lecithin is activated by phospholipase A2 into the toxic lysolecithin.
Prophospholipase is unstable and can be activated by minute quantities of
trypsin. After the insult, cytokines and other proinflammatory mediators are
released.
The healthy pancreas is protected from autodigestion by pancreatic proteases
that are synthesized as inactive proenzymes; digestive enzymes that are
segregated into secretory granules at pH 6.2 by low calcium concentration,
which minimizes trypsin activity; the presence of protease inhibitors both in the
cytoplasm and zymogen granules; and enzymes that are secreted directly into the
ducts.
Histopathologically, interstitial edema appears early. Later, as the episode of
pancreatitis progresses, localized and confluent necrosis, blood vessel disruption
leading to hemorrhage, and an inflammatory response in the peritoneum can
develop.
The diagnosis of pancreatitis in children is made when 2 of 3 of the following
are present: abdominal pain; serum amylase and/or lipase activity at least 3 times
greater than the upper limit of normal; and imaging findings characteristic of, or
compatible with, AP.

Clinical Manifestations
The severity of AP in children has been defined by a consensus committee.
Mild Acute Pancreatitis: AP that is not associated with organ failure, local or
systemic complications, and usually resolves within the 1st wk after
presentation. This is the most common form of pediatric AP.
The patient with mild AP has moderate to severe abdominal pain, persistent
greater than 7 times the upper limit of normal obtained within 24 hr of
presentation may predict a severe course. Serum lipase can be elevated in
nonpancreatic diseases. The serum amylase level is typically elevated for up to 4
days. A variety of other conditions can also cause hyperamylasemia without
pancreatitis (Table 378.2 ). Elevation of salivary amylase can mislead the
clinician to diagnose pancreatitis in a child with abdominal pain. The laboratory
can separate amylase isoenzymes into pancreatic and salivary fractions. Initially
serum amylase levels are normal in 10–15% of patients.

Table 378.2
Differential Diagnosis of Hyperamylasemia
PANCREATIC PATHOLOGY
• Acute or chronic pancreatitis
• Complications of pancreatitis (pseudocyst, ascites, abscess)
• Factitious pancreatitis
SALIVARY GLAND PATHOLOGY
• Parotitis (mumps, Staphylococcus aureus , cytomegalovirus, HIV, Epstein-Barr virus)
• Sialadenitis (calculus, radiation)
• Eating disorders (anorexia nervosa, bulimia)
INTRAABDOMINAL PATHOLOGY
• Biliary tract disease (cholelithiasis)
• Peptic ulcer perforation
• Peritonitis
• Intestinal obstruction
• Appendicitis
SYSTEMIC DISEASES
• Metabolic acidosis (diabetes mellitus, shock)
• Renal insufficiency, transplantation
• Burns
• Pregnancy
• Drugs (morphine)
• Head injury
• Cardiopulmonary bypass

Other laboratory abnormalities that may be present in AP include

hemoconcentration, coagulopathy, leukocytosis, hyperglycemia, glucosuria,
hypocalcemia, elevated γ-glutamyl transpeptidase, and hyperbilirubinemia.
X-ray of the chest and abdomen might demonstrate nonspecific findings such
as atelectasis, basilar infiltrates, elevation of the hemidiaphragm, left- (rarely
right-) sided pleural effusions, pericardial effusion, and pulmonary edema.
Abdominal x-rays might demonstrate a sentinel loop, dilation of the transverse
colon (cutoff sign), ileus, pancreatic calcification (if recurrent), blurring of the
left psoas margin, a pseudocyst, diffuse abdominal haziness (ascites), and
Table 378.3
Revised Definitions of Morphologic Features of Acute
Pancreatitis
INTERSTITIAL EDEMATOUS PANCREATITIS
Acute inflammation of the pancreatic parenchyma and peripancreatic tissues, but without recognizable tissue
necrosis
• CECT criteria
• Pancreatic parenchyma enhancement by intravenous contrast agent
• No peripancreatic necrosis
NECROTIZING PANCREATITIS
Inflammation associated with pancreatic parenchymal necrosis and/or peripancreatic necrosis
• CECT criteria
• Lack of pancreatic parenchymal enhancement by intravenous contrast agent
• Presence of findings of peripancreatic necrosis
ACUTE PANCREATITIS FLUID COLLECTION
Peripancreatic fluid associated with interstitial edematous pancreatitis with no associated peripancreatic necrosis.
Applies only to areas of peripancreatic fluid seen within the first 4 wk after onset of interstitial edematous
pancreatitis and without the features of a pseudocyst.
• CECT criteria
• Occurs in the setting of interstitial edematous pancreatitis
• Homogeneous collection with fluid density
• Confined by normal peripancreatic fascial planes
• No definable wall encapsulating the collection
• Adjacent to pancreas (no intrapancreatic extension)
PANCREATIC PSEUDOCYST
An encapsulated collection of fluid with a well-defined inflammation wall, usually outside the pancreas, with little
or no necrosis. Usually occurs more than 4 wk after onset of interstitial edematous pancreatitis.
• CECT criteria
• Well circumscribed; usually round or oval
• Homogeneous fluid density
• No nonliquid component
• Well-defined wall that is wholly encapsulated
• Maturation usually needs >4 wk after onset of acute pancreatitis; occurs after interstitial edematous
pancreatitis
ACUTE NECROTIC COLLECTION
A collection containing variable amounts of both fluid and necrosis associated with necrotizing pancreatitis; the
necrosis can include the pancreatic parenchyma and/or the peripancreatic tissue.
• CECT criteria
• Occurs only in the setting of acute necrotizing pancreatitis
• Heterogeneous and nonliquid density of varying degrees in different locations (some seem homogeneous early
in their course)
• No definable wall encapsulating the collection
• Intrapancreatic and/or extrapancreatic
WALLED-OFF NECROSIS
A mature, encapsulated collection of pancreatic and/or peripancreatic necrosis that has developed a well-defined
inflammatory wall. Usually occurs >4 wk after onset of necrotizing pancreatitis.
• CECT criteria
• Heterogeneous with liquid and nonliquid density, with varying locations (some can seem homogeneous)
 • Well-defined wall that is wholly encapsulated
• Intrapancreatic and/or extrapancreatic
• Maturation usually needs 4 wk after onset of acute necrotizing pancreatitis
CECT, contrast-enhanced CT.
From PA Banks, TL Bollen, C Dervenis, et al.; the Acute Pancreatitis Classification Working Group
Classification of acute pancreatitis—2012: revision of the Atlanta classification and definitions by
international consensus Gut 62:102-111, 2013.

Table 378.4
Complications of Acute Pancreatitis
LOCAL
Pseudocyst
Sterile necrosis
Infected necrosis
Abscess
GI bleeding
• Pancreatitis-related
• Splenic artery or splenic artery pseudoaneurysm rupture
• Splenic vein rupture
• Portal vein rupture
• Splenic vein thrombosis leading to gastroesophageal variceal bleeding
• Pseudocyst or abscess hemorrhage
• Postnecrosectomy bleeding
Nonpancreatitis-related
• Mallory-Weiss tear
• Alcoholic gastropathy
• Stress-related mucosal gastropathy
Splenic complications
• Infarction
• Rupture
• Hematoma
• Splenic vein thrombosis
Fistulization to or obstruction of the small intestine or colon
Hydronephrosis
SYSTEMIC
Respiratory failure
Renal failure
Shock
Hyperglycemia
Hypocalcemia
Disseminated intravascular coagulation
Fat necrosis (subcutaneous nodules)
Retinopathy

PSYCHOSIS
From Tenner S, Steinberg WM: Acute pancreatitis. In Feldman M, Friedman LS, Brandt LJ,
editors: Sleisenger and Fordtran's gastrointestinal and liver disease, ed 10, Philadelphia, 2016,
Elsevier (Box 58.7, p. 991).
 acute recurrent pancreatitis
autoimmune pancreatitis
PRSS1 gene
CTRC gene
CFTR gene
SPINK1 gene
tropical pancreatitis

Acute recurrent pancreatitis (ARP) is defined as ≥2 distinct episodes of AP with

intervening return of enzymes to baseline. Chronic pancreatitis (CP) is defined
as the presence of typical abdominal pain plus characteristic imaging findings
including pancreatic calcifications, inflammation and fibrosis, or exocrine
insufficiency plus imaging findings, or endocrine insufficiency plus imaging
findings. Most children with CP describe a history of ARP and tend to be older
at the time of diagnosis compared with children with ARP, suggesting that ARP
and CP are a disease continuum.
ARP and CP in children are often due to genetic mutations or due to
congenital anomalies of the pancreatic or biliary ductal system (Tables 378.5 and
378.6 ). Mutations in the PRSS1 gene (cationic trypsinogen) located on the long
arm of chromosome 7, SPINK1 gene (pancreatic trypsin inhibitor) located on
chromosome 5, in the cystic fibrosis gene (CFTR) , and chymotrypsin C (CTRC)
may all lead to CP (Fig. 378.2 ).

Table 378.5

Factors Contributing to the Etiology of Chronic Pancreatitis

No. (%)*
Chronic pancreatitis patients with history of ≥1episode acute pancreatitis 73 (96)
Risk factors for pancreatitis
Genetic 51 (67)
PRSS1 33 (43)
SPINK1 14 (19)
CFTR 11 (14)
CTRC 2 (3)
Autoimmune 3 (4)
Obstructive 25 (33)
Pancreas divisum 15 (20)
Sphincter of Oddi dysfunction 1 (1)
Gallstones 3 (4)
Pancreatic duct malunion 2 (3)
Pancreatic duct obstruction 1 (1)
 Other 5 (7)
Toxic/metabolic 8 (11)
Alcohol (determined by doctor) 1 (1)
Passive smoking (exposure) 3 (4)
Hyperlipidemia 1 (1)
Medication 1 (1)
Metabolic disease 1 (1)
Other 1 (1)
None cited 8 (11)
* The total exceeds 100% because some children have more than 1 factor.

From Schwarzenberg SJ, Bellin M, Husain SZ, et al: Pediatric chronic pancreatitis is associated
with genetic risk factors and substantial disease burden, J Pediatr 166:890–896, 2015 (Table II, p.
892).

Table 378.6

Classification of Chronic Pancreatitis

CHRONIC CALCIFYING CHRONIC OBSTRUCTIVE STEROID-RESPONSIVE
PANCREATITIS PANCREATITIS PANCREATITIS
Alcohol Stricture Autoimmune Pancreatitis
Smoking Blunt trauma Type 1
Genetic Endoscopic stenting Type 2 (IDCP)
Idiopathic Acute pancreatitis
Juvenile-onset Anastomotic stricture
Tropical Tumor
Adenocarcinoma
IPMN
Serious cystadenoma Islet cell
tumor
IDCP, idiopathic duct-centric pancreatitis; IPMN, intraductal papillary mucinous neoplasm.
From Majumder S, Chari ST: Chronic pancreatitis, Lancet 387:1957–1966, 2016 (Fig 1, p. 1958).
sufficiency or which do not typically produce pulmonary disease, can cause CP,
possibly due to ductal obstruction. Patients with genotypes associated with mild
phenotypic effects have a greater risk of developing pancreatitis than those with
genotypes associated with moderate to severe phenotypes.
Mutations in the chymotrypsin C gene, which cause a loss of function, may
also cause recurrent pancreatitis. Indications for genetic testing include recurrent
episodes of AP, CP, a family history of pancreatitis, or unexplained pancreatitis
in children.
Other conditions associated with chronic, relapsing pancreatitis are
hyperlipidemia (types I, IV, and V), hyperparathyroidism, and ascariasis.
Previously, most cases of recurrent pancreatitis in childhood were considered
idiopathic; with the discovery of gene families associated with recurrent
pancreatitis, this has changed. Congenital anomalies of the ductal systems, such
as pancreas divisum, are more common than previously recognized.
Autoimmune pancreatitis (AIP) typically manifests with jaundice, abdominal
pain, and weight loss. The pancreas is typically enlarged and is hypodense on
CT. The pathogenesis is unknown. Type 1 is a systemic disease and is associated
with high serum IgG4. In addition to pancreatitis in type 1 disease, the patient
may have retroperitoneal fibrosis, orbital inflammation, aortitis, sclerosing
cholangitis, cutaneous vasculitis, pulmonary fibrosis, and sialoadenitis. These
extrapancreatic features may also be present in the absence of pancreatitis (Table
378.7 ). Tissue biopsy shows fibrosis, plasmacytosis, and positive staining for
IgG4; serum IgG4 levels are not always elevated.

Table 378.7
Conditions Classification of Chronic Disorders Now
Recognized to Be Part of IgG4-Related Disease
Autoimmune pancreatitis (lymphoplasmacytic sclerosing pancreatitis)
Eosinophilic angiocentric fibrosis (affecting the orbits and upper respiratory tract)
Fibrosing mediastinitis
Hypertrophic pachymeningitis
Idiopathic hypocomplementaemic tubulointerstitial nephritis with extensive tubulointerstitial deposits
Inflammatory pseudotumor (affecting the orbits, lungs, kidneys, and other organs)
Küttner tumor (affecting the submandibular glands)
Mikulicz disease (affecting the salivary and lacrimal glands)
Multifocal fibrosclerosis (commonly affecting the orbits, thyroid gland, retroperitoneum, mediastinum, and other
tissues and organs)
Periaortitis and periarteritis
Inflammatory aortic aneurysm
Retroperitoneal fibrosis (Ormond disease)
 Riedel thyroiditis
Sclerosing mesenteritis
Conditions once regarded as individual disorders now recognized to be part of IgG4-related disease
From Kamisawa T, Zen Y, Pillai S, Stone JH: IgG4-related disease, Lancet 385:1460–1471, 2015
(Panel 1, p. 1461).

Type 2 is limited to diffuse or focal involvement of just the pancreas. IgG4

levels are normal. Both types respond to steroids . Children with AIP typically
have type 2.
Juvenile tropical pancreatitis is the most common form of CP in developing
equatorial countries. The highest prevalence is in the Indian state of Kerala.
Tropical pancreatitis occurs during late childhood or early adulthood,
manifesting with abdominal pain and irreversible pancreatic insufficiency
followed by diabetes mellitus within 10 years. The pancreatic ducts are
obstructed with inspissated secretions, which later calcify. This condition is
associated with mutations in the SPINK gene in 50% of cases.
A thorough diagnostic evaluation of every child with more than one episode of
pancreatitis is indicated. Serum lipid, calcium, and phosphorus levels are
determined. Stools are evaluated for ascaris, and a sweat test is performed. Plain
abdominal films are evaluated for the presence of pancreatic calcifications.
Abdominal ultrasound or CT scanning is performed to detect the presence of a
pseudocyst. The biliary tract is evaluated for the presence of stones. After
genetic counseling, evaluation of PRSS1, SPINK1, CFTR , and CRTC genotypes
can be measured. Electrophysiologic tests such as nasal potential difference
testing may be recommended when the diagnosis of cystic fibrosis (CF) is
uncertain.
Magnetic resonance cholangiopancreatography (MRCP) and Endoscopic
retrograding cholangiopancreatography (ERCP) are techniques that can be used
to define the anatomy of the gland and are mandatory if surgery is considered.
MRCP is the test of choice when endotherapy is not being considered and should
be performed as part of the evaluation of any child with idiopathic, nonresolving,
or recurrent pancreatitis and in patients with a pseudocyst before drainage. In
these cases a previously undiagnosed anatomic defect that may be amenable to
endoscopic or surgical therapy may be detected. Endoscopic treatments include
sphincterotomy, stone extraction, drainage on pseudocysts, and insertion of
pancreatic or biliary endoprosthetic stents. These treatments allow the successful
nonsurgical management of conditions previously requiring surgical
intervention. In patients with intractable pain, total pancreatectomy and islet cell
transfusion is performed in specialist centers.
CHAPTER 380

Pancreatic Tumors
Meghen B. Browning, Steven L. Werlin, Michael Wilschanski

Pancreatic tumors can be of either endocrine or nonendocrine origin. Tumors of

endocrine origin include gastrinomas and insulinomas (Table 380.1 ). These and
other functioning tumors occur in the autosomal dominantly inherited multiple
endocrine neoplasia type 1 (MEN-1). Hypoglycemia accompanied by higher-
than-expected insulin levels or refractory gastric ulcers (Zollinger-Ellison
syndrome) indicates the possibility of a pancreatic tumor (see Chapter 372 ).
Most gastrinomas arise outside of the pancreas. The treatment of choice is
surgical removal. If the primary tumor cannot be found, or if it has metastasized,
cure might not be possible. Treatment with a high dose of a proton pump
inhibitor to inhibit gastric acid secretion is then indicated.

Table 380.1
Syndromes Associated With Pancreatic Neuroendocrine
Tumors (pNETs)*

SYNDROME INCIDENCE/106 MALIGNANCY

HORMONE
/YEAR (%)
Insulinoma 1-2 <10 Insulin
Gastrinoma (ZES) 0.5-1.5 60–90 Gastrin
VIPoma (Verner-Morrison syndrome, WDHA, 0.05-0.2 >60 VIP
pancreatic cholera)
Glucagonoma 0.01-0.1 50–80 Glucagon
Somatostatinoma Rare >70 Somatostatin
GRFoma Unknown >30 GH-RF
ACTHoma Uncommon >95% ACTH
pNET secreting PTH-rP Rare 84% PTH-rP
Pancreatic carcinoid tumor Rare (<1% of all 77% Serotonin,
carcinoids) tachykinins
pNET secreting renin Rare Unknown Renin
pNET secreting erythropoietin Rare Unknown Erythropoietin
 pNET secreting luteinizing hormone Rare Unknown Luteinizing
hormone
pNET secreting cholecystokinin (CCKoma) Rare Unknown CCK
*
These syndromes may also be caused by a GI-NET (carcinoid).
GH-RF , growth hormone–releasing factor; PP , pancreatic polypeptide; PTH-rP , parathyroid
hormone–related protein; VIP , vasoactive intestinal polypeptide; WDHA , watery diarrhea,
hypokalemia, achlorhydria.
From Jensen RT, Norton JA, Oberg K: Neuroendocrine tumors. In Feldman M, Friedman LS,
Brandt LJ, editors: Sleisenger and Fordtran's gastrointestinal and liver disease , ed 10, Elsevier,
2016, Philadelphia, Table 33.1.

Insulinomas and persistent hyperinsulinemic hypoglycemia of infancy

produce symptomatic hypoglycemia caused by mutations in a variety of genes,
most commonly GUUD1 and KATP . Massive subtotal or total pancreatectomy
is the treatment of choice when medical treatment fails. These children might
then develop pancreatic insufficiency and diabetes as a complication of surgery.
The watery diarrhea–hypokalemia–acidosis syndrome is usually produced
by the secretion of vasoactive intestinal peptide by a non–α-cell tumor (VIPoma)
(see Table 367.7 ). Vasoactive intestinal peptide levels are often, but not always,
increased in the serum. Treatment is surgical removal of the tumor. When this is
not possible, symptoms may be controlled by the use of octreotide acetate
(cyclic somatostatin, Sandostatin), a synthetic analog of somatostatin. Pancreatic
tumors secreting a variety of hormones, including glucagon, somatostatin, and
pancreatic polypeptide, have also been described. The treatment is surgical
resection when possible.
Pancreatoblastomas, pancreatic adenocarcinomas, cystadenomas, and
sarcomas of the pancreas are rarely encountered. Pancreatoblastoma, a malignant
embryonal tumor that secretes α-fetoprotein and can contain both endocrine and
exocrine elements, is the most common pancreatic neoplasm in young children.
Presurgical chemotherapy should be considered for lesions not primarily
resectable. Resection can be curative; adjuvant chemotherapy has been used, but
its effectiveness is not established.
Sarcomas are very rarely primary pancreatic but may include Ewing sarcoma,
rhabdomyosarcoma, or undifferentiated soft tissue sarcomas. They are treated
with multimodal therapy including chemotherapy and either resection or
radiation.
Carcinoma of the exocrine pancreas is a major problem in adults, accounting
for 2% of diagnoses and 5% of deaths from cancer. It is very rare in childhood.
No definite causes are known. Several genetic syndromes including mutations in
 FIG. 381.1 Processes involved in early liver development. A, The ventral foregut
endoderm acquires competence to receive signals arising from the cardiac mesoderm.
B, Specific cells of the ventral foregut endoderm undergo specification and activation
of liver-specific genes under the influence of mesodermal signals. C, Liver
morphogenesis is initiated as the newly specified cells migrate into the septum
transversum under the influence of signaling molecules and extracellular matrix
released by septum transversum mesenchymal cells and of primitive endothelial cells.
(From Zaret K7S: Liver specification and early morphogenesis, Mech Dev 92:83–88,
2000.)

The growth and development of the newly budded liver require interactions
with endothelial cells. Certain proteins are important for liver development in
animal models (Table 381.1 ). In addition to these proteins, microRNAs, which
consist of small noncoding, single-stranded RNAs, have a functional role in the
regulation of gene expression and hepatobiliary development in zebrafish and
mouse models.

Table 381.1
Selected Growth Factors, Receptors, Protein Kinases, and
Transcription Factors Required for Normal Liver
Development in Animal Models
INDUCTION OF HEPATOCYTE FATE THROUGH CARDIAC MESODERM
• Fibroblast growth factors (FGFs) 1, 2, 8
• FGF receptors 1, 4
INDUCTION OF HEPATOCYTE FATE THROUGH SEPTUM TRANSVERSUM
• Bone morphogenetic proteins 2, 4, 7
STIMULATION OF HEPATOBLAST GROWTH AND PROLIFERATION
• Hepatocyte growth factor (HGF)
• HGF receptor c-met
• “Pioneer” transcription factors Foxa1, Foxa2, and Gata4, Gata6
• Transcription factors Xbp1, Foxm1b, Hlx, Hex, Prox1
• Wnt signaling pathway, β-catenin
SPECIFICATION OF HEPATOCYTE LINEAGE
 • HGF
• Transforming growth factor-β and its downstream effectors Smad 2, Smad 3
• Hepatocyte nuclear factors (HNFs) 1α, 4α, 6
SPECIFICATION OF CHOLANGIOCYTE LINEAGE
• Jagged 1 (Notch ligand) and Notch receptors 1, 2
• HNF6, HNF1β
• Wnt signaling pathway, β-catenin
• Vacuolar sorting protein Vps33b

Within the ventral mesentery, proliferation of migrating cells form

anastomosing hepatic cords, with the network of primitive liver cells, sinusoids,
and septal mesenchyme establishing the basic architectural pattern of liver lobule
(Fig. 381.2 ). The solid cranial portion of the hepatic diverticulum (pars hepatis)
eventually forms the hepatic parenchyma and the intrahepatic bile ducts. The
hepatic lobules are identifiable in the 6th wk of human gestation. The bile
canalicular structures, including microvilli and junctional complexes, are
specialized loci of the liver cell membrane; these appear very early in gestation,
and large canaliculi bounded by several hepatocytes are seen by 6-7 wk.

FIG. 381.2 Hepatic morphogenesis. A, Ventral outgrowth of hepatic diverticulum from
foregut endoderm in the 3.5-wk embryo. B, Between the 2 vitelline veins, the enlarging
hepatic diverticulum buds off epithelial (liver) cords that become the liver parenchyma,
around which the endothelium of capillaries (sinusoids) align (4 wk embryo). C,
Hemisection of embryo at 7.5 wk. D, Three-dimensional representation of the hepatic
Table 381.2
Causes of Impaired Bile Acid Metabolism and
Enterohepatic Circulation
DEFECTIVE BILE ACID SYNTHESIS OR TRANSPORT
• Inborn errors of bile acid synthesis (reductase deficiency, isomerase deficiency)
• Progressive familial intrahepatic cholestasis (PFIC1, PFIC2, PFIC3)
• Intrahepatic cholestasis (neonatal hepatitis)
• Acquired defects in bile acid synthesis secondary to severe liver disease
ABNORMALITIES OF BILE ACID DELIVERY TO THE BOWEL
• Celiac disease (sluggish gallbladder contraction)
• Extrahepatic bile duct obstruction (e.g., biliary atresia, gallstones)
LOSS OF ENTEROHEPATIC CIRCULATION OF BILE ACIDS
• External bile fistula
• Cystic fibrosis
• Small bowel bacterial overgrowth syndrome (with bile acid precipitation, increased jejunal absorption, and
“short-circuiting”)
• Drug-induced entrapment of bile acids in intestinal lumen (e.g., cholestyramine)
BILE ACID MALABSORPTION
• Primary bile acid malabsorption (absent or inefficient ileal active transport)
• Secondary bile acid malabsorption
• Ileal disease or resection
• Cystic fibrosis
DEFECTIVE UPTAKE OR ALTERED INTRACELLULAR METABOLISM
• Parenchymal disease (acute hepatitis, cirrhosis)
• Regurgitation from cells
• Portosystemic shunting
• Cholestasis

Bibliography
Bates MD, Balistreri WF. The gastrointestinal tract:
development of the human digestive system. Fanaroff AA,
Martin RJ. Neonatal-perinatal medicine: diseases of the fetus
and infant . ed 7. Mosby: St. Louis; 2002:1255–1263.
Cardinale V, Wang Y, Carpino G, et al. The biliary tree-a
reservoir of multipotent stem cells. Nat Rev Gastroenterol
Hepatol . 2012;9:231–240.
Carpentier R, Suñer RE, van Hul N, et al. Embryonic ductal
plate cells give rise to cholangiocytes, periportal hepatocytes,
and adult liver progenitor cells. Gastroenterology .
2011;141:1432–1438.
nodules of various sizes (up to 5 cm) separated by broad septa, or micronodular ,
with nodules of uniform size (<1 cm) separated by fine septa; mixed forms
occur. The progressive scarring results in altered hepatic blood flow, with further
impairment of liver cell function. Increased intrahepatic resistance to portal
blood flow leads to portal hypertension.
The liver can be secondarily involved in neoplastic (metastatic) and non-
neoplastic (storage diseases, fat infiltration) processes, as well as a number of
systemic conditions and infectious processes. The liver can be affected by
chronic passive congestion (congestive heart failure) or acute hypoxia, with
hepatocellular damage.

Clinical Manifestations
Hepatomegaly
Enlargement of the liver can be caused by several mechanisms (Table 382.1 ).
Normal liver size estimations are based on age-related clinical indices, such as
the degree of extension of the liver edge below the costal margin, the span of
dullness to percussion, or the length of the vertical axis of the liver, as estimated
from imaging techniques. In children, the normal liver edge can be felt up to 2
cm below the right costal margin. In a newborn infant, extension of the liver
edge more than 3.5 cm below the costal margin in the right midclavicular line
suggests hepatic enlargement. Measurement of liver span is carried out by
percussing the upper margin of dullness and by palpating the lower edge in the
right midclavicular line. This may be more reliable than an extension of the liver
edge alone. The 2 measurements may correlate poorly.

Table 382.1
Mechanisms of Hepatomegaly
INCREASE IN THE NUMBER OR SIZE OF THE CELLS INTRINSIC TO THE LIVER
Storage
Fat: malnutrition, obesity, metabolic liver disease (diseases of fatty acid oxidation and Reye syndrome–like
illnesses), lipid infusion (total parenteral nutrition), cystic fibrosis, medication related, pregnancy
Specific lipid storage diseases: Gaucher, Niemann-Pick, Wolman disease
Glycogen: glycogen storage diseases (multiple enzyme defects); total parenteral nutrition; infant of diabetic
mother, Beckwith syndrome, poorly controlled type 1 diabetes mellitus (Mauriac syndrome)
Miscellaneous: α1 -antitrypsin deficiency, Wilson disease, hypervitaminosis A
Inflammation
Hepatocyte enlargement (hepatitis)
• Viral: acute and chronic
• Bacterial: sepsis, abscess, cholangitis
• Toxic: drugs
• Autoimmune
Kupffer cell enlargement
• Sarcoidosis
• Systemic lupus erythematosus
• Hemophagocytic lymphohistiocytosis
• Macrophage activating syndrome
INFILTRATION OF CELLS
Primary Liver Tumors: Benign
Hepatocellular
• Focal nodular hyperplasia
• Nodular regenerative hyperplasia
• Hepatocellular adenoma
Mesodermal
• Infantile hemangioendothelioma
• Mesenchymal hamartoma
Cystic masses
• Choledochal cyst
• Hepatic cyst
• Hematoma
• Parasitic cyst
• Pyogenic or amebic abscess
Primary Liver Tumors: Malignant
Hepatocellular
• Hepatoblastoma
• Hepatocellular carcinoma
Mesodermal
• Angiosarcoma
• Undifferentiated embryonal sarcoma
Secondary or metastatic processes
• Lymphoma
• Leukemia
• Lymphoproliferative disease
• Langerhans cell histiocytosis
• Neuroblastoma
• Wilms tumor
INCREASED SIZE OF VASCULAR SPACE
Intrahepatic obstruction to hepatic vein outflow
• Venoocclusive disease
• Hepatic vein thrombosis (Budd-Chiari syndrome)
• Hepatic vein web
Suprahepatic
• Congestive heart failure
Pericardial disease/tamponade/constrictive pericarditis
Post-Fontan procedure
Hematopoietic: sickle cell anemia, thalassemia
INCREASED SIZE OF BILIARY SPACE
Congenital hepatic fibrosis
Caroli disease
Extrahepatic obstruction
IDIOPATHIC
Various
 • Riedel lobe
• Normal variant
• Downward displacement of diaphragm

The liver span increases linearly with body weight and age in both sexes,
ranging from approximately 4.5-5.0 cm at 1 wk of age to approximately 7-8 cm
in boys and 6.0-6.5 cm in girls by 12 yr of age. The lower edge of the right lobe
of the liver extends downward (Riedel lobe) and can normally be palpated as a
broad mass in some people. An enlarged left lobe of the liver is palpable in the
epigastrium of some patients with cirrhosis. Downward displacement of the liver
by the diaphragm (hyperinflation) or thoracic organs can create an erroneous
impression of hepatomegaly.
Examination of the liver should note the consistency, contour, tenderness, and
presence of any masses or bruits, as well as assessment of spleen size, along with
documentation of the presence of ascites and any stigmata of chronic liver
disease.
Ultrasound is useful in assessment of liver size and consistency, as well as
gallbladder size. Gallbladder length normally varies from 1.5-5.5 cm (average: 3
cm) in infants to 4-8 cm in adolescents; width ranges from 0.5-2.5 cm for all
ages. Gallbladder distention may be seen in infants with sepsis. The gallbladder
is often absent in infants with biliary atresia.

Jaundice (Icterus)
Yellow discoloration of the sclera, skin, and mucous membranes is a sign of
hyperbilirubinemia (see Chapter 123.3 ). Clinically apparent jaundice in children
and adults occurs when the serum concentration of bilirubin reaches 2-3 mg/dL
(34-51 µmol/L); the neonate might not appear jaundiced until the bilirubin level
is >5 mg/dL (>85 µmol/L). Jaundice may be the earliest and only sign of hepatic
dysfunction. Liver disease must be suspected in the infant who appears only
mildly jaundiced but has dark urine or acholic (light-colored) stools. Immediate
evaluation to establish the cause is required.
Measurement of the total serum bilirubin concentration allows quantitation of
jaundice. Bilirubin occurs in plasma in 4 forms: unconjugated bilirubin tightly
bound to albumin; free or unbound bilirubin (the form responsible for
kernicterus, because it can cross cell membranes); conjugated bilirubin (the only
fraction to appear in urine); and δ fraction (bilirubin covalently bound to
albumin), which appears in serum when hepatic excretion of conjugated
bilirubin is impaired in patients with hepatobiliary disease. The δ fraction
permits conjugated bilirubin to persist in the circulation and delays resolution of
jaundice. Although the terms direct and indirect bilirubin are used equivalently
with conjugated and unconjugated bilirubin, this is not quantitatively correct,
because the direct fraction includes both conjugated bilirubin and δ bilirubin.
Investigation of jaundice in an infant or older child must include
determination of the accumulation of both unconjugated and conjugated
bilirubin. Unconjugated hyperbilirubinemia might indicate increased production,
hemolysis, reduced hepatic removal, or altered metabolism of bilirubin (Table
382.2 ). Conjugated hyperbilirubinemia reflects decreased excretion by damaged
hepatic parenchymal cells or disease of the biliary tract, which may be a result of
obstruction, sepsis, toxins, inflammation, and genetic or metabolic disease (Table
382.3 ).

Table 382.2
Differential Diagnosis of Unconjugated Hyperbilirubinemia
INCREASED PRODUCTION OF UNCONJUGATED BILIRUBIN FROM HEME
Hemolytic Disease (Hereditary or Acquired)
Isoimmune hemolysis (neonatal; acute or delayed transfusion reaction; autoimmune)
• Rh incompatibility
• ABO incompatibility
• Other blood group incompatibilities
Congenital spherocytosis
Hereditary elliptocytosis
Infantile pyknocytosis
Erythrocyte enzyme defects
Hemoglobinopathy
• Sickle cell anemia
• Thalassemia
• Others
Sepsis
Microangiopathy
• Hemolytic-uremic syndrome
• Hemangioma
• Mechanical trauma (heart valve)
Ineffective erythropoiesis
Drugs
Infection
Enclosed hematoma
Polycythemia
• Diabetic mother
• Fetal transfusion (recipient)
• Delayed cord clamping
DECREASED DELIVERY OF UNCONJUGATED BILIRUBIN (IN PLASMA) TO HEPATOCYTE
Right-sided congestive heart failure
Portacaval shunt
DECREASED BILIRUBIN UPTAKE ACROSS HEPATOCYTE MEMBRANE
Presumed enzyme transporter deficiency
Competitive inhibition
• Breast milk jaundice
• Lucey-Driscoll syndrome
• Drug inhibition (radiocontrast material)
Miscellaneous
• Hypothyroidism
• Hypoxia
• Acidosis
DECREASED STORAGE OF UNCONJUGATED BILIRUBIN IN CYTOSOL (DECREASED Y AND Z
PROTEINS)
Competitive inhibition
Fever
DECREASED BIOTRANSFORMATION (CONJUGATION)
Neonatal jaundice (physiologic)
Inhibition (drugs)
Hereditary (Crigler-Najjar)
• Type I (complete enzyme deficiency)
• Type II (partial deficiency)
Gilbert disease
Hepatocellular dysfunction
ENTEROHEPATIC RECIRCULATION
Breast milk jaundice
Intestinal obstruction
• Ileal atresia
• Hirschsprung disease
• Cystic fibrosis
• Pyloric stenosis
Antibiotic administration

Table 382.3
Differential Diagnosis of Neonatal and Infantile Cholestasis
INFECTIOUS
Generalized bacterial sepsis
Viral hepatitis
• Hepatitides A, B, C, D, E
• Cytomegalovirus
• Rubella virus
• Herpesviruses: herpes simplex, human herpesvirus 6 and 7
• Varicella virus
• Coxsackievirus
• Echovirus
• Reovirus type 3
• Parvovirus B19
• HIV
• Adenovirus
Others
• Toxoplasmosis
• Syphilis
• Tuberculosis
• Listeriosis
 • Urinary tract infection
TOXIC
Sepsis
Parenteral nutrition related
Drug, dietary supplement, herbal related
METABOLIC
Disorders of amino acid metabolism
• Tyrosinemia
Disorders of lipid metabolism
• Wolman disease
• Niemann-Pick disease (type C)
• Gaucher disease
Cholesterol ester storage disease
Disorders of carbohydrate metabolism
• Galactosemia
• Fructosemia
• Glycogenosis IV
Disorders of bile acid biosynthesis
Other metabolic defects
• α1 -Antitrypsin deficiency
• Cystic fibrosis
• Hypopituitarism
• Hypothyroidism
• Zellweger (cerebrohepatorenal) syndrome
• Wilson disease
• Gestational alloimmune liver disease (previously neonatal iron storage disease )
• Indian childhood cirrhosis/infantile copper overload
• Congenital disorders of glycosylation
• Mitochondrial hepatopathies
• Citrin deficiency
GENETIC OR CHROMOSOMAL
Trisomies 17, 18, 21
INTRAHEPATIC CHOLESTASIS SYNDROMES
“Idiopathic” neonatal hepatitis
Alagille syndrome
Intrahepatic cholestasis (progressive familial intrahepatic cholestasis [PFIC])
• FIC-1 deficiency
• Bile salt export pump (BSEP) deficiency
• MDR3 deficiency
• Tight junction protein 2 deficiency
• Farnesoid X receptor (FXR) mutations
Familial benign recurrent cholestasis associated with lymphedema (Aagenaes syndrome)
ARC (arthrogryposis, renal dysfunction, and cholestasis) syndrome
Caroli disease (cystic dilation of intrahepatic ducts)
EXTRAHEPATIC DISEASES
Biliary atresia
Sclerosing cholangitis
Bile duct stricture/stenosis
Choledochal–pancreaticoductal junction anomaly
Spontaneous perforation of the bile duct
Choledochal cyst
Mass (neoplasia, stone)
Bile/mucous plug (“inspissated bile”)
MISCELLANEOUS
Shock and hypoperfusion
 Associated with enteritis
Associated with intestinal obstruction
Neonatal lupus erythematosus
Myeloproliferative disease (trisomy 21)
Hemophagocytic lymphohistiocytosis (HLH)
COACH syndrome (coloboma, oligophrenia, ataxia, cerebellar vermis hypoplasia, hepatic fibrosis)
Cholangiocyte cilia defects

Pruritus
Intense generalized itching can occur in patients with chronic liver disease often
in association with cholestasis (conjugated hyperbilirubinemia). Symptoms can
be generalized or localized (commonly to palms and soles), are usually worse at
night, are exacerbated with stress and heat, and are relieved by cool
temperatures. Pruritus is unrelated to the degree of hyperbilirubinemia; deeply
jaundiced patients can be asymptomatic.
The pathogenesis of pruritus remains unknown, however, multiple suspected
pruritogens have been reported including bile acids, histamine, serotonin,
progesterone metabolites, endogenous opioids, the potent neuronal activator
lysophosphatidic acid (LPA), and the LPA-forming enzyme, autotaxin (ATX).
Ultimately, a multifactorial process is suspected as evidenced by the
symptomatic relief of pruritus after administration of various therapeutic agents
including bile acid-binding agents (cholestyramine), choleretic agents
(ursodeoxycholic acid), opiate antagonists, antihistamines, serotonin reuptake
inhibitors (sertraline), and antibiotics. Plasmapheresis, molecular adsorbent
recirculating system therapy, and surgical diversion of bile (partial and total
biliary diversion) have been used in attempts to provide relief for medically
refractory pruritus.

Spider Angiomas
Vascular spiders (telangiectasias) , characterized by central pulsating arterioles
from which small, wiry venules radiate, may be seen in patients with chronic
liver disease. These are usually most prominent in the superior vena cava
distribution area (on the face and chest). Their size varies between 1 and 10 mm
and they exhibit central clearing with pressure. They presumably reflect altered
estrogen metabolism in the presence of hepatic dysfunction.
Biochemical Tests
Laboratory tests commonly used to screen for or to confirm a suspicion of liver
disease include measurements of serum aminotransferase (Table 382.4 ),
bilirubin (total and fractionated), alkaline phosphatase (AP) and gamma
glutamyl-transpeptidase (GGT) levels, as well as determinations of prothrombin
time (PT) or international normalized ratio (INR) and serum albumin level.
These tests are complementary, provide an estimation of synthetic and excretory
functions, and might suggest the nature of the disturbance (inflammation or
cholestasis).

Table 382.4
Causes of Elevated Serum Aminotransferase Levels*
CHRONIC, MILD ELEVATIONS, ALT > AST (<150 U/L OR 5 × NORMAL)
Hepatic Causes
α1 -Antitrypsin deficiency
Autoimmune hepatitis
Chronic viral hepatitis (B, C, and D)
Hemochromatosis
Medications and toxins
Steatosis and steatohepatitis
Wilson disease
Nonhepatic Causes
Celiac disease
Hyperthyroidism
SEVERE, ACUTE ELEVATIONS, ALT > AST (>1,000 U/L OR >20-25 × NORMAL)
Hepatic Causes
Acute bile duct obstruction
Acute Budd-Chiari syndrome
Acute viral hepatitis
Autoimmune hepatitis
Drugs and toxins
Hepatic artery ligation
Ischemic hepatitis
Wilson disease
SEVERE, ACUTE ELEVATIONS, AST > ALT (>1,000 U/L OR >20-25 × NORMAL)
Hepatic Cause
Medications or toxins in a patient with underlying alcoholic liver injury

Nonhepatic Cause
Acute rhabdomyolysis
CHRONIC, MILD ELEVATIONS, AST > ALT (<150 U/L, <5 × NORMAL)
Hepatic Causes
Alcohol-related liver injury (AST/ALT > 2 : 1, AST nearly always <300 U/L)
Cirrhosis
Nonhepatic Causes
 Hypothyroidism
Macro-AST
Myopathy
Strenuous exercise
CHRONIC, MILD ELEVATIONS, ALT > AST (<150 U/L OR 5 × NORMAL)
* Virtually any liver disease can cause moderate aminotransferase elevations (5-15 × normal).

The severity of the liver disease may be reflected in clinical signs or

biochemical alterations. Clinical signs include encephalopathy, variceal
hemorrhage, worsening jaundice, apparent shrinkage of liver mass owing to
massive necrosis, or onset of ascites. Biochemical alterations reflective of
severity include hypoglycemia, acidosis, hyperammonemia, electrolyte
imbalance, continued hyperbilirubinemia, marked hypoalbuminemia, or a
prolonged PT or INR that is unresponsive to parenteral administration of vitamin
K.
Acute liver cell injury (parenchymal disease) caused by viral hepatitis, drug-
or toxin-induced liver disease, shock, hypoxemia, or metabolic disease is best
suggested by a marked increase in serum aminotransferase levels. Cholestasis
(obstructive disease) involves regurgitation of bile components into serum; the
serum levels of total and conjugated bilirubin and serum bile acids are elevated.
Elevations in serum AP, 5′ nucleotidase, and GGT levels are also sensitive
indicators of obstruction or inflammation of the biliary tract. Fractionation of the
total serum bilirubin level into conjugated and unconjugated bilirubin fractions
helps to distinguish between elevations caused by processes such as hemolysis
and those caused by hepatic dysfunction. A predominant elevation in the
conjugated bilirubin level provides a relatively sensitive index of hepatocellular
disease or hepatic excretory dysfunction.
Alanine aminotransferase (ALT, serum glutamate pyruvate transaminase) is
liver specific, whereas aspartate aminotransferase (AST, serum glutamic-
oxaloacetic transaminase) is derived from other organs in addition to the liver.
The most marked rises of AST and ALT levels can be noted in patients with
acute hepatocellular injury; a several thousand–fold elevation can result from
acute viral hepatitis, toxic injury (e.g., acetaminophen), hypoxia, or
hypoperfusion (see Table 382.4 ). After blunt abdominal trauma, parallel
elevations in aminotransferase levels can provide an early clue to hepatic injury.
A differential rise or fall in AST and ALT levels sometimes provides useful
information. In acute hepatitis, the rise in ALT may be greater than the rise in
AST. In alcohol-induced liver injury, fulminant echovirus infection, and various
metabolic diseases, more predominant rises in the AST level are reported. In
precise mechanism, but it offers an explanation for well-documented cases of
unexpected postnatal evolution of the disease processes; infants initially
considered to have neonatal hepatitis, with a patent biliary system shown on
cholangiography, can later manifest biliary atresia.
Functional abnormalities in the generation of bile flow can also cause neonatal
cholestasis. Bile flow is directly dependent on effective hepatic bile acid
excretion by the hepatocytes. During the phase of relatively inefficient bile acid
transport and metabolism by the liver cell in early life, minor degrees of hepatic
injury can further decrease bile flow and lead to production of atypical and
potentially toxic bile acids. Selective impairment of a single step in the series of
events involved in hepatic excretion produces the full expression of a cholestatic
syndrome. Specific defects in bile acid synthesis are found in infants with
various forms of intrahepatic cholestasis (Table 383.1 ). Severe forms of familial
cholestasis are associated with neonatal hemochromatosis, an alloimmune-
mediated gestational (maternal antibodies against fetal hepatocytes) disease
responsive to maternal intravenous immunoglobulin. Sepsis is known to cause
cholestasis, presumably mediated by an endotoxin produced by Escherichia coli.

Table 383.1
Proposed Subtypes of Intrahepatic Cholestasis
A. Disorders of membrane transport and secretion
1. Disorders of canalicular secretion
a. Bile acid transport: BSEP deficiency
i. Persistent, progressive (PFIC type 2)
ii. Recurrent, benign (BRIC type 2)
b. Phospholipid transport: MDR3 deficiency (PFIC type 3)
c. Ion transport: cystic fibrosis (CFTR)
d. Tight junction defect (TJP2 deficiency)
2. Complex or multiorgan disorders
a. FIC1 deficiency
i. Persistent, progressive (PFIC type 1, Byler disease)
ii. Recurrent, benign (BRIC type 1)
b. Neonatal sclerosing cholangitis (CLDN1)
c. Arthrogryposis-renal dysfunction-cholestasis syndrome (VPS33B)
B. Disorders of bile acid biosynthesis, conjugation and regulation
1. Δ4 -3-Oxosteroid-5β- reductase deficiency
2. 3β- hydroxy-5-C27-steroid dehydrogenase/isomerase deficiency
3. Oxysterol 7α- hydroxylase deficiency
4. Bile acid-CoA Ligase deficiency
5. BAAT deficiency (familial hypercholanemia)
6. Farnesoid X receptor (FXR) deficiency.
C. Disorders of embryogenesis
1. Alagille syndrome (Jagged1 defect, syndromic bile duct paucity)
 2. Ductal plate malformation (ARPKD, ADPLD, Caroli disease)
D. Unclassified (idiopathic “neonatal hepatitis”): mechanism unknown
Note: FIC1 deficiency, BSEP deficiency, and some of the disorders of bile acid biosynthesis are
characterized clinically by low levels of serum GGT despite the presence of cholestasis. In all
other disorders listed, the serum GGT level is elevated.
ADPLD, autosomal dominant polycystic liver disease (cysts in liver only); ARPKD, autosomal
recessive polycystic kidney disease (cysts in liver and kidney); BAAT, bile acid transporter; BRIC,
benign recurrent intrahepatic cholestasis; BSEP, bile salt export pump in; GGT, γ-glutamyl
transpeptidase; PFIC, progressive familial intrahepatic cholestasis.
From Balistreri WF, Bezerra JA, Jansen P, et al: Intrahepatic cholestasis: summary of an
American Association for the study of liver diseases single-topic conference, Hepatology
42(1):222–235, 2005.

Evaluation
Identification of cholestasis warrants a prompt effort to accurately diagnose the
cause (Table 383.2 ). Although cholestasis in the neonate may be the initial
manifestation of numerous and potentially serious disorders, the clinical
manifestations are usually similar and provide few clues about the etiology.
Affected infants have icterus, dark urine, light or acholic stools, and
hepatomegaly, all resulting from decreased bile flow as a result of either
hepatocyte injury or bile duct obstruction. Hepatic synthetic dysfunction can
lead to hypoprothrombinemia and bleeding. Administration of vitamin K should
be included in the initial treatment of cholestatic infants to prevent hemorrhage
(intracranial).

Table 383.2

Value of Specific Tests in the Evaluation of Patients With Suspected Neonatal

Cholestasis
TEST RATIONALE
Serum bilirubin fractionation (i.e., assessment of Indicates cholestasis
the serum level of conjugated bilirubin)
Assessment of stool color (does the baby have Indicates bile flow into intestine
pigmented or acholic stools?)
Urine and serum bile acid measurement Confirms cholestasis; low level indicates inborn error of bile
acid biosynthesis
Hepatic synthetic function (albumin, coagulation Indicates severity of hepatic dysfunction
profile)
α1 -Antitrypsin phenotype Suggests (or excludes) protease inhibitor ZZ phenotype
Thyroxine and thyroid-stimulating hormone Suggests (or excludes) endocrinopathy
Lysosomal acid lipase enzyme activity Suggests (or excludes) lysosomal acid lipase deficiency
Sweat chloride and mutation analysis Suggests (or excludes) cystic fibrosis
Urine and serum amino acids and urine reducing Suggests (or excludes) metabolic liver disease
substances
Ultrasonography Suggests (or excludes) choledochal cyst; might detect the
triangular cord sign, suggesting biliary atresia
Liver biopsy Distinguishes biliary atresia; suggests alternative diagnosis

In contrast to unconjugated hyperbilirubinemia, which can be physiologic,

cholestasis (conjugated bilirubin elevation of any degree) in the neonate is
always pathologic and prompt differentiation of the cause is imperative. The top
priority is to recognize conditions that cause cholestasis and for which specific
therapy is available to prevent further damage and avoid long-term
complications such as sepsis, an endocrinopathy (hypothyroidism,
panhypopituitarism), nutritional hepatotoxicity caused by a specific metabolic
illness (galactosemia), or other metabolic diseases (tyrosinemia).
Another potential treatable metabolic disease, lysosomal acid lipase
deficiency (LAL-D), is a rare autosomal recessive lysosomal storage disease
which results in a mutation in the lysosomal acid lipase (LIPA) gene. The
mutation creates a decline in the LAL activity, resulting in accumulation of
cholesteryl esters and, to a lesser degree, triglycerides in multiple organs,
including the liver, spleen, adrenal glands, lymph nodes, intestinal mucosa,
vascular endothelium, and skeletal muscle. Clinically, the disease can present in
2 major phenotypes: infantile-onset Wolman disease (WD) and later-onset
cholesterol ester storage disease (CESD). LAL-D usually presents in infants with
an acute-severe course progressing to liver failure. Sebelipase Alfa (recombinant
human LAL enzyme) is approved for the treatment of patients with LAL-D.
Hepatobiliary disease can be the initial manifestation of homozygous α1 -
antitrypsin deficiency or of cystic fibrosis. Neonatal liver disease can also be
associated with congenital syphilis and specific viral infections, notably
echovirus and herpes viruses including cytomegalovirus. These account for a
small percentage of cases of neonatal hepatitis syndrome. The hepatitis viruses
(A, B, C) rarely cause neonatal cholestasis.
Mitochondrial disorders may present with acute neonatal hepatic failure, or
cholestasis; prominent among these disorders are respiratory chain defects and
mitochondrial DNA depletion syndromes (Table 383.3 ).

Table 383.3
Phenotypic Classification of Primary Mitochondrial
Hepatopathies
 RC (electron transport) defects (OXPHOS)
• Neonatal liver failure
• Complex I deficiency
• Complex IV deficiency (SCO1 mutations)
• Complex III deficiency (BCS1L mutations)
• Co-enzyme Q deficiency
• Multiple complex deficiencies (transfer and elongation factor mutations)
• mtDNA depletion syndrome (DUGOK , MPV17 , POLG , SUCLG1 , C10orf2/Twinkle mutations)
• Later-onset liver dysfunction or failure
• Alpers-Huttenlocher disease (POLG mutations)
• Pearson's marrow pancreas syndrome (mtDNA deletion)
• Mitochondrial neurogastrointestinal encephalopathy (TYMP mutations)
• NNH (MPV17 mutations)
Fatty acid oxidation defects
• Long-chain 3 hydroxyacyl-coenzyme A dehydrogenase
• Carnitine palmitoyltransferase I and II deficiencies
• Carnitine-acylcarnitinetranslocase deficiency
Urea cycle enzyme deficiencies
Electron transfer flavoprotein and electron transfer flavoprotein dehydrogenase deficiencies
Phosphoenol pyruvate carboxykinase (mitochondrial) deficiency; nonketotic hyperglycemia
Citrin deficiency; neonatal intrahepatic cholestasis caused by citrin deficiency (SLC25A13 mutations)
NN, Navajo neurohepatopathy; OXPHOS, oxidative phosphorylation; RC, respiratory chain.
From Lee WS, Sokol RJ: Mitochondrial hepatopathies: advances in genetics, therapeutic
approaches, and outcomes, J Pediatr 163[4]:942–948, 2013, Table 1, p. 943.

The final and critical step in evaluating neonates with cholestasis is to

differentiate extrahepatic biliary atresia from neonatal hepatitis.

Intrahepatic Cholestasis
Neonatal Hepatitis
The term neonatal hepatitis implies intrahepatic cholestasis (see Fig. 383.1 ),
which has various forms (see Tables 383.1 and 383.4 ).

Table 383.4
Molecular Defects Causing Liver Disease

GENE PROTEIN FUNCTION, SUBSTRATE DISORDER

ATP8B1 FIC1 P-type ATPase; aminophospholipid translocase that flips PFIC 1 (Byler
phosphatidylserine and phosphatidylethanolamine from the outer to disease), BRIC
the inner layer of the canalicular membrane 1, GFC
ABCB11 BSEP Canalicular protein with ATP-binding cassette (ABC family of PFIC 2, BRIC 2
proteins); works as a pump transporting bile acids through the
canalicular domain
ABCB4 MDR3 Canalicular protein with ATP-binding cassette (ABC family of PFIC 3, ICP,
 proteins); works as a phospholipid flippase in canalicular membrane cholelithiasis
AKR1D1 5β- Δ4 -3-Oxosteroid 5β-reductase gene; regulates bile acid synthesis BAS: neonatal
Reductase cholestasis with
giant cell
hepatitis
HSD3B7 C27-3β- 3β-Hydroxy-5-C27-steroid oxido-reductase (C27-3β-HSD) gene; BAS: chronic
HSD regulates bile acid synthesis intrahepatic
cholestasis
CYP7BI CYP7BI Oxysterol 7α-hydroxylase; regulates the acidic pathway of bile acid BAS: neonatal
synthesis cholestasis with
giant cell
hepatitis
JAG1 JAG1 Transmembrane, cell-surface proteins that interact with Notch Alagille
receptors to regulate cell fate during embryogenesis syndrome
TJP2 Tight Belongs to the family of membrane-associated guanylate kinase Intrahepatic
junction homologs that are involved in the organization of epithelial and cholestasis
protein endothelial intercellular junction; regulates paracellular permeability
NR1H4 Nuclear Farnesoid X receptor (FXR), a nuclear hormone receptor that Intrahepatic
hormone regulates bile acid metabolism cholestasis
receptor
BAAT BAAT Enzyme that transfers the bile acid moiety from the acyl coenzyme A FHC
thioester to either glycine or taurine
EPHX1 Epoxide Microsomal epoxide hydrolase regulates the activation and FHC
hydrolase detoxification of exogenous chemicals
ABCC2 MRP2 Canalicular protein with ATP-binding cassette (ABC family of Dubin-Johnson
proteins); regulates canalicular transport of GSH conjugates and syndrome
arsenic
ATP7B ATP7B P-type ATPase; function as copper export pump Wilson disease
CLDN1 Claudin 1 Tight junction protein NSC
CIRH1A Cirhin Cell signaling? NAICC
CFTR CFTR Chloride channel with ATP-binding cassette (ABC family of Cystic fibrosis
proteins); regulates chloride transport
PKHD1 Fibrocystin Protein involved in ciliary function and tubulogenesis ARPKD
PRKCSH Hepatocystin Assembles with glucosidase II α subunit in endoplasmic reticulum ADPLD
VPS33B Vascular Regulates fusion of proteins to cellular membrane ARC
protein
sorting 33
* Low GGT (PFIC types 1 and 2, BRIC types 1 and 2, ARC).

ADPLD, autosomal dominant polycystic liver disease; ARC, arthrogryposis–renal dysfunction–

cholestasis syndrome* ; ARPKD, autosomal recessive polycystic kidney disease; ATP, adenosine
triphosphate; BAAT, bile acid transporter; BAS, bile acid synthetic defect; BRIC, benign recurrent
intrahepatic cholestasis; BSEP, bile salt export pump; CFTR, cystic fibrosis transmembrane
conductance regulator; FHC, familial hypercholanemia; GFC, Greenland familial cholestasis;
GSH, glutathione; ICP, intrahepatic cholestasis of pregnancy; NAICC, North American Indian
childhood cirrhosis; NSC, neonatal sclerosing cholangitis with ichthyosis, leukocyte vacuoles, and
alopecia; PFIC, progressive familial intrahepatic cholestasis.*
From Balistreri WF, Bezerra JA, Jansen P, et al: Intrahepatic cholestasis: summary of an
American Association for the study of liver diseases single-topic conference, Hepatology
42(1):222–235, 2005.

Idiopathic neonatal hepatitis, which can occur in either a sporadic or

have normal serum cholesterol and GGT levels.

Table 383.5
Progressive Familial Intrahepatic Cholestasis

PFIC1 PFIC2 PFIC3

Transmission Autosomal recessive Autosomal recessive Autosomal recessive
Chromosome 18q21-22 2q24 7q21
Gene ATP8B1/F1C1 ABCB11/BSEP ABCB4/MDR3
Protein FIC1 BSEP MDR3
Location Hepatocyte, colon, intestine, Hepatocyte canalicular Hepatocyte canalicular membrane
pancreas; on apical membranes membrane
Function ATP-dependent ATP-dependent bile acid ATP-dependent phosphatidylcholine
aminophospholipid flippase; transport translocation
unknown effects on intracellular
signaling
Phenotype Progressive cholestasis, diarrhea, Rapidly progressive Later-onset cholestasis, portal
steatorrhea, growth failure, severe cholestatic giant cell hypertension, minimal pruritus,
pruritus hepatitis, growth failure, intraductal and gallbladder lithiasis
pruritus
Histology Initial bland cholestatic; coarse, Neonatal giant cell Proliferation of bile ductules,
granular canalicular bile on EM hepatitis, amorphous periportal fibrosis, eventually
canalicular bile on EM biliary cirrhosis
Biochemical Normal serum γGT; high serum, Normal serum γGT; high Elevated serum γGT; low to absent
features low biliary bile acid serum, low biliary bile biliary PC; absent serum LPX;
concentrations acid concentrations normal biliary bile acid
concentrations
Treatment Biliary diversion, ileal exclusion, Biliary diversion, liver UDCA if residual PC secretion;
liver transplantation, but post- transplantation liver transplantation
OLT diarrhea, steatorrhea, fatty
liver
ATP, adenosine triphosphate; BCEP, B-cell epitope peptide; BSEP, bile salt export pump; EM,
electron microscopy; γGT, γ-glutamyl transpeptidase; LPX, lipoprotein X; OLT, orthotopic liver
transplantation; PC, phosphatidylcholine; PFIC, progressive familial intrahepatic cholestasis;
UDCA, ursodeoxycholic acid.
From Suchy FJ, Sokol RJ, Balistreri WF, editors: Liver disease in children , ed 4, New York, 2014,
Cambridge University Press.

PFIC type 2 (BSEP deficiency) is mapped to chromosome 2q24 and is similar

to PFIC 1. The disease results from defects in the canalicular adenosine
triphosphate -dependent bile acid transporter BSEP (ABCB11). The progressive
liver disease results from accumulation of bile acids secondary to reduction in
canalicular bile acid secretion. Mutation in ABC11 is also described in another
disorder, BRIC type 2, characterized by recurrent bouts of cholestasis.
In contrast to PFIC I and PFIC 2, patients with PFIC type 3 (MDR3 disease)
have high levels of GGT. The disease results from defects in a canalicular
for the notch receptor, are linked to ~90% of patients with Alagille syndrome.
Alagille syndrome type 2 is due to mutations in NOTCH2. Although cirrhosis
and manifestations of end-stage liver disease are uncommon early in life, some
patients may later develop these complications. Long-term care includes
monitoring cardiac and renal function as well as screening for the development
of hepatocellular carcinoma.

Table 383.6

Classic Criteria, Based on 5 Body Systems for a Diagnosis of Alagille Syndrome

SYSTEM/PROBLEM DESCRIPTION
Liver/cholestasis Usually presenting as jaundice with conjugated hyperbilirubinemia in the neonatal
period, often with pale stools
Dysmorphic facies Broad forehead, deep-set eyes, sometimes with upslanting palpebral fissures, prominent
ears, straight nose with bulbous tip, and pointed chin giving the face a somewhat
triangular appearance
Congenital heart Most frequently peripheral pulmonary artery stenosis, but also pulmonary atresia, atrial
disease septal defect, ventricular septal defect, and tetralogy of Fallot
Axial “Butterfly” vertebrae may be seen on an antero-posterior radiograph, and occasionally
skeleton/vertebral hemivertebrae, fusion of adjacent vertebrae, and spina bifida occulta
anomalies
Eye/posterior Anterior chamber defects, most commonly posterior embryotoxon, which is prominence
embryotoxon of Schwalbe's ring at the junction of the iris and cornea
From Turnpenny PD, Ellard S: Alagille syndrome: pathogenesis, diagnosis and management, Eur
J Hum Genet 20(3):251–257, 2012, Table 1, p. 252.

FIG. 383.2 Posterior embryotoxon. (From Turnpenny PD, Ellard S: Alagille
syndrome: pathogenesis, diagnosis and management, Eur J Hum Genet
damage and cirrhosis. Growth failure is a major concern and is related in part to
malabsorption and malnutrition resulting from ineffective digestion and
absorption of dietary fat. Use of a medium-chain triglyceride-containing formula
can improve caloric balance. With chronic cholestasis and prolonged survival,
children with hepatobiliary disease can experience deficiencies of the fat-soluble
vitamins (A, D, E, and K). Metabolic bone disease is common. It is essential to
monitor the fat-soluble vitamin status in patients.

Table 383.7
Suggested Medical Management of Persistent Cholestasis

CLINICAL IMPAIRMENT MANAGEMENT

Malnutrition resulting from malabsorption of dietary Replace with dietary formula or supplements
long-chain triglycerides containing medium-chain triglycerides
Fat-soluble vitamin malabsorption
Vitamin A deficiency (night blindness, thick skin) Replace with 10,000-15,000 IU/day as Aquasol A
Vitamin E deficiency (neuromuscular degeneration) Replace with 50-400 IU/day as oral α-tocopherol or
TPaGS
Vitamin D deficiency (metabolic bone disease) Replace with 5,000-8,000 IU/day of D2 or 3-5
µg/kg/day of 25-hydroxycholecalciferol
Vitamin K deficiency (hypoprothrombinemia) Replace with 2.5-5.0 mg every other day as water-
soluble derivative of menadione
Micronutrient deficiency Calcium, phosphate, or zinc supplementation
Deficiency of water-soluble vitamins Supplement with twice the recommended daily
allowance
Retention of biliary constituents such as cholesterol (itch Administer choleretic bile acids (ursodeoxycholic acid,
or xanthomas) 15-30 mg/kg/day)
Progressive liver disease; portal hypertension (variceal Interim management (control bleeding; salt restriction;
bleeding, ascites, hypersplenism) spironolactone)
End-stage liver disease (liver failure) Transplantation
TPGS , D-α-tocopherol polyethylene glycol 1000 succinate.

A degenerative neuromuscular syndrome is found in patients with chronic

cholestasis, caused by vitamin E deficiency; affected children experience
progressive areflexia, cerebellar ataxia, ophthalmoplegia, and decreased
vibratory sensation. Specific morphologic lesions were found in the central
nervous system, peripheral nerves, and muscles. These lesions are preventable
and are not commonly seen today; they were potentially reversible in children
younger than 3-4 yr of age. Affected children have low serum vitamin E
concentrations, increased hydrogen peroxide hemolysis, and low ratios of serum
vitamin E to total serum lipids (<0.6 mg/g for children younger than 12 yr and
<0.8 mg/g for older patients). Vitamin E deficiency may be prevented by oral
administration of large doses (up to 1,000 IU/day); patients unable to absorb
CHAPTER 384

Metabolic Diseases of the Liver

Anna L. Peters, William F. Balistreri

Metabolic liver diseases in children, although individually rare, altogether

represent a significant cause of morbidity and mortality. This is because the liver
has a central role in synthetic, degradative, and regulatory pathways involving
carbohydrate, protein, lipid, trace element, and vitamin metabolism. Therefore,
inborn errors of metabolism will result in metabolic abnormalities, specific
enzyme deficiencies or defects, and disorders of protein transport that can have
primary or secondary effects on the liver (Table 384.1 ). Liver disease can arise
when absence of an enzyme produces a block in a metabolic pathway, when
unmetabolized substrate accumulates proximal to a block, when deficiency of an
essential substance produced distal to an aberrant chemical reaction develops, or
when synthesis of an abnormal metabolite occurs. The spectrum of pathologic
changes includes hepatocyte injury, with subsequent failure of other metabolic
functions, often resulting in cirrhosis and/or liver cancer; abnormal storage of
lipid, glycogen, or other products manifested as hepatomegaly, often with
complications specific to deranged metabolism (hypoglycemia with glycogen
storage disease); and absence of structural change despite profound metabolic
effects, as seen in patients with urea cycle defects. Clinical manifestations of
metabolic diseases of the liver mimic infections, intoxications, and hematologic
and immunologic diseases (Table 384.2 ).

Table 384.1
Inborn Errors of Metabolism That Affect the Liver
DISORDERS OF CARBOHYDRATE METABOLISM
• Disorders of galactose metabolism
• Galactosemia (galactose-1-phosphate uridyltransferase deficiency)
• Disorders of fructose metabolism
 • Hereditary fructose intolerance (aldolase deficiency)
• Fructose-1,6 diphosphatase deficiency
• Glycogen storage diseases
• Type I
• Von Gierke Ia (glucose-6-phosphatase deficiency)
• Type Ib (glucose-6-phosphatase transport defect)
• Type III Cori/Forbes (glycogen debrancher deficiency)
• Type IV Andersen (glycogen branching enzyme deficiency)
• Type VI Hers (liver phosphorylase deficiency)
• Congenital disorders of glycosylation (multiple subtypes)
DISORDERS OF AMINO ACID AND PROTEIN METABOLISM
• Disorders of tyrosine metabolism
• Hereditary tyrosinemia type I (fumarylacetoacetate deficiency)
• Tyrosinemia, type II (tyrosine aminotransferase deficiency)
• Inherited urea cycle enzyme defects
• CPS deficiency (carbamoyl phosphate synthetase I deficiency)
• OTC deficiency (ornithine transcarbamoylase deficiency)
• Citrullinemia type I (argininosuccinate synthetase deficiency)
• Argininosuccinic aciduria (argininosuccinate deficiency)
• Argininemia (arginase deficiency)
• N-AGS deficiency (N -acetylglutamate synthetase deficiency)
• Maple serum urine disease (multiple possible defects* )
DISORDERS OF LIPID METABOLISM
• Wolman disease (lysosomal acid lipase deficiency)
• Cholesteryl ester storage disease (lysosomal acid lipase deficiency)
• Homozygous familial hypercholesterolemia (low-density lipoprotein receptor deficiency)
• Gaucher disease type I (β-glucocerebrosidase deficiency)
• Niemann-Pick type C (NPC 1 and 2 mutations)
DISORDERS OF BILE ACID METABOLISM
• Defects in bile acid synthesis (several specific enzyme deficiencies)
• Zellweger syndrome—cerebrohepatorenal (multiple mutations in peroxisome biogenesis genes)
DISORDERS OF METAL METABOLISM
• Wilson disease (ATP7B mutations)
• Hepatic copper overload
• Indian childhood cirrhosis
• Neonatal iron storage disease
DISORDERS OF BILIRUBIN METABOLISM
• Crigler-Najjar (bilirubin-uridine diphosphoglucuronate glucuronosyltransferase mutations)
• Type I
• Type II
• Gilbert disease (bilirubin-uridine diphosphoglucuronate glucuronosyltransferase polymorphism)
• Dubin-Johnson syndrome (multiple drug-resistant protein 2 mutation)
• Rotor syndrome
MISCELLANEOUS
• α1 -Antitrypsin deficiency
• Citrullinemia type II (citrin deficiency)
• Cystic fibrosis (cystic fibrosis transmembrane conductance regulator mutations)
• Erythropoietic protoporphyria (ferrochelatase deficiency)
• Polycystic kidney disease
• Mitochondrial hepatopathies (see Table 383.3 and Chapter 388 )
* Maple syrup urine disease can be caused by mutations in branched-chain α-keto
dehydrogenase, keto acid decarboxylase, lipoamide dehydrogenase, or dihydrolipoamide
dehydrogenase.
Table 384.2
Clinical Manifestations That Suggest the Possibility of
Metabolic Disease
Recurrent vomiting, failure to thrive, short stature
Dysmorphic features
Jaundice, hepatomegaly (±splenomegaly), fulminant hepatic failure, edema/anasarca
Hypoglycemia, organic acidemia, lactic acidemia, hyperammonemia, bleeding (coagulopathy)
Developmental delay/psychomotor retardation, hypotonia, progressive neuromuscular deterioration, seizures,
myopathy, neuropathy
Cardiac dysfunction/failure
Unusual odors
Rickets
Cataracts

Many metabolic diseases are detected in expanded newborn metabolic

screening programs (see Chapter 102 ). Clues are provided by family history of a
similar illness or by the observation that the onset of symptoms is closely
associated with a change in dietary habits; in patients with hereditary fructose
intolerance, symptoms follow ingestion of fructose (sucrose). Clinical and
laboratory evidence often guides the evaluation. Liver biopsy offers morphologic
study and permits enzyme assays, as well as quantitative and qualitative assays
of various other constituents (e.g., hepatic copper content in Wilson disease).
Genetic/molecular diagnostic approaches are also available. Such studies require
cooperation of experienced laboratories and careful attention to collection and
handling of specimens. Treatment depends on the specific type of defect and
although relatively uncommon, altogether metabolic diseases of the liver account
for up to 10% of the indications for liver transplantation in children, a number
that may be underestimated given the acute nature of some of these conditions,
precluding complete diagnostic investigation prior to transplantation.

384.1
Inherited Deficient Conjugation of
Bilirubin (Familial Nonhemolytic
Unconjugated Hyperbilirubinemia)
CHAPTER 385

Viral Hepatitis
M. Kyle Jensen, William F. Balistreri

Viral hepatitis continues to be a major health problem in both developing and

developed countries; there has been significant progress in efforts to recognize
and to treat infected subjects. This disorder is caused by the 5 pathogenic
hepatotropic viruses recognized to date: hepatitides A (HAV), B (HBV), C
(HCV), D (HDV), and E (HEV) viruses (Table 385.1 ). Many other viruses (and
diseases) can cause hepatitis, usually as a component of a multisystem disease.
These include herpes simplex virus, cytomegalovirus, Epstein-Barr virus,
varicella-zoster virus, HIV, rubella, adenoviruses, enteroviruses, parvovirus B19,
and arboviruses (Table 385.2 ).

Table 385.1
Features of the Hepatotropic Viruses

VIROLOGY HAV RNA HBV DNA HCV RNA HDV RNA HEV RNA
Incubation (days) 15-19 60-180 14-160 21-42 21-63
Transmission
• Parenteral Rare Yes Yes Yes No
• Fecal–oral Yes No No No Yes
• Sexual No Yes Rare Yes No
• Perinatal No Yes Uncommon (5–15%) Yes No
Chronic infection No Yes Yes Yes No
Fulminant disease Rare Yes Rare Yes Yes
HAV, hepatitis A virus; HBV, hepatitis B virus; HCV, hepatitis C virus; HDV, hepatitis D virus; HEV,
hepatitis E virus.

Table 385.2
Causes and Differential Diagnosis of Hepatitis in Children
INFECTIOUS
Hepatotropic viruses
• Hepatitis A virus (HAV)
• Hepatitis B virus (HBV)
• Hepatitis C virus (HCV)
• Hepatitis D virus (HDV)
• Hepatitis E virus (HEV)
• Hepatitis non–A-E viruses
Systemic infection that can include hepatitis
• Adenovirus
• Arbovirus
• Coxsackievirus
• Cytomegalovirus
• Enterovirus
• Epstein-Barr virus
• “Exotic” viruses (e.g., yellow fever)
• Herpes simplex virus
• HIV
• Paramyxovirus
• Rubella
• Varicella zoster
Other
NONVIRAL LIVER INFECTIONS
Abscess
Amebiasis
Bacterial sepsis
Brucellosis
Fitz-Hugh-Curtis syndrome
Histoplasmosis
Leptospirosis
Tuberculosis
Other
AUTOIMMUNE
Autoimmune hepatitis
Sclerosing cholangitis
Other (e.g., systemic lupus erythematosus, juvenile inflammatory arthritis)
METABOLIC
α1 -Antitrypsin deficiency
Tyrosinemia
Wilson disease
Other
TOXIC
Iatrogenic or drug induced (e.g., acetaminophen)
Environmental (e.g., pesticides)
ANATOMIC
Choledochal cyst
Biliary atresia
Other
HEMODYNAMIC
Shock
Congestive heart failure
Budd-Chiari syndrome
Other
NONALCOHOLIC FATTY LIVER DISEASE
Idiopathic
 Reye syndrome
Other
From Wyllie R, Hyams JS, editors: Pediatric gastrointestinal and liver disease , ed 3, Philadelphia,
2006, WB Saunders.

The hepatotropic viruses are a heterogeneous group of infectious agents that

cause similar acute clinical illness. In most pediatric patients, the acute phase
causes no or mild clinical disease. Morbidity is related to rare cases of acute
liver failure (ALF) in susceptible patients, or to the development of a chronic
disease state and attendant complications that several of these viruses
(hepatitides B, C, and D) commonly cause.

Issues Common to All Forms of Viral

Hepatitis
Differential Diagnosis
Often what brings the patient with hepatitis to medical attention is clinical
icterus, with yellow skin and/or mucous membranes. The liver is usually
enlarged and tender to palpation and percussion. Splenomegaly and
lymphadenopathy may be present. Extrahepatic symptoms (rashes, arthritis) are
more commonly seen in HBV and HCV infections. Clinical signs of bleeding,
altered sensorium, or hyperreflexia should be carefully sought, because they
mark the onset of encephalopathy and ALF.
The differential diagnosis varies with age of presentation. In the newborn
period, infection is a common cause of conjugated hyperbilirubinemia; the
infectious cause is either a bacterial agent (e.g., Escherichia coli , Listeria,
syphilis) or a nonhepatotropic virus (e.g., enteroviruses, cytomegalovirus, and
herpes simplex virus, which may also cause a nonicteric severe hepatitis).
Metabolic diseases (α1 -antitrypsin deficiency, cystic fibrosis, tyrosinemia),
anatomic causes (biliary atresia, choledochal cysts), and inherited forms of
intrahepatic cholestasis should always be excluded.
In later childhood, extrahepatic obstruction (gallstones, primary sclerosing
cholangitis, pancreatic pathology), inflammatory conditions (autoimmune
hepatitis, juvenile inflammatory arthritis, Kawasaki disease), immune
dysregulation (hemophagocytic lymphohistiocytosis), infiltrative disorders
(malignancies), toxins and medications, metabolic disorders (Wilson disease,
cystic fibrosis), and infection (Epstein-Barr virus, varicella, malaria,

FIG. 385.1 The serologic course of acute hepatitis A. ALT, alanine aminotransferase;
HAV, hepatitis A virus; IgM, immunoglobulin class M. (From Goldman L, Ausiello D:
Cecil textbook of medicine, ed 22, Philadelphia, 2004, WB Saunders, p 913.)

Other organ systems can be affected during acute HAV infection. Regional
lymph nodes and the spleen may be enlarged. The bone marrow may be
moderately hypoplastic, and aplastic anemia has been reported. Tissue in the
small intestine might show changes in villous structure, and ulceration of the
gastrointestinal tract can occur, especially in fatal cases. Acute pancreatitis and
myocarditis have been reported, though rarely, and nephritis, arthritis,
leukocytoclastic vasculitis, and cryoglobulinemia can result from circulating
immune complexes.

Diagnosis
Acute HAV infection is diagnosed by detecting antibodies to HAV, specifically,
anti-HAV (immunoglobulin [Ig] M) by radioimmunoassay or, rarely, by
identifying viral particles in stool. A viral polymerase chain reaction (PCR)
assay is available for research use (Table 385.3 ). Anti-HAV is detectable when
the symptoms are clinically apparent, and it remains positive for 4-6 mo after the
acute infection. A neutralizing anti-HAV (IgG) is usually detected within 8 wk of
symptom onset and is measured as part of a total anti-HAV in the serum. Anti-
HAV (IgG) confers long-term protection. Rises in serum levels of ALT, AST,
bilirubin, alkaline phosphatase, 5′-nucleotidase, and γ-glutamyl transpeptidase
are almost universally found and do not help to differentiate the cause of
hepatitis.

Table 385.3
Diagnostic Blood Tests: Serology and Viral Polymerase
Chain Reaction
HAV HBV HCV HDV HEV
ACUTE/ACTIVE INFECTION
Anti-HAV IgM (+) Anti-HBc IgM (+) Anti-HCV (+) Anti-HDV IgM (+) Anti-HEV IgM (+)
Blood PCR HBsAg (+) HCV RNA (+) Blood PCR Blood PCR positive*
positive* Anti-HBs (−) (PCR) positive
HBV DNA (+) HBsAg (+)
(PCR) Anti-HBs (−)
PAST INFECTION (RECOVERED)
Anti-HAV IgG(+) Anti-HBs (+) Anti-HCV (+) Anti-HDV IgG Anti-HEV IgG
Anti-HBc IgG (+) † Blood PCR (−) (+) (+)
Blood PCR (−) Blood PCR (−)
CHRONIC INFECTION
N/A Anti-HBc IgG (+) Anti-HCV (+) Anti-HDV IgG N/A
HBsAg (+) Blood PCR (+) (+)
Anti-HBs (−) Blood PCR (−)
PCR (+) or (−) HBsAg (+)
Anti-HBs (−)
VACCINE RESPONSE
Anti-HAV IgG (+) Anti-HBs (+) N/A N/A N/A
Anti-HBc (−)
* Research tool.

† Still poses a risk for reactivation.

HAV, hepatitis A virus; HBs, hepatitis B surface; HBsAg, hepatitis B surface antigen; Ig,
immunoglobulin; PCR, polymerase chain reaction.

Complications
Although most patients achieve full recovery, distinct complications can occur.
ALF from HAV infection is an infrequent complication of HAV. Those at risk for
this complication are adolescents and adults, but also immunocompromised
patients or those with underlying liver disorders. The height of HAV viremia
may be linked to the severity of hepatitis. In the United States, HAV represents
<0.5% of pediatric-age ALF; HAV is responsible for up to 3% mortality in the
adult population with ALF. In endemic areas of the world, HAV constitutes up to
40% of all cases of pediatric ALF. HAV can also progress to a prolonged
cholestatic syndrome that waxes and wanes over several months. Pruritus and fat
malabsorption are problematic and require symptomatic support with antipruritic
medications and fat-soluble vitamin supplementation. This syndrome occurs in
the absence of any liver synthetic dysfunction and resolves without sequelae.
Treatment
There is no specific treatment for hepatitis A. Supportive treatment consists of
intravenous hydration as needed, and antipruritic agents and fat-soluble vitamins
for the prolonged cholestatic form of disease. Serial monitoring for signs of ALF
is prudent and, if ALF is diagnosed, a prompt referral to a transplantation center
can be lifesaving.

Prevention
Patients infected with HAV are contagious for 2 wk before and approximately 7
days after the onset of jaundice and should be excluded from school, childcare,
or work during this period. Careful hand-washing is necessary, particularly after
changing diapers and before preparing or serving food. In hospital settings,
contact and standard precautions are recommended for 1 wk after onset of
symptoms.

Immunoglobulin
Indications for intramuscular administration of Ig include preexposure and
postexposure prophylaxis (Table 385.4 ). Ig is recommended for preexposure
prophylaxis for susceptible travelers to countries where HAV is endemic, and it
provides effective protection for up to 2 mo. HAV vaccine given any time before
travel is preferred for preexposure prophylaxis in healthy persons, but Ig ensures
an appropriate prophylaxis in children younger than 12 mo old, patients allergic
to a vaccine component, or those who elect not to receive the vaccine. If travel is
planned in <2 wk, older patients, immunocompromised hosts, and those with
chronic liver disease or other medical conditions should receive both Ig and the
HAV vaccine.

Table 385.4
Indications and Updated Dosage Recommendations for
GamaSTAN S/D Human Immune Globulin for Preexposure
and Postexposure Prophylaxis Against Hepatitis A
Infection

INDICATION UPDATED DOSAGE RECOMMENDATION

Preexposure prophylaxis
 Up to 1 mo of travel 0.1 mL/kg
Up to 2 mo of travel 0.2 mL/kg
2 mo of travel or longer 0.2 mL/kg (repeat every 2 mo)
Postexposure prophylaxis 0.1 mL/kg
From Nelson NP: Updated dosing instruction for immune globulin (human) gamaSTAN S/D for
hepatitis A virus prophylaxis, MMWR 66(36):959–960, 2017, Table, p. 959.

Ig prophylaxis in postexposure situations should be used as soon as possible

(it is not effective if administered more than 2 wk after exposure). It is
exclusively used for children younger than 12 mo old, immunocompromised
hosts, those with chronic liver disease or in whom vaccine is contraindicated. Ig
is preferred in patients older than 40 yr of age, with HAV vaccine preferred in
healthy persons 12 mo to 40 yr old. An alternative approach is to immunize
previously unvaccinated patients who are 12 mo old or older with the age-
appropriate vaccine dosage as soon as possible. Ig is not routinely recommended
for sporadic nonhousehold exposure (e.g., protection of hospital personnel or
schoolmates). The vaccine has several advantages over Ig, including long-term
protection, availability, and ease of administration, with cost similar to, or less
than, that of Ig.

Vaccine
The availability of 2 inactivated, highly immunogenic, and safe HAV vaccines
has had a major impact on the prevention of HAV infection. Both vaccines are
approved for children older than 12 mo. They are administered intramuscularly
in a 2-dose schedule, with the second dose given 6-12 mo after the first dose.
Seroconversion rates in children exceed 90% after an initial dose and approach
100% after the second dose; protective antibody titer persists for longer than 10
yr in most patients. The immune response in immunocompromised persons,
older patients, and those with chronic illnesses may be suboptimal; in those
patients, combining the vaccine with Ig for pre- and postexposure prophylaxis is
indicated. HAV vaccine may be administered simultaneously with other
vaccines. A combination HAV and HBV vaccine is approved in adults older than
age 18 yr. For healthy persons at least 12 mo old, vaccine is preferable to Ig for
preexposure and postexposure prophylaxis (see Table 385.3 ).
In the United States and some other countries, universal vaccination is now
recommended for all children older than 12 mo. Nevertheless, studies show
<50% of U.S. adolescents have received even a single dose of the vaccine, and
<30% have received the complete vaccine series. The vaccine is effective in
curbing outbreaks of HAV because of rapid seroconversion and the long
understood. To permit hepatocytes to continue to be infected, the core protein or
major histocompatibility class I protein might not be recognized, the cytotoxic
lymphocytes might not be activated, or some other, yet unknown mechanism
might interfere with destruction of hepatocytes. This tolerance phenomenon
predominates in the perinatally acquired cases, resulting in a high incidence of
persistent HBV infection in children with no or little inflammation in the liver,
normal liver enzymes, and markedly elevated HBV viral load. Although end-
stage liver disease rarely develops in those patients, the inherent HCC risk is
high, possibly related, in part, to uncontrolled viral replication cycles.
ALF has been seen in infants of chronic carrier mothers who have anti-HBe or
are infected with a precore-mutant strain. This fact led to the postulate that
HBeAg exposure in utero in infants of chronic carriers likely induces tolerance
to the virus once infection occurs postnatally. In the absence of this tolerance, the
liver is massively attacked by T cells and the patient presents with ALF.
Immune-mediated mechanisms are also involved in the extrahepatic
conditions that can be associated with HBV infections. Circulating immune
complexes containing HBsAg can result in polyarteritis nodosa, membranous or
membranoproliferative glomerulonephritis, polymyalgia rheumatica,
leukocytoclastic vasculitis, and Guillain-Barré syndrome.

Clinical Manifestations
Many acute cases of HBV infection in children are asymptomatic, as evidenced
by the high carriage rate of serum markers in persons who have no history of
acute hepatitis (Table 385.5 ). The usual acute symptomatic episode is similar to
that of HAV and HCV infections but may be more severe and is more likely to
include involvement of skin and joints (Fig. 385.2 ).

Table 385.5
Typical Interpretation of Test Results for Hepatitis B Virus
Infection

TOTAL IgM
ANTI- HBV
HBsAg ANTI- ANTI- INTERPRETATION
HBs DNA
HBc HBc
− − − − − Never infected
+ − − − + or Early acute infection; transient (up to 18 days) after vaccination
−
+ + + − + Acute infection
 − + + + or − + or Acute resolving infection
−
− + − + − Recovered from past infection and immune
+ + − − + Chronic infection
− + − − + or False-positive (i.e., susceptible); past infection; “low-level” chronic
− infection; or passive transfer of anti-HBc to infant born to HBsAg-
positive mother
− − − + − Immune if anti-HBs concentration is ≥10 mIU/mL after vaccine
series completion; passive transfer after hepatitis B immune globulin
administration
−, negative; +, positive; anti-HBc, antibody to hepatitis B core antigen; anti-HBs, antibody to
hepatitis B surface antigen; HBsAg, hepatitis B surface antigen; HBV DNA, hepatitis B virus
deoxyribonucleic acid; IgM, immunoglobulin class M.
From Schillie S, Vellozzi C, Reingold A, et al: Prevention of hepatitis B virus infection in the United
States: recommendations of the advisory committee on immunization practices, MMWR 67(1):1–
29, 2018, Table 1, p. 7.

FIG. 385.2 The serologic course of acute hepatitis B. ALT, alanine aminotransferase;
HBc, hepatitis B core; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface
antigen; HBV DNA, hepatitis B virus deoxyribonucleic acid; IgM, immunoglobulin class
M; PCR, polymerase chain reaction. (From Goldman L, Ausiello D: Cecil textbook of
medicine, ed 22, Philadelphia, 2004, WB Saunders, p 914.)

The first biochemical evidence of HBV infection is elevation of serum ALT

levels, which begin to rise just before development of fatigue, anorexia, and
malaise, at approximately 6-7 wk after exposure. The illness is preceded, in a
few children, by a serum sickness–like prodrome marked by arthralgia or skin
lesions, including urticarial, purpuric, macular, or maculopapular rashes. Papular
acrodermatitis, the Gianotti-Crosti syndrome, can also occur. Other extrahepatic
conditions associated with HBV infections in children include polyarteritis
nodosa, glomerulonephritis, and aplastic anemia. Jaundice is present in
approximately 25% of acutely infected patients and usually begins
approximately 8 wk after exposure and lasts approximately 4 wk.
In the usual course of resolving HBV infection, symptoms persist for 6-8 wk.
The percentage of children in whom clinical evidence of hepatitis develops is
higher for HBV than for HAV, and the rate of ALF is also greater. Most patients
do recover, but the chronic carrier state complicates up to 10% of cases acquired
in adulthood. The rate of development of chronic infection depends largely on
the mode and age of acquisition and occurs in up to 90% of perinatally-infected
cases. Cirrhosis and HCC are only seen with chronic infection. Chronic HBV
infection has 3 identified phases: immune tolerant, immune active, and inactive.
Most children fall in the immune-tolerant phase, against which no effective
therapy has been developed. Most treatments target the immune active phase of
the disease, characterized by active inflammation, elevated ALT/AST levels, and
progressive fibrosis. Spontaneous HBeAg seroconversion, defined as the
development of anti-HBe and loss of HBeAg, occurs in the immune-tolerant
phase, albeit at low rates of 4–5% per year. It is more common in childhood-
acquired HBV rather than in perinatally transmitted infections. Seroconversion
can occur over many years, during which time significant damage to the liver
may take place. There are no large studies that accurately assess the lifetime
risks and morbidities of children with chronic HBV infection, making decisions
regarding the rationale, efficacy, and timing of still less-than-ideal treatments
difficult. Reactivation of chronic infection has been reported in
immunosuppressed children treated with chemotherapy, biologic
immunomodulators such as infliximab, or T-cell depleting agents, leading to an
increased risk of ALF or to rapidly progressing fibrotic liver disease (Table
385.6 ).

Table 385.6
Causes of Hepatitis Flares in Patients With Chronic
Hepatitis B

CAUSE OF FLARE COMMENT

Spontaneous Factors that precipitate viral replication are unclear
Immunosuppressive Flares are often observed during withdrawal of the agent; preemptive antiviral therapy is
therapy required
Antiviral therapy for
HBV
Interferon Flares are often observed during the second to third month of therapy in 30% of
Nucleoside analog patients; may herald virologic response
 During treatment Flares are no more common than with placebo
Drug-resistant HBV Severe consequences can occur in patients with advanced liver disease
On withdrawal Flares are caused by the rapid re-emergence of wild-type HBV; severe consequences can
occur in patients with advanced liver disease
HIV treatment Flares can occur as a result of the direct toxicity of HAART or with immune
reconstitution; HBV increases the risk of antiretroviral drug hepatotoxicity
Genotypic variation
Precore and core Fluctuations in serum alanine aminotransferase levels are common with precore mutants
promoter mutants
Superinfection with May be associated with suppression of HBV replication
other hepatitis viruses
HAART, Highly active antiretroviral therapy; HBV, hepatitis B virus.
From Wells JT, Perillo R: Hepatitis B. In Feldman M, Friedman LS, Brandt LJ, editors: Sleisenger
and Fordtran's gastrointestinal and liver disease , 10/e, Philadelphia, 2016, Elsevier, Table 79.1.

Diagnosis
The serologic profile of HBV infection is more complex than for HAV infection
and differs depending on whether the disease is acute or chronic (Fig. 385.3 , see
Table 385.5 ). Several antigens and antibodies are used to confirm the diagnosis
of acute HBV infection (see Table 385.3 ). Routine screening for HBV infection
requires assay of multiple serologic markers (HBsAg, anti-HBc, anti-HBs).
HBsAg is an early serologic marker of infection and is found in almost all
infected persons; its rise closely coincides with the onset of symptoms.
Persistence of HBsAg beyond 6 mo defines the chronic infection state. During
recovery from acute infection, because HBsAg levels fall before symptoms
wane, IgM antibody to HBcAg (anti-HBc IgM) might be the only marker of
acute infection. Anti-HBc IgM rises early after the infection and remains
positive for many months before being replaced by anti-HBc IgG, which then
persists for years. Anti-HBs marks serologic recovery and protection. Only anti-
HBs is present in persons immunized with hepatitis B vaccine, whereas both
anti-HBs and anti-HBc are detected in persons with resolved infection. HBeAg
is present in active acute or chronic infection and is a marker of infectivity. The
development of anti-HBe, termed seroconversion, marks improvement and is a
goal of therapy in chronically infected patients. HBV DNA can be detected in
the serum of acutely infected patients and chronic carriers. High DNA titers are
seen in patients with HBeAg, and they typically fall once anti-HBe develops.
hepatologist experienced in treating the disease.
The goal of treatment is to reduce viral replication defined by having
undetectable HBV DNA in the serum and development of anti-HBe, termed
seroconversion. The development of anti-HBe transforms the disease into an
inactive form, thereby decreasing infectivity, active liver injury and
inflammation, fibrosis progression, and the risk of HCC. Treatment is only
indicated for patients in the immune-active form of the disease, as evidenced by
elevated ALT and/or AST, who have fibrosis on liver biopsy, putting the child at
higher risk for cirrhosis during childhood.

Treatment Strategies
Interferon-α2b (IFN-α2b) has immunomodulatory and antiviral effects (Table
385.7 ). It has been used in children, with long-term viral response rates similar
to the 25% rate reported in adults. Interferon (IFN) use is limited by its
subcutaneous administration, treatment duration of 24 wk, and side effects (flu-
like symptoms, marrow suppression, depression, retinal changes, autoimmune
disorders). IFN is further contraindicated in decompensated cirrhosis. One
advantage of IFN, compared to other treatments, is that viral resistance does not
develop with its use.

Table 385.7
Positive and Negative Factors to Consider in the Decision
to Treat Hepatitis B With Peginterferon or a Nucleoside or
Nucleotide Analog

AGENT POSITIVE FACTORS NEGATIVE FACTORS

Peginterferon Finite duration of treatment Inconvenience of subcutaneous injection
Durable off-treatment response Frequent side effects
More rapid disappearance of HBsAg Clearance of HBsAg in a small minority of patients
Immunostimulatory as well as depending on genotype
intrinsically antiviral Potential risk of ALT flares in patients with
advanced liver fibrosis
Better tolerability compared with its use Relative contraindication in patients older than age
in hepatitis C 60 or those with comorbid illnesses
Nucleoside or Negligible side effects Slight risk of nephropathy with nucleotide analogs
nucleotide analog (adefovir, tenofovir)
Convenience; ready acceptance by Drug expense can be considerable during long-term
patients use
Potent inhibition of virus replication Long or indefinite treatment needed for both
Reduced drug resistance with the HBeAg-positive and HBeAg-negative patients
third-generation nucleoside analogs Access issues in developing nations
Prevention
The most effective prevention strategies have resulted from the screening of
pregnant mothers and the use of HBIG and hepatitis B vaccine in infants (Tables
385.8 to 385.11 ). In HBsAg-positive and HBeAg-positive mothers, a 10% risk
of chronic HBV infection exists compared to 1% in HBeAg-negative mothers.
This knowledge offers screening strategies that may affect both mother and
infant by using antiviral medications during the third trimester. Guidelines
suggest that mothers with an HBV DNA viral load >200,000 IU/mL receive an
antiviral such as telbivudine, lamivudine, or tenofovir during the third trimester,
especially if they had a previous child who developed chronic HBV after
receiving HBIG and the hepatitis B vaccine. This practice has proven safe with
normal growth and development in infants of treated mothers.

Table 385.8
Strategy to Eliminate Hepatitis B Virus Transmission in the
United States*
• Screening of all pregnant women for HBsAg
HBV DNA testing for HBsAg-positive pregnant women, with suggestion of maternal antiviral therapy to reduce
perinatal transmission when HBV DNA is >200,000 IU/mL
Prophylaxis (HepB vaccine and hepatitis B immunoglobulin) for infants born to HBsAg-positive † women
• Universal vaccination of all infants beginning at birth ‡ , § as a safeguard for infants born to HBV-infected
mothers not identified prenatally
• Routine vaccination of previously unvaccinated children aged <19 yr
• Vaccination of adults at risk for HBV infection, including those requesting protection from HBV without
acknowledgment of a specific risk factor
* Sources: Mast EE, Margolis HS, Fiore AE, et al: A comprehensive immunization strategy to
eliminate transmission of hepatitis B virus infection in the United States: recommendations of the
Advisory Committee on Immunization Practices (ACIP). Part 1: immunization of infants, children,
and adolescents, MMWR Recomm Rep 54(No. RR-16):1–31, 2005; Mast EE, Weinbaum CM,
Fiore AE, et al: A comprehensive immunization strategy to eliminate transmission of hepatitis B
virus infection in the United States: recommendations of the Advisory Committee on Immunization
Practices (ACIP). Part II: immunization of adults, MMWR Recomm Rep 55(No. RR-16):1–33,
2006.
† Refer to Table 385.9 for prophylaxis recommendations for infants born to women with unknown
HBsAg status.
‡ Within 24 hr of birth for medically stable infants weighing ≥2,000 g.

§ Refer to Table 385.9 for birth dose recommendations for infants weighing <2,000 g.

HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus.

From Schillie S, Vellozzi C, Reingold A, et al: Prevention of hepatitis B virus infection in the United
States: recommendations of the advisory committee on immunization practices, MMWR 67[1]:1–
29, 2018, Box 2, p. 5.

Table 385.9
Hepatitis B Vaccine Schedules for Infants, by Infant
Birthweight and Maternal Hepatitis B Surface Antigen
Status

SINGLE-ANTIGEN SINGLE-ANTIGEN +
MATERNAL HBsAg VACCINE
BIRTHWEIGHT COMBINATION VACCINE †
STATUS
DOSE AGE DOSE AGE
≥2,000 g Positive 1 Birth (≤12 hr) 1 Birth (≤12 hr)
HBIG Birth (≤12 hr) HBIG Birth (≤12 hr)
‡
2 1-2 mo 2 2 mo
3 6 mo § 3 4 mo
4 6 mo §
Unknown* 1 Birth (≤12 hr) 1 Birth (≤12 hr)
2 1-2 mo 2 2 mo
3 6 mo § 3 4 mo
4 6 mo §
Negative 1 Birth (≤24 hr) 1 Birth (≤24 hr)
2 1-2 mo 2 2 mo
3 6-18 mo § 3 4 mo
4 6 mo §
<2,000 g Positive 1 Birth (≤12 hr) 1 Birth (≤12 hr)
HBIG Birth (≤12 hr) HBIG Birth (≤12 hr)
2 1 mo 2 2 mo
3 2-3 mo 3 4 mo
4 6 mo § 4 6 mo §
Unknown 1 Birth (≤12 hr) 1 Birth (≤12 hr)
HBIG Birth (≤12 hr) HBIG Birth (≤12 hr)
2 1 mo 2 2 mo
3 2-3 mo 3 4 mo
4 6 mo § 4 6 mo §
Negative 1 Hospital discharge 1 Hospital discharge or age 1
or age 1 mo mo
2 2 mo 2 2 mo
3 6-18 mo § 3 4 mo
4 6 mo §
* Mothers should have blood drawn and tested for HBsAg as soon as possible after admission for
delivery; if the mother is found to be HBsAg positive, the infant should receive HBIG as soon as
possible but no later than age 7 days.
† Pediarix should not be administered before age 6 wk.
‡ HBIG should be administered at a separate anatomical site from vaccine.

§ The final dose in the vaccine series should not be administered before age 24 wk (164 days).

HBIG, hepatitis B immune globulin; HBsAg, hepatitis B surface antigen.

From Schillie S, Vellozzi C, Reingold A, et al: Prevention of hepatitis B virus infection in the United
States: recommendations of the advisory committee on immunization practices, MMWR 67(1):1–
29, 2018, Table 3, p. 12.

Table 385.10
Recommended Doses of Hepatitis B Vaccine by Group and
Vaccine Type

SINGLE-ANTIGEN VACCINE COMBINATION VACCINE

RECOMBIVAX ENGERIX PEDIARIX * TWINRIX †
Age Group (yr) Dose (µg) Vol (mL) Dose (µg) Vol (mL) Dose (µg) Vol (mL) Dose (µg) Vol (mL)
Birth-10 5 0.5 10 0.5 10* 0.5 N/A N/A
11-15 10 ‡ 1 N/A N/A N/A N/A N/A N/A
11-19 5 0.5 10 0.5 N/A N/A N/A N/A
≥20 10 1 20 1 N/A N/A 20 † 1
HEMODIALYSIS PATIENTS AND OTHER IMMUNE-COMPROMISED PERSONS
<20 5 0.5 10 0.5 N/A N/A N/A N/A
≥20 40 1 40 2 N/A N/A N/A N/A
* Pediarix is approved for use in persons aged 6 wk through 6 yr (prior to the 7th birthday).

† Twinrix is approved for use in persons aged ≥18 yr.

‡ Adult formulation administered on a 2-dose schedule.

N/A, not applicable.

From Schillie S, Vellozzi C, Reingold A, et al: Prevention of hepatitis B virus infection in the United
States: recommendations of the advisory committee on immunization practices, MMWR 67(1):1–
29, 2018, Table 2, p. 10.

Table 385.11
Hepatitis B Vaccine Schedules for Children, Adolescents,
and Adults

SCHEDULE* (INTERVAL REPRESENTS TIME IN MONTHS FROM FIRST

AGE GROUP
DOSE)
Children (l-10 yr) 0, 1, and 6 mo
0, 1, 2, and 12 mo
Adolescents (11-19 0, 1, and 6 mo
yr) 0, 12, and 24 mo
 0 and 4-6 mo †
0, 1, 2, and 12 mo
0, 7 days, 21-30 days, 12 mo ‡
Adults (≥20 yr) 0, 1, and 6 mo
0, 1, 2, and 12 mo
0, 1, 2, and 6 mo §
0, 7 days, 21-30 days, 12 mo ‡
*
Refer to package inserts for further information. For all ages, when the HepB vaccine schedule is
interrupted, the vaccine series does not need to be restarted. If the series is interrupted after the
1st dose, the 2nd dose should be administered as soon as possible, and the 2nd and 3rd doses
should be separated by an interval of at least 8 wk. If only the 3rd dose has been delayed, it
should be administered as soon as possible. The final dose of vaccine must be administered at
least 8 wk after the 2nd dose and should follow the 1st dose by at least 16 wk; the minimum
interval between the 1st and 2nd doses is 4 wk. Inadequate doses of hepatitis B vaccine or doses
received after a shorter-than-recommended dosing interval should be readministered, using the
correct dosage or schedule. Vaccine doses administered ≤ 4 days before the minimum interval or
age are considered valid. Because of the unique accelerated schedule for Twinrix, the 4-day
guideline does not apply to the 1st 3 doses of this vaccine when administered on a 0-day, 7-day,
21-30-day, and 12-mo schedule (new recommendation).
† A 2-dose schedule of Recombivax adult formulation (10 µg) is licensed for adolescents aged 11-
15 yr. When scheduled to receive the second dose, adolescents aged >15 yr should be switched
to a 3-dose series, with doses 2 and 3 consisting of the pediatric formulation administered on an
appropriate schedule.
‡
Twinrix is approved for use in persons aged ≥ 18 yr and is available on an accelerated schedule
with doses administered at 0, 7, 21-30 days, and 12 mo.
§ A 4-dose schedule of Engerix administered in 2 1 mL doses (40 µg) on a 0-, 1-, 2-, and 6-mo
schedule is recommended for adult hemodialysis patients.
From Schillie S, Vellozzi C, Reingold A, et al: Prevention of hepatitis B virus infection in the United
States: recommendations of the advisory committee on immunization practices, MMWR 67(1):1–
29, 2018, Table 4, p. 13.

Household, sexual, and needle-sharing contacts of patients with chronic HBV

infection should be identified and vaccinated if they are susceptible to HBV
infection. Patients should be advised about the perinatal and intimate contact risk
of transmission of HBV. HBV is not spread by breastfeeding, kissing, hugging,
or sharing water or utensils. Children with HBV should not be excluded from
school, play, childcare, or work, unless they are prone to biting. A support group
might help children to cope better with their disease. Families should not feel
obligated to disclose the diagnosis as this information may lead to prejudice or
mistreatment of the patient or the patient's family. All patients positive for
HBsAg should be reported to the state or local health department, and chronicity
is diagnosed if they remain positive past 6 mo HBIG.
HBIG is indicated only for specific postexposure circumstances and provides
Long-term effects of these medicines also need to be evaluated as significant
differences were noted in children's weight, height, body mass index, and body
composition. Most of these delays improved following cessation of treatment,
but height z-scores continued to lag behind.
Treatment may be considered for children infected with genotypes 2 and 3,
because they have an 80–90% response rate to therapy with peginterferon and
ribavirin. If the child has genotype 1b virus, the treatment choice remains more
controversial as newer regimens are quickly becoming available.
Pediatric guidelines recommend treatment to eradicate HCV infection, prevent
progression of liver disease and development of HCC, and to remove the stigma
associated with HCV. Treatment should be considered for patients with evidence
of advanced fibrosis or injury on liver biopsy. One approved treatment consists
of 24-48 wk of peginterferon and ribavirin (therapy should be stopped if still
detectable on viral PCR at 24 wk of therapy). In addition, sofosbuvir alone or in
combination with ledipasvir has FDA approval for children ages 12-17 yr. The
combination is indicated for HCV genotypes 1, 4, 5, and 6, while sofosbuvir
with ribavirin is indicated for HCV genotypes 2 or 3; both regimens are used in
children with mild or no cirrhosis.

Newer Treatments
Varying IFN-free regimens are now available for adults for all HCV genotypes
allowing even greater likelihood of achieving viral eradication, with completely
oral medication regimens, and without the use of IFN and its attendant side
effects. With the rapid development of new medications and regimens, frequent
review of up-to-date resources, such as www.hcvguidelines.org , will be vital to
provide optimal care (Table 385.12 ).

Table 385.12
Ongoing Studies With Direct Acting Antiviral Combinations
in Children With Chronic Hepatitis C Virus Infection

AGE
ESTIMATED
GENOTYPE RANGE IDENTIFIER COMPLETION
ENROLMENT
(YR)
Sofosbuvir + ledipasvir, with or 1,4,5,6 222 3–17 NCT02249182 July 2018
without ribavirin
Sofosbuvir + ribavirin 2,3 104 3–17 NCT02175758 April 2018
Ombitasvir + paritaprevir + 1,4 74 3–17 NCT02486406 September 2019
 ritonavir, with or without
dasabuvir, with or without
ribavirin
Sofosbuvir + daclatasvir 4 40 8–17 NCT03080415 June 2018
Sofosbuvir + ledipasvir 1,4 40 12–17 NCT02868242 April 2019
Sofosbuvir + velpatasvir 1–6 200 3–17 NCT03022981 December 2019
Glecaprevir + pibrentasvir 1–6 110 3–17 NCT03067129 May 2022
Gratisovir + ribavirin 1–6 41 10–17 NCT02985281 June 2017
From Indolfi G, Serranti D, Resti M: Direct-acting antivirals for children and adolescents with
chronic hepatitis C. Lancet Child Adolesc 2:298-304, 2018 (Table 1, p. 299).

Prevention
No vaccine is yet available to prevent HCV, although ongoing research suggests
this will be possible in the future. Currently available Ig preparations are not
beneficial, likely because preparations produced in the United States do not
contain antibodies to HCV because blood and plasma donors are screened for
anti-HCV and excluded from the donor pool. Broad neutralizing antibodies to
HCV were found to be protective and might pave the road for vaccine
development.
Once HCV infection is identified, patients should be screened yearly with a
liver ultrasound and serum α-fetoprotein for HCC, as well as for any clinical
evidence of liver disease. Vaccinating the affected patient against HAV and HBV
will prevent superinfection with these viruses and the increased risk of
developing severe liver failure.

Prognosis
Viral titers should be checked yearly to document spontaneous remission. Most
patients develop chronic hepatitis. Progressive liver damage is higher in those
with additional comorbid factors such as alcohol consumption, viral genotypic
variations, obesity, and underlying genetic predispositions. Referral to a pediatric
hepatologist is strongly advised to take advantage of up-to-date monitoring
regimens and to optimize their enrollment in treatment protocols when available.

Hepatitis D
Etiology
CHAPTER 388

Mitochondrial Hepatopathies
Samar H. Ibrahim, William F. Balistreri

A wide variety of mitochondrial disorders are associated with liver disease.

Hepatocytes contain a high density of mitochondria because the liver, with its
biosynthetic and detoxifying functions, is highly dependent on adenosine
triphosphate. Defects in mitochondrial function can lead to impaired oxidative
phosphorylation, increased generation of reactive oxygen species, impairment of
other metabolic pathways, and activation of mechanisms of cellular death.
Mitochondrial disorders can be divided into primary, in which the
mitochondrial defect is the primary cause of the disorder, and secondary, in
which mitochondrial function is affected by exogenous injury or a genetic
mutation that affects nonmitochondrial proteins (see Chapter 105.4 ). Primary
mitochondrial disorders can be caused by mutations affecting mitochondrial
DNA (mtDNA) or by nuclear genes that encode mitochondrial proteins or
cofactors (see Chapter 383 —Table 383.3 and Table 388.1 ). Specific patterns
may be noted (Table 388.2 ). Secondary mitochondrial disorders include diseases
with an uncertain etiology, such as Reye syndrome; disorders caused by
endogenous or exogenous toxins, drugs, or metals; and other conditions in which
mitochondrial oxidative injury may be involved in the pathogenesis of liver
injury.

Table 388.1
Genotypic Classification of Primary Mitochondrial
Hepatopathies and Organ Involvement

RESPIRATORY OTHER
HEPATIC
GENE CHAIN ORGANS CLINICAL FEATURES
HISTOLOGY
COMPLEX INVOLVED
Deletion Multiple Steatosis, Kidney, heart, Sideroblastic anemia, variable
 (Pearson) fibrosis CNS, muscle thrombocytopenia and neutropenia,
persistent diarrhea
MPV17 I, III, IV Steatosis CNS, muscle, Adult-onset multisystemic involvement:
gastrointestinal myopathy, ophthalmoplegia, severe
tract constipation, parkinsonism
DGUOK I, III, IV Steatosis, Kidneys, CNS, Nystagmus, hypotonia, renal Fanconi
fibrosis muscle syndrome, acidosis
MPV17 I, III, IV Steatosis, CNS, PNS Hypotonia
fibrosis
SUCLG1 I, III, IV Steatosis Kidneys, CNS, Myopathy, sensorineural hearing loss,
muscle respiratory failure
POLG1 I, III, IV Steatosis, CNS, muscle Liver failure preceded by neurologic
fibrosis symptoms, intractable seizures, ataxia,
psychomotor regression
C10orf2/Twinkle I, III, IV Steatosis CNS, muscle Infantile-onset spinocerebellar ataxia, loss
of skills
BCS1L III (GRACILE) CNS ±, muscle Fanconi-type renal tubulopathy
±, kidneys
SCO1 IV Steatosis, Muscle
fibrosis
TRMU I, III, IV Steatosis, Infantile liver failure with subsequent
fibrosis recovery
EFG1 I, III, IV Steatosis CNS Severe, rapidly progressive
encephalopathy
EFTu I, III, IV Unknown CNS Severe lactic acidosis, rapidly fatal
encephalopathy
CNS, central nervous system; GRACILE, growth restriction, aminoaciduria, cholestasis, iron
overload, lactic acidosis, and early death; PNS, peripheral nervous system.
From Lee WS, Sokol RJ: Mitochondrial hepatopathies: advances in genetics, therapeutic
approaches and outcomes, J Pediatr 163:942–948, 2013 (Table 2, p. 944).

Table 388.2
Hepatic Phenotypes of Mitochondrial Cytopathies
• Infantile liver failure
• Neonatal cholestasis
• Pearson syndrome
• Alpers disease
• Chronic liver disease
• Drug-induced mitochondrial toxicity
From Wyllie R, Hyams JS, Kay M, editors: Pediatric gastrointestinal and liver disease , ed 5,
Philadelphia, 2016, Elsevier (Box 71.2, p. 876).

Epidemiology
Mitochondrial respiratory chain disorders of all types affect 1 in 20,000 children
Table 388.3
Clinical Staging of Reye Syndrome and Reye-Like Diseases
Symptoms at the time of admission:
I. Usually quiet, lethargic and sleepy, vomiting, laboratory evidence of liver dysfunction
II. Deep lethargy, confusion, delirium, combativeness, hyperventilation, hyperreflexia
III. Obtunded, light coma ± seizures, decorticate rigidity, intact pupillary light reaction
IV. Seizures, deepening coma, decerebrate rigidity, loss of oculocephalic reflexes, fixed pupils
V. Coma, loss of deep tendon reflexes, respiratory arrest, fixed dilated pupils, flaccidity/decerebration
(intermittent); isoelectric electroencephalogram

Table 388.4
Diseases That Present a Clinical or Pathologic Picture
Resembling Reye Syndrome
• Metabolic disease
• Organic aciduria
• Disorders of oxidative phosphorylation
• Urea cycle defects (carbamoyl phosphate synthetase, ornithine transcarbamylase)
• Defects in fatty acid oxidation metabolism
• Acyl–coenzyme A dehydrogenase deficiencies
• Systemic carnitine deficiency
• Hepatic carnitine palmitoyltransferase deficiency
• 3-OH, 3-methylglutaryl-coenzyme A lyase deficiency
• Fructosemia
• Infantile liver failure syndrome 1. Caused by leucyl-tRNA synthetase (LARS) gene mutations
• Central nervous system infections or intoxications (meningitis), encephalitis, toxic encephalopathy
• Hemorrhagic shock with encephalopathy
• Drug or toxin ingestion (salicylate, valproate)

Acquired abnormalities of mitochondrial function can be caused by several

drugs and toxins, including valproic acid, cyanide, amiodarone,
chloramphenicol, iron, the emetic toxin of Bacillus cereus, and nucleoside
analogs. Valproic acid is a branched fatty acid that can be metabolized into the
mitochondrial toxin 4-envalproic acid. Children with underlying respiratory
chain defects appear more sensitive to the toxic effects of this drug, and valproic
acid is reported to precipitate liver failure in patients with Alpers syndrome and
cytochrome-c oxidase deficiency. Nucleoside analogs directly inhibit
mitochondrial respiratory chain complexes. The reverse transcriptase inhibitors
zidovudine, didanosine, stavudine, and zalcitabine―used to treat HIV-infected
patients―inhibit DNA POLG of mitochondria and can block elongation of
mtDNA, leading to mtDNA depletion. Other conditions that can lead to
mitochondrial oxidative stress include cholestasis, nonalcoholic steatohepatitis,
α1 -antitrypsin deficiency, and Wilson disease.

Diagnostic Evaluation
Screening tests include common biochemical tests (comprehensive metabolic
profile, INR, α-fetoprotein, CPK, phosphorus, complete blood cell count,
ammonia, lactate, pyruvate, serum ketone bodies: both quantitative 3-
hydroxybutyrate and quantitative acetoacetate, total free fatty acids, serum
acylcarnitine profile; serum-free and total carnitines, urine organic acids, and
serum amino acids) (Table 388.5 ). These results will guide subsequent
confirmatory testing to establish a molecular diagnosis. Genotyping, including
single gene or panel screening for common mitochondrial disease, is used in
clinical practice. Whole exome or genome sequencing is also helpful and is
replacing single gene or gene panel testing. However, the identification of
multiple gene variants of uncertain significance will require detailed clinical and
biochemical confirmation for interpretation. Tissue (liver biopsy, skin fibroblast,
and muscle biopsy) may be needed to make a specific biochemical diagnosis.

Table 388.5

Tiered Investigations in Suspected Mitochondrial Liver Disease

TIER 1
Pre-/postprandial plasma lactate, glucose, FFA, and 3-OH
Plasma carnitine, acylcarnitines
Plasma amino acids, creatine kinase, thymidine
Urinary organic acids, amino acids, tubular resorption phosphate, albumin/creatinine ratio CSF lactate/protein (if
feasible)
Electrocardiography and echocardiography
Electroencephalography and visual-evoked potentials
Common mutations in POLG, DGUOK, MPV17, and TRMU
TIER 2
Tissue analysis
Liver biopsy : (if feasible). Tissue for light microscopy, electron microscopy, and Oil Red O stain
Frozen tissue for respiratory chain enzyme activity analysis and mtDNA copy number
Muscle biopsy : Tissue for light microscopy, electron microscopy, Oil Red O stain, and histochemistry for
respiratory chain complexes
Frozen tissue for respiratory chain enzyme activity analysis and mtDNA copy number
 Skin biopsy: set up for fibroblast culture
TIER 3
Cranial MRI/MRS
TIER 4
Extended molecular screening. This will be guided by the clinical phenotype, results of the tissue analysis, and
local facilities
Currently suggested genes should include SUCLG1, BCS1L, SOC1, TFSM, TWINKLE, ACAD9, EARS2, GFM1,
RRM2B, TK2 , and SUCLA2

From Wyllie R, Hyams JS, Kay M, editors: Pediatric gastrointestinal and liver
disease , ed 5, Philadelphia, 2016, Elsevier (Box 71-3, p. 876).

Treatment of Mitochondrial
Hepatopathies
There is no effective therapy for most patients with mitochondrial hepatopathies;
neurologic involvement often precludes orthotopic liver transplantation. Patients
with mitochondrial disorders remain at risk for transplant-related worsening of
their underlying metabolic disease, especially patients with POLG -related
disease. Several therapeutic drug combinations―including antioxidants,
vitamins, cofactors, and electron acceptors―have been proposed, but no
randomized controlled trials have been completed to evaluate them. Treatment
strategies are supportive and include the infusion of sodium bicarbonate for
acute metabolic acidosis, transfusions for anemia and thrombocytopenia, and
exogenous pancreatic enzymes for pancreatic insufficiency. It is important to
discontinue or avoid medications that may exacerbate hepatopathy, including
sodium valproate, tetracycline, and macrolide antibiotics, azathioprine,
chloramphenicol, quinolones, and linezolid. Ringer lactate should be avoided
because patients with liver dysfunction may not be able to metabolize lactate.
Propofol should be avoided during anesthesia because of potential interference
with mitochondrial function. In patients with lactic acidosis, lactate levels should
be monitored during procedures. It is important to maintain anabolism using a
balanced intake of fat and carbohydrates while avoiding unbalanced intakes
(e.g., glucose only at a high intravenous rate) or fasting for >12 hr.
Drugs commonly used in children that can cause chronic liver injury, which can
mimic autoimmune hepatitis, include isoniazid, methyldopa, pemoline,
nitrofurantoin, dantrolene, minocycline, pemoline, and the sulfonamides.
Metabolic diseases can lead to chronic hepatitis, including α1 -antitrypsin
deficiency, inborn errors of bile acid biosynthesis, and Wilson disease.
Nonalcoholic steatohepatitis, usually associated with obesity and insulin
resistance, is another common cause of chronic hepatitis. It can progress to
cirrhosis but responds to weight reduction. In many cases the cause of chronic
hepatitis is unknown; in some, an autoimmune mechanism is suggested by the
finding of serum antinuclear and anti–SMAs and by multisystem involvement
(arthropathy, thyroiditis, rashes, Coombs-positive hemolytic anemia).

Table 389.1
Disorders Producing Chronic Hepatitis
• Chronic viral hepatitis
• Hepatitis B
• Hepatitis C
• Hepatitis D
• Autoimmune hepatitis
• Anti–actin antibody-positive
• Anti–liver-kidney microsomal antibody-positive
• Anti–soluble liver antigen antibody-positive
• Others (includes antibodies to liver-specific lipoproteins or asialoglycoprotein)
• Overlap syndrome with sclerosing cholangitis and autoantibodies
• Systemic lupus erythematosus
• Celiac disease
• Drug-induced hepatitis
• Metabolic disorders associated with chronic liver disease
• Wilson disease
• Nonalcoholic steatohepatitis
• α1 -Antitrypsin deficiency
• Tyrosinemia
• Niemann-Pick disease type 2
• Glycogen storage disease type IV
• Cystic fibrosis
• Galactosemia
• Bile acid biosynthetic abnormalities

Autoimmune hepatitis is a clinical constellation that suggests an immune-

mediated process; it is responsive to immunosuppressive therapy (Table 389.2 ).
Autoimmune hepatitis typically refers to a primarily hepatocyte-specific process,
whereas autoimmune cholangiopathy and sclerosing cholangitis predominately
involve intrahepatic and extrahepatic bile duct injury. Overlap of the process
involving both hepatocyte and bile duct–directed injury may be more common in
children. De novo hepatitis can be seen in a subset of liver transplant recipients
whose initial disease was not autoimmune.

Table 389.2
Classification of Autoimmune Hepatitis

TYPE 2 AUTOIMMUNE
VARIABLE TYPE 1 AUTOIMMUNE HEPATITIS
HEPATITIS
Characteristic autoantibodies Antinuclear antibody* Antibody against liver-kidney
microsome type 1*
Smooth-muscle antibody*
Antiactin antibody † Antibody against liver cytosol
type 1*
Autoantibodies against soluble liver antigen and Antibody against liver-kidney
liver-pancreas antigen ‡ microsomal type 3
Atypical perinuclear antineutrophil cytoplasmic
antibody
Geographic variation Worldwide Worldwide; rare in North
America
Age at presentation Any age Predominantly childhood and
young adulthood
Gender of patients Female in ~75% of cases Female in ~95% of cases
Association with other Common Common §
autoimmune diseases
Clinical severity Broad range, variable Generally severe
Histopathologic features at Broad range, mild disease to cirrhosis Generally advanced
presentation
Treatment failure Infrequent Frequent
Relapse after drug Variable Common
withdrawal
Need for long-term Variable ~100%
maintenance
* The conventional method of detection is immunofluorescence.

† Tests for this antibody are rarely available in commercial laboratories.

‡ This antibody is detected by enzyme-linked immunosorbent assay.

§ Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy is seen only in patients with

type 2 disease.
Modified from Krawitt EL: Autoimmune hepatitis, N Engl J Med 354:54–66, 2006.

Etiology
T Lymphocytes
hepatitis is being increasingly recognized with wider application of MR
cholangiography (Table 389.3 ). Patients with primary sclerosing cholangitis can
have elevated γ-globulin levels and autoantibodies; therefore liver biopsy
findings in these children may be especially important. Dilated or obliterated
veins on ultrasonography suggest the possibility of the Budd-Chiari syndrome.
Diagnosis of autoimmune liver disease in the setting of acute liver failure is
difficult and care should be taken in applying standardized approaches.
“Seronegative” autoimmune hepatitis has been described, so absence of classic
autoimmune markers does not exclude this diagnosis.

Table 389.3
Overlap Syndromes of Autoimmune Hepatitis

AUTOIMMUNE HEPATITIS WITH OVERLAPPING FEATURES OF:

Primary Sclerosing
Primary Biliary Cholangitis* Cholestasis
Cholangitis
Clinical AMA + AMA − AMA −
and Serum AP frequently > 2-fold ULN Serum AP frequently > 2- Serum AP frequently > 2-fold ULN
laboratory fold ULN
features IBD common No UC
Abnormal cholangiogram Normal cholangiogram
(except in small-duct
disease)
Histology Destructive cholangitis Ductopenia Lymphoplasmacytic portal and acinar
infiltrates
Ductopenia Cholangiolar Lymphocytic destructive cholangitis
proliferation
Cholestasis Swollen fibrotic portal Swollen hepatocytes
tracts
Treatment Prednisone (10 mg daily) in Prednisone (10 mg daily) Prednisone (10 mg daily) in
combination with azathioprine (50 in combination with combination with azathioprine (50
mg daily) if AP ≤ 2 × ULN azathioprine (50 mg mg daily) and/or low-dose UDCA
daily) and low-dose (13-15 mg/kg daily) depending on
UDCA (13-15 mg/kg AP level and histologic features
daily)
Prednisone (10 mg daily) in
combination with azathioprine (50
mg daily) and low-dose UDCA (13-
15 mg/kg daily) if AP > 2 × ULN
and/or florid duct lesions
* Primary biliary cholangitis formerly called primary biliary cirrhosis.

AMA , antimitochondrial antibodies; AP , alkaline phosphatase level; UDCA , ursodeoxycholic

acid; ULN , upper limit of normal.
From Czaja AJ: Autoimmune hepatitis. In Feldman M, Friedman LS, Brandt LJ, editors:
Sleisenger and Fordtran's gastrointestinal and liver disease , ed 10, Philadelphia, 2016: Elsevier
CHAPTER 390

Drug- and Toxin-Induced Liver

Injury
Frederick J. Suchy, Amy G. Feldman

The liver is the main site of drug metabolism and is particularly susceptible to
structural and functional injury after the ingestion, parenteral administration, or
inhalation of chemical agents, drugs, plant derivatives (home remedies), herbal
or nutritional supplements, or environmental toxins. The possibility of drug use
or toxin exposure at home or in the parents’ workplace should be explored for
every child with liver dysfunction. The clinical spectrum of illness can vary from
asymptomatic biochemical abnormalities of liver function to fulminant failure.
Liver injury may be the only clinical feature of an adverse drug reaction or may
be accompanied by systemic manifestations and damage to other organs. In
hospitalized patients, clinical and laboratory findings may be confused with the
underlying illness. After acetaminophen, antimicrobials, supplements, and
central nervous system agents are the most commonly implicated drug classes
causing liver injury in children.
There is growing concern about environmental hepatotoxins that are insidious
in their effects. Many environmental toxins―including the plasticizers, biphenyl
A, and the phthalates―are ligands for nuclear receptors that transcriptionally
activate the promoters of many genes involved in xenobiotic and lipid
metabolism and may contribute to obesity and nonalcoholic fatty liver disease.
Some herbal, weight loss, and body building supplements have been associated
with hepatic injury or even liver failure (Table 390.1 ) related to their intrinsic
toxicity or because of contamination with fungal toxins, pesticides, or heavy
metals.

Table 390.1
Hepatotoxic Herbal Remedies, Dietary Supplements, and
Weight Loss Products
POPULAR HEPATOTOXIC TYPE OF LIVER
REMEDY SOURCE
USES COMPONENT INJURY
Ayurvedic herbal Multiple Multiple Uncertain (may Hepatitis
medicine contain heavy metal
contaminants)
Barakol Anxiolytic Cassia siamea Uncertain Reversible hepatitis or
cholestasis
Black cohosh Menopausal Cimicifuga racemosa Uncertain Hepatitis (causality
symptoms uncertain)
“Bush tea” Fever Senecio, Pyrrolizidine alkaloids SOS
Heliotropium,
Crotalaria spp.
Cascara Laxative Cascara sagrada Anthracene glycoside Cholestatic hepatitis
Chaparral leaf “Liver tonic,” Larrea tridenta Nordihydroguaiaretic Acute and chronic
(greasewood, burn salve, acid hepatitis, FHF
creosote bush) weight loss
Chaso/onshido Weight loss — N -nitro-fenfluramine Acute hepatitis, FHF
Chinese medicines
(traditional)
Jin bu huan Sleep aid, Lycopodium serratum Levo- Acute or chronic hepatitis
analgesic tetrahydropalmitine or cholestasis, steatosis
Ma huang Weight loss Ephedra spp. Ephedrine Severe hepatitis, FHF
Shou-wu-pian Anti-aging, Polygonum Anthraquinone Acute hepatitis or
neuroprotection, multiflorum Thunb cholestasis
laxative (fleeceflower root)
Syo-saiko-to Multiple Scutellaria root Diterpenoids Hepatocellular necrosis,
cholestasis, steatosis,
granulomas
Comfrey Herbal tea Symphytum spp. Pyrrolizidine alkaloid Acute SOS, cirrhosis
Germander Weight loss, Teucrium chamaedry, Diterpenoids, epoxides Acute and chronic
fever T. capitatum, T. hepatitis, FHF,
polium autoimmune injury
Greater celandine Gallstones, IBS Chelidonium majus Isoquinoline alkaloids Cholestatic hepatitis,
fibrosis
Green tea leaf Multiple Camellia sinensis Catechins Hepatitis (causality
extract questioned)
Herbalife Nutritional — Various; ephedra Severe hepatitis, FHF
supplement,
weight loss
Hydroxycut Weight loss Camellia sinensis , Uncertain Acute hepatitis, FHF
among other
constituents
Impila Multiple Callilepsis laureola Potassium atractylate Hepatic necrosis
Kava Anxiolytic Piper methysticum Kava lactone, Acute hepatitis,
pipermethystine cholestasis, FHF
Kombucha Weight loss Lichen alkaloid Usnic acid Acute hepatitis
Limbrel Osteoarthritis Plant bioflavonoids Baicalin, epicatechin Acute mixed
(Flavocoxid) hepatocellular-cholestatic
injury
 Lipokinetix Weight loss Lichen alkaloid Usnic acid Acute hepatitis, jaundice,
FHF
Mistletoe Asthma, Viscus album Uncertain Hepatitis (in combination
infertility with skullcap)
Oil of cloves Dental pain Various foods, oils Eugenol Zonal necrosis
Pennyroyal Abortifacient Hedeoma pulegoides, Pulegone, Severe hepatocellular
(squawmint oil) Mentha pulegium monoterpenes necrosis
Prostata Prostatism Multiple Uncertain Chronic cholestasis
Sassafras Herbal tea Sassafras albidum Safrole HCC (in animals)
Senna Laxative Cassia angustifolia Sennoside alkaloids; Acute hepatitis
anthrone
Skullcap Anxiolytic Scutellaria Diterpenoids Hepatitis
Valerian Sedative Valeriana officinalis Uncertain Elevated liver enzymes
FHF, fulminant hepatic failure; HCC, hepatocellular carcinoma; SOS, sinusoidal obstruction
syndrome.
From Lewis JH: Liver disease caused by anesthetics, chemicals, toxins, and herbal preparations.
In Feldman M, Friedman LS, Brandt LJ, editors: Sleisenger and Fordtran's gastrointestinal and
liver disease , ed 10, Philadelphia, 2016, Elsevier, (Table 89.6).

Hepatic metabolism of drugs and toxins is mediated by a sequence of

enzymatic reactions that in large part transform hydrophobic, less-soluble
molecules into more nontoxic, hydrophilic compounds that can be readily
excreted in urine or bile (see Chapter 72 ). Relative liver size, liver blood flow,
and extent of protein binding also influence drug metabolism. Phase 1 of the
process involves enzymatic activation of the substrate to reactive intermediates
containing a carboxyl, phenol, epoxide, or hydroxyl group. Mixed-function
monooxygenase, cytochrome-c reductase, various hydrolases, and the
cytochrome P450 (CYP) system are involved in this process. Nonspecific
induction of these enzymatic pathways, which can occur during intercurrent viral
infection, with starvation, and with the administration of certain drugs such as
anticonvulsants, can alter drug metabolism and increase the potential for
hepatotoxicity. A single agent can be metabolized by more than 1 biochemical
reaction. The reactive intermediates that are potentially damaging to the cell are
enzymatically conjugated in phase 2 reactions with glucuronic acid, sulfate,
acetate, glycine, or glutathione. Some drugs may be directly metabolized by
these conjugating reactions without first undergoing phase 1 activation. Phase 3
is the energy-dependent excretion of drug metabolites and their conjugates by an
array of membrane transporters in the liver and kidney such as the multidrug
resistant protein 1.
Pathways for biotransformation are expressed early in the fetus and infant, but
many phase 1 and phase 2 enzymes are immature, particularly in the 1st yr of
life. CYP3A4 is the primary hepatic CYP expressed postnatally and metabolizes
infiltration by neutrophils perpetuate toxic injury by many drugs by release of
reactive oxygen and nitrogen species as well as cytokines. Stellate cells can also
be activated, potentially leading to hepatic fibrosis and cirrhosis.
The pathologic spectrum of drug-induced liver disease is extremely wide, is
rarely specific, and can mimic other liver diseases (Table 390.2 ). Predictable
hepatotoxins, such as acetaminophen, produce centrilobular necrosis of
hepatocytes. Steatosis is an important feature of tetracycline (microvesicular)
and ethanol (macrovesicular) toxicities. A cholestatic hepatitis can be observed,
with injury caused by erythromycin estolate and chlorpromazine. Cholestasis
without inflammation may be a toxic effect of estrogens and anabolic steroids.
Use of oral contraceptives and androgens has also been associated with benign
and malignant liver tumors. Some idiosyncratic drug reactions can produce
mixed patterns of injury, with diffuse cholestasis and cell necrosis. Chronic
hepatitis has been associated with the use of methyldopa and nitrofurantoin.

Table 390.2
Patterns of Hepatic Drug Injury

DISEASE DRUG
Centrilobular necrosis Acetaminophen
Carbon tetrachloride
Cocaine
Ecstasy
Iron
Halothane
Microvesicular steatosis Valproic acid
Tetracycline
Toluene
Methotrexate
Acute hepatitis Isoniazid
Anti–tumor necrosis factor agents
Valproic acid
General hypersensitivity Sulfonamides
Phenytoin
Minocycline
Fibrosis Methotrexate
Cholestasis Chlorpromazine
Aniline
Erythromycin
Paraquat
Estrogens
Sertraline
Sinusoidal obstruction syndrome (venoocclusive disease) Irradiation plus busulfan
Arsenic
 Cyclophosphamide
Portal and hepatic vein thrombosis Estrogens
Androgens
Biliary sludge Ceftriaxone
Hepatic adenoma or hepatocellular carcinoma Oral contraceptives
Anabolic steroids

Clinical manifestations can be mild and nonspecific, such as fever and

malaise. Fever, rash, and arthralgia may be prominent in cases of
hypersensitivity. In ill hospitalized patients, the signs and symptoms of hepatic
drug toxicity may be difficult to separate from the underlying illness. The
differential diagnosis should include acute and chronic viral hepatitis, biliary
tract disease, septicemia, ischemic and hypoxic liver injury, malignant
infiltration, and inherited metabolic liver disease.
The laboratory features of drug- or toxin-related liver disease are extremely
variable. Hepatocyte damage can lead to elevations of serum aminotransferase
activities and serum bilirubin levels and to impaired synthetic function as
evidenced by decreased serum coagulation factors and albumin.
Hyperammonemia can occur with liver failure or with selective inhibition of the
urea cycle (sodium valproate). Toxicologic screening of blood and urine
specimens can aid in the detecting drug or toxin exposure. Percutaneous liver
biopsy may be necessary to distinguish drug injury from complications of an
underlying disorder or from intercurrent infection. Vanishing bile duct syndrome
can be seen in a small portion of patients with idiosyncratic DILI.
Slight elevation of serum aminotransferase activities (generally <2-3 times
normal) can occur during therapy with drugs, particularly anticonvulsants,
capable of inducing microsomal pathways for drug metabolism. Liver biopsy
reveals proliferation of smooth endoplasmic reticulum but no significant liver
injury. Liver test abnormalities often resolve with continued drug therapy.

Treatment
Treatment of drug- or toxin-related liver injury is mainly supportive. Contact
with the offending agent should be avoided. Corticosteroids might have a role in
immune-mediated disease. Treatment with n -acetylcysteine, by stimulating
glutathione synthesis, is effective in preventing or attenuating hepatotoxicity
when administered within 16 hr after an acute overdose of acetaminophen and
appears to improve survival in patients with severe liver injury even up to 36 hr
after ingestion (see Chapter 63 ). Intravenous L -carnitine may be of value in
Irritability, poor feeding, and a change in sleep rhythm may be the only findings
in infants; asterixis may be demonstrable in older children. Patients are often
somnolent, confused, or combative on arousal and can eventually become
responsive only to painful stimuli. Patients can rapidly progress to deeper stages
of coma in which extensor responses and decerebrate and decorticate posturing
appear. Respirations are usually increased early, but respiratory failure can occur
in stage IV coma (Table 391.1 ). The pathogenesis of hepatic encephalopathy is
likely related to increased serum levels of ammonia, false neurotransmitters,
amines, increased γ-aminobutyric acid receptor activity, or increased circulating
levels of endogenous benzodiazepine-like compounds. Decreased hepatic
clearance of these substances can produce marked central nervous system
dysfunction. The mechanisms responsible for cerebral edema and intracranial
hypertension in acute liver failure (ALF) suggest both cytotoxic and vasogenic
injury. There is increasing evidence for an inflammatory response (synthesis and
release of inflammatory factors from activated microglia and endothelial cells)
which acts in synergy with hyperammonemia to cause severe astrocyte
swelling/brain edema.

Table 391.1
Stages of Hepatic Encephalopathy

STAGES
I II III IV
Symptoms Periods of lethargy, Drowsiness, Stupor but Coma:
euphoria; reversal of inappropriate behavior, arousable; IVa responds to
day-night sleeping; agitation, wide mood confused, noxious stimuli;
may be alert swings, disorientation incoherent IVb no response
speech
Signs Trouble drawing Asterixis, fetor Asterixis, Areflexia, no
figures, performing hepaticus, incontinence hyperreflexia, asterixis, flaccidity
mental tasks extensor
reflexes,
rigidity
Electroencephalogram Normal Generalized slowing, q Markedly Markedly abnormal
waves abnormal bilateral slowing, d
triphasic waves waves, electrocortical
silence

Laboratory Findings
Serum direct and indirect bilirubin levels and serum aminotransferase activities
CHAPTER 392

Cystic Diseases of the Biliary Tract

and Liver
Frederick J. Suchy, Amy G. Feldman

Cystic lesions of liver may be initially recognized during infancy and childhood.
Hepatic fibrosis can also occur as part of an associated developmental defect
(Table 392.1 ). Cystic renal disease is usually associated and often determines
the clinical presentation and prognosis. Virtually all proteins encoded by genes
mutated in combined cystic diseases of the liver and kidney are at least partially
localized to primary cilia in renal tubular cells and cholangiocytes.

Table 392.1

Syndromes Associated With Congenital Hepatic Fibrosis

DISORDER ASSOCIATED FEATURES
Autosomal recessive polycystic Ductal plate malformation, Caroli syndrome
kidney disease
Autosomal dominant polycystic Ductal plate malformation, Caroli syndrome
kidney disease
Autosomal dominant polycystic liver Rarely, congestive heart failure
disease
Jeune syndrome Asphyxiating thoracic dystrophy, with cystic renal tubular dysplasia, Caroli
syndrome
Joubert syndrome Central nervous system defects, cardiac malformations
COACH syndrome C erebellar vermis hypoplasia, o ligophrenia, congenital a taxia, ocular c
oloboma, h epatic fibrosis
Meckel-Gruber syndrome Cystic renal dysplasia, abnormal bile duct development with fibrosis,
posterior encephalocele, polydactyly
Carbohydrate-deficient glycoprotein Phosphomannose isomerase 1 deficiency chronic diarrhea, protein-losing
syndrome type 1b enteropathy
Ivemark syndrome type 2 Autosomal-recessive renal-hepatic-pancreatic dysplasia
Nephronophthisis type 3 Tapetoretinal degeneration
Bardet-Biedl syndrome Retinal degeneration, obesity, limb deformities, hypogonadism
Oral-facial-digital syndrome type 1 Oral clefts, hamartomas or cysts of the tongue, digital anomalies pancreatic
cysts
 Miscellaneous syndromes Intestinal lymphangiectasia, enterocolitis, cystic short rib (Beemer-Langer)
syndrome, osteochondrodysplasia
After Suchy FJ, Sokol RJ, Balistreri WF, editors: Liver disease in children, ed 3, New York, 2014,
Cambridge University Press, p. 713.

A solitary, congenital liver cyst (nonparasitic) can occur in childhood and has
been identified in some cases on prenatal ultrasound. Abdominal distention and
pain may be present, and a poorly defined right-upper-quadrant mass may be
palpable. These benign lesions are best left undisturbed unless they compress
adjacent structures or a complication occurs, such as hemorrhage into the cyst.
Operative management is generally reserved for symptomatic patients and
enlarging cysts.

Choledochal Cysts
Choledochal cysts are congenital dilatations of the common bile duct that can
cause progressive biliary obstruction and biliary cirrhosis. Cylindrical (fusiform)
and spherical (saccular) cysts of the extrahepatic ducts are the most common
types (see Table 392.1 ). Choledochal cysts are classified according to the
Todani method (Fig. 392.1 ). Type 1 choledochal cysts, the most common
variant, involve a saccular or fusiform dilation of the common bile duct. Type II
cysts are congenital diverticula protruding from the common bile duct. Type III
cysts or choledochoceles involve a herniation of the intraduodenal segment of
the common bile duct into the duodenum. Type IVa cysts or Caroli disease
involve multiple intrahepatic and extrahepatic cysts. Type IVb cysts involve only
the extrahepatic duct. Solitary liver cysts (type V) are very rare.
CHAPTER 393

Diseases of the Gallbladder

Frederick J. Suchy, Amy G. Feldman

The incidence of gallbladder disease, particularly cholelithiasis and biliary

dyskinesia, has been increasing in children, and has been associated with a rise
in the number of cholecystectomies.

Anomalies
The gallbladder is congenitally absent in approximately 0.1% of the population.
Hypoplasia or absence of the gallbladder can be associated with extrahepatic
biliary atresia or cystic fibrosis. Duplication of the gallbladder occurs rarely.
Gallbladder ectopia may occur with a transverse, intrahepatic, left-sided, or
retroplaced location. Multiseptate gallbladder, characterized by the presence of
multiple septa dividing the gallbladder lumen, is another rare congenital
anomaly of the gallbladder.

Acute Hydrops
Table 393.1 lists the conditions associated with hydrops of the gallbladder.

Table 393.1
Conditions Associated With Hydrops of the Gallbladder
Cholelithiasis
Cholecystitis
Kawasaki disease
Streptococcal pharyngitis
Staphylococcal infection
Leptospirosis
 Ascariasis
Threadworm
Sickle cell crisis
Typhoid fever
Thalassemia
Total parenteral nutrition
Prolonged fasting
Viral hepatitis
Sepsis
Henoch-Schönlein purpura
Mesenteric adenitis
Necrotizing enterocolitis

Acute noncalculous, noninflammatory distention of the gallbladder can occur

in infants and children. It is defined by the absence of calculi, bacterial infection,
or congenital anomalies of the biliary system. The disorder may complicate
acute infections and Kawasaki disease, but the cause is often not identified.
Hydrops of the gallbladder may also develop in patients receiving long-term
parenteral nutrition, presumably because of gallbladder stasis during the period
of enteral fasting. Hydrops is distinguished from acalculous cholecystitis by the
absence of a significant inflammatory process and is a generally benign
prognosis.
Affected patients usually have right upper quadrant pain with a palpable mass.
Fever, vomiting, and jaundice may be present and are usually associated with a
systemic illness such as streptococcal infection. Ultrasonography shows a
markedly distended echo-free gallbladder, without dilation of the biliary tree.
Acute hydrops is usually treated conservatively with a focus on supportive care
and managing the intercurrent illness; cholecystostomy and drainage are rarely
needed. Spontaneous resolution and return of normal gallbladder function
usually occur over a period of several weeks. If a laparotomy is required, a large
edematous gallbladder is found to contain white, yellow, or green bile.
Obstruction of the cystic duct by mesenteric adenopathy is occasionally
observed. Cholecystectomy is required if the gallbladder is gangrenous.
Pathologic examination of the gallbladder wall shows edema and mild
inflammation. Cultures of bile are usually sterile.

Cholecystitis and Cholelithiasis

Acute acalculous cholecystitis is uncommon in children and is usually caused by
infection. Pathogens include streptococci (groups A and B), Gram-negative
organisms―particularly Salmonella and Leptospira interrogans ―and a number
of viral infections (hepatitis A, Epstein-Barr [EB] virus, and cytomegalovirus).
Parasitic infestation with Ascaris or Giardia lamblia may be found. Acalculous
cholecystitis may be associated with abdominal trauma or burn injury or with a
severe systemic illness such as leukemia, end-stage liver disease, and systemic
vasculitis.
Clinical features include right upper quadrant or epigastric pain, nausea,
vomiting, fever, and jaundice. Right upper quadrant guarding and tenderness are
present. Ultrasonography discloses an enlarged, thick-walled gallbladder without
calculi. Serum alkaline phosphatase activity and direct-reacting bilirubin levels
are elevated. Leukocytosis is usual.
Patients may recover with treatment of systemic and biliary infection. Because
the gallbladder can become gangrenous, daily ultrasonography is useful in
monitoring gallbladder distention and wall thickness. Cholecystectomy is
required in patients who fail to improve with conservative management.
Cholecystostomy drainage is an alternative approach in a critically ill patient.
Cholelithiasis is relatively rare in otherwise healthy children, occurring more
commonly in patients with various predisposing disorders (Table 393.2 ).
Gallstones are rarely detected by ultrasonography in the fetus, but generally
remain asymptomatic and resolve spontaneously during the 1st yr of life. In an
ultrasonographic survey of 1570 children (ages 6-19 yr) the overall prevalence
of gallstone disease was 0.13% (0.27% in female subjects). Older reports
consistently found that >70% of gallstones were the pigment type, 15–20% were
cholesterol stones, and the remainder were composed of a mixture of cholesterol,
organic matrix, and calcium bilirubinate. Black pigment gallstones, composed
mostly of calcium bilirubinate and glycoprotein matrix, are a frequent
complication of chronic hemolytic anemias. However, because of obesity,
cholesterol gallstones predominate in children, while the number of patients with
hemolytic anemia-associated gallstones have remained stable.

Table 393.2
Conditions Associated With Cholelithiasis
Chronic hemolytic disease (sickle cell anemia, spherocytosis, thalassemia, Gilbert disease)
Ileal resection or disease
Cystic fibrosis
Cirrhosis
Cholestasis
Crohn disease
Obesity
 Insulin resistance
Prolonged parenteral nutrition
Prematurity with complicated medical or surgical course
Prolonged fasting or rapid weight reduction
Treatment of childhood cancer
Abdominal surgery
Pregnancy
Sepsis
Genetic (ABCB4, ABCG5/G8) progressive familial intrahepatic cholestasis
Cephalosporins

Brown pigment stones form mostly in infants as a result of biliary tract

infection. Unconjugated bilirubin is the predominant component, formed by the
high β-glucuronidase activity of infected bile. Cholesterol gallstones are
composed purely of cholesterol or contain >50% cholesterol along with a mucin
glycoprotein matrix and calcium bilirubinate. Calcium carbonate stones have
also been described in children.
Patients with hemolytic disease (including sickle cell anemia, the
thalassemias, and red blood cell enzymopathies) and Wilson disease are at
increased risk for black pigment cholelithiasis. In sickle cell disease, pigment
gallstones can develop before age 4 yr and have been reported in 17–33% of
patients 2-18 yr of age. Genetic variation in the promoter of uridine diphosphate-
glucuronosyltransferase 1A1 (the [TA]7/[TA]7 and [TA]7/[TA]8 genotypes)
underlies Gilbert syndrome , a relatively common, chronic form of
unconjugated hyperbilirubinemia, and is a risk factor for pigment gallstone
formation in sickle cell disease.
Cirrhosis and chronic cholestasis also increase the risk for pigment gallstones.
Sick premature infants may also have gallstones; their treatment is often
complicated by such factors as bowel resection, necrotizing enterocolitis,
prolonged parenteral nutrition without enteral feeding, cholestasis, frequent
blood transfusions, and use of diuretics. Cholelithiasis in premature infants is
often asymptomatic and may resolve spontaneously. Brown pigment stones are
found in infants with obstructive jaundice and infected intra- and extrahepatic
bile ducts. These stones are usually radiolucent, owing to a lower content of
calcium phosphate and carbonate and a higher amount of cholesterol than in
black pigment stones. MDR3 deficiency caused by ABCB4 mutations is a
cholestatic syndrome related to impaired biliary phospholipid excretion. It is
associated with symptomatic and recurring cholelithiasis. Patients may show
intrahepatic lithiasis, sludge, or microlithiasis along the biliary tree.
Obesity has assumed an increasingly important role as a risk factor for
cholesterol cholelithiasis in children, particularly in adolescent girls. Cholesterol
CHAPTER 394

Portal Hypertension and Varices

Amy G. Feldman, Frederick J. Suchy

Portal hypertension, defined as an elevation of portal pressure >10-12 mm Hg or

a hepatic venous pressure gradient >4 mm Hg, is a major cause of morbidity and
mortality in children with liver disease. Portal hypertension occurs when there is
increased portal resistance or increased blood flow through the portal system.
When portal hypertension occurs, children can develop varices, splenomegaly,
ascites, and gastrointestinal bleeding.

Etiology
Portal hypertension can result from obstruction to portal blood flow anywhere
along the course of the portal venous system (prehepatic, intrahepatic, or
posthepatic). Table 394.1 outlines the various disorders associated with portal
hypertension.

Table 394.1
Causes of Portal Hypertension
EXTRAHEPATIC PORTAL HYPERTENSION
Portal vein agenesis, atresia, stenosis
Portal vein thrombosis or cavernous transformation
Splenic vein thrombosis
Increased portal flow
Arteriovenous fistula
INTRAHEPATIC PORTAL HYPERTENSION
Hepatocellular disease
Acute and chronic viral hepatitis
Cirrhosis
Congenital hepatic fibrosis
Wilson disease
 α1 -Antitrypsin deficiency
Glycogen storage disease type IV
Hepatotoxicity
Methotrexate
Parenteral nutrition
Biliary tract disease
Extrahepatic biliary atresia
Cystic fibrosis
Choledochal cyst
Sclerosing cholangitis
Intrahepatic bile duct paucity
Idiopathic portal hypertension
Postsinusoidal obstruction
Budd-Chiari syndrome
Venoocclusive disease

Portal vein thrombosis is the most common cause of extrahepatic portal

hypertension. The obstruction can occur at any level of the portal vein. In
neonates, portal vein thrombosis can occur from umbilical infection (omphalitis)
with or without a history of catheterization of the umbilical vein, dehydration,
and/or sepsis. Rare developmental anomalies producing extrahepatic portal
hypertension include agenesis, atresia, stenosis, or a web of the portal vein. In
older children, portal vein thrombosis can occur with intraabdominal infection
(appendicitis, peritonitis, pancreatitis), inflammatory bowel disease, primary
sclerosing cholangitis, or biliary infection. Portal vein thrombosis is also
associated with hypercoagulable states, such as deficiencies of factor V Leiden,
protein C, or protein S. The portal vein can be replaced by a fibrous remnant or
contain an organized thrombus. At least half of reported cases have no defined
cause. Uncommonly, presinusoidal hypertension can be caused by increased
flow through the portal system as a result of a congenital or acquired
arteriovenous fistula.
The intrahepatic causes of portal hypertension are numerous. The most
common cause of portal hypertension in children is cirrhosis. The numerous
causes of cirrhosis include recognized disorders such as biliary atresia,
autoimmune hepatitis, chronic viral hepatitis, and metabolic liver disease such as
α1 -antitrypsin deficiency, Wilson disease, glycogen storage disease type IV,
hereditary fructose intolerance, and cystic fibrosis.
Portal infiltration with malignant cells or granulomas can also contribute. An
idiopathic form of portal hypertension characterized by splenomegaly,
hypersplenism, and portal hypertension without occlusion of portal or splenic
veins and with no obvious disease in the liver has been described. In some
patients, noncirrhotic portal fibrosis has been observed.
CHAPTER 397

Ascites
Asim Maqbool, Jessica W. Wen, Chris A. Liacouras

Ascites is the pathologic accumulation of fluid within the peritoneal cavity.

Multiple causes of ascites have been described in different age groups (Tables
397.1 to 397.3 ). In children, hepatic and renal disease are the most common
causes, but ascites can also be caused by cardiac disease, trauma, infection, or
neoplasia.

Table 397.1
Causes of Fetal Ascites
Gastrointestinal disorders
Meconium peritonitis
Intestinal malrotation
Small intestinal or colonic atresia
Intussusception
Volvulus
Cystic fibrosis
Biliary atresia
Portal venous malformations
Infection
Parvovirus
Syphilis
Cytomegalovirus
Toxoplasmosis
Acute maternal hepatitis
Genitourinary disorders
Hydronephrosis
Polycystic kidney disease
Urinary obstruction
Ovarian cyst
Persistent cloaca
Chylous ascites
Cardiac disorders
Arrhythmia
Heart failure
 Chromosomal abnormalities
Trisomy
Turner syndrome
Neoplasm
Hematologic
Hemolytic anemia
Neonatal hemochromatosis
Metabolic disease
Niemann-Pick type C
Congenital disorders of glycosylation
Wolman disease
Lysosomal storage disease
Other
Maternal/fetal abuse
Idiopathic
From Giefer MJ, Murray KF, Colletti RB: Pathophysiology, diagnosis, and management of
pediatric ascites, J Pediatr Gastroenterol Nutr 52(5):503–513, 2011 (Table 1).

Table 397.2
Causes of Neonatal Ascites
Hepatobiliary disorders
Cirrhosis
Alpha-1-antitrypsin deficiency
Congenital hepatic fibrosis
Viral hepatitis
Budd-Chiari syndrome
Biliary atresia
Bile duct perforation
Portal venous malformation
Ruptured mesenchymal hamartoma
Gastrointestinal disorders
Intestinal malrotation
Intestinal perforation
Acute appendicitis
Intestinal atresia
Pancreatitis
Chylous ascites
Intestinal lymphangiectasia
Lymphatic duct obstruction
Lymphatic duct trauma
Parenteral nutrition extravasation
Metabolic disease
Genitourinary disorders
Obstructive uropathy
Posterior urethral valves
Ureterocele
Lower ureteral stenosis
Ureteral atresia
Imperforate hymen
Bladder rupture
 Bladder injury from umbilical artery catheterization
Nephrotic syndrome
Ruptured corpus luteum cyst
Cardiac
Arrhythmia
Heart failure
Hematologic
Neonatal hemochromatosis
Other
Cutis marmorata telangiectatica congenita
Intravenous vitamin E
Pseudo-ascites
Small bowel duplication
Abdominal trauma
Idiopathic
From Giefer MJ, Murray KF, Colletti RB: Pathophysiology, diagnosis, and management of
pediatric ascites, J Pediatr Gastroenterol Nutr 52(5):503–513, 2011 (Table 2).

Table 397.3
Causes of Ascites in Infants and Children
Hepatobiliary disorders Neoplasm Neoplasm
Cirrhosis Lymphoma
Congenital hepatic fibrosis Wilms tumor
Acute hepatitis Clear cell renal sarcoma
Budd-Chiari syndrome Glioma
Bile duct perforation Germ cell tumor
Liver transplantation Ovarian tumor
Gastrointestinal disorders Mesothelioma
Acute appendicitis Neuroblastoma
Intestinal atresia Metabolic disease
Pancreatitis Genitourinary disorders
Pyloric duplication Nephrotic syndrome
Serositis Peritoneal dialysis
Crohn disease Cardiac
Eosinophilic enteropathy Heart failure
Henoch-Schönlein purpura Pseudo-ascites
Chylous ascites Celiac disease
Intestinal lymphangiectasia Cystic mesothelioma
Lymphatic duct obstruction Omental cyst
Lymphatic duct trauma Ovarian cyst
Parenteral nutrition extravasation Other
Infectious Systemic lupus erythematosus
Tuberculosis Ventriculoperitoneal shunt
Abscess Vitamin A toxicity
Schistosomiasis Chronic granulomatous disease
Nonaccidental trauma
Protein losing enteropathy
Idiopathic
Modified from Giefer MJ, Murray KF, Colletti RB: Pathophysiology, diagnosis, and management of
pediatric ascites, J Pediatr Gastroenterol Nutr 52(5):503–513, 2011 (Table 3).
clubbing is a sign of chronic hypoxia and chronic lung disease (Fig. 400.3 ) but
may be a result of nonpulmonary etiologies (Table 400.2 ).

Table 400.1
Respiratory Sounds

BASIC
MECHANISMS ORIGIN ACOUSTICS RELEVANCE
SOUNDS
Lung Turbulent flow, Central (expiration), Low pass filtered noise (<100 to Regional
vortices, other lobar to segmental >1,000 Hz) ventilation,
airways (inspiration) airway caliber
Tracheal Turbulent flow, Pharynx, larynx, trachea, Noise with resonances (<100 to Upper airway
flow impinging on large airways >3,000 Hz) configuration
airway walls
ADVENTITIOUS SOUNDS
Wheezes Airway wall flutter, Central and lower Sinusoidal (<100 to >1,000 Hz, Airway
vortex shedding, airways duration typically >80 msec) obstruction, flow
other limitation
Rhonchi Rupture of fluid Larger airways Series of rapidly dampened Secretions,
films, airway wall sinusoids (typically <300 Hz and abnormal airway
vibration duration <100 msec) collapsibility
Crackles Airway wall stress- Central and lower Rapidly dampened wave Airway closure,
relaxation airways deflections (duration typically <20 secretions
msec)
Modified from Pasterkamp H, Kraman SS, Wodicka GR: Respiratory sounds. Advances beyond
the stethoscope, Am J Respir Crit Care Med 156[3]:974–987, 1997.

FIG. 400.3 A, Normal and clubbed finger viewed in profile. B, The normal
finger demonstrates a distal phalangeal finger depth (DPD)
/interphalangeal finger depth (IPD) ratio <1. The clubbed finger
demonstrates a DPD/IPD ratio >1. C, The normal finger on the left
demonstrates a normal profile (abc) with angle less than 180 degrees. The
clubbed finger demonstrates a profile angle >180 degrees. D, Schamroth
sign is demonstrated in the clubbed finger with the loss of diamond shape
window in between finger beds (arrow) that is demonstrated in the normal
finger. (From Wilmott RW, Bush A, Deterding RR, et al: Kendig's disorders
of the respiratory tract in children , ed 9, Philadelphia, 2019, Elsevier [Fig.
1.14, p. 20].)

Table 400.2
Nonpulmonary Diseases Associated With Clubbing
CARDIAC
 Cyanotic congenital heart disease
Bacterial endocarditis
Chronic heart failure
HEMATOLOGIC
Thalassemia
Congenital methemoglobinemia (rare)
GASTROINTESTINAL
Crohn disease
Ulcerative colitis
Celiac disease
Chronic dysentery, sprue
Polyposis coli
Severe gastrointestinal hemorrhage
Small bowel lymphoma
Liver cirrhosis (including α1 -antitrypsin deficiency)
Chronic active hepatitis
OTHER
Thyroid deficiency (thyroid acropachy)
Thyrotoxicosis
Chronic pyelonephritis (rare)
Toxic (e.g., arsenic, mercury, beryllium)
Lymphomatoid granulomatosis
Fabry disease
Raynaud disease, scleroderma
Hodgkin disease
Familial
UNILATERAL CLUBBING
Vascular disorders (e.g., subclavian arterial aneurysm, brachial arteriovenous fistula)
Subluxation of shoulder
Median nerve injury
Local trauma
From Pasterkamp H: The history and physical examination. In Wilmott RW, Boat TF, Bush A, et al,
editors: Kendig and Chernick's disorders of the respiratory tract in children, ed 8, Philadelphia,
2012, Elsevier.

Blood Gas Analysis

The main function of the respiratory system is to remove carbon dioxide from
and add oxygen to the systemic venous blood brought to the lung. The
composition of the inspired gas, ventilation, perfusion, diffusion, and tissue
metabolism has a significant influence on the arterial blood gases.
The total pressure of the atmosphere at sea level is 760 torr. With increasing
altitude, the atmospheric pressure decreases. The total atmospheric pressure is
equal to the sum of partial pressures exerted by each of its component gases.
Alveolar air is 100% humidified, so in alveolar gas calculations, the inspired gas
is also presumed to be 100% humidified. At a temperature of 37°C (98.6°F) and
center and ineffective neuromuscular function, resulting in respiratory
insufficiency. Such patients can be easily distinguished from those with airway
obstruction by their poor respiratory effort.

Table 400.3

Interpretation of Arterial Blood Gas Values

LESION EFFECT TYPICAL ABG
Central (above the carina) Uniform alveolar Early increase in PCO 2 .
airway obstruction, or hypoventilation Proportionate decrease in PO 2 depending on
Depressed respiratory center, or alveolar air equation
Ineffective neuromuscular Response to supplemental oxygen: Excellent
function
Intrapulmonary airway obstruction Venous admixture Mild: ↓ PCO 2 , ↓ PO 2 .
mismatch Moderate: “normal” PCO 2 , ↓↓ PO 2 .
Severe: ↑↑ PCO 2 , ↓↓↓ PO 2 .
Response to supplemental oxygen: good
Alveolar–interstitial pathology Diffusion defect R → Early decrease in PO 2 depending on severity
L shunt Normal or low PCO 2 , ↑ PCO 2 if fatigue
develops
Response to supplemental oxygen: fair to
poor
ABG , Arterial blood gas.

In intrapulmonary airway obstruction (asthma, bronchiolitis), blood gases

reflect ventilation-perfusion imbalance and venous admixture. In these diseases,
the obstruction is not uniform throughout the lungs, resulting in areas that are
hyperventilated and others that are hypoventilated. Pulmonary capillary blood
coming from hyperventilated areas has a higher PO 2 and lower PCO 2 , whereas
that coming from hypoventilated regions has a lower PO 2 and higher PCO 2 . A
lower blood PCO 2 can compensate for the higher PCO 2 because the Hb-CO2
dissociation curve is relatively linear. In mild disease, the hyperventilated areas
predominate, resulting in hypocarbia. An elevated PaO 2 in hyperventilated areas
cannot compensate for the decreased PaO 2 in hypoventilated areas because of the
shape of the O2 -Hb dissociation curve. This results in venous admixture, arterial
desaturation, and decreased PaO 2 (see Fig. 400.4 ). With increasing disease
severity, more areas become hypoventilated, resulting in normalization of PaCO 2
with a further decrease in PaO 2 . A normal or slightly elevated PaCO 2 in asthma
should be viewed with concern as a potential indicator of impending respiratory
failure. In severe intrapulmonary airway obstruction, hypoventilated areas
Table 401.1 . If none of these findings is detected, the chronic respiratory
process is likely to be benign. Active, well-nourished, and appropriately growing
infants who present with intermittent noisy breathing but no other physical or
laboratory abnormalities require only symptomatic treatment and parental
reassurance. Benign-appearing but persistent symptoms are occasionally the
harbinger of a serious lower respiratory tract problem. By contrast, occasionally
children (e.g., with infection-related asthma) have recurrent life-threatening
episodes but few or no symptoms in the intervals. Repeated examinations over
an extended period, both when the child appears healthy and when the child is
symptomatic, may be helpful in sorting out the severity and chronicity of lung
disease.

Table 401.1
Indicators of Serious Chronic Lower Respiratory Tract
Disease in Children
Persistent fever
Ongoing limitation of activity
Failure to grow
Failure to gain weight appropriately
Clubbing of the digits
Persistent tachypnea and labored ventilation
Shortness of breath and exercise intolerance
Chronic purulent sputum
Persistent hyperinflation
Substantial and sustained hypoxemia
Refractory infiltrates on chest x-ray
Persistent pulmonary function abnormalities
Hemoptysis
Family history of heritable lung disease
Cyanosis and hypercarbia
Unusual (opportunistic) or recurrent nonpulmonary infections

Recurrent or Persistent Cough

Cough is a reflex response of the lower respiratory tract to stimulation of irritant
or cough receptors in the airways’ mucosa. The most common cause of recurrent
or persistent cough in children is airway reactivity (asthma). Because cough
receptors also reside in the pharynx, paranasal sinuses, stomach, and external
auditory canal, the source of a persistent cough may need to be sought beyond
the lungs. Specific lower respiratory stimuli include excessive secretions,
aspirated foreign material, inhaled dust particles or noxious gases, cold or dry
air, and an inflammatory response to infectious agents or allergic processes.
Table 401.2 lists some of the conditions responsible for chronic cough. Table
401.3 presents characteristics of cough that can aid in distinguishing a cough's
origin. Additional useful information can include a history of atopic conditions
(asthma, eczema, urticaria, allergic rhinitis), a seasonal or environmental
variation in frequency or intensity of cough, and a strong family history of atopic
conditions, all suggesting an allergic cause; symptoms of malabsorption or
family history indicating cystic fibrosis; symptoms related to feeding, suggesting
aspiration or gastroesophageal reflux; a choking episode, suggesting foreign-
body aspiration; headache or facial edema associated with sinusitis; and a
smoking history in older children and adolescents or the presence of a smoker in
the home (Table 401.4 ).

Table 401.2
Differential Diagnosis of Recurrent and Persistent Cough in
Children
RECURRENT COUGH
Reactive airway disease (asthma)
Drainage from upper airways
Aspiration
Frequently recurring respiratory tract infections in immunocompetent or immunodeficient patients
Symptomatic Chiari malformation
Idiopathic pulmonary hemosiderosis
Hypersensitivity (allergic) pneumonitis
PERSISTENT COUGH
Hypersensitivity of cough receptors after infection
Reactive airway disease (asthma)
Chronic sinusitis
Chronic rhinitis (allergic or nonallergic)
Bronchitis or tracheitis caused by infection or smoke exposure
Bronchiectasis, including cystic fibrosis, primary ciliary dyskinesia, immunodeficiency
Habit cough
Foreign-body aspiration
Recurrent aspiration owing to pharyngeal incompetence, tracheolaryngoesophageal cleft, or tracheoesophageal
fistula
Gastroesophageal reflux, with or without aspiration
Pertussis
Extrinsic compression of the tracheobronchial tract (vascular ring, neoplasm, lymph node, lung cyst)
Tracheomalacia, bronchomalacia
Endobronchial or endotracheal tumors
Endobronchial tuberculosis
Hypersensitivity pneumonitis
Fungal infections
Inhaled irritants, including tobacco smoke
 Irritation of external auditory canal
Angiotensin-converting enzyme inhibitors

Table 401.3

Characteristics of Cough and Other Clinical Features and Possible Causes

SYMPTOMS AND SIGNS POSSIBLE UNDERLYING ETIOLOGY*
Auscultatory findings (wheeze, Asthma, bronchitis, pneumonia, congenital lung disease,
crepitations/crackles, differential breath sounds) foreign body aspiration, airway abnormality
Cough characteristics (e.g., cough with choking, Congenital airway or lung abnormalities
cough quality, cough starting from birth)
Cardiac abnormalities (including murmurs) Any cardiac illness
Chest pain Asthma, functional, pleuritis
Chest wall deformity Any chronic lung disease, neuromuscular disorders
Daily moist or productive cough Chronic bronchitis, suppurative lung disease
Digital clubbing Suppurative lung disease, arteriovenous shunt
Dyspnea (exertional or at rest) Compromised lung function of any chronic lung or cardiac
disease
Failure to thrive Compromised lung function, immunodeficiency, cystic
fibrosis
Feeding difficulties (including choking and Compromised lung function, aspiration, anatomic disorders
vomiting)
Hemoptysis Bronchitis, foreign body aspiration, suctioning trauma,
pulmonary hemorrhage
Immune deficiency Atypical and typical recurrent respiratory or nonrespiratory
infections
Medications or drugs Angiotensin-converting enzyme inhibitors, puffers, illicit
drug use
Neurodevelopmental abnormality Aspiration
Recurrent pneumonia Immunodeficiency, congenital lung problem, airway
abnormality
Symptoms of upper respiratory tract infection Can coexist or be a trigger for an underlying problem
* This is not an exhaustive list; only the more common respiratory diseases are mentioned.

Modified from Chang AB, Landau LI, Van Asperen PP, et al: Cough in children: definitions and
clinical evaluation. Thoracic Society of Australia and New Zealand, Med J Aust 184(8):398–403,
2006, Table 2, p. 399.

Table 401.4

Clinical Clues About Cough

CHARACTERISTIC THINK OF
Staccato, paroxysmal Pertussis, cystic fibrosis, foreign body, Chlamydia spp., Mycoplasma spp.
Followed by “whoop” Pertussis
All day, never during Habit cough
sleep
Barking, brassy Croup, habit cough, tracheomalacia, tracheitis, epiglottitis
 Hoarseness Laryngeal involvement (croup, recurrent laryngeal nerve involvement), papillomatosis
Abrupt onset Foreign body, pulmonary embolism
During or following Reactive airway disease
exercise
Accompanies eating, Aspiration, gastroesophageal reflux, tracheoesophageal fistula
drinking
Throat clearing Postnasal drip, vocal tic
Productive (sputum) Infection, cystic fibrosis, bronchiectasis
Night cough Sinusitis, reactive airway disease, gastroesophageal reflux
Seasonal Allergic rhinitis, reactive airway disease
Immunosuppressed Bacterial pneumonia, Pneumocystis jiroveci , Mycobacterium tuberculosis ,
patient Mycobacterium avium-intracellulare , cytomegalovirus, fungi
Dyspnea Hypoxia, hypercarbia
Animal exposure Chlamydia psittaci (birds), Yersinia pestis (rodents), Francisella tularensis (rabbits), Q
fever (sheep, cattle), hantavirus (rodents), histoplasmosis (pigeons)
Geographic Histoplasmosis (Mississippi, Missouri, Ohio River Valley), coccidioidomycosis
(Southwest), blastomycosis (North and Midwest)
Workdays with Occupational exposure
clearing on days off
From Kliegman RM, Greenbaum LA, Lyle PS: Practical strategies in pediatric diagnosis and
therapy, ed 2, Philadelphia, 2004, WB Saunders, p. 19.

The physical examination can provide much information pertaining to the

cause of chronic cough. Posterior pharyngeal drainage combined with a
nighttime cough suggests chronic upper airway disease such as sinusitis. An
overinflated chest suggests chronic airway obstruction, as in asthma or cystic
fibrosis. An expiratory wheeze, with or without diminished intensity of breath
sounds, strongly suggests asthma or asthmatic bronchitis, but may also be
consistent with a diagnosis of cystic fibrosis, bronchomalacia, vascular ring,
aspiration of foreign material, or pulmonary hemosiderosis. Careful auscultation
during forced expiration may reveal expiratory wheezes that are otherwise
undetectable and that are the only indication of underlying reactive airways.
Coarse crackles suggest bronchiectasis, including cystic fibrosis, but can also
occur with an acute or subacute exacerbation of asthma. Clubbing of the digits is
seen in most patients with bronchiectasis but in only a few other respiratory
conditions with chronic cough (see Table 401.2 ). Tracheal deviation suggests
foreign body aspiration, pleural effusion, or a mediastinal mass.
Allowing sufficient examination time to detect a spontaneous cough is
important. If a spontaneous cough does not occur, asking the child to take a
maximal breath and forcefully exhale repeatedly usually induces a cough reflex.
Most children can cough on request by 4-5 yr of age. Children who cough as
often as several times a minute with regularity are likely to have a habit (tic)
cough (see Chapter 37 ). If the cough is loose, every effort should be made to
obtain sputum; many older children can comply. It is sometimes possible to pick
for a specific anatomic cause of abnormal breath sounds, it is not uncommon to
identify additional congenital anomalies of the airway. An accompanying history
of hoarseness or aphonia suggests involvement of the vocal cords. Associated
dysphagia may also suggest a vascular ring. In a child with intermittent stridor
(with wheezing) that accompanies physical activity and is not responsive to
asthma therapies, paradoxical vocal cord dysfunction may be of consideration.
Paradoxical vocal cord dysfunction may be highly supported by history and
confirmed by laryngoscopy during an exercise challenge test if symptoms are
successfully elicited. Speech therapy and behavior modification may be
therapeutic.

Table 401.5
Causes of Recurrent or Persistent Stridor in Children
RECURRENT
Allergic (spasmodic) croup
Respiratory infections in a child with otherwise asymptomatic anatomic narrowing of the large airways
Laryngomalacia
PERSISTENT
Laryngeal obstruction
• Laryngomalacia
• Papillomas, hemangiomas, other tumors
• Cysts and laryngoceles
• Laryngeal webs
• Bilateral abductor paralysis of the cords
• Foreign body
Tracheobronchial disease
• Tracheomalacia
• Subglottic tracheal webs
• Endobronchial, endotracheal tumors
• Subglottic tracheal stenosis, congenital or acquired
Extrinsic masses
• Mediastinal masses
• Vascular ring
• Lobar emphysema
• Bronchogenic cysts
• Thyroid enlargement
• Esophageal foreign body
Tracheoesophageal fistula
OTHER
Gastroesophageal reflux
Macroglossia, Pierre Robin syndrome
Cri-du-chat syndrome
Paradoxical vocal cord dysfunction
Hypocalcemia
Vocal cord paralysis
Chiari crisis
Severe neonatal episodic laryngospasm caused by SCN4A mutation
should suggest foreign-body aspiration.
Either wheezing or coughing when associated with tachypnea and hypoxemia
may be suggestive of interstitial lung disease (see Chapter 427.5 ). However,
many patients with interstitial lung disease demonstrate no symptoms other than
rapid breathing on initial physical examination. Although chest roentgenograms
may be normal in interstitial lung disease, diffuse abnormalities on chest X-ray
may support further evaluation in patients suspected to have interstitial lung
disease with characteristic findings described on high-resolution CT scan and
lung biopsy.
Repeated examination may be required to verify a history of wheezing in a
child with episodic symptoms and should be directed toward assessing air
movement, ventilatory adequacy, and evidence of chronic lung disease, such as
fixed overinflation of the chest, growth failure, and digital clubbing. Patients
should be assessed for oropharyngeal dysphagia in cases of suspected recurrent
aspiration. Clubbing suggests chronic lung infection and is rarely prominent in
uncomplicated asthma. Tracheal deviation from foreign body aspiration should
be sought. It is essential to rule out wheezing secondary to congestive heart
failure. Allergic rhinitis, urticaria, eczema, or evidence of ichthyosis vulgaris
suggests asthma or asthmatic bronchitis. The nose should be examined for
polyps, which can exist with allergic conditions or cystic fibrosis.
Sputum eosinophilia and elevated serum immunoglobulin E levels suggest
allergic reactions. A forced expiratory volume in 1 sec increase of 15% in
response to bronchodilators confirms reactive airways. Specific microbiologic
studies, special imaging studies of the airways and cardiovascular structures,
diagnostic studies for cystic fibrosis, and bronchoscopy should be considered if
the response is unsatisfactory.

Recurrent and Persistent Lung Infiltrates

Radiographic lung infiltrates resulting from acute pneumonia usually resolve
within 1-3 wk, but a substantial number of children, particularly infants, fail to
completely clear infiltrates within a 4 wk period. These children may be febrile
or afebrile, and may display a wide range of respiratory symptoms and signs.
Persistent or recurring infiltrates present a diagnostic challenge (Table 401.6 ).

Table 401.6
Diseases Associated With Recurrent, Persistent, or
Migrating Lung Infiltrates Beyond the Neonatal Period
Aspiration
Pharyngeal incompetence (e.g., cleft palate)
Laryngotracheoesophageal cleft
Tracheoesophageal fistula
Gastroesophageal reflux
Lipid aspiration
Neurologic dysphagia
Developmental dysphagia
Congenital anomalies
Lung cysts (cystic adenomatoid malformation)
Pulmonary sequestration
Bronchial stenosis or aberrant bronchus
Vascular ring
Congenital heart disease with large left-to-right shunt
Pulmonary lymphangiectasia
Genetic conditions
α1 -Antitrypsin deficiency
Cystic fibrosis
Primary ciliary dyskinesia (including Kartagener syndrome)
Sickle cell disease (acute chest syndrome)
Immunodeficiency, phagocytic deficiency
Humoral, cellular, combined immunodeficiency states
Chronic granulomatous disease and related phagocytic defects
Hyper immunoglobulin E syndromes
Complement deficiency states
Immunologic and autoimmune diseases
Asthma
Allergic bronchopulmonary aspergillosis
Hypersensitivity pneumonitis
Pulmonary hemosiderosis
Collagen-vascular diseases
Infection, congenital
Cytomegalovirus
Rubella
Syphilis
Infection, acquired
Cytomegalovirus
Tuberculosis
HIV
Other viruses
Chlamydia
Mycoplasma, Ureaplasma
Pertussis
Fungal organisms
Pneumocystis jiroveci
Visceral larva migrans
Inadequately treated bacterial infection
Interstitial pneumonitis and fibrosis
Usual interstitial pneumonitis
Lymphoid (AIDS)
Genetic disorders of surfactant synthesis, secretion
 Desquamative
Acute (Hamman-Rich)
Alveolar proteinosis
Drug-induced, radiation-induced inflammation and fibrosis
Neoplasms and neoplastic-like conditions
Primary or metastatic pulmonary tumors
Leukemia
Histiocytosis
Eosinophilic pneumonias
Other etiologies
Bronchiectasis
Congenital
Postinfectious
Sarcoidosis

Symptoms associated with chronic lung infiltrates in the 1st several weeks of
life (but not related to neonatal respiratory distress syndrome) suggest infection
acquired in utero or during descent through the birth canal. Early appearance of
chronic infiltrates can also be associated with cystic fibrosis or congenital
anomalies that result in aspiration or airway obstruction. A history of recurrent
infiltrates such as in middle lobe syndrome (see Chapters 430 and 437 ),
wheezing, and cough may reflect asthma, even in the 1st yr of life.
A controversial association has been posed regarding recurrent lung infiltrates
in pulmonary hemosiderosis related to cow's milk hypersensitivity or unknown
causes appearing in the 1st yr of life. Children with a history of
bronchopulmonary dysplasia often have episodes of respiratory distress attended
by wheezing and new lung infiltrates. Recurrent pneumonia in a child with
frequent otitis media, nasopharyngitis, adenitis, or dermatologic manifestations
suggests an immunodeficiency state, complement deficiency, or phagocytic
defect (see Chapters 148 , 156 , and 160 ). Primary ciliary dyskinesia is also of
consideration in patients with frequent otitis media and suppurative
sinopulmonary disease, with or without accompanying heterotaxy, or history of
neonatal respiratory distress (see Chapter 433 ). Pulmonary sequestration may be
suspected in patients with recurrent findings on radiograph that occur in the
same location, both during illness and when well (see Chapter 423 ). Traction
bronchiectasis may also be suggested on radiography with persistent findings in
a given region of the film following a history of respiratory infection. Particular
attention must be directed to the possibility that the infiltrates represent
lymphocytic interstitial pneumonitis or opportunistic infection associated with
HIV infection (see Chapter 302 ). A history of paroxysmal coughing in an infant
suggests pertussis syndrome or cystic fibrosis. Persistent infiltrates, especially
with loss of volume, in a toddler may suggest foreign-body aspiration.
401.1
Extrapulmonary Diseases With
Pulmonary Manifestations
Susanna A. McColley

Respiratory symptoms commonly originate from extrapulmonary processes. The

respiratory system adapts to metabolic demands and is exquisitely responsive to
cortical input; therefore, tachypnea is common in the presence of metabolic
stress such as fever, whereas dyspnea may be related to anxiety. Cough most
commonly arises from upper or lower respiratory tract disorders, but it can
originate from the central nervous system, as with cough tic or psychogenic
cough, and it can be a prominent symptom in children with gastroesophageal
reflux disease. Chest pain does not commonly arise from pulmonary processes
in otherwise healthy children but more often has a neuromuscular or
inflammatory etiology. Cyanosis can be caused by cardiac or hematologic
disorders, and dyspnea and exercise intolerance can have a number of
extrapulmonary causes. These disorders may be suspected on the basis of the
history and physical examination, or they may be considered in children in
whom diagnostic studies have atypical findings or who show poor response to
usual therapy. Table 401.7 lists more common causes of such symptoms.

Table 401.7
Respiratory Signs and Symptoms Originating From
Outside the Respiratory Tract

SIGN OR NONRESPIRATORY
PATHOPHYSIOLOGY CLUES TO DIAGNOSIS
SYMPTOM CAUSE(S)
Chest pain Cardiac disease Inflammation (pericarditis), Precordial pain, friction rub on
ischemia (anomalous coronary examination; exertional pain,
artery, vascular disease) radiation to arm or neck
Chest pain Gastroesophageal Esophageal inflammation and/or Heartburn, abdominal pain
reflux disease spasm
 Cyanosis Congenital heart Right-to-left shunt Neonatal onset, lack of response to
disease oxygen
Methemoglobinemia Increased levels of methemoglobin Drug or toxin exposure, lack of
interfere with delivery of oxygen to response to oxygen
tissues
Dyspnea Toxin exposure, drug Variable, but often metabolic Drug or toxin exposure confirmed
side effect, or overdose acidosis by history or toxicology screen,
normal oxygen saturation measured
by pulse oximetry
Anxiety, panic disorder Increased respiratory drive and Occurs during stressful situation,
increased perception of respiratory other symptoms of anxiety or
efforts depression
Exercise Anemia Inadequate oxygen delivery to Pallor, tachycardia, history of
intolerance tissues bleeding, history of inadequate diet
Exercise Deconditioning Self-explanatory History of inactivity, obesity
intolerance
Hemoptysis Nasal bleeding Posterior flow of bleeding causes History and physical findings
appearance of pulmonary origin suggest nasal source; normal chest
examination and chest radiography
Upper gastrointestinal Hematemesis mimics hemoptysis History and physical examination
tract bleeding suggest gastrointestinal source;
normal chest examination and chest
radiography
Wheezing, Congenital or acquired Pulmonary overcirculation Murmur
cough, cardiac disease (atrioseptal defect, ventriculoseptal Refractory to bronchodilators
dyspnea defect, patent ductus arteriosus), left Radiographic changes (prominent
ventricular dysfunction pulmonary vasculature, pulmonary
edema)
Wheezing, Gastroesophageal Laryngeal and bronchial response to Emesis, pain, heartburn
cough reflux disease stomach contents
Vagally mediated Refractory to bronchodilators
bronchoconstriction

Evaluation
In the evaluation of a child or adolescent with respiratory symptoms, it is
important to obtain a detailed past medical history, family history, and review of
systems to evaluate the possibility of extrapulmonary origin. A comprehensive
physical examination is also essential in obtaining clues as to extrapulmonary
disease.
Disorders of other organ systems, and many systemic diseases, can have
significant respiratory system involvement. Although it is most common to
encounter these complications in patients with known diagnoses, respiratory
system disease is sometimes the sole or most prominent symptom at the time of
presentation. Acute aspiration during feeding can be the presentation of
neuromuscular disease in an infant who initially appears to have normal muscle
tone and development. Complications can be life-threatening, particularly in
immunocompromised patients. The onset of respiratory findings may be
insidious; for example, pulmonary vascular involvement in patients with
systemic vasculitis may appear as an abnormality in diffusing capacity of the
lung for carbon monoxide before the onset of symptoms. Table 401.8 lists
disorders that commonly have respiratory complications.

Table 401.8

Disorders With Frequent Respiratory Tract Complications

UNDERLYING
RESPIRATORY COMPLICATIONS DIAGNOSTIC TESTS
DISORDER(S)
Autoimmune Pulmonary vascular disease, restrictive lung Spirometry, lung volume determination,
disorders disease, pleural effusion (especially systemic oximetry, diffusing capacity of the lung for
lupus erythematosus), upper airway disease carbon monoxide, chest radiography, upper
(Wegener granulomatosis) airway endoscopy, and/or CT
Central nervous Aspiration of oral or gastric contents Chest radiography, videofluoroscopic
system disease swallowing study, esophageal pH probe,
(static or fiberoptic bronchoscopy
progressive)
Immunodeficiency Infection, bronchiectasis Chest radiography, fiberoptic bronchoscopy,
chest CT
Liver disease Pleural effusion, hepatopulmonary syndrome Chest radiography, assessment of orthodeoxia
Malignancy and Infiltration, metastasis, malignant or infectious Chest radiography, chest CT, fiberoptic
its therapies effusion, parenchymal infection, graft versus bronchoscopy, lung biopsy
host disease (bone marrow transplant)
Neuromuscular Hypoventilation, atelectasis, pneumonia Spirometry, lung volume determination,
disease respiratory muscle force measurements
Obesity Restrictive lung disease, obstructive sleep Spirometry, lung volume determination,
apnea syndrome, asthma nocturnal polysomnography
CT, Computed tomography.

Bibliography
Gaude GS. Hemoptysis in children. Indian Pediatr .
2010;47(3):245–254.
Jindal A, Singhi S. Acute chest pain. Indian J Pediatr .
2011;78(10):1262–1267.
Loughlin GM. Chest pain. Loughlin GM, Eigen H. Respiratory
disease in children: diagnosis and management . Williams &
Wilkins: Baltimore; 1994:207–214.
CHAPTER 402

Sudden Infant Death Syndrome

Fern R. Hauck, Rebecca F. Carlin, Rachel Y. Moon, Carl E. Hunt

Sudden infant death syndrome (SIDS) is defined as the sudden, unexpected

death of an infant that is unexplained by a thorough postmortem examination,
which includes a complete autopsy, investigation of the scene of death, and
review of the medical history. An autopsy is essential to identify possible natural
explanations for sudden unexpected death such as congenital anomalies or
infection and to diagnose traumatic child abuse (Tables 402.1 to 402.3 ; see
Chapter 16 ). The autopsy typically cannot distinguish between SIDS and
intentional suffocation, but the scene investigation and medical history may be
of help if inconsistencies are evident. Sudden unexpected infant death (SUID)
is a term that generally encompasses all SUIDs that occur during sleep,
including SIDS (ICD-10 R95), accidental suffocation and strangulation in bed
(ICD-10 W75), and ill-defined deaths, also known as undetermined (ICD-10
R99).

Table 402.1
Differential Diagnosis of Sudden Unexpected Infant Death

PRIMARY FREQUENCY
CAUSE OF POTENTIAL CONFOUNDING
DIAGNOSTIC DISTRIBUTION
DEATH DIAGNOSES
CRITERIA (%)
EXPLAINED AT AUTOPSY
Natural 18–20*
Infections History, autopsy, and If minimal findings: SIDS 35–46 †
cultures
Congenital anomaly History and autopsy If minimal findings: SIDS 14–24 †
Unintentional injury History, scene Traumatic child abuse 15*
investigation, autopsy
Traumatic child Autopsy and scene Unintentional injury 13–24*
abuse investigation
 Other natural History and autopsy If minimal findings: SIDS, or intentional 12–17*
causes suffocation
UNEXPLAINED AT AUTOPSY
SIDS History, scene Intentional suffocation 80–82
investigation, absence of
explainable cause at
autopsy
Intentional Perpetrator confession, SIDS Unknown, but <5%
suffocation absence of explainable of all SUID
(filicide) cause at autopsy
Accidental History and scene Assigned to ICD-10 code (SIDS) for Varies with
suffocation or investigation, ideally US vital statistics database individual medical
strangulation in bed including doll re- Unexplained examiners and
(ASSB) enactment Undetermined coroners
Genetic mutations SCN5A , SCN1B-4B , May have negative family history Unknown, perhaps
SCN4A, long QT secondary to recessive mutations, de novo <10%
syndromes, plus Table mutation, or incomplete penetrance
402.4
* As a percentage of all sudden unexpected infant deaths explained at autopsy.

† As a percentage of all natural causes of sudden unexpected infant deaths explained at autopsy.

ICD-10, International Classification of Diseases, Version 10; SIDS, sudden infant death syndrome;
SUID, sudden unexpected infant death.
Modified from Hunt CE: Sudden infant death syndrome and other causes of infant mortality:
diagnosis, mechanisms and risk for recurrence in siblings, Am J Respir Crit Care Med
164(3):346–357, 2001.

Table 402.2

Conditions That Can Cause Apparent Life-Threatening Events* or Sudden

Unexpected Infant Death

CENTRAL NERVOUS SYSTEM

Arteriovenous malformation
Subdural hematoma
Seizures
Congenital central hypoventilation
Neuromuscular disorders (Werdnig-Hoffmann disease)
Chiari crisis
Leigh syndrome
CARDIAC
Subendocardial fibroelastosis
Aortic stenosis
Anomalous coronary artery
Myocarditis
Cardiomyopathy
Arrhythmias (prolonged QT syndrome, Wolff-Parkinson-White syndrome, congenital heart block)
PULMONARY
Pulmonary hypertension
Vocal cord paralysis
Aspiration
Laryngotracheal disease
GASTROINTESTINAL
Diarrhea and/or dehydration
Gastroesophageal reflux
Volvulus
ENDOCRINE–METABOLIC
Congenital adrenal hyperplasia
Malignant hyperpyrexia
Long- or medium-chain acyl coenzyme A deficiency
Hyperammonemias (urea cycle enzyme deficiencies)
Glutaric aciduria
Carnitine deficiency (systemic or secondary)
Glycogen storage disease type I
Maple syrup urine disease
Congenital lactic acidosis
Biotinidase deficiency
INFECTION
Sepsis
Meningitis
Encephalitis
Brain abscess
Pyelonephritis
Bronchiolitis (respiratory syncytial virus)
Infant botulism
Pertussis
TRAUMA
Child abuse
Accidental or intentional suffocation
Physical trauma
Factitious syndrome (formerly Munchausen syndrome) by proxy
POISONING (INTENTIONAL OR UNINTENTIONAL)
 Boric acid
Carbon monoxide
Salicylates
Barbiturates
Ipecac
Cocaine
Insulin
Others
*
Recommended terminology now is “brief resolved unexplained events.”

From Kliegman RM, Greenbaum LA, Lye PS: Practical strategies in pediatric
diagnosis and therapy , ed 2, Philadelphia, 2004, Elsevier Saunders, p. 98.

Table 402.3

Differential Diagnosis of Recurrent Sudden Infant Death in a Sibling

IDIOPATHIC
Recurrent sudden infant death syndrome
CENTRAL NERVOUS SYSTEM
Congenital central hypoventilation
Neuromuscular disorders
Leigh syndrome
CARDIAC
Endocardial fibroelastosis
Wolff-Parkinson-White syndrome
Prolonged QT syndrome or other cardiac channelopathy
Congenital heart block
PULMONARY
Pulmonary hypertension
ENDOCRINE–METABOLIC
See Table 402.2
INFECTION
Disorders of immune host defense
CHILD ABUSE
Filicide or infanticide
Factitious syndrome (formerly Munchausen syndrome) by proxy
with both SIDS and other sleep-related SUID, risk reduction measures that will
be later described are applicable to all sleep-related SUID.

Pathology
Although there are no autopsy findings pathognomonic for SIDS and no findings
are required for the diagnosis, there are some that are commonly seen on
postmortem examination. Petechial hemorrhages are found in 68–95% of infants
who died of SIDS and are more extensive than in explained causes of infant
mortality. Pulmonary edema is often present and may be substantial. The reasons
for these findings are unknown. Infants who died of SIDS have higher levels of
vascular endothelial growth factor (VEGF) in the cerebrospinal fluid. These
increases may be related to VEGF polymorphisms (see “Genetic Risk Factors”
later and Table 402.4 ) or might indicate recent hypoxemic events because
VEGF is upregulated by hypoxia.

Table 402.4

Identified Genes for Which the Distribution of Polymorphisms Differs in Sudden

Infant Death Syndrome Infants Compared With Control Infants

CARDIAC CHANNELOPATHIES
Potassium ion channel genes (KCNE2, KCNH2, KCNQ1, KCNJ8)
Sodium ion channel gene (SCN5A) (long QT syndrome 3, Brugada syndrome)
GPD1-L-encoded connexin43 (Brugada syndrome)
SCN3B (Brugada syndrome)
CAV3 (long QT syndrome 9)
SCN4B (long QT syndrome 10)
SNTA-1 (long QT syndrome 11)
RyR2 (catecholaminergic polymorphic ventricular tachycardia)
SEROTONIN (5-HT)
5-HT transporter protein (5-HTT)
Intron 2 of SLC6A4 (variable number tandem repeat [VNTR] polymorphism)
5-HT fifth Ewing variant (FEV) gene
GENES PERTINENT TO DEVELOPMENT OF AUTONOMIC NERVOUS SYSTEM
Paired-like homeobox 2a (PHOX2A)
PHOX2B
Rearranged during transfection factor (RET)
Endothelin converting enzyme-1 (ECE1)
T-cell leukemia homeobox (TLX3)
Engrailed-1 (EN1)
Tyrosine hydroxylase (THO1)
Monamine oxidase A (MAOA)
Sodium/proton exchanger 3 (NHE3) (medullary respiratory control)
INFECTION AND INFLAMMATION
Complement C4A
Complement C4B
Interleukin-1RN (gene encoding IL-1 receptor antagonist [ra]; proinflammatory)
Interleukin-6 (IL-6; proinflammatory)
Interleukin-8 (IL-8; proinflammatory; associated with prone sleeping position)
Interleukin-10 (IL-10)
Vascular endothelial growth factor (VEGF) (proinflammatory)
Tumor necrosis factor (TNF)- α (proinflammatory)
OTHER
Mitochondrial DNA (mtDNA) polymorphisms (energy production)
Flavin-monooxygenase 3 (FMO3) (enzyme metabolizes nicotine; risk factor with smoking mothers)
Aquaporin-4 (T allele and CT/TT genotype associated with maternal smoking and with increased brain/body
weight ratio in SIDS infants)
SCN4A (nondystrophic myotonia, laryngospasm)

Modified from Hunt CE, Hauck FR: Sudden infant death syndrome: gene-
environment interactions. In Brugada R, Brugada J, Brugada P, editors: Clinical
care in inherited cardiac syndromes , Guildford, UK, 2009, Springer-Verlag
London.

SIDS infants have several identifiable changes in the lungs and other organs.
Nearly 65% of these infants have structural evidence of preexisting, chronic,
low-grade asphyxia, and other studies have identified biochemical markers of
asphyxia. Some studies have shown carotid body abnormalities, consistent with
a role for impaired peripheral arterial chemoreceptor function in SIDS.
Numerous studies have shown brain abnormalities that could cause or contribute
to an impaired autonomic response to an exogenous stressor, including in the
hippocampus and brainstem, the latter being the major area responsible for
respiratory and autonomic regulation. The affected brainstem nuclei include the
retrotrapezoid nucleus and the dorsal motor nucleus of the vagus, primary sites
upper airway reflexes. Decreases in 5-HT1A and 5-HT2A receptor
immunoreactivity have been observed in the dorsal nucleus of the vagus, solitary
nucleus, and ventrolateral medulla. There are extensive serotoninergic brainstem
abnormalities in SIDS infants, including increased 5-HT neuronal count, a lower
density of 5-HT1A receptor-binding sites in regions of the medulla involved in
homeostatic function, and a lower ratio of 5-HT transporter (5-HTT) binding
density to 5-HT neuronal count in the medulla. Male SIDS infants have lower
receptor-binding density than do female SIDS infants. Overall, these 5-HT–
related studies suggest that the synthesis and availability of 5-HT are decreased
within 5-HT pathways, and medullary tissue levels of 5-HT and its primary
biosynthetic enzyme (tryptophan hydroxylase) are lower in SIDS infants
compared with age-matched controls.

Environmental Risk Factors

Declines of 50% or more in rates of SIDS in the United States and around the
world have occurred following national education campaigns directed at
reducing risk factors associated with SIDS (Table 402.5 ). Although many risk
factors are nonmodifiable and most of the modifiable factors have not changed
appreciably, self-reported maternal smoking prevalence during pregnancy has
decreased by 25% in the past decade in the United States.

Table 402.5

Risk Factors Associated With Sudden Infant Death Syndrome

MATERNAL AND ANTENATAL RISK FACTORS

Elevated 2nd trimester serum α-fetoprotein
Smoking
Alcohol use
Drug use (cocaine, heroin)
Nutritional deficiency
Inadequate prenatal care
Low socioeconomic status
Younger age
Lower education
Single marital status
 Shorter interpregnancy interval
Intrauterine hypoxia
Fetal growth restriction
INFANT RISK FACTORS
Age (peak 1-4 mo)
Male gender
Race and ethnicity (African American, American Indian, Alaska Native, other minorities)
Growth failure
No breastfeeding
No pacifier (dummy)
Prematurity
Prone and side sleep position
Recent febrile illness (mild infections)
Inadequate immunizations
Smoking exposure (prenatal and postnatal)
Soft sleeping surface, soft bedding
Bed sharing with parent(s) or other children
Thermal stress, overheating
Colder season, no central heating

Nonmodifiable Environmental Risk Factors

Lower socioeconomic status has consistently been associated with higher risk,
although SIDS affects infants from all social strata. In the United States,
African-American, American Indian, and Alaska Native infants are 2-3 times
more likely than white infants to die of SIDS, whereas Asian, Pacific Islander,
and Hispanic infants have the lowest incidence. Some of this disparity may be
related to the higher concentration of poverty and other adverse environmental
factors found within some, but not all, of the communities with higher incidence.
Infants are at greatest risk of SIDS at 1-4 mo of age, with most deaths having
occurred by 6 mo. This characteristic age has decreased in some countries as the
SIDS incidence has declined, with deaths occurring at earlier ages and with a
flattening of the peak age incidence. Similarly, the commonly observed winter
seasonal predominance of SIDS has declined or disappeared in some countries
as prone prevalence has decreased, supporting prior findings of an interaction
between sleep position and factors more common in colder months (overheating
as a consequence of elevated interior temperatures or bundling with blankets and
Epidemiology
The incidence of BRUEs is unknown. However, studies of ALTE patients
provide some insight because BRUEs are a subset of what had been considered
ALTEs. Hospitalization for an ALTE was common; 1 out of every 2.5-9.4/1,000
infants was hospitalized for an ALTE. Acute events that do not lead to
hospitalization are even more common according to large epidemiologic studies
of healthy infants. Of normal infants followed longitudinally with home
monitoring, up to 43% had a 20-sec apnea episode over a 3-mo period. Of
parents asked when their infant was 1 yr of age, 5% recalled an apneic event.
BRUEs are not precursors to SIDS . The incidence of mortality after a BRUE
from an underlying cause is unknown but is also likely to be extremely
uncommon. The few reports of mortality in studies of ALTE are limited to
patients who would not qualify as a BRUE because of the presence of other
symptoms or an explanatory diagnosis.
However, for patients presenting with a BRUE, numerous risks must be
considered. First is the risk of an underlying serious diagnosis. Although each is
rare, clinicians must consider a wide variety of illnesses, such as cardiac
arrhythmias, metabolic disorders, and brain injury (Table 403.1 ). The risk for an
underlying serious diagnosis in patients with a BRUE is much lower than the
rate reported in ALTE research, where many of the patients had underlying
conditions or ongoing symptoms (e.g., lower respiratory tract infection). In
infants meeting lower-risk criteria, the likelihood of an underlying serious cause
is extremely low. In higher-risk infants, the likelihood is unknown but probably
much lower than suggested by research on ALTEs. Second is the risk of a
recurrent event, which is currently unknown. These events can be stressful for
caregivers, particularly when the cause is unknown. Third is the risk that the
caregivers become unnecessarily concerned about their healthy child. Clinicians
should be aware the challenges caregivers face when perceiving a threat of
losing their child, there is medical uncertainty, or when their child is
hospitalized. Fourth are the risks associated with medical care, such as
nosocomial infections and inaccurate testing.

Table 403.1
Symptom-Based Approach to BRUEs: Possible and Other
Conditions That Might Be Confused With BRUE
 COMMON
SUGGESTIVE
AND/OR SUGGESTIVE
DIAGNOSTIC PHYSICAL TESTING TO
CONCERNING HISTORICAL
CATEGORIES EXAMINATION CONSIDER
CAUSES TO FINDINGS
FINDINGS
CONSIDER
Gastrointestinal GER Coughing, Gastric contents in Upper GI to
Intussusception vomiting, the nose and mouth assess for
Volvulus choking, gasping Choking, gagging, anatomic
Oropharyngeal temporally or oxygen anomalies
dysphagia related to feeds desaturation Clinical swallow
or regurgitation temporally related evaluation
of gastric to feeding or Abdominal
contents regurgitation of ultrasound
Feeding gastric contents pH probe
difficulties
Recent preceding
feed
Irritability
following feeds
Milk in
mouth/nose
Bilious emesis
Pulling legs to
chest
Bloody/mucousy
stool
Lethargy
following event
Infectious Upper and lower Preceding URI Fever/hypothermia NP swab for RSV,
respiratory tract symptoms Lethargy pertussis
infection (RSV, Multiple events Ill appearance Chest radiograph
pertussis, on the day of Coryza CBC and blood
pneumonia) presentation Cough culture
Bacteremia Sick exposures Wheeze Cerebrospinal
Meningitis Foul-smelling Tachypnea fluid analysis and
Urinary tract urine culture
infection Urinalysis and
culture
Neurologic Seizures Multiple events Papilledema EEG
Breath holding Loss of Abnormal Neuroimaging
spells consciousness muscular
Congenital Change in tone movements
central Abnormal Hypertonicity or
hypoventilation muscular flaccidity
syndrome movements Abnormal reflexes
Neuromuscular Eye deviation Micro- or
disorders Preceding macrocephaly
Congenital triggers Dysmorphic
malformations features
of the brain and Signs of trauma or
brainstem poisoning (see
Malignancy “Child
Intracranial maltreatment”
hemorrhage below)
Respiratory/ENT Apnea of Prematurity Wheezing Chest radiograph
 prematurity Foreign body Stridor Neck radiograph
Apnea of Aspiration Crackles Laryngoscopy
infancy Noisy breathing Rhonchi Bronchoscopy
Periodic Tachypnea Esophagoscopy
breathing Polysomnography
Airway anomaly
Aspiration
Foreign body
Obstructive
sleep apnea
Child Nonaccidental Multiple events Bruising Skeletal survey
maltreatment head trauma Unexplained (especially in a Computed
Smothering vomiting or nonmobile child) tomography/MRI
Poisoning irritability Ear trauma, of the head
Factitious Recurrent hemotympanum Dilated
syndrome BRUEs Acute abdomen funduscopic
(formerly Historical Painful extremities examination if
Munchausen discrepancies Oral head imaging
syndrome) by Family history of bleeding/trauma concerning for
proxy unexplained Frenulum tears trauma
death, SIDS, or Unexplained Toxicology
BRUEs irritability screen
Single witness of Retinal Social work
event hemorrhages evaluation
Delay in seeking Depressed mental
care status
Cardiac Dysrhythmia Feeding Abnormal heart Four-extremity
(prolonged QT difficulties rate/rhythm blood pressure
syndrome, Growth Murmur Pre- and
Wolff- difficulties Decreased femoral postductal oxygen
Parkinson- Diaphoresis pulses saturation
White Prematurity measurements
syndrome) ECG
Cardiomyopathy Echocardiogram
Congenital heart Serum
disease electrolytes,
Myocarditis calcium,
magnesium
Metabolic/genetic Hypoglycemia Severe initial Dysmorphic Serum
Inborn errors of event features electrolytes;
metabolism Multiple events Microcephaly glucose, calcium,
Electrolyte Event associated Hepatomegaly and magnesium
abnormalities with period of levels
Genetic stress or fasting Lactate
syndromes Developmental Ammonia
including those delay Pyruvate
with craniofacial Associated Urine organic and
malformations anomalies serum amino
Growth acids
difficulties Newborn screen
Severe/frequent
illnesses
Family history of
BRUE,
consanguinity,
seizure disorder,
 or SIDS

BRUE , Brief resolved unexplained event; ECG , electrocardiogram; EEG , electroencephalogram;

ENT , ear, nose, and throat; GER , gastroesophageal reflux; GI , gastrointestinal; NP ,
nasopharyngeal; RSV , respiratory syncytial virus; SIDS , sudden infant death syndrome; URI ,
upper respiratory infection.
From Kliegman RK, Lye PS, Bordini BJ, et al: Nelson pediatric symptom-based diagnosis ,
Philadelphia, 2018, Elsevier. Table 5.3.

Initial History
An appropriate history and physical examination are key to evaluating an infant
who has experienced an acute event (Table 403.2 ). Attention should be given to
characterizing the event and interpreting the subjective experience of the
caregiver to provide an objective description. The following questions can guide
this process:

Table 403.2
Important Historical Features of a BRUE
PREEVENT
Condition of child Awake vs. asleep
Location of child Prone vs. supine, flat or upright, in crib/car seat, with pillows, blankets
Activity Feeding, crying, sleeping
EVENT
Respiratory effort None, shallow, gasping, increased
Duration of respiratory pauses
Color Pallor, red, cyanotic
Peripheral, whole body, circumoral, lighting of room
Tone/movement Rigid, tonic-clonic, decreased, floppy
Focal vs. diffuse
Ability to suppress movements
Level of consciousness Alert, interactive, sleepy, nonresponsive
Duration Time until normal breathing, normal tone, normal behavior
Detailed history of caregiver actions during event to aid in defining time course
Associated symptoms Vomiting, sputum production, blood in mouth/nose, eye rolling
POSTEVENT
Condition Back to baseline, sleepy, postictal, crying
If altered after event, duration of time until back to baseline
INTERVENTIONS
What was performed Gentle stimulation, blowing in face, mouth-to-mouth, cardiopulmonary
resuscitation
Who performed Medical professional vs. caregiver
intervention
Response to intervention Resolution of event vs. self-resolving
 Duration of intervention How long was intervention performed
MEDICAL HISTORY
History of present illness Preceding illnesses, fever, rash, irritability, sick contacts
Past medical history Prematurity, prenatal exposures, gestational age, birth trauma
Noisy breathing since birth
Any medical problems, prior medical conditions, prior hospitalizations
Developmental delay
Medications
Feeding history Gagging, coughing with feeds, poor weight gain
Family history Neurologic problems
Cardiac arrhythmias
Sudden death, childhood deaths, BRUEs
Neonatal problems
Consanguinity
Social history Home situation
Caregivers
Smoke exposure
Medications in the home
BRUE , Brief resolved unexplained event.
From Kliegman RK, Lye PS, Bordini BJ, et al: Nelson pediatric symptom-based diagnosis ,
Philadelphia, 2018, Elsevier. Table 5.4.

What was the infant doing before, during, and after the event? An event
occurring during or after feeding will likely have a different explanation than
one occurring during sleep or after crying. The sequence of events can also be
diagnostic. A breath holding spell begins with crying, followed by a period of
apnea, perioral cyanosis, change of consciousness, and return to baseline.
Did the infant change color? It is often normal for infants to have blueish
discoloration (perioral cyanosis or acrocyanosis ) around the lips or hands
because of circulatory immaturity. Turning red or purple is also common when
infants cry or become upset. The clinician's goal is to distinguish less concerning
color change from central cyanosis , which is blue discoloration of the face,
trunk, gums, or tongue that can indicate hypoxemia.
Did the infant experience central or obstructive apnea, or just choking or
gagging? It is normal for infants to exhibit respiratory pauses of up to 20 sec
while awake and asleep. These can reflect periodic breathing of the newborn
or normal REM sleep. Much more concerning are periods of no air movement
that last longer than 20 sec. Obstructive apnea results in paradoxical movement
of the diaphragm and upper airway. In infants, this is most commonly caused by
upper and lower respiratory tract infections (e.g., bronchiolitis) and may precede
the recognition of symptoms typically seen in viral respiratory infections. Infants
also commonly gag or choke briefly during or shortly after feeds or with GER or
vomiting. The resulting reflexive pause in respiration to protect the airway is
management. Common causes of secondary nosebleeds from the anterior septum
include digital trauma, foreign bodies, dry air, and inflammation, including upper
respiratory tract infections, sinusitis, and allergic rhinitis (Table 405.1 ). There is
often a family history of childhood epistaxis. Nasal steroid sprays are commonly
used in children, and their chronic use may be associated with nasal mucosal
bleeding. Young infants with significant gastroesophageal reflux into the nose
rarely present with epistaxis secondary to mucosal inflammation. Susceptibility
is increased during respiratory infections and in the winter when dry air irritates
the nasal mucosa, resulting in formation of fissures and crusting. Severe
bleeding may be encountered with congenital vascular abnormalities, such as
hereditary hemorrhagic telangiectasia (see Chapter 459.3 ), varicosities,
hemangiomas, and, in children with thrombocytopenia, deficiency of clotting
factors, particularly von Willebrand disease (see Chapter 504 ), hypertension,
renal failure, or venous congestion. Recurrent epistaxis despite cauterization is
associated with mild coagulation disorders. The family history may be positive
for abnormal bleeding (epistaxis or other sites); specific testing for von
Willebrand disease is indicated because the prothrombin time or partial
thromboplastin time may be normal despite having a bleeding disorder. Nasal
polyps or other intranasal growths may be associated with epistaxis. Recurrent,
and often severe, unilateral nosebleeds may be the initial presenting symptom in
juvenile nasal angiofibroma, which occurs in adolescent males.

Table 405.1
Possible Causes of Epistaxis
Epistaxis digitorum (nose picking)
Rhinitis (allergic or viral)
Chronic sinusitis
Foreign bodies
Intranasal neoplasm or polyps
Irritants (e.g., cigarette smoke)
Septal deviation
Septal perforation
Trauma including child abuse
Vascular malformation or telangiectasia (hereditary hemorrhage telangiectasia)
Hemophilia
von Willebrand disease
Platelet dysfunction
Thrombocytopenia
Hypertension
Leukemia
 Liver disease (e.g., cirrhosis)
Medications (e.g., aspirin, anticoagulants, nonsteroidal antiinflammatory drugs, topical corticosteroids)
Cocaine abuse
From Kucik CJ, Clenney T: Management of epistaxis, Am Fam Physician 71(2):305–311, 2005.

Clinical Manifestations
Epistaxis usually occurs without warning, with blood flowing slowly but freely
from 1 nostril or occasionally from both. In children with nasal lesions, bleeding
might follow physical exercise. When bleeding occurs at night, the blood may be
swallowed and become apparent only when the child vomits or passes blood in
the stools. Posterior epistaxis can manifest as anterior nasal bleeding, or, if
bleeding is copious, the patient might vomit blood as the initial symptom.

Treatment
Most nosebleeds stop spontaneously in a few minutes. The nares should be
compressed and the child kept as quiet as possible, in an upright position with
the head tilted forward to avoid blood trickling back into the throat. Cold
compresses applied to the nose can also help. If these measures do not stop the
bleeding, local application of a solution of oxymetazoline (Afrin) or
phenylephrine (Neo-Synephrine) (0.25–1%) may be useful. If bleeding persists,
an anterior nasal pack may need to be inserted; if bleeding originates in the
posterior nasal cavity, combined anterior and posterior packing is necessary.
After bleeding is under control, and if a bleeding site is identified, its obliteration
by cautery with silver nitrate may prevent further difficulties. Because the septal
cartilage derives its nutrition from the overlying mucoperichondrium, only one
side of the septum should be cauterized at a time to reduce the chance of a septal
perforation. During the winter, or in a dry environment, a room humidifier,
saline drops, and petrolatum (Vaseline) applied to the septum can help to prevent
epistaxis. Ointments prevent infection, increase moisture, decrease bleeding, and
are commonly used in clinical practice. Antiseptic cream (e.g., mupirocin) has
been used for epistaxis because it has been found that many patients with
idiopathic epistaxis have nasal bacterial colonization with subsequent
inflammation, new vessel formation, and irritation, likely leading to epistaxis.
However, studies showing the efficacy of antiseptics in epistaxis are equivocal.
Patients with severe epistaxis despite conservative medical measures should be
CHAPTER 407

The Common Cold

Santiago M.C. Lopez, John V. Williams

The common cold is an acute viral infection of the upper respiratory tract in
which the symptoms of rhinorrhea and nasal obstruction are prominent.
Systemic symptoms and signs such as headache, myalgia, and fever are absent or
mild. The common cold is frequently referred to as infectious rhinitis but may
also include self-limited involvement of the sinus mucosa and is more correctly
termed rhinosinusitis.

Etiology
The most common pathogens associated with the common cold are the more
than 200 types of human rhinoviruses (see Chapter 290 ), but the syndrome can
be caused by many different virus families (Table 407.1 ). Rhinoviruses (HRV)
are associated with more than 50% of colds in adults and children. In young
children, other viral etiologies of the common cold include respiratory syncytial
virus (RSV; see Chapter 287 ), human metapneumovirus (MPV; see Chapter 288
), parainfluenza viruses (PIVs; see Chapter 286 ), and adenoviruses (see Chapter
289 ). Common cold symptoms may also be caused by influenza viruses,
nonpolio enteroviruses, and human coronaviruses. Many viruses that cause
rhinitis are also associated with other symptoms and signs such as cough,
wheezing, and fever.

Table 407.1
Pathogens Associated With the Common Cold

RELATIVE OTHER COMMON

ASSOCIATION PATHOGEN
FREQUENCY* SYMPTOMS AND SIGNS
 Agents primarily associated with the Human Frequent Wheezing/bronchiolitis
common cold rhinoviruses
Coronaviruses Frequent
Agents primarily associated with other Respiratory Occasional Bronchiolitis in children <2 yr
clinical syndromes that also cause syncytial virus of age
common cold symptoms Human Occasional Pneumonia and bronchiolitis
metapneumovirus
Influenza viruses Uncommon Influenza, pneumonia, croup
Parainfluenza Uncommon Croup, bronchiolitis
viruses
Adenoviruses Uncommon Pharyngoconjunctival fever
(palpebral conjunctivitis,
watery eye discharge,
pharyngeal erythema)
Enteroviruses Uncommon Herpangina (fever and
Coxsackievirus ulcerated papules on
A posterior oropharynx)
Other nonpolio Aseptic meningitis
enteroviruses
* Relative frequency of colds caused by the agent.

Epidemiology
Colds occur year-round, but the incidence is greatest from the early fall until the
late spring, reflecting the seasonal prevalence of the viral pathogens associated
with cold symptoms. In the northern hemisphere, the highest incidence of HRV
infection occurs in the early fall (August–October) and in the late spring (April–
May). The seasonal incidence for PIV usually peaks in the late fall and late
spring and is highest between December and April for RSV, influenza viruses,
MPV, and coronaviruses. Adenoviruses are detected at a low prevalence
throughout the cold season, and enteroviruses may also be detected during
summer months or throughout the year.
Young children have an average of 6-8 colds per yr, but 10–15% of children
have at least 12 infections per yr. The incidence of illness decreases with
increasing age, with 2-3 illnesses per yr by adulthood. The incidence of infection
is primarily a function of exposure to the virus. Children in out-of-home daycare
centers during the 1st yr of life have 50% more colds than children cared for
only at home. The difference in the incidence of illness between these groups of
children decreases as the length of time spent in daycare increases, although the
incidence of illness remains higher in the daycare group through at least the 1st 3
yr of life. When they begin primary school, children who attended daycare have
less frequent colds than those who did not. Mannose-binding lectin deficiency
course of a cold. Anterior cervical lymphadenopathy or conjunctival injection
may also be noted on exam.

Diagnosis
The most important task of the physician caring for a patient with a cold is to
exclude other conditions that are potentially more serious or treatable. The
differential diagnosis of the common cold includes noninfectious disorders and
other upper respiratory tract infections (Table 407.2 ).

Table 407.2
Conditions That Can Mimic the Common Cold

CONDITION DIFFERENTIATING FEATURES

Allergic rhinitis Prominent itching and sneezing, nasal eosinophils. Hansel stain can aid diagnosis
Vasomotor May be triggered by irritants, weather changes, spicy foods, etc.
rhinitis
Rhinitis History of nasal decongestant use
medicamentosa
Foreign body Unilateral, foul-smelling secretions
Bloody nasal secretions
Sinusitis Presence of fever, headache or facial pain, or periorbital edema or persistence of rhinorrhea or
cough for longer than 10-14 days
Streptococcosis Mucopurulent nasal discharge that excoriates the nares, no cough
Pertussis Onset of persistent or severe paroxysmal cough
Congenital Persistent rhinorrhea with onset in the 1st 3 mo of life
syphilis

Laboratory Findings
Routine laboratory studies are not helpful for the diagnosis and management of
the common cold . A nasal smear for eosinophils (Hansel stain) may be useful if
allergic rhinitis is suspected (see Chapter 168 ). A predominance of
polymorphonuclear cells in the nasal secretions is characteristic of
uncomplicated colds and does not indicate bacterial superinfection. Self-limited
radiographic abnormalities of the paranasal sinuses are common during an
uncomplicated cold; imaging is not indicated for most children with simple
rhinitis.
The viral pathogens associated with the common cold can be detected by
sinuses are normally cleared readily, but during viral rhinosinusitis,
inflammation and edema can block sinus drainage and impair mucociliary
clearance of bacteria. The growth conditions are favorable, and high titers of
bacteria are produced.

Clinical Manifestations
Children and adolescents with sinusitis can present with nonspecific complaints,
including nasal congestion, purulent nasal discharge (unilateral or bilateral),
fever, and cough. Less-common symptoms include bad breath (halitosis), a
decreased sense of smell (hyposmia), and periorbital edema (Table 408.1 ).
Complaints of headache and facial pain are rare in children. Additional
symptoms include maxillary tooth discomfort and pain or pressure exacerbated
by bending forward. Physical examination might reveal erythema and swelling
of the nasal mucosa with purulent nasal discharge. Sinus tenderness may be
detectable in adolescents and adults. Transillumination reveals an opaque sinus
that transmits light poorly.

Table 408.1
Conventional Criteria for the Diagnosis of Sinusitis Based
on the Presence of at Least 2 Major or 1 Major and ≥2 Minor
Symptoms

MAJOR SYMPTOMS MINOR SYMPTOMS

• Purulent anterior nasal discharge • Headache
• Purulent or discolored posterior nasal discharge • Ear pain, pressure, or fullness
• Nasal congestion or obstruction • Halitosis
• Facial congestion or fullness • Dental pain
• Facial pain or pressure • Cough
• Hyposmia or anosmia • Fever (for subacute or chronic sinusitis)
• Fever (for acute sinusitis only) • Fatigue
From Chow AW, Benninger MS, Brook I, et al: IDSA clinical practice guideline for acute bacterial
rhinosinusitis in children and adults. CID 54:e72–e112, 2012, Table 2, p. e78.

Differentiating bacterial sinusitis from a cold may be difficult, but certain

patterns suggestive of sinusitis have been identified. These include persistence
of nasal congestion, rhinorrhea (of any quality), and daytime cough ≥10 days
without improvement; severe symptoms of temperature ≥39°C (102°F) with
purulent nasal discharge for 3 days or longer; and worsening symptoms either by
controlled trial comparing 14-day treatment of children with clinically diagnosed
sinusitis with amoxicillin, amoxicillin-clavulanate, or placebo found that
antimicrobial therapy did not affect resolution of symptoms, duration of
symptoms, or days missed from school. A similar study in adults demonstrated
improved symptoms at day 7 but not day 10 of treatment. Major guidelines
recommend antimicrobial treatment for acute bacterial sinusitis with severe
onset or a worsening course to promote resolution of symptoms and prevent
suppurative complications, although 50–60% of children with acute bacterial
sinusitis may recover without antimicrobial therapy.
Initial therapy with amoxicillin (45 mg/kg/day divided bid) is adequate for
most children with uncomplicated mild to moderate severity acute bacterial
sinusitis (Table 408.2 ). Alternative treatments for the penicillin-allergic patient
include cefdinir, cefuroxime axetil, cefpodoxime, or cefixime. In older children,
levofloxacin is an alternative antibiotic. Azithromycin and trimethoprim-
sulfamethoxazole are no longer indicated because of a high prevalence of
antibiotic resistance. For children with risk factors (antibiotic treatment in the
preceding 1-3 mo, daycare attendance, or age younger than 2 yr) for the presence
of resistant bacterial species, and for children who fail to respond to initial
therapy with amoxicillin within 72 hr, or with severe sinusitis, treatment with
high-dose amoxicillin-clavulanate (80-90 mg/kg/day of amoxicillin) should be
initiated. Ceftriaxone (50 mg/kg, IV or IM) may be given to children who are
vomiting or who are at risk for poor compliance; it should be followed by a
course of oral antibiotics. Failure to respond to these regimens necessitates
referral to an otolaryngologist for further evaluation because maxillary sinus
aspiration for culture and susceptibility testing may be necessary (Table 408.3 ).
The appropriate duration of therapy for sinusitis has yet to be determined;
individualization of therapy is a reasonable approach, with treatment
recommended for a minimum of 10 days or 7 days after resolution of symptoms
(see Fig. 408.1 ).

Table 408.2
Antimicrobial Regimens for Acute Bacterial Rhinosinusitis
in Children

FIRST-LINE (DAILY
INDICATION SECOND-LINE (DAILY DOSE)
DOSE)
Initial empirical therapy Amoxicillin- • Amoxicillin-clavulanate (90 mg/kg/day PO bid)
clavulanate (45
 mg/kg/day PO bid)
β-Lactam allergy
Type I hypersensitivity • Levofloxacin (10-20 mg/kg/day PO every 12-24 h)
Non-type I • Clindamycin* (30-40 mg/kg/day PO tid) plus cefixime (8
hypersensitivity mg/kg/day PO bid) or cefpodoxime (10 mg/kg/day PO bid)
Risk for antibiotic • Amoxicillin-clavulanate (90 mg/kg/day PO bid)
resistance or failed initial • Clindamycin* (30-40 mg/kg/day PO tid) plus cefixime (8
therapy mg/kg/day PO bid) or cefpodoxime (10 mg/kg/day PO bid)
• Levofloxacin (10-20 mg/kg/day PO every 12-24 h)
Severe infection requiring • Ampicillin/sulbactam (200-400 mg/kg/day IV every 6 h)
hospitalization • Ceftriaxone (50 mg/kg/day IV every 12 h)
• Cefotaxime (100-200 mg/kg/day IV every 6 h)
• Levofloxacin (10-20 mg/kg/day IV every 12-24 h)
*
Resistance to clindamycin (~31%) is found frequently among Streptococcus pneumoniae
serotype 19A isolates in different regions of the United States.
bid, 2 times daily; IV, intravenously; PO, orally; qd, daily; tid, 3 times a day.
From Chow AW, Benninger MS, Brook I, et al: IDSA clinical practice guideline for acute bacterial
rhinosinusitis in children and adults. CID 54:e72–e112, 2012, Table 9, p. e94.

Table 408.3
Indications for Referral to a Specialist
• Severe infection (high persistent fever with temperature >39°C [>102°F]; orbital edema; severe headache, visual
disturbance, altered mental status, meningeal signs)
• Recalcitrant infection with failure to respond to extended courses of antimicrobial therapy
• Immunocompromised host
• Multiple medical problems that might compromise response to treatment (e.g., hepatic or renal impairment,
hypersensitivity to antimicrobial agents, organ transplant)
• Unusual or resistant pathogens
• Fungal sinusitis or granulomatous disease
• Nosocomial infection
• Anatomic defects causing obstruction and requiring surgical intervention
• Multiple recurrent episodes of acute bacterial rhinosinusitis (3-4 episodes per year) suggesting chronic sinusitis
• Chronic rhinosinusitis (with or without polyps or asthma) with recurrent ABRS exacerbations
• Evaluation of immunotherapy for allergic rhinitis
From Chow AW, Benninger MS, Brook I, et al: IDSA clinical practice guideline for acute bacterial
rhinosinusitis in children and adults. CID 54:e72–e112, 2012, Table 14, p. e106.

Frontal sinusitis can rapidly progress to serious intracranial complications and

necessitates initiation of parenteral ceftriaxone until substantial clinical
improvement is achieved (Figs. 408.2 and 408.3 ). Treatment is then completed
with oral antibiotic therapy.
causes of pharyngitis. Viral upper respiratory tract infections are typically spread
by contact with oral or respiratory secretions and occur most commonly in fall,
winter, and spring—that is, the respiratory season. Important viruses that cause
pharyngitis include influenza, parainfluenza, adenoviruses, coronaviruses,
enteroviruses, rhinoviruses, respiratory syncytial virus (RSV), cytomegalovirus,
Epstein-Barr virus (EBV), herpes simplex virus (HSV), and human
metapneumovirus (HMPV) (Table 409.1 ). Most viral pharyngitis, except
mononucleosis, is mild. Common nonspecific symptoms such as rhinorrhea and
cough develop gradually before they become prominent. However, specific
findings are sometimes helpful in identifying the infectious viral agent (Table
409.2 ).

Table 409.1
Infectious Agents That Cause Pharyngitis

VIRUSES BACTERIA
Adenovirus Streptococcus pyogenes (Group A streptococcus)
Coronavirus Arcanobacterium haemolyticum
Cytomegalovirus Fusobacterium necrophorum
Epstein-Barr virus Corynebacterium diphtheriae
Enteroviruses Neisseria gonorrhoeae
Herpes simplex virus (1 and 2) Group C streptococci
Human immunodeficiency virus Group G streptococci
Human metapneumovirus Francisella tularensis
Influenza viruses (A and B)
Yersinia pestis
Measles virus
Chlamydophila pneumoniae
Parainfluenza viruses
Chlamydia trachomatis
Respiratory syncytial virus
Rhinoviruses Mycoplasma pneumoniae
Mixed anaerobes (Vincent angina)

Table 409.2
Epidemiologic and Clinical Features Suggestive of Group A
Streptococcal and Viral Pharyngitis
FEATURE, BY SUSPECTED ETIOLOGIC AGENT
Group A Streptococcal
• Sudden onset of sore throat
• Age 5-15 yr
• Fever
• Headache
• Nausea, vomiting, abdominal pain
• Tonsillopharyngeal inflammation
 • Patchy tonsillopharyngeal exudates
• Palatal petechiae
• Anterior cervical adenitis (tender nodes)
• Winter and early spring presentation
• History of exposure to strep pharyngitis
• Scarlatiniform rash
Viral
• Conjunctivitis
• Coryza
• Cough
• Diarrhea
• Hoarseness
• Discrete ulcerative stomatitis
• Viral exanthema
From Shulman ST, Bisno AL, Clegg HW, et al: Clinical practice guideline for the diagnosis and
management of group A streptococcal pharyngitis: 2012 update by the Infectious Diseases
Society of America. Clin Infect Dis 55(10):e86–e102, 2012, Table 4, p. e91.

Gingivostomatitis and ulcerating vesicles throughout the anterior pharynx

and on the lips and perioral skin are seen in primary oral HSV infection. High
fever and difficulty taking oral fluids are common. This infection can last for 14
days.
Discrete papulovesicular lesions or ulcerations in the posterior oropharynx,
severe throat pain, and fever are characteristic of herpangina , caused by
various enteroviruses. In hand-foot-mouth disease , there are vesicles or ulcers
throughout the oropharynx, vesicles on the palms and soles, and sometimes on
the trunk and extremities. Coxsackie A16 is the most common agent, but
Enterovirus 71 and Coxsackie A6 can also cause this syndrome. Enteroviral
infections are most common in the summer.
Various adenoviruses cause pharyngitis. When there is concurrent
conjunctivitis , the syndrome is called pharyngoconjunctival fever . The
pharyngitis tends to resolve within 7 days but conjunctivitis may persist for up to
14 days. Pharyngoconjunctival fever can be epidemic or sporadic; outbreaks
have been associated with exposure in swimming pools.
Intense, diffuse pharyngeal erythema and Koplik spots, the pathognomonic
enanthem, occur in advance of the characteristic rash of measles. Splenomegaly,
lymphadenopathy, or hepatomegaly may be the clue to EBV infectious
mononucleosis in an adolescent with exudative tonsillitis. Primary infection with
HIV can manifest as the acute retroviral syndrome , with non-exudative
pharyngitis, fever, arthralgia, myalgia, adenopathy, and often a maculopapular
rash.
temperature >38°C (100.4°F), absence of cough, tender anterior cervical
adenopathy, tonsillar swelling or exudates, and age 3-14 yr. It subtracts a point
for age ≥45 yr. At best, a McIsaac score ≥4 is associated with a positive
laboratory test for GAS in less than 70% of children with pharyngitis (Table
409.3 ), so it, too, overestimates the likelihood of GAS. Consequently,
laboratory testing is essential for accurate diagnosis . Clinical findings and/or
scoring systems can best be used to assist the clinician in identifying patients in
need of testing. Evaluating patients indiscriminately can lead to overdiagnosis
and overtreatment. Streptococcal antibody tests are not useful in assessing
patients with acute pharyngitis.

Table 409.3
Positive Predictive Value of McIsaac Score in Children in
Clinical Studies*

McISAAC, 2004 (N = EDMONSON, 2005 (N = TANZ, 2009 (N = FINE, 2012 (N =

SCORE
454) (%) 1184) (%) 1848) (%) 64,789) (%)
0 — — 7 17
1 — 0.5 19 23
2 20.5 8.9 20 34
3 27.5 42.4 29 50
≥4 67.8 48.2 49 68
GAS 34 38 30 37
prevalence
* One point is given for each of the following criteria: history of temperature >38°C (100.4°F);
absence of cough; tender anterior cervical adenopathy; tonsillar swelling or exudates; and age 3-
14 yr. Note that the Centor score lacks only the age criterion. Positive predictive value refers to
the proportion of patients with documented GAS by rapid antigen-detection test and/or throat
culture.

Throat culture and rapid antigen-detection tests (RADTs) are the diagnostic
tests for GAS most available in routine clinical care. Throat culture plated on
blood agar remains the gold standard for diagnosing streptococcal pharyngitis.
There are both false-negative cultures as a consequence of sampling errors or
prior antibiotic treatment and false-positive cultures as a consequence of
misidentification of other bacteria as GAS. Streptococcal RADTs detect the
group A carbohydrate of GAS. They are used by the vast majority of office-
based pediatricians. All RADTs have very high specificity, generally ≥95%, so
when a RADT is positive it is assumed to be accurate and throat culture is
unnecessary. Because RADTs are generally much less sensitive than culture,
treatment should not be delayed for children with symptomatic pharyngitis and a
positive test for GAS. Presumptive antibiotic treatment can be started when there
is a clinical diagnosis of scarlet fever, a symptomatic child has a household
contact with documented streptococcal pharyngitis, or there is a history of ARF
in the patient or a family member, but a diagnostic test should be performed to
confirm the presence of GAS and antibiotics should be discontinued if GAS are
not identified.
A variety of antimicrobial agents are effective for GAS pharyngitis (Table
409.4 ). Group A streptococci are universally susceptible to penicillin and all
other β-lactam antibiotics. Penicillin is inexpensive, has a narrow spectrum of
activity, and has few adverse effects. Amoxicillin is often preferred for children
because of taste, availability as chewable tablets and liquid, and the convenience
of once-daily dosing. The duration of oral penicillin and amoxicillin therapy is
10 days. A single intramuscular dose of benzathine penicillin or a benzathine-
procaine penicillin G combination is effective and ensures compliance. Follow-
up testing for GAS is unnecessary after completion of therapy and is not
recommended unless symptoms recur.

Table 409.4
Recommended Treatment for Acute Streptococcal
Pharyngitis
MOST PATIENTS
WEIGHT <27 kg WEIGHT ≥27 kg ROUTE DURATION
Amoxicillin 50 mg/kg once daily (maximum 1,000 mg) Oral 10 days
Penicillin V 250 mg bid 500 mg bid Oral 10 days
Benzathine penicillin G 600,000 units 1.2 million units IM Once
Benzathine penicillin G + procaine 900,000 units + 300,000 900,000 units + IM Once
penicillin G units 300,000 units
PENICILLIN-ALLERGIC PATIENTS
ORAL DOSE FREQUENCY DURATION
Cephalosporins* Varies with agent chosen 10 days
Erythromycins 40 mg/kg/day up to 1,000 bid 10 days
Ethylsuccinate mg/day
Estolate 20-40 mg/kg/day up to bid 10 days
1,000 mg/day
Clarithromycin 15 mg/kg/day up to 500 bid 10 days
mg/day
Azithromycin † 12 mg/kg day 1; 6 mg/kg qd 5 days
days 2-5
Clindamycin 20 mg/kg/day up to 1.8 tid 10 days
g/day
Tonsillectomy alone is most commonly performed for recurrent or chronic
pharyngotonsillitis. Tonsillectomy has been shown to be effective in reducing the
number of infections and the symptoms of chronic tonsillitis such as halitosis,
persistent or recurrent sore throats, and recurrent cervical adenitis in severely
affected patients. In resistant cases of cryptic tonsillitis, tonsillectomy may be
curative. Rarely in children, tonsillectomy is indicated for biopsy of a
unilaterally enlarged tonsil to exclude a neoplasm or to treat recurrent
hemorrhage from superficial tonsillar blood vessels. Tonsillectomy has not been
shown to offer clinical benefit over conservative treatment in children with mild
symptoms or in those with severe infections 2 yr after surgery.
There are large variations in surgical rates among children across countries:
144 in 10,000 in Italy; 115 in 10,000 in the Netherlands; 65 in 10,000 in
England; and 50 in 10,000 in the United States. Rates are generally higher in
boys. With the issuance of practice guidelines, these variations may decrease.
The American Academy of Otolaryngology (AAO)–Head and Neck Surgery
Taskforce on Clinical Practice Guidelines: Tonsillectomy in Children issued
evidence-based guidelines in 2019 (Table 411.1 ). Table 411.2 illustrates the
differences and similarities between these guidelines with those of the other
major professional groups across the globe. The 2019 guidelines recommend
watchful waiting for recurrent throat infections if there has been <7 episodes in
the past year, <5 episodes/yr in the past 2 yr, or <3 episodes/yr in the past 3 yr.

Table 411.1
Paradise Criteria for Tonsillectomy

CRITERION DEFINITION
Minimum At least 7 episodes in the previous year, at least 5 episodes in each of the previous 2 yr, or at
frequency of sore least 3 episodes in each of the previous 3 yr
throat episodes
Clinical features • Sore throat plus at least 1 of the following features qualifies as a counting episode:
• Temperature of greater than 38.3°C (100.9°F)
• Cervical adenopathy (tender lymph nodes or lymph node size >2 cm)
• Tonsillar exudate
• Culture positive for group A β-hemolytic streptococcus
Treatment Antibiotics administered in the conventional dosage for proved or suspected streptococcal
episodes
Documentation Each episode of throat infection and its qualifying features substantiated by
contemporaneous notation in a medical record
If the episodes are not fully documented, subsequent observance by the physician of 2
episodes of throat infection with patterns of frequency and clinical features consistent with
the initial history*
* Allows for tonsillectomy in patients who meet all but the documentation criterion. A 12 mo

observation period is usually recommended before consideration of tonsillectomy.

Adapted from Baugh RF, Archer SM, Mitchell RB, et al: American Academy of Otolaryngology–
Head and Neck Surgery Foundation. Clinical practice guideline: tonsillectomy in children.
Otolaryngol Head Neck Surg 144(1 Suppl):S8, 2011, Table 5.

Table 411.2
Comparison of American, Italian, and Scottish Guidelines
for Tonsillectomy in Children and Adolescents

AAO-HNS
PARAMETER ITALIAN GUIDELINES SCOTTISH GUIDELINES
GUIDELINES
Audience Multidisciplinary Multidisciplinary Multidisciplinary
Target population Children and Children and adults Children 4-16 yr of age and
adolescents 1-18 yr of adults
age
Scope Treatment of children Appropriateness and safety of Management of sore throat and
who are candidates for tonsillectomy indications for tonsillectomy
tonsillectomy
Methods Based on a priori Systematic literature review, Italian Based on a priori protocol,
protocol, systematic National Program Guidelines scale systematic literature review,
literature review, of evidence quality Scottish Intercollegiate
American Academy of Guidelines Network scale of
Pediatrics scale of evidence quality
evidence quality
Recommendations
Recurrent Tonsillectomy is an Tonsillectomy is indicated in Tonsillectomy should be
infection option for children with patients with at least 1 yr of considered for recurrent,
recurrent throat recurrent tonsillitis (5 or more disabling sore throat caused by
infection that meets the episodes per year) that is disabling acute tonsillitis when the
Paradise criteria (see and impairs normal activities, but episodes are well documented,
Table 411.1 ) for only after an additional 6 mo of are adequately treated, and
frequency, severity, watchful waiting to assess the meet the Paradise criteria (see
treatment, and pattern of symptoms using a Table 411.1 ) for frequency of
documentation of clinical diary illness
illness
Pain control Recommendation to Recommendation for Recommendation for adequate
advocate for pain relief acetaminophen before and after dose of acetaminophen for pain
(e.g., provide surgery relief in children
information, prescribe)
and educate caregivers
about the importance of
managing and
reassessing pain
Antibiotic use Recommendation Recommendation for short-term NA
against perioperative perioperative antibiotics*
antibiotics
Steroid use Recommendation for a Recommendation for a single Recommendation for a single
single intraoperative intraoperative dose of intraoperative dose of
dose of dexamethasone dexamethasone dexamethasone
 Sleep-disorderedRecommendation to Recommendation for diagnostic NA
breathing counsel caregivers testing in children with suspected
about tonsillectomy as a sleep respiratory disorders
means to improve
health in children with
sleep-disordered
breathing and comorbid
conditions
Polysomnography Recommendation to Recommendation for NA
counsel caregivers polysomnography when pulse
about tonsillectomy as a oximetry results are not conclusive
means to improve in agreement with Brouillette
health in children with criteria
abnormal
polysomnography
Surgical NA Recommendation for “cold” NA
technique technique
Hemorrhage Recommendation that NA NA
the surgeon document
primary and secondary
hemorrhage after
tonsillectomy at least
annually
Adjunctive NA NA Recommendation against
therapy Echinacea purpurea for
treatment of sore throat
Recommendation for
acupuncture in patients at risk
of postoperative nausea and
vomiting who cannot take
antiemetic drugs
* Statement made prior to most recent Cochrane review.

AAO-HNS, American Academy of Otolaryngology–Head and Neck Surgery; NA, not applicable.
Adapted with permission from Baugh RF, Archer SM, Mitchell RB, et al: American Academy of
Otolaryngology–Head and Neck Surgery Foundation. Clinical practice guideline: tonsillectomy in
children. Otolaryngol Head Neck Surg 144(1 Suppl):S23, 2011, Table 9.

Adenoidectomy
Adenoidectomy alone may be indicated for the treatment of chronic nasal
infection (chronic adenoiditis), chronic sinus infections that have failed medical
management, and recurrent bouts of acute otitis media, including those in
children with tympanostomy tubes who suffer from recurrent otorrhea.
Adenoidectomy may be helpful in children with chronic or recurrent otitis media
with effusion. Adenoidectomy alone may be curative in the management of
patients with nasal obstruction, chronic mouth breathing, and loud snoring
suggesting sleep-disordered breathing. Adenoidectomy may also be indicated for
Bleeding can occur in the immediate postoperative period or be delayed
(consider von Willebrand disease) after separation of the eschar. The Clinical
Guidelines for Tonsillectomy include a recommendation for a single intravenous
dose of intraoperative dexamethasone (0.5 mg/kg), which decreases
postoperative nausea and vomiting and reduces swelling. There is no evidence
that use of dexamethasone in postoperative tonsillectomy patients results in an
increased risk of postoperative bleeding. Routine use of antibiotics in the
postoperative period is ineffective and thus the AAO Clinical Practice
Guidelines advise against its use, although this recommendation is not consistent
among the major professional organizations who have issued guidelines (see
Table 411.2 ). Codeine is associated with excessive sedation and fatalities and is
not recommended.

Table 411.3
Risks and Potential Benefits of Tonsillectomy or
Adenoidectomy or Both
RISKS
• Cost*
• Risk of anesthetic accidents
• Malignant hyperthermia
• Cardiac arrhythmia
• Vocal cord trauma
• Aspiration with resulting bronchopulmonary obstruction or infection
• Risk of miscellaneous surgical or postoperative complications
• Hemorrhage
• Airway obstruction from edema of tongue, palate, or nasopharynx, or retropharyngeal hematoma
• Central apnea
• Prolonged muscular paralysis
• Dehydration
• Palatopharyngeal insufficiency
• Otitis media
• Nasopharyngeal stenosis
• Refractory torticollis
• Facial edema
• Emotional upset
• Unknown risks
POTENTIAL BENEFITS
• Reduction in frequency of ear, nose, throat illness, and thus in
• Discomfort
• Inconvenience
• School absence
• Parental anxiety
• Work missed by parents
• Costs of physician visits and drugs
• Reduction in nasal obstruction with improved
 • Respiratory function
• Comfort
• Sleep
• Craniofacial growth and development
• Appearance
• Reduction in hearing impairment
• Improved growth and overall well-being
• Reduction in long-term parental anxiety
* Cost for tonsillectomy alone and adenoidectomy alone are somewhat lower.

Modified from Bluestone CD, editor: Pediatric otolaryngology , ed 4, Philadelphia, 2003, WB

Saunders, p. 1213.

Swelling of the tongue and soft palate can lead to acute airway obstruction in
the first few hours after surgery. Children with underlying hypotonia or
craniofacial anomalies are at greater risk for suffering this complication.
Dehydration from odynophagia is not uncommon in the first postoperative week.
Rare complications include velopharyngeal insufficiency, nasopharyngeal or
oropharyngeal stenosis, and psychologic problems.

Bibliography
Amoils M, Chang KW, Saynina O, et al. Postoperative
complications in pediatric tonsillectomy and adenoidectomy
in ambulatory vs inpatient settings. JAMA Otolaryngol Head
Neck Surg . 2016;142(4):344–350.
Baugh RF, Archer SM, Mitchell RB, et al. Clinical practice
guideline: tonsillectomy in children. Otolaryngol Head Neck
Surg . 2011;144(1 Suppl):S1–S30.
Bonuck KA, Freeman K, Henderson J. Growth and growth
biomarker changes after adenotonsillectomy: systematic
review and meta-analysis. Arch Dis Child . 2009;94:83–91.
Borgstrom A, Nerfeldt P, Friberg D. Adenotonsillotomy versus
adenotonsillectomy in pediatric obstructive sleep apnea: an
RCT. Pediatrics . 2017;139(4):e20163314.
Brigger MT, Cunningham MJ, Hartnick CJ. Dexamethasone
administration and postoperative bleeding risk in children
undergoing tonsillectomy. Arch Otolaryngol Head Neck Surg
. 2010;136(8):766–772; 10.1001/archoto.2010.133 [PMID]
CHAPTER 416

Bronchomalacia and Tracheomalacia

Jonathan D. Finder

Tracheomalacia and bronchomalacia refer to chondromalacia of a central airway,

leading to insufficient cartilage to maintain airway patency throughout the
respiratory cycle. These are common causes of persistent wheezing in infancy.
Tracheomalacia and bronchomalacia can be either primary or secondary (Table
416.1 ). Primary tracheomalacia and bronchomalacia are often seen in premature
infants, although most affected patients are born at term. Secondary
tracheomalacia and bronchomalacia refer to the situation in which the central
airway is compressed by an adjacent structure (e.g., vascular ring; see Chapter
345 ) or deficient in cartilage because of tracheoesophageal fistula (see Chapter
345 ). Bronchomalacia is common following lung transplantation, assumed to be
secondary to the loss of bronchial artery supply leading to ischemia of the
bronchial cartilage. This form of bronchomalacia may take months to present
following transplantation. Laryngomalacia can accompany primary
bronchomalacia or tracheomalacia. Involvement of the entire central airway
(laryngotracheobronchomalacia) is also seen.

Table 416.1
Classification of Tracheomalacia
PRIMARY TRACHEOMALACIA
Congenital absence of tracheal-supporting cartilages
SECONDARY TRACHEOMALACIA
Esophageal atresia, tracheoesophageal fistula
Vascular rings (double aortic arch)
Tracheal compression from an aberrant innominate artery
Tracheal compression from mediastinal masses
Abnormally soft tracheal cartilages associated with connective tissue disorders
Prolonged mechanical ventilation, chronic lung disease
resistance. Marginal additional narrowing, such as that caused by inflammation
related to viral infection, is then more likely to result in wheezing.
Infant chest wall compliance is also quite high, thus the inward pressure
produced in normal expiration subjects the intrathoracic airways to collapse.
Differences in tracheal cartilage and airway smooth muscle tone increase the
collapsibility of the infant airways in comparison with older children. These
mechanisms combine to make the infant more susceptible to airway obstruction,
increased resistance, and subsequent wheezing. The mechanical portion of the
infant propensity to wheeze resolves with normal growth and muscular
development.
Although wheezing in infants most frequently results from inflammation due
to acute viral infections, there are many potential causes of wheezing (Table
418.1 ).

Table 418.1
Differential Diagnosis of Wheezing in Infancy
INFECTION
Viral
Respiratory syncytial virus
Human metapneumovirus
Parainfluenza
Adenovirus
Influenza
Rhinovirus
Bocavirus
Coronavirus
Enterovirus
Other
Chlamydia trachomatis
Tuberculosis
Histoplasmosis
Papillomatosis
ASTHMA
ANATOMIC ABNORMALITIES
Central Airway Abnormalities
Malacia of the larynx, trachea, and/or bronchi
Laryngeal or tracheal web
Tracheoesophageal fistula (specifically H-type fistula)
Laryngeal cleft (resulting in aspiration)
Extrinsic Airway Anomalies Resulting in Airway Compression
Vascular ring or sling
Mediastinal lymphadenopathy from infection or tumor
Mediastinal mass or tumor
Esophageal foreign body
Intrinsic Airway Anomalies
 Airway hemangioma, other tumor
Congenital pulmonary airway malformation (cystic adenomatoid malformation)
Bronchial or lung cyst
Congenital lobar emphysema
Aberrant tracheal bronchus
Sequestration
Congenital heart disease with left-to-right shunt (increased pulmonary edema)
Foreign body
Immunodeficiency States
Immunoglobulin A deficiency
B-cell deficiencies
AIDS
Bronchiectasis
MUCOCILIARY CLEARANCE DISORDERS
Cystic fibrosis
Primary ciliary dyskinesia
Bronchiectasis
ASPIRATION SYNDROMES
Gastroesophageal reflux disease
Pharyngeal/swallow dysfunction
OTHER
Bronchopulmonary dysplasia
Eosinophilic granulomatosis with polyangiitis
Interstitial lung disease, including bronchiolitis obliterans
Heart failure
Anaphylaxis
Inhalation injury—burns

Acute Bronchiolitis
Acute bronchiolitis is a diagnostic term used to describe the clinical picture
produced by several different viral lower respiratory tract infections in infants
and very young children. The respiratory findings observed in bronchiolitis
include tachypnea, wheezing, crackles, and rhonchi which result from
inflammation of the small airways (Fig. 418.1 ). Despite its commonality, a
universal set of diagnostic criteria for bronchiolitis does not exist, with
significant disagreement about the upper age limit for appropriate use of the
diagnosis. Some clinicians restrict the term to children younger than 1 yr, and
others extend it to the age of 2 yr or beyond.
lower lung function at birth which improves with growth resulting in resolution
of wheezing by age 3; persistent wheezing, comprising about 14% of the cohort,
characterized by declining lung function and wheezing before and after age 3;
and late-onset wheezing, comprising 15% of the cohort, characterized by
relatively stable lung function and wheezing that does not begin until after age 3.
The remaining 50% of the population did not suffer a wheezing illness.
Following the cohort into adulthood revealed continued declines in the rates of
persistent symptoms. Similar patterns are also seen in birth cohort studies in
other countries.
Multiple studies attempting to predict which infants suffering from early
wheezing illnesses will go on to have asthma in later life have failed to achieve
discriminant validity. Interestingly, in both U.S. and U.K. prospective cohorts,
wheezing with an onset after the first 18-36 mo of life is one of the strongest
predictors of eventual asthma in both cohorts. Other proposed risk factors for
persistent wheezing include parental history of asthma and allergies, maternal
smoking, persistent rhinitis (apart from acute upper respiratory tract infections),
allergen sensitization, eczema, and peripheral eosinophilia, although no single
factor is strongly discriminative. Despite several randomized trials, there is no
evidence that early administration of inhaled corticosteroids to high-risk
populations can prevent the development of asthma.

Clinical Manifestations
History and Physical Examination
The initial history of a wheezing infant should describe the recent event
including onset, duration, and associated factors (Table 418.2 ). Birth history
includes weeks of gestation, neonatal complications including history of
intubation or oxygen requirement, maternal complications, and prenatal smoke
exposure. Past medical history includes any comorbid conditions. Family history
of cystic fibrosis, immunodeficiencies, asthma in a first-degree relative, or any
other recurrent respiratory conditions in children should be obtained. Social
history should include any second-hand tobacco or other smoke exposure,
daycare exposure, number of siblings, pets, and concerns regarding home
environment (e.g., dust mites, construction dust, heating and cooling techniques,
mold, cockroaches). The patient's growth chart should be reviewed for signs of
failure to thrive.
Table 418.2
Pertinent Medical History in the Wheezing Infant
Did the onset of symptoms begin at birth or thereafter?
Is the infant a noisy breather, and when is it most prominent?
Is the noisy breathing present on inspiration, expiration, or both?
Is there a history of cough apart from wheezing?
Was there an earlier lower respiratory tract infection?
Is there a history of recurrent upper or lower respiratory tract infections?
Have there been any emergency department visits, hospitalizations, or intensive care unit admissions for
respiratory distress?
Is there a history of eczema?
Does the infant cough after crying or cough at night?
How is the infant growing and developing?
Is there associated failure to thrive?
Is there a history of electrolyte abnormalities?
Are there signs of intestinal malabsorption including frequent, greasy, or oily stools?
Is there a maternal history of genital herpes simplex virus infection?
What was the gestational age at delivery?
Was the patient intubated as a neonate?
Does the infant bottle-feed in the bed or the crib, especially in a propped position?
Are there any feeding difficulties including choking, gagging, arching, or vomiting with feeds?
Is there any new food exposure?
Is there a toddler in the home or lapse in supervision in which foreign body aspiration could have occurred?
Change in caregivers or chance of nonaccidental trauma?

Acute bronchiolitis is usually preceded by exposure to contacts with a minor

respiratory illness within the previous week (see Fig. 418.1 ). The infant first
develops signs of upper respiratory tract infection with sneezing and clear
rhinorrhea. This may be accompanied by diminished appetite and fever.
Gradually, respiratory distress ensues, with paroxysmal cough, dyspnea, and
irritability. The infant is often tachypneic, which can interfere with feeding.
Apnea may precede lower respiratory signs early in the disease, particularly with
very young infants. Term infants at a postconceptual age of <44 wk and preterm
infants at postconceptual age <48 wk are at highest risk for apneic events.
On physical examination, evaluation of the patient's vital signs with special
attention to the respiratory rate and oxygen saturation is an important initial step.
The exam is often dominated by wheezing and crackles. Expiratory time may be
prolonged. Work of breathing may be markedly increased, with nasal flaring and
retractions. Complete obstruction to airflow can eliminate the turbulence that
causes wheezing; thus the lack of audible wheezing is not reassuring if the infant
shows other signs of respiratory distress. Poorly audible breath sounds suggest
severe disease with nearly complete bronchiolar obstruction.
common in the winter when respiratory viral syndromes predominate. The
tracheobronchial epithelium is invaded by the infectious agent, leading to
activation of inflammatory cells and release of cytokines. Constitutional
symptoms including fever and malaise follow. The tracheobronchial epithelium
can become significantly damaged or hypersensitized, leading to a protracted
cough lasting 1-3 wk.
The child first presents with nonspecific upper respiratory infectious
symptoms, such as rhinitis. Three to 4 days later, a frequent, dry, hacking cough
develops, which may or may not be productive. After several days, the sputum
can become purulent, indicating leukocyte migration but not necessarily
bacterial infection. Many children swallow their sputum which can produce
emesis. Chest pain may be a prominent complaint in older children and is
exacerbated by coughing. The mucus gradually thins, usually within 5-10 days,
and then the cough gradually abates. The entire episode usually lasts about 2 wk
and seldom longer than 3 wk.
Findings on physical examination vary with the age of the patient and stage of
the disease. Early findings include no or low-grade fever and upper respiratory
signs such as nasopharyngitis, conjunctivitis, and rhinitis. Auscultation of the
chest may be unremarkable at this early phase. As the syndrome progresses and
cough worsens, breath sounds become coarse, with coarse and fine crackles and
scattered high-pitched wheezing. Chest radiographs are normal or can have
increased bronchial markings.
The principal objective of the clinician is to exclude pertussis and pneumonia,
which is more likely caused by bacterial agents requiring antibiotic therapy.
Absence of abnormality of vital signs (tachycardia, tachypnea, fever) and a
normal physical examination of the chest reduce the likelihood of pneumonia.

Differential Diagnosis
Persistent or recurrent symptoms should lead the clinician to consider entities
other than acute bronchitis. Many entities manifest with cough as a prominent
symptom (Table 418.3 ).

Table 418.3

Disorders With Cough as a Prominent Finding

CATEGORY DIAGNOSES
 Inflammatory Asthma
Chronic pulmonary processes Bronchopulmonary dysplasia
Postinfectious bronchiectasis
Cystic fibrosis
Tracheomalacia or bronchomalacia
Ciliary abnormalities
Other chronic lung diseases
Other chronic disease or congenital disorders Laryngeal cleft
Swallowing disorders
Gastroesophageal reflux
Airway compression (such as a vascular ring or hemangioma)
Congenital heart disease
Infectious or immune disorders Immunodeficiency
Eosinophilic lung disease
Tuberculosis
Allergy
Sinusitis
Tonsillitis or adenoiditis
Chlamydia, Ureaplasma (infants)
Bordetella pertussis
Mycoplasma pneumoniae
Acquired Foreign body aspiration, tracheal or esophageal

Treatment
There is no specific therapy for acute bronchitis. The disease is self-limited, and
antibiotics, although often prescribed, do not hasten improvement. Frequent
shifts in position can facilitate pulmonary drainage in infants. Older children are
sometimes more comfortable with humidity, but this does not shorten the disease
course. Cough suppressants can relieve symptoms but can also increase the risk
of suppuration and inspissated secretions and therefore should be used
judiciously. Antihistamines dry secretions and are not helpful; expectorants are
likewise not indicated. Nonprescription cough and cold medicines should not be
used in children younger than 4 yr of age, and their use is cautioned in children
age 4-11 yr.

Chronic Bronchitis
Chronic bronchitis is well recognized in adults, formally defined as 3 mo or
longer of productive cough each year for 2 or more yr. The disease can develop
insidiously, with episodes of acute obstruction alternating with quiescent periods.
Some predisposing conditions can lead to progression of airflow obstruction or
chronic obstructive pulmonary disease, with smoking as the major factor (up to
80% of patients have a smoking history). Other conditions include air pollution,
CHAPTER 419

Plastic Bronchitis
Brett J. Bordini

Plastic bronchitis is a rare condition characterized by recurrent episodes of

airway obstruction secondary to the formation of large proteinaceous branching
casts that take on the shape of and obstruct the tracheobronchial tree. It is not a
single disease entity, but rather represents a state of altered respiratory epithelial
function and is most frequently encountered in the setting of underlying
pulmonary or cardiac disease, although plastic bronchitis may also arise in
lymphatic disorders, pulmonary infections, and the acute chest syndrome of
sickle cell disease (Table 419.1 ). In comparison with the smaller bronchial and
bronchiolar casts seen with mucus plugging, the lesions of plastic bronchitis are
more extensive, with casts that can outline large segments of the airway to the
level of the terminal bronchioles (Fig. 419.1 ). These casts may be spontaneously
expectorated or may require bronchoscopic removal for relief of potentially fatal
airway obstruction. Cast composition varies, although it typically consists of
either a fibrin-predominant or mucin-predominant laminated matrix with or
without inflammatory cell infiltration. Plastic bronchitis may be classified
according to an associated disease, the cast histology, or a combination.

Table 419.1
Conditions Associated With Plastic Bronchitis
PROVEN CONDITIONS
Congenital heart disease with Fontan physiology
Pulmonary lymphatic anomalies
Influenza A pulmonary infection
POSSIBLE CONDITIONS
Toxic inhalation
Sickle cell acute chest syndrome
Hypersecretory and near-fatal asthma (eosinophilic casts)
 UNLIKELY AND UNPROVEN CONDITIONS
Cystic fibrosis
Chronic obstructive pulmonary disease
Bronchiectasis
Bacterial pneumonia
From Rubin BK: Plastic bronchitis, Clin Chest Med 37:405–408, 2016 (Box 1, p. 406).

FIG. 419.1 Tracheobronchial casts following bronchoscopic extraction.
Casts show branched architecture corresponding to the bronchial tree.
(From Corrin B, Nicholson AG: Pathology of the lungs , ed 3, London, 2011,
Churchill Livingstone. Fig 3.20.)

Epidemiology
Plastic bronchitis is rare, and its true prevalence in the pediatric population is not
known but is estimated to be 6.8 cases per 100,000 patients. Prevalence does
vary in relation to the underlying associated disease state, with rates as high as
4–14% estimated in patients who have undergone staged palliation of complex
congenital heart disease and much lower rates seen complicating asthma and
atopic disease. A slight male predominance exists for cast formation in the
setting of structural heart disease, whereas cast formation in the setting of
asthma and atopic disease demonstrates a female predominance. Children with
single-ventricle Fontan physiology are at high risk for developing plastic
bronchitis.
systemic lupus erythematosus [see Chapter 183 ], scleroderma [see Chapter 185
], Stevens-Johnson syndrome [see Chapter 177 ]), and inhalation of toxic fumes
or particulate exposure (NO2 , incinerator fly ash, NH3 , diacetyl flavorings from
microwave popcorn, papaverine, fiberglass) (Table 422.1 ). Postinfection
obliterans may be more common in the southern hemisphere and among persons
of Asian descent. BO is also commonly seen in post lung or bone marrow
transplant recipients.

Table 422.1
Etiology of Bronchiolitis Obliterans
POSTINFECTION
Adenovirus types 3, 7, and 21
Influenza
Parainfluenza
Measles
Respiratory syncytial virus
Varicella
Mycoplasma pneumoniae
POSTTRANSPLANTATION
Chronic rejection of lung or heart/lung transplantation
Graft versus host disease associated with bone marrow transplantation
CONNECTIVE TISSUE DISEASE
Juvenile idiopathic arthritis
Sjögren syndrome
Systemic lupus erythematosus
TOXIC FUME INHALATION
NO2
NH3
Diacetyl flavorings (microwave popcorn)
CHRONIC HYPERSENSITIVITY PNEUMONITIS
Avian antigens
Mold
ASPIRATION
Stomach contents: gastroesophageal reflux
Foreign bodies
DRUGS
Penicillamine
Cocaine
STEVENS-JOHNSON SYNDROME
Idiopathic
Drug induced
Infection related
From Moonnumakal SP, Fan LL: Bronchiolitis obliterans in children, Curr Opin Pediatr 20:272–
278, 2008.

Bronchiolitis obliterans syndrome (BOS) is a clinical diagnosis related to


FIG. 422.2 High-resolution CT scan of the chest of a child with
bronchiolitis obliterans demonstrating mosaic perfusion and vascular
attenuation. Air-trapping is demonstrated by lack of increase in attention or
decrease in lung volume in dependent lung. (Image courtesy Alan Brody,
MD, Cincinnati Children's Hospital Medical Center, Ohio.)

Table 422.2
High-Resolution CT Patterns in Child With Interstitial Lung
Disease

GROUND-
STUDIES THICK MOSAIC
GLASS NODULES HONEYCOMBING
(N) SEPTA PATTERN
OPACITY
Bronchiolitis obliterans 4 — — — X —
Nonspecific interstitial 6 X — — — X
pneumonitis
Desquamative interstitial 4 X — — — X
pneumonitis
Follicular bronchitis or 4 X — — X —
neuroendocrine cell
hyperplasia of infancy
Lymphocytic interstitial 4 — — X — —
pneumonitis
Lymphangiomatosis 2 — X — — —
Lymphangiectasia 2 — X — — —
Pulmonary alveolar 2 X X — — —
proteinosis
From Long FR: Interstitial lung disease. In Slovis TL, editor: Caffey's pediatric diagnostic imaging ,
ed 11, Philadelphia, 2008, Mosby, Table 74.1; original data from Lynch DA, Hay T, Newell JD Jr, et
al: Pediatric diffuse lung disease: diagnosis and classification using high-resolution CT, AJR Am J
CHAPTER 424

Pulmonary Edema
Brandon T. Woods, Robert L. Mazor

Pulmonary edema is an abnormal fluid collection in the interstitium and air

spaces of the lung resulting in oxygen desaturation, decreased lung compliance,
and respiratory distress. The condition is common in the acutely ill child.

Pathophysiology
Although pulmonary edema is traditionally separated into two categories
according to cause (cardiogenic and noncardiogenic ), the end result of both
processes is a net fluid accumulation within the interstitial and alveolar spaces.
Noncardiogenic pulmonary edema, in its most severe state, is also known as
acute respiratory distress syndrome (see Chapters 89 and 400 ).
The hydrostatic pressure and colloid osmotic (oncotic) pressure on either side
of a pulmonary vascular wall, along with vascular permeability, are the forces
and physical factors that determine fluid movement through the vessel wall.
Baseline conditions lead to a net filtration of fluid from the intravascular space
into the interstitium. This extra interstitial fluid is usually rapidly reabsorbed by
pulmonary lymphatics. Conditions that lead to altered vascular permeability,
increased pulmonary vascular pressure, and decreased intravascular oncotic
pressure increase the net flow of fluid out of the vessel (Table 424.1 ). Once the
capacity of the lymphatics for fluid removal is exceeded, water accumulates in
the lung.

Table 424.1
Etiology of Pulmonary Edema
INCREASED PULMONARY CAPILLARY PRESSURE
 Cardiogenic, such as left ventricular failure
Noncardiogenic, as in pulmonary venoocclusive disease, pulmonary venous fibrosis, mediastinal tumors
INCREASED CAPILLARY PERMEABILITY
Bacterial and viral pneumonia
Acute respiratory distress syndrome
Inhaled toxic agents
Circulating toxins
Vasoactive substances such as histamine, leukotrienes, thromboxanes
Diffuse capillary leak syndrome, as in sepsis
Immunologic reactions, such as transfusion reactions
Smoke inhalation
Aspiration pneumonia/pneumonitis
Drowning and near drowning
Radiation pneumonia
Uremia
LYMPHATIC INSUFFICIENCY
Congenital and acquired
DECREASED ONCOTIC PRESSURE
Hypoalbuminemia, as in renal and hepatic diseases, protein-losing states, and malnutrition
INCREASED NEGATIVE INTERSTITIAL PRESSURE
Upper airway obstructive lesions, such as croup and epiglottitis
Reexpansion pulmonary edema
MIXED OR UNKNOWN CAUSES
Neurogenic pulmonary edema
High-altitude pulmonary edema
Eclampsia
Pancreatitis
Pulmonary embolism
Heroin (narcotic) pulmonary edema
Modified from Robin E, Carroll C, Zelis R: Pulmonary edema, N Engl J Med 288:239, 292, 1973;
and Desphande J, Wetzel R, Rogers M: In Rogers M, editor: Textbook of pediatric intensive care ,
ed 3, Baltimore, 1996, Williams & Wilkins, pp. 432–442.

To understand the sequence of lung water accumulation, it is helpful to

consider its distribution among four distinct compartments, as follows:

◆ Vascular compartment: This compartment consists

of all blood vessels that participate in fluid exchange
with the interstitium. The vascular compartment is
separated from the interstitium by capillary
endothelial cells. Several endogenous inflammatory
mediators, as well as exogenous toxins, are implicated
in the pathogenesis of pulmonary capillary endothelial
damage, leading to the leakiness seen in several
pressures, and hypoxia-induced increases in capillary permeability (see Chapter
90 ).
Active ion transport followed by passive, osmotic water movement is
important in clearing the alveolar space of fluid. There are some experimental
data that β-agonists and growth factors increase alveolar fluid removal.
Interindividual genetic differences in the rates of these transport processes may
be important in determining which individuals are susceptible to altitude-related
pulmonary edema. Although the existence of these mechanisms suggests that
therapeutic interventions may be developed to promote resolution of pulmonary
edema, no such therapies currently exist.

Clinical Manifestations
The clinical features depend on the mechanism of edema formation. In general,
interstitial edema and alveolar edema prevent the inflation of alveoli, leading to
atelectasis and decreased surfactant production. This results in diminished
pulmonary compliance and tidal volume. The patient must increase respiratory
effort and/or the respiratory rate so as to maintain minute ventilation. The
earliest clinical signs of pulmonary edema include increased work of breathing,
tachypnea, and dyspnea. As fluid accumulates in the alveolar space, auscultation
reveals fine crackles and wheezing, especially in dependent lung fields. In
cardiogenic pulmonary edema, a gallop may be present, as well as peripheral
edema and jugular venous distention.
Chest radiographs can provide useful ancillary data, although findings of
initial radiographs may be normal. Early radiographic signs that represent
accumulation of interstitial edema include peribronchial and perivascular
cuffing. Diffuse streakiness reflects interlobular edema and distended pulmonary
lymphatics. Diffuse, patchy densities, the so-called butterfly pattern, represent
bilateral interstitial or alveolar infiltrates and are a late sign. Cardiomegaly is
often seen with cardiogenic causes of pulmonary edema. Heart size is usually
normal in noncardiogenic pulmonary edema (Table 424.2 ). Chest tomography
demonstrates edema accumulation in the dependent areas of the lung. As a
result, changing the patient's position can alter regional differences in lung
compliance, functional residual capacity, and alveolar ventilation.

Table 424.2

Radiographic Features That May Help Differentiate Cardiogenic From

Radiographic Features That May Help Differentiate Cardiogenic From
Noncardiogenic Pulmonary Edema
RADIOGRAPHIC FEATURE CARDIOGENIC EDEMA NONCARDIOGENIC EDEMA
Heart size Normal or greater than normal Usually normal
Width of the vascular pedicle* Normal or greater than normal Usually normal or less than normal
Vascular distribution Balanced or inverted Normal or balanced
Distribution of edema Even or central Patchy or peripheral
Pleural effusions Present Not usually present
Peribronchial cuffing Present Not usually present
Septal lines Present Not usually present
Air bronchograms Not usually present Usually present
* The width of the vascular pedicle in adults is determined by dropping a perpendicular line from

the point at which the left subclavian artery exits the aortic arch and measuring across to the point
at which the superior vena cava crosses the right mainstem bronchus. A vascular pedicle width
>70 mm on a portable digital anteroposterior radiograph of the chest obtained when the patient is
supine is optimal for differentiating high from normal-to-low intravascular volume.
From Ware LB, Matthay MA: Acute pulmonary edema, N Engl J Med 353:2788–2796, 2005.

Measurement of brain natriuretic peptide, often elevated in heart disease, can

help to differentiate cardiac from pulmonary causes of pulmonary edema. A
brain natriuretic peptide level >500 pg/mL suggests heart disease; a level <100
pg/mL suggests lung disease.

Treatment
The treatment of a patient with noncardiogenic pulmonary edema is largely
supportive, with the primary goal to ensure adequate ventilation and
oxygenation. Additional therapy is directed toward the underlying cause.
Patients should receive supplemental oxygen to increase alveolar oxygen tension
and pulmonary vasodilation. Patients with pulmonary edema of cardiogenic
causes should be managed with diuretics, inotropic agents, and systemic
vasodilators to reduce left ventricular afterload (see Chapter 442 ). Diuretics are
also valuable in the treatment of pulmonary edema associated with total body
fluid overload (sepsis, renal insufficiency). Morphine is often helpful as a
vasodilator and a mild sedative.
Positive airway pressure improves gas exchange in patients with pulmonary
edema. In tracheally intubated patients, positive end-expiratory pressure can be
used to optimize pulmonary mechanics. Noninvasive forms of ventilation, such
as mask or nasal prong continuous positive airway pressure, are also effective.
The mechanism by which positive airway pressure improves pulmonary edema
CHAPTER 426

Chronic Recurrent Aspiration

John L. Colombo

Etiology
Repeated aspiration of even small quantities of gastric, nasal, or oral contents
can lead to recurrent bronchitis or bronchiolitis, recurrent pneumonia, atelectasis,
wheezing, cough, apnea, and/or laryngospasm. Pathologic outcomes include
granulomatous inflammation, interstitial inflammation, fibrosis, lipoid
pneumonia, and bronchiolitis obliterans. Most cases clinically manifest as
airway inflammation and are rarely associated with significant morbidity. Table
426.1 lists underlying disorders that are frequently associated with recurrent
aspiration. Oropharyngeal incoordination is reportedly the most common
underlying problem associated with recurrent pneumonias in hospitalized
children. In 2 reports, between 26% and 48% of such children were found to
have dysphagia with aspiration as the underlying problem. Lipoid pneumonia
may occur after the use of home/folk remedies involving oral or nasal
administration of animal or vegetable oils to treat various childhood illnesses.
Lipoid pneumonia has been reported as a complication of these practices in the
Middle East, Asia, India, Brazil, and Mexico. The initial underlying disease,
language barriers, and a belief that these are not medications may delay the
diagnosis (see Chapter 11 ).

Table 426.1
Conditions Predisposing to Aspiration Lung Injury in
Children
Anatomical and Mechanical
Tracheoesophageal fistula
Laryngeal cleft
Vascular ring
Cleft palate
Micrognathia
Macroglossia
Cysts, tumors
Achalasia
Esophageal foreign body
Tracheostomy
Endotracheal tube
Nasal or oral feeding tube
Collagen vascular disease (scleroderma, dermatomyositis)
Gastroesophageal reflux disease
Obesity
Neuromuscular
Altered consciousness
Immaturity of swallowing/Prematurity
Dysautonomia
Increased intracranial pressure
Hydrocephalus
Vocal cord paralysis
Cerebral palsy
Muscular dystrophy
Hypotonia
Myasthenia gravis
Guillain-Barré syndrome
Spinal muscular atrophy
Ataxia-telangiectasia
Cerebral vascular accident
Miscellaneous
Poor oral hygiene
Gingivitis
Prolonged hospitalization
Gastric outlet or intestinal obstruction
Poor feeding techniques (bottle propping, overfeeding, inappropriate foods for toddlers)
Bronchopulmonary dysplasia
Viral infection/bronchiolitis

Gastroesophageal reflux disease (GERD ; see Chapter 349 ) is also a

common underlying finding that may predispose to recurrent respiratory disease,
but it is less frequently associated with recurrent pneumonia than is dysphagia
(see Chapter 349 ). GERD is associated with microaspiration and bronchiolitis
obliterans in lung transplant recipients. Aspiration has also been observed in
infants with respiratory symptoms but no other apparent abnormalities.
Recurrent microaspiration has been reported in otherwise apparently normal
newborns, especially premature infants. Aspiration is also a risk in patients
suffering from acute respiratory illness from other causes, such as respiratory
syncytial virus infection (see Chapter 287 ). Modified barium swallow and
videofluoroscopy may reveal silent aspiration in these patients. This finding
emphasizes the need for a high degree of clinical suspicion for ongoing
the gold standard for evaluating the swallowing mechanism. This study is
preferably done with the assistance of a pediatric feeding specialist and a
caregiver in the attempt to simulate the usual feeding technique of the child. The
child is seated in normal eating position, and various consistencies of barium or
barium-impregnated foods are offered. This study is more sensitive for
demonstrating aspiration than bedside assessment or a traditional barium
swallow study. The sensitivity of the modified barium swallow study is such that
it occasionally detects aspiration in patients without apparent respiratory
abnormalities.

Table 426.2
Summary of Diagnostic Tests of Aspiration

EVALUATION BENEFITS LIMITATIONS

Chest radiograph Inexpensive and widely available Insensitive to early subtle changes of
Assesses accumulation of injury over time lung injury
High-resolution CT Sensitive in detecting lung injury, such as More radiation exposure than plain
bronchiectasis, tree-in-bud opacities, and radiograph
bronchial thickening Expensive
Less radiation than conventional CT
Assesses accumulation of injury over time
Video swallow study Evaluates all phases of swallowing Information limited if child consumes
Evaluates multiple consistencies only small quantities
Feeding recommendations made at time of Difficult to perform in child who has not
study been feeding by mouth
Radiation exposure proportional to
study duration
Cannot be performed at bedside
Limited evaluation of anatomy
Evaluates 1 moment in time
Expensive
FEES/with sensory Ability to thoroughly evaluate functional Blind to esophageal phase and actual
testing anatomy swallow
Evaluates multiple consistencies Invasive and may not represent
Can assess risk of aspiration in non-orally physiological swallowing conditions
feeding child; airway protective reflexes can Evaluates 1 moment in time
be assessed Not widely available
Feeding recommendations made at time of Expensive
study
Visual feedback for caregivers
Can be performed at bedside
No radiation exposure
BAL Evaluates anatomy of entire upper and lower Uncertainty regarding interpretation of
airways lipid-laden macrophage index
Samples the end-organ of damage Index cumbersome to calculate
Sample available for multiple cytological and Requires sedation or anesthesia
microbiologic tests Invasive
Widely available Expensive
 Esophageal pH Current gold standard for diagnosis of acid Blind to majority of reflux (nonacid)
monitoring gastroesophageal reflux events
Established normative data in children Difficult to establish causal relationship
between gastroesophageal reflux and
aspiration
Somewhat invasive
Evaluates short time interval
Esophageal Likely gold standard for diagnosis of GERD Lack of normative data for children
impedance monitoring with supraesophageal manifestations Somewhat invasive
Able to detect acid and nonacid reflux events Expensive and cumbersome to interpret
Detects proximal reflux events Not widely available
Able to evaluate for GERD without stopping Evaluates short time interval
medications
Gastroesophageal Performed under physiologic conditions Poor sensitivity
scintigraphy Low radiation exposure May not differentiate between aspiration
from dysphagia or GERD
Radionuclide Child does not have to be challenged with food Unknown sensitivity
salivagram bolus Unknown relationship to disease
Low radiation exposure outcomes
Evaluates 1 moment in time
Dye studies Can be constructed as screening test or Uncertainty in interpretation owing to
confirmatory test variability of technique
Can evaluate aspiration of secretions or feeds Can only be performed in children with
Repeating over time allows for broader tracheostomies
evaluation
Other biomarkers Theoretical high specificity and sensitivity Limited availability and standardization
(pepsin, bile acids) Variable results to date
milk protein
BAL, bronchoalveolar lavage; FEES, fiberoptic-endoscopic evaluation of swallowing; GERD,
gastroesophageal reflux disease.
Modified from Boesch RP, Daines C, Willging JP, et al: Advances in the diagnosis and
management of chronic pulmonary aspiration in children, Eur Respir J 28:847–861, 2006; and
Tutor JD, Gosa MM: Dysphagia and aspiration in children, Pediatr Pulmonol 47(4):321–337, 2012.
Failure to recognize the disease early may lead to chronic irreversible lung
changes with persistent symptoms in the patient.

Etiology
The most common sources of offending agents that cause HP include
agricultural aerosols, inhaled protein antigens from animals, antigens from
microorganisms of bacteria, fungi, or protozoan origin, as well as chemicals of
low and high molecular weight (Table 427.1 ). Many inciting agents are
associated with occupational diseases in which children do not regularly work.
However, the same diseases can occur in children due to exposures to similar
antigen sources in nonoccupational environments, or in occupational
environments with teenage workers. In addition to HP, the same antigens may
lead to allergic asthma or chronic bronchitis as seen with animal proteins,
contaminated metal working fluids, and other inhaled antigens.

Table 427.1
Antigen Sources Associated with Specific Causes of
Hypersensitivity Pneumonitis

HYPERSENSITIVITY PNEUMONITIS ANTIGEN SOURCE

Bagassosis (mold on pressed sugar cane) Thermoactinomyces sacchari
Thermoactinomyces vulgaris
Bat lung (bat droppings) Bat serum protein
Bible printer's lung Moldy typesetting water
Bird fancier's lung (parakeets, budgerigars, pigeons) Droppings, feathers, serum proteins
Byssinosis (“brown lung”) (unclear if a true cause of Cotton mill dust (carding and spinning areas of
hypersensitivity pneumonitis; asthma is common) cotton, flax, and soft-hemp)
Canary fancier's lung Serum proteins
Cheese washer's lung (moldy cheese) Penicillium casei
Aspergillus clavatus
Chemical hypersensitivity pneumonitis Diphenylmethane diisocyanate (MDI)
Toluene diisocyanate (TDI)
Coffee worker's lung Coffee-bean dust
Composter's lung T. vulgaris
Aspergillus species
Contaminated basement (sewage) pneumonitis Cephalosporium
Coptic lung (mummy handler's lung) Cloth wrappings of mummies
Detergent worker's lung (washing powder lung) Bacillus subtilis enzymes
Dry rot lung Merulius lacrymans
Duck fever Feathers, serum proteins
Epoxy resin lung Phthalic anhydride (heated epoxy resin)
Esparto dust (mold in plaster dust) Aspergillus fumigatus
 Thermophilic actinomycetes
Farm worker lung Thermophilic actinomycetes plus others
Feather duvet (pillow) lung Goose or duck feathers
Fish meal worker's lung Fish meal
Furrier's lung (sewing furs; animal fur dust) Animal pelts
Grain measurer's lung Cereal grain (Sporobolomyces )
Grain dust (mixture of dust, silica, fungi,
insects, and mites)
Hot-tub lung (mists; mold on ceiling and around tub) Cladosporium spp.
Mycobacterium avium complex
Humidifier fever Thermoactinomyces (T. vulgaris, T. sacchari, T.
candidus)
Klebsiella oxytoca
Naegleria gruberi
Acanthamoeba polyphaga
Acanthamoeba castellani
Laboratory worker's lung (rats, gerbils) Urine, serum, pelts, proteins
Lifeguard lung Aerosolized endotoxin from pool-water sprays
and fountains
Lycoperdonosis (Lycoperdon puffballs) Puffball spores
Machine operator's lung Pseudomonas fluorescens
Aerosolized metal working fluid
Malt worker's disease (moldy barley) Aspergillus fumigatus, Aspergillus clavatus
Maple bark disease (moldy maple bark) Cryptostroma corticale
Miller's lung (dust-contaminated grain) Sitophilus granarius (i.e., wheat weevil)
Moldy hay, grain, silage (farmer's lung) Thermophilic actinomycetes
Fungi (e.g., Aspergillus umbrosus )
Mollusk shell hypersensitivity pneumonitis Sea-snail shell
Mushroom worker's lung Mushroom spores
Thermophilic actinomycetes
Paprika slicer's lung (moldy paprika pods) Mucor stolonifer
Pauli's reagent alveolitis Sodium diazobenzene sulfate
Pearl oyster shell pneumonitis Oyster shells
Pituitary snuff taker's disease Dried, powdered cattle or pig pituitary proteins
Potato riddler's lung (moldy hay around potatoes) Thermophilic actinomycetes
T. vulgaris
Faenia rectivirgula
Aspergillus spp.
Poultry worker's lung (feather plucker's disease) Serum proteins (chicken products)
Pyrethrum (pesticide) Pyrethrum
Sauna taker's lung Aureobasidium spp., other sources
Sequoiosis (moldy wood dust) Graphium
Pullularia
Trichoderma spp.
Aureobasidium pullulans
Suberosis (moldy cork dust) Thermoactinomyces viridis
Penicillium glabrum
Aspergillus conidia
Summer-type pneumonitis Trichosporon cutaneum
Tea grower's lung Tea plants
Thatched-roof lung (huts in New Guinea) Saccharomonospora viridis (dead grasses and
leaves)
Tobacco grower's lung Aspergillus spp.
 Scopulariopsis brevicaulis
Turkey handling disease Serum proteins (turkey products)
Unventilated shower Epicoccum nigrum
Upholstery fabric (nylon filament, cotton/polyester, and latex Aflatoxin-producing fungus, Fusarium spp.
adhesive)
Velvet worker's lung Unknown (? nylon velvet fiber, tannic acid,
potato starch)
Vineyard sprayer's lung Copper sulfate (bordeaux mixture)
Wind instrument lung Bacteria or mold contamination of instrument
Wine maker's lung (mold on grapes) Botrytis cinerea
Wood dust pneumonitis (oak, cedar, and mahogany dust, pine Alternaria spp.
and spruce pulp) Bacillus subtilis
Wood pulp worker's disease (oak and maple trees) Penicillium spp.
Wood trimmer's disease (contaminated wood trimmings) Rhizopus spp., Mucor spp.

More than 300 antigens have been associated with HP. In children, primary
sources of HP have been the result of exposure to pet birds (or feathers in
bedding and pillows) such as parakeets, canaries, cockatiels, or cockatoos.
Aerosol spread of bird droppings can also occur by clothes dryer vents or by
heating vents from a garage where the pet birds were housed. Humidifiers and
hot tubs are notorious for contamination with thermophilic organisms (bacteria
and mold) as well as Mycobacterium avium complex. Buildings with inadequate
ventilation and insufficient air turnover present an increased risk of mold
exposure from prior flooding or damp condensation. Despite exposures to the
same antigen sources, members of the same family may exhibit different
presentations of allergic disease. Some family members may have symptoms of
asthma or rhinitis, while another may have HP.

Pathogenesis
HP has been traditionally classified as acute, subacute, or chronic. During the
acute phase, the offending antigen triggers an inflammatory response promoting
the development of immune complexes. These immune complexes activate the
complement pathway, ultimately resulting in the accumulation of neutrophils in
the airway that release enzymes such as neutrophil elastase, that damage
surrounding lung tissue. Activated macrophages in the lung promote recruitment
of lymphocytes into the tissues. Pathology shows alveolitis with a mixed cellular
infiltration comprised of lymphocytes, macrophage, plasma cells, and
neutrophils. Continued exposure to the offending antigen will lead to subacute or
chronic HP. This chronic exposure results in the formation of loose,
noncaseating granulomas located near the respiratory or terminal bronchioles. It
is critical when a biopsy is being performed (transbronchial or surgical) that the
pathologist knows that HP is being considered as there are other interstitial lung
diseases (ILDs) that produce similar granulomas with subtle location differences
depending on their origin.

Clinical Manifestations and Classification

Acute HP is typically caused by heavy exposure to an offending antigen. This is
the most common form of exposure but is frequently not recognized. Symptoms
are confused with bacterial or viral disease leading to treatment with antibiotics.
Four to 8 hr after exposure, patients can present with the abrupt onset of cough,
chest tightness, dyspnea, fever, chills, and fatigue (Table 427.2 ). Rarely,
findings of wheezing are present on the initial examination. Rather, tachypnea
with fine crackles may be heard by auscultation in the lung bases. However,
auscultation may be normal at this stage. After cessation of exposure, symptoms
may subside after 24-48 hr.

Table 427.2

Clinical History Clues Leading to a Diagnosis of Hypersensitivity Pneumonitis

Recurrent pneumonia
Pneumonia after repeat exposures (week, season, situation)
Cough, fever, and chest symptoms after making a job change or home change
Cough, fever, wheezing after return to school or only at school
Pet exposure (especially birds that shed dust such as pigeons, canaries, cockatiels, cockatoos)
Bird contaminant exposure (e.g., pigeon infestation)
Farm exposure to birds and hay
History of water damage despite typical cleaning
Use of hot tub, sauna, swimming pool
Other family members or workers with similar recurrent symptoms
Improvement after temporary environment change (e.g., vacation)

When recurrent subacute HP is present, the symptoms become progressive

with shortness of breath and cough (productive), weight loss, malaise, and loss
of appetite. When HP becomes chronic and progressive , the patient is hypoxic,
and clubbing of the fingers is evident. If the disease progresses to interstitial
fibrosis, the symptoms tend to not respond to therapy and mortality risk is
increased. Histology is hard to distinguish from idiopathic pulmonary fibrosis
at this stage.
Distinguishing chronic disease from subacute disease is difficult without clear
differentiating criteria, but a diagnosis of HP at any stage results in the clinician
recommending very specific interventions for improvement. HP is characterized
as (1) acute nonprogressive and intermittent, (2) acute progressive and
intermittent, (3) chronic nonprogressive, and (4) chronic progressive (Table
427.3 ). A diagnosis of HP is certain when the known exposure with immune
response to the offending antigen is identified; the medical history and physical
finding are abnormal on examination; bronchoalveolar lavage (BAL) and lung
biopsy are abnormal. Some clinicians have foregone the lung biopsy when a
cluster of cases occurs and 1 patient biopsy is already abnormal.

Table 427.3
Criteria Used in the Diagnosis of Hypersensitivity
Pneumonitis
1. Identified exposure to offending antigen(s) by:
• Medical history of exposure to suspected antigen in the patient's living environment
• Investigations of the environment confirm the presence of an inciting antigen
• Identification of specific immune responses (immunoglobulin G serum precipitin antibodies against the
identified antigen) are suggestive of the potential etiology but are insufficient in isolation to confirm a
diagnosis
2. Clinical, radiographic, or physiologic findings compatible with hypersensitivity pneumonitis:
• Respiratory and often constitutional signs and symptoms
• Crackles on auscultation of the chest
• Weight loss
• Cough
• Breathlessness
• Episodic fever
• Wheezing
• Fatigue
NOTE: These findings are especially suggestive of hypersensitivity pneumonitis when they appear or worsen
several hours after antigen exposure.
• A reticular, nodular, or ground-glass opacities on chest radiograph or high-resolution CT
• Abnormalities in the following pulmonary function tests
• Spirometry (restrictive, obstructive, or mixed patterns)
• Lung volumes (low or high)
• Reduced diffusion capacity by carbon monoxide
• Altered gas exchange either at rest or with exercise (reduced partial pressure of arterial oxygen by blood
gas or pulse oximeter testing)
3. Bronchoalveolar lavage with lymphocytosis:
• Usually with low CD4:CD8 ratio (i.e., CD8 is higher than normal)
• Lymphocyte stimulation by offending antigen results in proliferation and cytokine production
4. Abnormal response to inhalation challenge testing to the offending antigen:
• Reexposure to the environment
 • Inhalation challenge to the suspected antigen (rarely done now because of the risk of exacerbating the
disease)
5. Histopathology showing compatible changes with hypersensitivity pneumonitis by 1 of these findings:
• Poorly formed, noncaseating granulomas (most often found closer to the respiratory epithelium where
deposition of the offending antigen occurs)
• Mononuclear cell infiltrate in the pulmonary interstitium

Laboratory
Most of the abnormal laboratory findings in HP are not specific and represent
evidence of activated inflammatory markers or lung injury. Nonspecific
elevation of immune globulins or the erythrocyte sedimentation rate and C-
reactive protein may also be found. Circulating immune complexes may be
detected. Lactate dehydrogenase may be elevated in the presence of lung
inflammation and normalizes with response to therapy.
Serum IgG precipitins to the offending agent are frequently positive and have
a poor positive predictive value for disease. Among asymptomatic pigeon
breeders, precipitating antibodies are nearly universal. False negatives can also
be seen due to fluctuating serum antibody levels over time, and lack of
standardized commercial antigens and reagents available for laboratory testing.
It is critical that laboratories familiar with the performance of these tests be
utilized. Those laboratories often recognize the value of processing antigens for
precipitation from the environmental source directly as the test substrate with
patient serum. Skin testing for IgE-mediated disease is not warranted unless
there is evidence of mixed lung pathology such as asthma and interstitial lung
opacities.

Radiology
Chest radiograph almost always precedes the use of high-resolution
computerized tomography (HRCT) of the chest in children because of the need
for sedation and concerns regarding risk of irradiation dose from HRCT. The
plain radiograph will often demonstrate a ground-glass appearance, interstitial
prominence, with a predominant location in the upper and middle lung fields. It
is common for a chest radiograph to be considered normal by a radiologist early
in the disease progression. Late in the disease, interstitial fibrosis may become
prominent in the presence of increasing dyspnea, hypoxemia on room air, and
clubbing of the fingers. Mediastinum widening from lymphadenopathy is not
 reactive upper airway disease syndrome
high molecular weight
low molecular weight

Occupational and environmental lung diseases constitute a larger part of primary

care pediatrics, pediatric emergency medicine, and other pediatric subspecialties
than most pediatric practitioners expect or realize. Although occupational and
environmental lung diseases include occupational asthma , reactive airways
dysfunction syndrome (RADS) , HP, hard metal inhalation lung disease,
berylliosis, and air pollution, this chapter focuses on occupational asthma and
RADS. Berylliosis has a propensity to form granulomas (see Chapter 427.3 ).
Although some diseases will be seen with regularity, the important role that a
part-time workplace, school, daycare, neighbors’ housing, multiple family
housing, and indoor and outdoor environments may have in the causation of
signs and symptoms in the patient is not always considered by the clinician.
The vast array of exposures shown to cause disease of the lungs is daunting,
such as the inhalation of baking flour or household cleaning fluids causing
asthma, microwave popcorn exposure to diacetyl resulting in bronchiolitis
obliterans, and exposure to thermophilic organisms or mold resulting in
hypersensitivity pneumonitis. The acute eosinophilic pneumonias associated
with new onset of smoking and chemical inhalation of 1,1,1-trichloroethane
(Scotchgard) require a high index of suspicion and unique lines of questioning.
The same antigen encountered in a work, school, home, or outdoor environment
may result in a different disease presentation because of host factors, dose
exposure, and genetic susceptibility. One of the most prominent examples is an
investigation of workers who inhaled metal working fluid. Despite similar
exposures, some developed HP, others developed asthma, and some displayed no
symptoms at all. Immunologic evaluation in some exposures has shown similar
immune responses in different individuals, but a wide range of disease
provocation. When high molecular weight proteins cause asthma, symptoms of
rhinoconjunctivitis frequently precede the onset of pulmonary symptoms. The
medical history of occupational and environmental lung diseases has used an
expanded construct with a simple acronym, WHACOS (Table 427.4 ).

Table 427.4

A Construct (WHACOS) That Has Been Used in Medical Interviewing of Patients,

Coworkers, and Family Members When Environmental or Occupational Lung Disease
Is Being Considered
W W hat do you do?
H H ow do you do what you do?
A Are symptoms A cute or are they Chronic?
C Do any C oworkers, family, classmates, or friends have the same symptoms?
O Do you have any hobbies, travel, or animal/pet exposures O utside of school or work?
S Are you S atisfied with work or school?

It is important to remember that in patients with occupational- or

environmental-induced disease, the onset of symptoms has a lag time between
exposure and symptoms. In occupational asthma , there may be an immediate
response within 1-2 hr of exposure, demonstrated as a decline in pulmonary
function, specifically the FEV1 . Usually, lung function returns to normal
spontaneously unless persistent exposure occurs. Some patients demonstrate no
immediate reduction in lung function, but rather experience a delayed response,
4-6 hr after the exposure. Treating physicians can take advantage of this
physiology in occupational and environmental asthma by use of spirometry
before and after work or school, or peak flow measurements hourly during
exposure and after leaving the exposure. Because workers and schoolchildren
have prolonged periods of exposure followed by a number of days without
exposure, the use of pulmonary function plus bronchial hyperresponsiveness
(e.g., methacholine) testing is helpful. Pulmonary function tests prior to starting
work on a Monday of a typical work week may be normal. By Friday of a
typical work or school week, the baseline pulmonary functions may have fallen,
and bronchial responsiveness may have become more sensitive to a lower
concentration of histamine, methacholine, or mannitol. By the following
Monday, the tests may have returned to normal or near normal with no change
other than reduced exposure.
In the case of HP, a lag of 4-8 hr between the time of exposure and the onset
of fever, cough, and dyspnea is common. Unfortunately, the return home from
hospitalization for culture-negative pneumonia to a source of antigen-causing HP
often results in complete reoccurrence of symptoms. Clinicians must have a high
index of suspicion for HP with reoccurrence of pulmonary infiltrates shortly
after reexposure (see Chapter 427.1 ).

Classification and Pathogenesis

Occupational and environmental lung diseases include numerous syndromes of
human lung disease such as occupational asthma , RADS (reactive upper
airway disease syndrome) , hypersensitivity pneumonitis (see Chapter 427.1 ),
air pollution–induced disease, hard metal inhalation lung disease, berylliosis,
occupation-induced lung cancer (e.g., mesothelioma from asbestosis), and
chronic obstructive pulmonary disease without smoking. Most of these diseases
are not problematic for children, but adolescents may be exposed through part-
time work or by single exposures as seen in RADS.

Occupational and Environmental Asthma

The general principles of diagnosis, clinical signs and symptoms, treatment, and
causes of asthma are discussed in Chapter 169 . High molecular weight causes of
occupational and environmental asthma can be characterized as allergens, which
are normally proteins and enzymes, inhaled from multiple sources (Table 427.5
). These include various animals, shellfish, fish, enzymes (e.g., Bacillus subtilis
in laundry detergent), and flour or cereals. Occupational and environmental
asthma is also caused by a number of low molecular weight agents including
reactive chemicals, transition metals, and wood dusts (Table 427.6 ). These low
molecular weight agents are sufficient to induce an immune response, but often
not by an IgE-mediated mechanism. These low molecular weight chemicals
appear to act as haptens that bind directly to human proteins, causing an immune
response in the human host.

Table 427.5
High Molecular Weight Antigens Known to Induce
Occupational or Environmental Asthma

OCCUPATION
OR SOURCE
ENVIRONMENT
ANIMAL-DERIVED ANTIGENS
Agricultural Cow dander
worker
Bakery Lactalbumin
Butcher Cow bone dust, pig, goat dander
Cook Raw beef
Dairy industry Lactoserum, lactalbumin
Egg producer Egg protein
Farmer Deer dander, mink urine
Frog catcher Frog
Hairdresser Sericin
Ivory worker Ivory dust
Laboratory Bovine serum albumin, laboratory animal, monkey dander
technician
Nacre buttons Nacre dust
Pharmacist Endocrine glands
Pork producer Pig gut (vapor from soaking water)
Poultry worker Chicken
Tanner Casein (cow's milk)
Various Bat guano
Veterinarian Goat dander
Zookeeper Birds
CRUSTACEANS, SEAFOOD, FISH
Canning factory Octopus
Diet product Shark cartilage
Fish food factory Gammarus shrimp
Fish processor Clam, shrimp, crab, prawn, salmon, trout, lobster, turbot, various fishes
Fisherman Red soft coral, cuttlefish
Jewelry polisher Cuttlefish bone
Laboratory grinder Marine sponge
Oyster farm Hoya (oyster farm prawn or sea-squirt)
Restaurant seafood Scallop and shrimp
handler
Scallop plant King scallop and queen scallop
processor
Technician Shrimp meal (Artemia salina)
ARTHROPODS
Agronomist Bruchus lentis
Bottling Ground bug
Chicken breeder Herring worm (Anisakis simplex)
Engineer at electric Caddis flies (Phryganeidae)
power plant
Entomologist Lesser mealworm (Alphitobius diaperinus Panzer), moth, butterfly
Farmer Grain pests (Eurygaster and Pyrale )
Fish bait handler Insect larvae (Galleria mellonella) , mealworm larvae (Tenebrio molitor) , green bottle fly
larvae (Lucila caesar) , daphnia, fish-feed Echinodorus larva (Echinodorus plasmosus) ,
Chiromids midge (Chironomus thummi thummi)
Fish processing Herring worm (Anisakis simplex)
Flight crew Screw worm fly (Cochliomyia hominivorax)
Honey processors Honeybee
Laboratory worker Cricket, fruit fly, grasshopper (Locusta migratoria) , locust
Mechanic in a rye Confused flour beetle (Tribolium confusum)
plant
Museum curator Beetles (Coleoptera)
Seed house Mexican bean weevil (Zabrotes subfasciatus)
Sericulture Silkworm, larva of silkworm
Sewage plant Sewer fly (Psychoda alternata)
worker
Technician Arthropods (Chrysoperla carnea, Leptinotarsa decemlineata, Ostrinia nubilalis, and
Ephestia kuehniella), sheep blowfly (Lucilia cuprina)
Wool worker Dermestidae spp.
ACARIANS
Apple grower Fruit tree red spider mite (Panonychus ulmi)
Citrus farmer Citrus red mite (Panonychus citri)
Farmer Barn mite, two-spotted spider mite (Tetranychus urticae) , grain mite
Flour handler Mites and parasites
Grain-store worker Grain mite
Horticulturist Amblyseius cucumeris
Poultry worker Fowl mite
Vine grower McDaniel spider mite (Tetranychus mcdanieli)
MOLDS
Agriculture Plasmopara viticola
Baker Alternaria, Aspergillus (unspecified)
Beet sugar worker Aspergillus (unspecified)
Coal miner Rhizopus nigricans
Coffee maker Chrysonilia sitophila
Laborer Sooty molds (Ascomycetes , deuteromycetes)
Logging worker Chrysonilia sitophila
Plywood factory Neurospora
worker
Sausage processing Penicillium nalgiovense
Sawmill worker Trichoderma koningii
Stucco worker Mucor spp. (contaminating esparto fibers)
Technician Dictyostelium discoideum (mold), Aspergillus niger
MUSHROOMS
Agriculture Agaricus bisporus (white mushroom)
Baker Baker's yeast (Saccharomyces cerevisiae), Boletus edulis
Greenhouse worker Sweet pea (Lathyrus odoratus)
Hotel manager Boletus edulis
Mushroom Pleurotus cornucopiae
producer
Mushroom soup Mushroom unspecified
processor
Office worker Boletus edulis
Seller Pleurotus ostreatus (spores of white spongy rot)
ALGAE
Pharmacist Chlorella
Thalassotherapist Algae (species unspecified)
FLOURS
Animal fodder Marigold flour (Tagetes erecta)
Baker Wheat, rye, soya, and buckwheat flour; Konjac flour; white pea flour (Lathyrus sativus)
Food processing White Lupin flour (Lupinus albus)
POLLENS
Florist Cyclamen, rose
Gardener Canary island date palm (Phoenix canariensis) , Bell of Ireland (Moluccella laevis) , Bell
pepper, chrysanthemum, eggplant (Solanum melongena) , Brassica oleracea (cauliflower
and broccoli)
Laboratory worker Sunflower (Helianthus spp.), thale cress (Arabidopsis thaliana)
Olive farmer White mustard (Sinapis alba)
Processing worker Helianthus annuus
PLANTS
Brewery chemist Hops
Brush-maker Tampico fiber in agave leaves
Butcher Aromatic herb
Chemist Linseed oilcake, Voacanga africana seed dust
Cosmetics Dusts from seeds of Sacha Inchi (Plukenetia volubilis) , chamomile (unspecified)
Decorator Cacoon seed (Entage gigas)
Floral worker Decorative flower, safflower (Carthamus tinctorius) and yarrow (Achillea millefolium) ,
spathe flower, statice (Limonium tataricum) , baby's breath (Gypsophila paniculata) , ivy
(Hedera helix) , flower (various), sea lavender (Limonium sinuatum)

Food industry Aniseed, fenugreek, peach, garlic dust, asparagus, coffee bean, sesame seed, grain dust,
carrot (Daucus carota L.) , green bean (Phaseolus multiflorus) , lima bean (Phaseolus
lunatus), onion, potato, swiss chard (Beta vulgaris L.) , courgette, carob bean, spinach
powder, cauliflower, cabbage, chicory, fennel seed, onion seeds (Allium cepa , red onion),
rice, saffron (Crocus sativus), spices, grain dust
Gardener Copperleaf (Acalypha wilkesiana), grass juice, weeping fig (Ficus benjamina), umbrella tree
(Schefflera spp.), amaryllis (Hippeastrum spp.), Madagascar jasmine sap (Stephanotis
floribunda) , vetch (Vicia sativa)
Hairdresser Henna (unspecified)
Herbal tea Herbal tea, sarsaparilla root, sanyak (Dioscorea batatas), Korean ginseng (Panax ginseng),
processor tea plant dust (Camellia sinensis) , chamomile (unspecified)
Herbalist Licorice roots (Glycyrrhiza spp.), wonji (Polygala tenuifolia) , herb material
Horticulture Freesia (Freesia hybrida), paprika (Capsicum annuum) , Brazil ginseng (Pfaffia paniculata)
Laborer Citrus food handling (dl -limonene, l -citronellol, and dichlorophen)
Oil industry Castor bean, olive oilcake
Pharmaceutical Rose hip, passion flower (Passiflora alata) , cascara sagrada (Rhamnus purshiana)
Powder Lycopodium powder
Sewer Kapok
Sheller Almond shell dust
Stucco handler Esparto (Stipa tenacissima and Lygeum spartum )
Tobacco Tobacco leaf
manufacturer
PLANT-DERIVED NATURAL PRODUCTS
Baker Gluten, soybean lecithin
Candy maker Pectin
Glove Latex
manufacturer
Health professional Latex
Rose extraction Rose oil
BIOLOGIC ENZYMES
Baker Fungal amylase, fungal amyloglucosidase and hemicellulase
Cheese producer Various enzymes in rennet production (proteases, pepsine, chymosins)
Detergent industry Esterase, Bacillus subtilis
Factory worker Bacillus subtilis
Fruit processor Pectinase and glucanase
Hospital personnel Empynase (pronase B)
Laboratory worker Xylanase, phytase from Aspergillus niger
Pharmaceutical Bromelin, flaviastase, lactase, pancreatin, papain, pepsin, serratia peptidase, and lysozyme
chloride; egg lysozyme, trypsin
Plastic Trypsin
VEGETABLE GUMS
Carpet Guar
manufacturing
Dental hygienist Gutta-percha
Gum importer Tragacanth
Hairdresser Karaya
Printer Acacia
Table 427.6
Low Molecular Weight Chemicals Known to Induce
Occupational or Environmental Asthma

CHEMICALS OCCUPATION OR ENVIRONMENT SOURCE

Diisocyanates
• Diphenylmethane • Polyurethane
• Hexamethylene • Roofing materials
• Naphthalene • Insulations
• Toluene • Paint
Anhydrides Manufacturers or users
• Trimellitic • Paint
• Phthalic • Plastics
• Epoxy resins
Dyes Personal or business use of dyes
• Anthraquinone • Hair dye
• Carmine • Fur dye
• Henna • Fabric dye
• Persulfate
Glue or resin Plastic
• Methacrylate • Manufacturers
• Acrylates • Healthcare professionals
• Epoxy • Orthopedic specialists
Metals Metal work
• Chromic acid • Plating
• Potassium dichromate • Welding
• Nickel sulfate
• Vanadium
• Platinum salts
Drugs Exposure to drugs in environment
• β-Lactams • Pharmaceutical workers
• Opioids • Farmers
• Other • Healthcare workers
Chemicals Exposure in the healthcare field
• Formaldehyde • Laboratory work
• Glutaraldehyde • Healthcare professionals
• Ethylene oxide
Wood dust Workers/hobbyists
• Western red cedar (plicatic acid) • Sawmill
• Exotic woods • Carpentry
• Maple • Woodworking
• Oak

The pathogenesis of asthma in patients exposed to high molecular weight

antigens follows the experience of nonoccupational asthma in patients where
atopy, gender, genetics, concentration of antigen, duration of exposure, and other
individual factors all contribute to the development of disease. Most individuals
require a concentration and duration of exposure sufficient to cause IgE antibody
sensitization to the offending allergen with development of bronchial
hyperresponsiveness and airway inflammatory disease upon reexposure. If the
allergen exposure is sufficient, these proteins can drive the immune response to a
T-lymphocyte type 2 phenotype (Th2), even in patients without prior atopic
disposition. This occurred in the case of latex allergy, where many nonatopic
individuals and patients exposed to allergen in their personal healthcare
developed occupational allergy to multiple proteins from natural rubber latex.
Atopic individuals are at the highest risk of developing latex allergy. A
longitudinal study demonstrated that powdered latex gloves with high allergen
content were the reason for the epidemic of latex allergy and occupational
asthma. Unfortunately, despite primary removal of the offending sensitizing
agent, asthma symptoms and bronchial hyperresponsiveness induced from
multiple causes persist in approximately 70% of individuals with occupational
asthma.

Reactive Airways Disease Syndrome and

Irritant-Induced Asthma
RADS presents with acute respiratory symptoms within minutes or hours
following a single inhalation of a high concentration of irritant gas, aerosol, or
smoke. The clinical manifestations and pathophysiology of RADS have been
studied through experimental design or epidemiology studies following exposure
to chlorine gas, acetic acid, dimethylaminoethanol, chlorofluorocarbons,
epichlorohydrin, and diisocyanates.
Table 427.7 lists the criteria for diagnosis of RADS. Asthma-like symptoms
and airway hyperresponsiveness then ensue, which often persist for prolonged
periods. Unlike typical asthma, RADS is often not reversible by use of a
bronchodilator. This is probably a consequence of the direct injury to the
epithelium and subsequent submucosal fibrosis.

Table 427.7
Criteria for the Diagnosis of Reactive Airways Disease
Syndrome
• Absence of previous documented respiratory symptom
• Onset of symptoms most often occur after a single specific exposure
• Exposure is most often to a high concentration of gas, smoke, fume, or vapor with irritant qualities
• Symptoms occur within 24 hr of exposure and persist for 3 mo or longer
• Symptoms mimic asthma with cough, wheezing, shortness of breath, and/or dyspnea
 • Pulmonary function tests may demonstrate airflow obstruction but not always
• Bronchial hyperresponsiveness is documented by methacholine challenge
• Alternative pulmonary diseases are not able to be found

Irritant-induced asthma is a closely related form of asthma resulting from

nonimmunologic provocation of bronchial hyperresponsiveness with airflow
obstruction. In contrast to RADS, irritant-induced asthma occurs after single or
multiple exposures to irritant chemicals in low concentration . If the resultant
pulmonary symptoms occur after multiple exposures at a plant, it is termed
nonimmunologic-induced asthma .
Predisposing factors for the development of RADS are not well characterized.
Atopy and cigarette smoking may increase the risk of developing RADS when
exposure through inhalation of irritant chemicals occurs. In addition to host
factors, the type of chemical appears to be important. Higher concentrations of
chemicals, the type of chemical (vapor or wet aerosols), and bleaching agents are
the most offending agents to cause RADS. Dry particle aerosols are less likely to
cause RADS. Analysis of the World Trade Center firefighters indicates that the
presence of bronchial hyperresponsiveness prior to a chemical exposure does not
increase the risk for an individual to develop RADS.
Pathogenesis of RADS follows a typical pattern, driven by the initial injury to
the airway epithelium. Initial histology demonstrates rapid denudation of the
mucosa accompanied by a submucosal fibrinous, hemorrhagic exudate.
Subepithelial edema subsequently occurs with some regeneration of the
epithelial layer, proliferation of basal and parabasal cells, and eventually areas of
fibrosis. The desquamation, subepithelial fibrosis, thickening of the basement
membrane, and regeneration of basal cells are all more prominent in RADS than
in occupational asthma. This may explain the limited response to bronchodilator
therapy in this syndrome compared to asthma.
The clinical manifestations of RADS and irritant-induced asthma are different
from each other mostly in the onset of symptoms. Patients with RADS typically
can pinpoint the exact time of onset of symptoms as well as the exact number of
hours post exposure. The symptoms are so severe that nearly 80% of subjects in
one study presented to an emergency department for care. The lower airway
symptoms of cough, dyspnea, chest tightness, and wheezing are prominent
features in RADS, with cough being most prevalent. Because of the toxic nature
of the inhaled chemical, it is predictable that an upper airway syndrome of throat
and nose burning will often accompany the lower airway symptoms. This part of
the complex has been referred to as respiratory upper airway dysfunction
syndrome.
self-resolve and is classified as neither acute nor chronic. Löffler syndrome has
been more correctly termed pulmonary infiltrates with eosinophilia syndrome
and is the most common eosinophilic infiltrative disease in children.

Table 427.8
Key Elements in the Medical History and Physical Exam to
Raise Clinical Suspicion for Diagnostic Testing to Confirm
Eosinophilic Lung Disease
Medical history and examination
• Drug exposure (especially antibiotics, NSAIDs, antiepileptics, antileukotriene modifiers in EGPA) (see Table
478.10)
• Environmental inhalation exposures to dust or inhaled chemicals
• New onset of smoking cigarettes
• Travel or immigration status from areas endemic with various parasites or coccidioidomycosis
• Asthma (may be severe or poorly controlled with ABPA, CSS, or is relatively new in onset with IAEP)
• ABPA concurrent in 7–10% of patients with cystic fibrosis
• Extrapulmonary symptoms suggestive of vasculitis, neuropathy, heart failure, or neoplasm
• Rash (creeping eruption in visceral larval migrans disease or ulceration in EGPA)
Diagnostic imaging and testing
• Radiography helpful in AEP, CEP, and ABPA
• Radiography not diagnostic in EGPA or drug-induced eosinophilic disease of the lung
• Simple chest radiography findings
• Nonlobar infiltrate
• Classic description as mirror image of pulmonary edema with peripheral infiltrates
• Bilateral pleural effusion in AEP
• Central bronchiectasis in ABPA
• High-resolution computerized tomography of the chest
• Middle and upper lobe nonlobar infiltrates with areas of ground-glass appearance
• Mucous plugging in ABPA
• Central bronchiectasis in ABPA (confused with cystic fibrosis)
• Blood eosinophil count
• Elevated in many eosinophilic lung diseases
• Magnitude of eosinophil blood count does not distinguish different pulmonary diseases
• Usually not elevated in AEP (eosinophilic disease compartmentalized to lungs)
• May occasionally not be elevated in CEP or after use of corticosteroids
• Total serum IgE elevated in ABPA but not always in patients with cystic fibrosis with ABPA
• Serology for helminthic infections or parasites may be diagnostic but are usually not available acutely
• P-ANCA (MPO ANCA) is positive in 40–70% of EGPA (CSS)
• BAL eosinophil percentage
• ≥25% eosinophils diagnostic in AEP
• ≥40% eosinophils diagnostic in CEP or tropical pulmonary eosinophilia
• Eosinophil percentages below these criteria may require lung biopsy
• <25% eosinophils seen in connective tissue disease, sarcoid, drug-induced disease, histiocytosis X of
pulmonary Langerhans cells, and interstitial pulmonary fibrosis
• Lung biopsy
• Open lung biopsy or video-assisted thorascopic surgery when BAL nondiagnostic
• Transbronchial biopsy is usually insufficient with peripheral infiltrative disease
• Histology with alveolar and interstitial infiltrates of eosinophils, non-necrotizing non-granulomatous
vasculitis, multinucleated giant cells without granuloma
 • EGPA shows eosinophil rich small to medium vessel, necrotizing, granulomatous vasculitis
ABPA , Allergic bronchopulmonary aspergillosis; AEP , acute eosinophilic pneumonia; BAL ,
bronchoalveolar lavage; CEP , chronic eosinophilic pneumonia; CSS , Churg-Strauss syndrome;
EGPA , eosinophilic granulomatosis with polyangiitis; IAEP , idiopathic acute eosinophilic
pneumonia; MPO ANCA , myeloperoxidase antineutrophil cytoplasmic antibody; NSAID ,
nonsteroidal antiinflammatory drug; P-ANCA , perinuclear antineutrophil cytoplasmic antibody.

Table 427.9
Classification of the Eosinophilic Pneumonias in Clinical
Practice
Eosinophilic pneumonias of unknown cause
Solitary idiopathic eosinophilic pneumonias
Idiopathic chronic eosinophilic pneumonia
Idiopathic acute eosinophilic pneumonia
Eosinophilic pneumonia in systemic syndromes
Eosinophilic granulomatosis with polyangiitis
Idiopathic hypereosinophilic syndromes (lymphocytic or myeloproliferative variant)
Eosinophilic pneumonias of known cause
Allergic bronchopulmonary aspergillosis and related syndromes (including bronchocentric granulomatosis)
Eosinophilic pneumonias of parasitic origin
Eosinophilic pneumonias of other infectious causes
Drug-induced eosinophilic pneumonias
Eosinophilic airways diseases
Eosinophilic asthma
Hypereosinophilic asthma
Idiopathic hypereosinophilic constrictive bronchitis
Other pulmonary syndromes with possible usually mild eosinophilia
Organizing pneumonia, asthma, idiopathic pulmonary fibrosis, Langerhans cell histiocytosis, malignancies, and so
forth
From Cottin V: Eosinophilic lung diseases, Clin Chest Med 37:535–556, 2016 (Box 1, p. 536).

Table 427.10

Drugs Commonly Causing Eosinophilic Pneumonia

Antiinflammatory drugs and related drugs: acetylsalicylic acid, diclofenac, ibuprofen, naproxen, phenylbutazone,
piroxicam, sulindac, and tolfenamic acid
Antibiotics: ethambutol, fenbufen, minocycline, nitrofurantoin, penicillins, pyrimethamine, sulfamides,
sulfonamides, and trimethoprim-sulfamethoxazole
Other drugs: captopril, carbamazepine, and GM-CSF
A more extensive list of drugs reported to cause eosinophilic pneumonia may be found at www.pneumotox.com .

From Cottin V, Cordier JF: Eosinophilic lung diseases, Immunol Allergy Clin
North Am 32(4):557–586, 2012 (Box 6, p. 575).

Table 427.11
Diagnostic Criteria for Idiopathic Chronic Eosinophilic
Pneumonia and for Idiopathic Acute Eosinophilic
Pneumonia
IDIOPATHIC CHRONIC EOSINOPHILIC PNEUMONIA
1. Diffuse pulmonary alveolar consolidation with air bronchogram and/or ground-glass opacities at chest imaging,
especially with peripheral predominance.
2. Eosinophilia at bronchoalveolar lavage differential cell count ≥ 40% (or peripheral blood eosinophils ≥
1,000/mm3 ).
3. Respiratory symptoms present for at least 2 to 4 wk.
4. Absence of other known causes of eosinophilic lung disease (especially exposure to drug susceptible to induce
pulmonary eosinophilia).
IDIOPATHIC ACUTE EOSINOPHILIC PNEUMONIA
1. Acute onset with febrile respiratory manifestations (≤1 mo, and especially ≤ 7 days duration before medical
examination).
2. Bilateral diffuse infiltrates on imaging.
3. PaO 2 on room air ≤ 60 mm Hg (8 kPa), or PaO 2 /FIO 2 ≤ 300 mm Hg (40 kPa), or oxygen saturation on room air
< 90%.
4. Lung eosinophilia, with ≥ 25% eosinophils at BAL differential cell count (or eosinophilic pneumonia at lung
biopsy when done).
5. Absence of determined cause of acute eosinophilic pneumonia (including infection or exposure to drugs known
to induce pulmonary eosinophilia). Recent onset of tobacco smoking or exposure to inhaled dusts may be
present.
BAL , Bronchoalveolar lavage.
From Cottin V: Eosinophilic lung diseases, Clin Chest Med 37:535–556, 2016 (Box 2, p. 538).

Pathology and Pathogenesis

Eosinophilic lung disease, regardless of the stage of disease or etiology, shows
mixed cellular infiltration of the alveoli and interstitial spaces with a
predominance of eosinophils when transbronchial biopsy or open lung biopsy is
performed. This may be accompanied by a fibrinous exudate with intact lung
architecture. Other findings include eosinophilic microabscesses, a
nonnecrotizing nongranulomatous vasculitis, and occasional multinucleated
giant cells again without granuloma formation. BAL is the diagnostic procedure
of choice, especially with the acute types of eosinophilic pneumonia where
peripheral eosinophilia is often absent; the differential cell count on the BAL is ≥
 Many believe that this disease is a precursor to the development of EGPA
(formerly Churg-Strauss syndrome). The utility of ICS in chronic eosinophilic
pneumonia is unknown but is warranted for the persistent asthma phenotype of
disease. A subset of patients develops permanent lower airway obstruction
without reversibility, which requires patients with this disease to have close
follow-up and monitoring of pulmonary function tests routinely.

Eosinophilic Granulomatosis With

Polyangiitis (the Churg-Strauss
Syndrome)
The EGPA syndrome is a systemic disease involving multiple organs but most
prominently the lung. Patients present with difficult to control asthma, allergic
rhinitis, and peripheral eosinophilia (>10% or >1,500 cells/µL) in the blood.
Evidence of vasculitis on clinical grounds must be present in at least 2 organs.
The polyangiitis appears later in the disease process with asthma being the
precursor symptom in more than 90% of the cases reported. EGPA affects
multiple organs including the skin, heart, gastrointestinal tract, kidneys, and
central nervous system (Table 427.12 ). Rhinitis is present in 75% of the patients
but is not specific. Symptom complexes of fever, weight loss, fatigue, arthralgia,
and myalgia may be seen in approximately two-thirds of patients. Cardiac and
renal involvement is insidious in onset and should be screened for. It is the
multiple organ involvement that results in the morbidity and mortality of this
disease. The typical progression of the disease is in 3 phases: rhinitis and asthma
first, tissue eosinophilia second, and, finally, systemic vasculitis.

Table 427.12

Eosinophilic Granulomatosis With Polyangiitis

EOSINOPHILIC TISSULAR DISEASE
VASCULITIC PHENOTYPE
PHENOTYPE
Respective ~40% ~60%
frequency
ANCA Present (mostly perinuclear-ANCA with anti- Absent
MPO specificity)
Predominant Glomerular renal disease Cardiac involvement (eosinophilic
manifestations Peripheral neuropathy myocarditis)
Purpura Eosinophilic pneumonia
 Biopsy-proven vasculitis Fever

ANCA, Antineutrophil cytoplasmic antibody; MPO , myeloperoxidase.

Data from Sablé-Fourtassou R, Cohen P, Mahr A, et al: Antineutrophil cytoplasmic antibodies and
the Churg-Strauss syndrome, Ann Intern Med 2005;143:632–638; and Sinico RA, Di Toma L,
Maggiore U, et al: Prevalence and clinical significance of antineutrophil cytoplasmic antibodies in
Churg-Strauss syndrome, Arthritis Rheum 2005;52:2926–2935.
From Cottin V, Cordier JF: Eosinophilic lung diseases, Immunol Allergy Clin North Am 32(4):557–
586, 2012 (Table 2, p. 569).

The pathogenesis of EGPA is still unknown but several factors are suspected
to contribute to the development of the disease. The possible link between
leukotriene-receptor antagonists (zafirlukast, montelukast, or pranlukast) is
controversial but still considered possible. It is suspected that use of this class of
adjunctive medications in severe asthma allows for the reduction in use of
corticosteroid leading to the full-blown (unmasking) manifestation of EGPA.
Isolated use of leukotriene-receptor antagonists may induce disease, lead to
remission with cessation of leukotriene-receptor antagonists, and cause
recurrence of EGPA upon reintroduction of this class of medications. Many
refrain from use of leukotriene-receptor antagonists when the EGPA syndrome
has been diagnosed.
Clinical and laboratory findings pinpoint the diagnosis with high specificity
(99.7%) and sensitivity (85%) when 4 of 6 criteria are met (asthma, eosinophilia
>10%, mononeuropathy or polyneuropathy, nonfixed pulmonary infiltrates,
paranasal sinus abnormalities, and biopsy findings of extravascular eosinophil
infiltrates). In contrast to GPA, the rhinitis is not destructive and nasal septal
perforation does not occur in EGPA.
Radiography of the chest by plain radiography or HRCT demonstrates the
migratory, peripheral predominant opacities with ground-glass appearance to full
consolidation. Bronchiectasis and bronchial wall thickening are reported. Pleural
effusion should raise suspicion for the presence of heart failure from
cardiomyopathy .
Laboratory findings include striking eosinophilia with values generally
between 5,000 and 20,000/mm3 at the time of diagnosis. These counts often
parallel vasculitis activity. The BAL shows striking eosinophilia with differential
counts of >60%. Other organ system levels reflect activity of eosinophils and are
not specific for the EGPA diagnosis.
ANCAs may be present in the EGPA syndrome. The perinuclear-ANCA
targeting myeloperoxidase is specifically found in EGPA in approximately 40%
Table 427.13
Criteria for the Diagnosis of Allergic Bronchopulmonary
Aspergillosis
Allergic bronchopulmonary aspergillosis–central bronchiectasis
• Medical history of asthma*
• Immediate skin prick test reaction to Aspergillus antigens*
• Precipitating (IgG) serum antibodies to Aspergillus fumigatus *
• Total IgE concentration > 417 IU/mL (>1,000 ng/mL)*
• Central bronchiectasis on chest CT*
• Peripheral blood eosinophilia >500/mm3
• Lung infiltrates on chest x-ray or chest HRCT
• Elevated specific serum IgE and IgG to A. fumigatus
Allergic bronchopulmonary aspergillosis seropositive †
• Medical history of asthma †
• Immediate skin prick test reaction to A. fumigatus antigens †
• Precipitating (IgG) serum antibodies to A. fumigatus †
• Total IgE concentration > 417 IU/mL (>1,000 ng/mL) †
* The criteria required for diagnosis of ABPA with central bronchiectasis.

† The first 4 criteria are required for a diagnosis of seropositive ABPA.

ABPA , Allergic bronchopulmonary aspergillosis; CSD , corticosteroid dependent; HRCT , high-

resolution computerized tomography.

ABPA should be considered in patients with cystic fibrosis when clinical

deterioration occurs without evidence of an identifiable cause. Symptoms
heralding such deterioration include increasing cough, wheezing, loss of exercise
tolerance, worsening exercise-induced asthma, reduction of pulmonary function,
or increased sputum production without another discernible reason. Clinical
findings of elevated total IgE antibody, anti-Aspergillus IgE, precipitating
antibodies to A. fumigatus , and/or new abnormalities on chest radiography that
fail to clear with antibiotics should alert the clinician to the possibility of ABPA.
When evaluating a child with asthma symptoms, the clinician must distinguish
asthma from ABPA. If the diagnosis is suspected, skin prick test for evidence of
IgE-specific antibody directed against A. fumigatus is essential. Intradermal skin
testing when the skin prick test is negative, although not routinely performed
because of poor specificity, may be performed. The absence of a positive skin
prick test and intradermal test to A. fumigatus virtually excludes the diagnosis of
ABPA. The prevalence of ABPA in patients with an existing diagnosis of asthma
and an abnormal immediate skin prick test response to A. fumigatus has been
evaluated. Between 2% and 32% of patients with asthma with concurrent skin
prick test–positive reactions to Aspergillus have evidence of ABPA.
It is uncommon for the patient with cystic fibrosis to develop ABPA before the
age of 6 yr. When the total IgE antibody in patients with cystic fibrosis exceeds
500 IU/mL (1,200 ng/mL), a strong clinical suspicion of ABPA is necessary.
ABPA pathology has characteristic findings of mucoid bronchi impaction,
eosinophilic pneumonia, and bronchocentric granulomas in addition to the
typical histologic features of asthma. Septated hyphae are often found in the
mucus-filled bronchial tree. However, the fungi do not invade the mucosa in this
unique disease. Aspergillus may be cultured from sputum in more than 60% of
ABPA patients. Interestingly, hyphae may not always be seen on microscopy.
Staging of the disease (Table 427.14 ) represents distinct phases of the disease
but do not necessarily progress in sequence from stage 1 to stage 5. Staging of
ABPA is important for treatment considerations. In many hypersensitivity
diseases where IgE antibody contributes to the pathogenesis (e.g., asthma), total
IgE is often used for screening for an atopic state but is not a test that helps the
clinician with serial measures. In sharp contrast, the measurement of IgE during
acute exacerbations, remission, and recurrent ABPA disease is helpful in
identifying the activity of disease and may herald the recurrence. During stage 1
disease, the level of IgE antibody is often very high. During stage 2 remission, a
fall in the levels may be as much as 35% or more. Recurrence of activity may
result in a marked rise of total IgE with a doubling of the baseline level seen
during remission. During the use of glucocorticoid therapy, monthly or
bimonthly levels of IgE are followed serially to assist the clinician in tapering
therapy. Because exacerbations of ABPA are asymptomatic to the patient in
approximately 25% of the recurrences, serial IgE accompanied by chest
radiography are helpful to the clinician to guide therapy.

Table 427.14
Staging of Allergic Bronchopulmonary Aspergillosis
Staging of allergic bronchopulmonary aspergillosis
Stage 1 Acute Upper and middle lobe infiltration High IgE
Stage 2 Remission No infiltrate off steroids >6 mo Normal to high IgE
Stage 3 Exacerbation Upper and middle lobe infiltration High IgE
Stage 4 CSD asthma Minimal infiltrate Normal to high IgE
Stage 5 End stage Fibrosis and/or bullae Normal
CSD , Corticosteroid dependent.
dose exceeds 200 mg, then the total dose should be divided equally and given
twice daily. Serum levels of itraconazole are necessary to ensure proper
absorption of the drug is occurring from the capsule form. The liquid form is
more readily absorbed and has achieved substantially higher levels. The use of
proton pump inhibitors and histamine 2 antagonists may reduce absorption by
blocking acid production. Voriconazole has been used as a substitute antifungal
medication. Proper dosing has been established for invasive Aspergillus disease,
but not for ABPA. Typical dosage regimen in children of 7 mg/kg/day may cause
hepatotoxicity so liver function must be monitored.
Omalizumab, an anti-IgE humanized monoclonal antibody, has been used in
case series of patients with cystic fibrosis and ABPA as well as a small cohort of
adults without cystic fibrosis but with ABPA. Both case series demonstrated
significant reductions in asthma exacerbations, ABPA exacerbations, and
glucocorticoid usage. The dose prescribed has been 300-375 mg every 2 wk by
subcutaneous injection.

Hypereosinophilic Syndrome
See Chapter 155 .
The HES is a descriptive name of a group of disorders that are characterized
by the persistent overproduction of eosinophils accompanied by eosinophil
infiltration in multiple organs with end-organ damage from mediator release.
The term HES should only be used when there is eosinophilia with end-organ
damage from the eosinophils and not from another cause. The discovery of
underlying genetic, biochemical, or neoplastic reasons for HES has led to the
classification of primary, secondary, and idiopathic HES (Table 427.15 ).
Specific syndromes such as EGPA have eosinophilia but the contribution of
eosinophils to the organ damage is incompletely understood.

Table 427.15

Hypereosinophilic Syndrome Variants

Myeloproliferative Nonclonal
Clonal–F1P1L1/PDGFRA-positive chronic eosinophilic leukemia
Lymphocytic Nonclonal T cells
Clonal T-cell expansion with T-cell activation
Overlap Organ restricted
Familial Family history of eosinophilia without known cause
 Associated Eosinophilia in chronic disease like inflammatory bowel disease or EGPA (Churg-Strauss
syndrome)
Undefined Asymptomatic
Cyclic angioedema with eosinophilia (Gleich syndrome)
Symptomatic without myeloproliferation or lymphocytic form
EGPA , Eosinophilic granulomatosis with polyangiitis; PDGFRA , platelet-derived growth factor
receptor-α.

Some variants of HES have genetic mutations in tyrosine kinase receptor

platelet-derived growth factor receptor-α (PDGFRA ); males are almost
exclusively affected. Otherwise, HES appears to be distributed equally among
females and males.
Hypereosinophilia is defined as an absolute eosinophil number in the blood
that exceeds 1.5 × 109 eosinophils on 2 separate occasions separated by at least 1
mo. Tissues are abnormal when more than 20% of nucleated cells in the bone
marrow are of eosinophil origin, a pathologist determines the presence of
eosinophilia, or the presence of extensive eosinophilic granule proteins are
determined on biopsy to be deposited in large quantities. These disorders can be
subclassified into primary (neoplastic), secondary (reactive), and idiopathic (Fig.
427.9 ).

FIG. 427.9 A revised classification of hypereosinophilic syndrome (HES) .

Changes from the previous classification are indicated in red. Dashed
arrows identify HES forms in some patients that have T-cell–driven
disease. Classification of myeloproliferative forms has been simplified, and
patients with HES and eosinophil hematopoietin-producing T cells in the
absence of a T-cell clone are included in the lymphocytic forms of HES.
similar clinical, physiologic, radiographic, and pathologic processes involving
disruption of alveolar interstitium and airways. Prevalence estimates vary widely
with a range of 0.13-16.2 cases/100,000 children, likely due to the lack of
standardization of diseases included in the definition of ILD in children. The
pathophysiology is believed to be more complex than that of adult disease
because pulmonary injury occurs during the process of lung growth and
differentiation. In ILD, the initial injury causes damage to the alveolar
epithelium and capillary endothelium. Abnormal healing of injured tissue may
be more prominent than inflammation in the initial steps of the development of
chronic ILD. Genetic causes of ILD are becoming increasingly important,
especially disorders of surfactant metabolism (DSM) and immune dysregulatory
disorders.

Table 427.16
The Pediatric Interstitial Lung Diseases in Children Under 2
Yr of Age
AGE-RELATED INTERSTITIAL LUNG DISEASES IN INFANCY AND EARLY CHILDHOOD
Diffuse developmental disorders
Acinar dysplasia
Congenital alveolar dysplasia
Alveolar capillary dysplasia with misalignment of pulmonary veins (some due to FOXF1 mutation)
Growth abnormalities reflecting deficient alveolarization
Pulmonary hypoplasia
Chronic neonatal lung disease
Chromosomal disorders
Congenital heart disease
Neuroendocrine cell hyperplasia of infancy
Pulmonary interstitial glycogenosis (infantile cellular interstitial pneumonia)
Surfactant dysfunction disorders (pulmonary alveolar proteinosis)
Surfactant protein–B mutation
Surfactant protein–C mutation
ABCA3 mutation
Granulocyte-macrophage colony-stimulating factor receptor (CSF2RA ) mutation
NKX2.1 (transcription factor for SP-B, SPC, ABCA3)
INTERSTITIAL LUNG DISEASE DISORDERS WITH KNOWN ASSOCIATIONS
Infectious/postinfectious processes
Adenovirus viruses
Influenza viruses
Chlamydia pneumoniae
Mycoplasma pneumoniae
Environmental agents
Hypersensitivity pneumonitis
Toxic inhalation
Aspiration syndromes
PULMONARY DISEASES ASSOCIATED WITH PRIMARY AND SECONDARY IMMUNE
 DEFICIENCY
Opportunistic infections
Granulomatous lymphocytic interstitial lung disease associated with common variable immunodeficiency
syndrome
Lymphoid intestinal pneumonia (HIV infection)
Therapeutic interventions: chemotherapy, radiation, transplantation, and rejection
IDIOPATHIC INTERSTITIAL LUNG DISEASES
Usual interstitial pneumonitis
Desquamative interstitial pneumonitis
Lymphocytic interstitial pneumonitis and related disorders
Nonspecific interstitial pneumonitis (cellular/fibrotic)
Eosinophilic pneumonia
Bronchiolitis obliterans syndrome
Pulmonary hemosiderosis and acute idiopathic pulmonary hemorrhage of infancy
Pulmonary alveolar proteinosis
Pulmonary vascular disorders
Pulmonary lymphatic disorders
Pulmonary microlithiasis
Persistent tachypnea of infancy
Brain-thyroid-lung syndrome
SYSTEMIC DISORDERS WITH PULMONARY MANIFESTATIONS
Anti-GBM disease
Gaucher disease and other storage diseases
Malignant infiltrates
Hemophagocytic lymphohistiocytosis
Langerhans cell histiocytosis
Sarcoidosis
Systemic sclerosis
Polymyositis/dermatomyositis
Systemic lupus erythematosus
Rheumatoid arthritis
Lymphangioleiomyomatosis
Pulmonary hemangiomatosis
Neurocutaneous syndromes
Hermansky-Pudlak syndrome

Modified from Deutsch GH, Young LR, Deterding RR, et al: diffuse lung disease in young children:
application of a novel classification scheme, Am J Respir Crit Care Med 176:1120–1128, 2007.

Table 427.17
The Pediatric Interstitial Lung Diseases in Children Over 2
Yr of Age
DISORDERS OF THE IMMUNOCOMPETENT HOST
Disorders of Infancy
• Growth abnormalities
• NEHI
• Disorders of surfactant metabolism
Systemic Disease
 • Immune mediated disorders
• Connective tissue disease related lung disease
• Pulmonary hemorrhage syndromes
• Storage diseases
• Sarcoidosis
DISORDERS OF THE IMMUNOCOMPROMISED HOST
• Opportunistic infections
• Related to treatment
• Chemotherapy
• Radiation
• Drug hypersensitivity
• Related to transplantation
• Rejection
• GVHD
• PTLD
• Lymphoid Infiltrates
GVHD , Graft-versus-host disease; NEHI , neuroendocrine cell hyperplasia of infancy; PTLD ,
post-transplant lymphoproliferative disease.
Modified from Fan LL, Dishop MK, Galambos C, et al: Diffuse lung disease in biopsied children 2
to 18 years of age. Application of the chILD Classification Scheme, Ann Am Thorac Soc
2015;12(10):1498–1505.

Classification and Pathology

Through the work of both the children's ILD research network in the United
States and the children's ILD-European Union group in Europe, consensus on a
classification scheme has been reached. The classification is broken down by age
with 2 yr of age serving as a cut-off, and by histologic pattern. The classification
scheme was first applied to biopsies from children under 2 and was extended to
children over 2 yr of age (see Tables 427.16 and 427.17 ). Growth disorders such
as alveolar simplification, unique diseases of infants such as neuroendocrine cell
hyperplasia of infancy (NEHI ), and DSM were common in children under 2. In
contrast, disorders of the immunocompromised host such as ILD related to
immune deficiency, and disorders of systemic diseases such as the collagen
vascular disorders, were much more common in older children.

Neuroendocrine Cell Hyperplasia of Infancy

See Chapter 427.6 .

Disorders of Surfactant Metabolism

One of the more important groups of disorders in pediatric ILD is the DSM
(Table 427.18 ). These disorders likely account for previously unknown cases of
neonatal respiratory distress in full-term infants. Surfactant protein B deficiency,
caused by mutations in the surfactant protein B gene, is a cause of severe
neonatal respiratory distress. Chest CT often has a pattern of diffuse ground-
glass opacities with septal thickening. Histopathology reveals alveolar
proteinosis with interstitial widening, and electron microscopy shows
disorganized lamellar bodies. Most children die within the first 2 mo of life
without a lung transplant. Surfactant protein C deficiency can cause disease in
older infants, children, or adults. Chest CT can show diffuse ground-glass
opacities with septal thickening early in the disease or significant fibrosis and
honeycombing in more advanced disease. Histopathologic findings vary with
age, with alveolar proteinosis and interstitial widening seen in young children,
and fibrosis seen in older children and adults. Electron microscopy reveals
normal lamellar bodies. ABCA3 mutations cause variable lung disease in
children with some having severe disease similar to surfactant protein B
deficiency, while other children have less severe disease similar to surfactant
protein C. Chest CT most often shows diffuse ground-glass opacities with septal
thickening early in the disease (Fig. 427.10 ). Histopathology depends on the age
of the child similar to surfactant protein C, however, electron microscopy shows
characteristic changes in the lamellar bodies with an eccentric electron dense
body without the characteristic concentric circles—the so-called fried egg
appearance. DSM due to mutations in the gene NKX2.1 has also been described.
NKX2.1 encodes for thyroid transcription factor 1 (TTF-1), which is a major
regulator or surfactant protein transcription. Mutations in NKX2.1 cause variable
disease in the lungs, brain, and thyroid (see Table 427.18 ). Lung disease is
variable and can present similar to surfactant protein B deficiency, or as
recurrent pulmonary infections. Finally, mutations in the alpha and beta subunits
of the granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor
cause failure of response to GM-CSF by the pulmonary alveolar macrophages.
This leads to an inability to recycle surfactant with subsequent accumulation of
proteinaceous material and pulmonary alveolar proteinosis.

Table 427.18

Clinical Features, Age, and Onset of Surfactant Protein Dysfunction Syndromes

(SPDS)
 SPDS CLINICAL FEATURES AGE AND ONSET
SFTPB Neonatal Neonate, acute
▸ Respiratory distress
ABCA3 Neonatal Neonate, acute
▸ Respiratory distress Infancy and childhood, subacute
Infancy Late childhood and adulthood, chronic
▸ Cough
▸ Tachypnoea, hypoxemia
▸ Failure to thrive
Childhood
▸ Wheeze, crackles
▸ Exercise intolerance
▸ Dyspnea
▸ Retractions, crackles, digital clubbing
▸ Low body weight
SFTPC Neonatal Neonate, acute (infrequent)
▸ Respiratory distress Infancy and childhood, subacute
Childhood Late childhood and adulthood, chronic
▸ Cough
▸ Tachypnoea, hypoxemia

NKX2.1 Respiratory Any age

▸ Neonatal respiratory distress Acute or chronic
▸ Recurrent infections
▸ Chronic interstitial lung disease
Neurological
▸ Chorea
▸ Ataxia
▸ Developmental delay
▸ Hypotonia
Hypothyroidism

ABCA3 , ATP binding cassette number A3.

From Gupta A, Zheng SL: Genetic disorders of surfactant protein dysfunction: when to consider
and how to investigate, Arch Dis Child 102:84–90, 2017 (Table 2, p. 86).
Keywords
Fibrosis
pulmonary function
oxygen
nonspecific interstitial pneumonia

Pulmonary fibrosis is scarring in the lung parenchyma (as opposed to

bronchiectasis which is scarring of the airways). Idiopathic pulmonary fibrosis is
a common form of fibrotic lung disease in adults. This presents with usual
interstitial pneumonia (a pathologic finding with patchy interstitial fibrosis,
fibroblastic foci, and honeycomb change) (see Chapter 427.5 ). Additional adult
fibrotic lung diseases include sarcoidosis, silicosis, coal workers pneumoconiosis
and hypersensitivity pneumonitis (e.g., farmer's lung). In children, fibrotic lung
disease is rare, and idiopathic pulmonary fibrosis has not been described. The
differential diagnosis of fibrotic lung disease includes surfactant dysfunction
mutations (Chapter 423 ), radiation-induced fibrosis, bronchiolitis obliterans
(Chapter 422.1 ), nonspecific interstitial pneumonia (connective tissue disorders)
(Chapter 427), hypersensitivity pneumonitis (Chapter 427.1 ), and aspiration
(Chapter 425 ) (Tables 427.19 –427.21 ).

Table 427.19
Diseases Associated With Pulmonary Fibrosis
• Idiopathic pulmonary fibrosis / nonspecific interstitial pneumonia
• Familial pulmonary fibrosis / familial interstitial pneumonia
• Hypersensitivity pneumonitis (many agents)
• Cryptogenic organizing pneumonia
• Adverse reaction to therapy (drugs, radiation)
• Pleuroparenchymal fibroelastosis
• Hermansky–Pudlak syndrome
• Sarcoidosis
• Eosinophilic pneumonia (primary or parasitic)
• Langerhans cell histiocytosis
• Dyskeratosis congenita
• Tuberous sclerosis
• Neurofibromatosis
• Erdheim–Chester disease
• Gaucher disease
• Niemann–Pick disease
• Familial hypocalciuric hypercalcemia
• Lysinuric protein intolerance
• IgG4 mediated immune disorder
• Myelodysplastic syndrome
• Progressive systemic sclerosis
• Other connective tissue diseases (SLE, dermatomyositis)
• Granulomatosis with polyangiitis
• Eosinophilic granulomatosis with polyangiitis

Table 427.20
Pediatric Fibrotic Lung Diseases

PATHOLOGY ADDITIONAL
DISEASES CT FINDINGS TREATMENT
FINDINGS EVALUATION
Surfactant Early: Diffuse ground Variable: fibrosis, Genetic testing Hydroxychloroquine,
dysfunction glass, septal honeycomb cysts at end azithromycin, high-
thickening (crazy stage, NSIP, CPI, few dose intravenous
paving) Chronic: See globules of pulmonary steroids. Genetic
NSIP alveolar proteinosis, foamy counseling
macrophages and
cholesterol clefts
(endogenous lipoid
pneumonia)
Aspiration Acute: Consolidation Airway-centered Video Stop aspiration
and centrilobular (tree lesions/bronchiolitis, food fluoroscopic through thickening
in bud) nodules with a particles with or without swallow feeds, gastric feeds,
dependent distribution. granulomas, foamy evaluation cleft repair
Chronic: possible UIP macrophages (endogenous
with honeycombing lipoid pneumonia),
organizing pneumonia
Radiation fibrosis
Architectural Pleural, septal, and
distortion, volume paraseptal fibrosis; reactive
loss, traction atypia of alveolar
bronchiectasis. Often epithelium and endothelium
with geometric
distribution related to
radiation field
Bronchopulmonary Hyperlucent regions, Alveolar simplification and Supportive care.
dysplasia architectural distortion enlargement. Patchy Consider inhaled
(linear and subpleural hyperinflation. Interstitial corticosteroids
triangular opacities) fibrosis, with or without
interlobular septal fibrosis.
Nonspecific Basilar predominant Interstitial lymphocytic
interstitial findings of ground- inflammation and fibrosis
pneumonia (NSIP) glass opacities (often with homogenous
with subpleural distribution
sparing), reticulation,
architectural
distortion, and traction
bronchiectasis
Hypersensitivity Patchy and often Airway-centered small non- Lymphocytosis Remove trigger,
pneumonitis parahilar reticulation, caseating granulomas, in intravenous steroids
(chronic) ground glass, multinucleated giant cells, bronchoalveolar
 centrilobular nodules. lymphocytic bronchiolitis lavage,
Honeycombing (rare) and peribronchiolitis, precipitins to
airway fibrosis, organizing specific antigen
pneumonia
Autoimmune See NSIP. NSIP. Lymphoid Serologic Disease-specific
connective tissue Honeycombing (rare) hyperplasia. Fibrosis and studies immune modulation
disorders (collagen cystic change. Pleuritis and
vascular disease) pleural fibrosis (variable).
Chronic vasculopathy
(variable). Airway fibrosis
(variable).
Drug reactions Peripheral Variable: organizing Drug avoidance
predominant pneumonia, NSIP, UIP,
consolidation or DAD, pulmonary
ground glass. Reverse hemorrhage, eosinophilic
halo sign. See NSIP. pneumonia
Honeycombing (rare)
Infection Acute: Consolidation Acute: Neutrophilic Antimicrobials
and centrilobular (tree alveolitis (bacterial) or
in bud) nodules. lymphocytic bronchiolitis
Appearance and (viral). Chronic: Variable
distribution varies airway fibrosis
with type of infection. (constrictive/obliterative
Chronic: May bronchiolitis) and
progress to IPF/UIP interstitial fibrosis.
with honeycombing
Immunodeficiency Bronchiectasis, Follicular bronchiolitis or Immunologic Treat underlying
consolidation, diffuse lymphoid and genetic immunodeficiency
centrilobular nodules hyperplasia. NSIP. LIP. testing
GLILD

Usual interstitial Honeycombing, Fibroblast foci. Interstitial, Genetic testing

pneumonia (UIP) reticulation, traction septal, and pleural fibrosis
bronchiectasis, ground with heterogenous
glass (less prominent distribution. Minimal to
than NSIP) absent inflammation.

Table 427.21

Genes Associated With Familial* or Idiopathic Pulmonary Fibrosis

GENE GENE FUNCTION
IL1RN Inhibitor of pro-inflammatory effect of IL-1alpha and IL-1beta
IL8 Pro-inflammatory cytokine
FAM13A Signal transduction
TLR3 Pathogen recognition and activation of innate immunity
TERT Enzyme in telomerase complex maintaining telomere length
HLA- Major histocompatibility complex—immune system
DRB1
DSP Tightly links adjacent cells
OBFC1 Stimulates the activity of DNA polymerase-alpha-primase
MUC5B Influence on rheological properties of airway mucus, mucociliary transport, and airway defense
 MUC2 Mucin production
TOLLIP Regulator of innate immune responses mediated by toll-like receptor and the transforming growth
factor β signaling pathway
ATP11A Phospholipid translocation
MDGA2 Cell–cell interaction
MAPT Promotes microtubule assembly and stability
SPPL2C Protein cleavage
DPP9 Cell–cell adhesion
TGFB1 Set of peptides that controls proliferation, differentiation, and other functions in many cell types
SFTPC † Component of surfactant fluid
SFTPA2 † To modulate innate and adaptive immunity
ABCA3 † Transport of lipids across plasma membrane
TERC † Template in telomerase complex
DKC1 † Stabilization of the template in telomerase complex
TINF2 † Telomere maintenance
RTELI † DNA helicase
PARN † mRNA stability
* Also called familial interstitial pneumonia.

† Rarer variant.

Adapted from Kaur A, Mathai SK, Schwartz DA: Genetics in idiopathic pulmonary fibrosis
pathogenesis, prognosis, and treatment. Frontiers Med 4:154, 2017. Tables 1 and 2.

Clinical Presentation
Patients with pulmonary fibrosis will typically present with nonspecific
respiratory symptoms such as cough, crackles, wheezes, prolonged expiratory
phase, exercise intolerance, and hypoxemia, especially at nighttime. Symptom
onset can be insidious or rapid.

Evaluation
Pulmonary function tests typically show restriction and reduced diffusion
capacity. Air trapping can also be seen. Patients may desaturate with exercise
challenges or 6-min walks.
There are a variety of findings on computed tomography scan that suggest
pulmonary fibrosis. These include reticular opacities, architectural distortion,
traction bronchiectasis, and honeycomb cysts. A common late finding in several
etiologies of fibrotic lung disease in children is nonspecific interstitial
pneumonia: subpleural sparing, ground-glass opacities, reticular change, and
bronchiectasis. Typical CT findings in pediatric patients with nonspecific
CHAPTER 428

Community-Acquired Pneumonia
Matthew S. Kelly, Thomas J. Sandora

Epidemiology
Pneumonia, defined as inflammation of the lung parenchyma, is the leading
infectious cause of death globally among children younger than 5 yr, accounting
for an estimated 920,000 deaths each year (Fig. 428.1 ). Pneumonia mortality is
closely linked to poverty. More than 99% of pneumonia deaths are in low- and
middle-income countries, with the highest pneumonia mortality rate occurring in
poorly developed countries in Africa and South Asia (Table 428.1 ).

FIG. 428.1 Pneumonia is the leading infectious killer of children worldwide,
as shown by this illustration of global distribution of cause-specific
infectious mortality among children younger than age 5 yr in 2015.
Pneumonia causes one-third of all under-5 deaths from infection. (From
World Health Organization and Maternal and Child Epidemiology
Estimation Group estimates, 2015.)

Table 428.1
Pneumonia Cases and Mortality Rate in Children Younger Than Age 5 Yr by UNICEF
Region, 2015
UNICEF PNEUMONIA CASES IN CHILDREN PNEUMONIA MORTALITY RATE (UNDER-
REGIONS YOUNGER THAN 5 YR OF AGE 5 DEATHS PER 1,000 LIVE BIRTHS)
West and Central 298,000 16.2
Africa
Sub-Saharan 490,000 13.7
Africa
Eastern and 177,000 10.9
Southern Africa
South Asia 282,000 7.9
Middle East and 46,000 4.1
North Africa
East Asia and the 81,000 2.7
Pacific
Latin America 23,000 2.1
and the
Caribbean
Least Developed 363,000 12.0
Countries
World 920,000 6.6
From United Nations Children's Fund: One is too many—ending child deaths from pneumonia and
diarrhoea. https://data.unicef.org/resources/one-many-ending-child-deaths-pneumonia-diarrhoea/
. Accessed January 21, 2017.

In the United States, mortality from pneumonia in children declined by 97%

between 1939 and 1996. This decline likely resulted from the development of
antibiotics and vaccines and the expansion of medical insurance coverage for
children. Effective vaccines against measles (see Chapter 273 ) and pertussis
(see Chapter 224 ) contributed to the decline in pneumonia-related mortality
during the 20th century. Haemophilus influenzae type b (see Chapter 221 ) was
also an important cause of bacterial pneumonia in young children but became
uncommon following licensure of a conjugate vaccine in 1987. The introduction
of pneumococcal conjugate vaccines (PCVs) (see Chapter 209 ) has been an
important contributor to the further reductions in pneumonia-related mortality
achieved over the past 15 yr.

Etiology
Although most cases of pneumonia are caused by microorganisms, noninfectious
causes include aspiration (of food or gastric acid, foreign bodies, hydrocarbons,
and lipoid substances), hypersensitivity reactions, and drug- or radiation-induced
pneumonitis (see Chapter 427 ). The cause of pneumonia in an individual patient
is often difficult to determine because direct sampling of lung tissue is invasive
and rarely performed. Bacterial cultures of sputum or upper respiratory tract
samples from children typically do not accurately reflect the cause of lower
respiratory tract infection. Streptococcus pneumoniae (pneumococcus) is the
most common bacterial pathogen in children 3 wk to 4 yr of age, whereas
Mycoplasma pneumoniae and Chlamydophila pneumoniae are the most frequent
bacterial pathogens in children age 5 yr and older. In addition to pneumococcus,
other bacterial causes of pneumonia in previously healthy children in the United
States include group A streptococcus (Streptococcus pyogenes ; see Chapter 210
) and Staphylococcus aureus (see Chapter 208.1 ) (Tables 428.2 , 428.3 , and
428.4 ). S. aureus pneumonia often complicates an illness caused by influenza
viruses.

Table 428.2
Causes of Infectious Pneumonia

BACTERIAL
COMMON
Streptococcus pneumoniae Consolidation, empyema
Group B streptococci Neonates
Group A streptococci Empyema
Staphylococcus aureus Pneumatoceles, empyema; infants; nosocomial
pneumonia
Mycoplasma pneumoniae * Adolescents; summer–fall epidemics
Chlamydophila pneumoniae * Adolescents
Chlamydia trachomatis Infants
Mixed anaerobes Aspiration pneumonia
Gram-negative enterics Nosocomial pneumonia
UNCOMMON
Haemophilus influenzae type b Unimmunized
Moraxella catarrhalis
Neisseria meningitidis
Francisella tularensis Animal, tick, fly contact; bioterrorism
Nocardia species Immunocompromised patients
Chlamydophila psittaci * Bird contact (especially parakeets)
Yersinia pestis (plague) Rat contact; bioterrorism
Legionella species* Exposure to contaminated water; nosocomial
Coxiella burnetii * (Q fever) Animal (goat, sheep, cattle) exposure
VIRAL
COMMON
Respiratory syncytial virus Bronchiolitis
Parainfluenza types 1-4 Croup
Influenza A, B High fever; winter months
Adenovirus Can be severe; often occurs between January
and April
 Human metapneumovirus Similar to respiratory syncytial virus
UNCOMMON
Rhinovirus Rhinorrhea
Enterovirus Neonates
Herpes simplex Neonates, immunocompromised persons
Cytomegalovirus Infants; immunocompromised persons
(particularly HIV-infected infants)
Measles Rash, coryza, conjunctivitis
Varicella Unimmunized; immunocompromised persons
Hantavirus Southwestern United States, rodents
Coronaviruses [severe acute respiratory syndrome (SARS), Asia, Arabian Peninsula
Middle East respiratory syndrome (MERS)]
FUNGAL
Histoplasma capsulatum Ohio/Mississippi River valley; bird, bat
contact
Blastomyces dermatitidis Ohio/Mississippi River valley
Coccidioides immitis Southwestern United States, Great Lakes states
Cryptococcus neoformans and C. gattii Bird contact; immunocompromised;
Northwestern United States (C. gattii)
Aspergillus species Immunocompromised persons; nodular lung
infection
Mucormycosis Immunocompromised persons
Pneumocystis jiroveci Immunocompromised persons (particularly
HIV-infected infants); steroids
RICKETTSIAL
Rickettsia rickettsiae Tick bite
MYCOBACTERIAL
Mycobacterium tuberculosis Travel to endemic region; exposure to high-
risk persons
Mycobacterium avium complex Immunocompromised (particularly HIV-
infected) persons
Other non-tuberculous mycobacteria Immunocompromised persons; cystic fibrosis
PARASITIC
Various parasites (e.g., Ascaris , Strongyloides species) Eosinophilic pneumonia
* Atypical pneumonia syndrome; may have extrapulmonary manifestations, low-grade fever,

patchy diffuse infiltrates, and poor response to β-lactam antibiotics.

Adapted from Kliegman RM, Greenbaum LA, Lye PS: Practical strategies in pediatric diagnosis &
therapy , ed 2, Philadelphia, 2004, Elsevier, p. 29.

Table 428.3

Pneumonia Etiologies Grouped by Age of the Patient

AGE
FREQUENT PATHOGENS (IN ORDER OF FREQUENCY)
GROUP
Neonates Group B streptococcus, Escherichia coli, other Gram-negative bacilli, Streptococcus pneumoniae,
(<3 wk) Haemophilus influenzae (type b,* nontypeable)
3 wk-3 Respiratory syncytial virus, other respiratory viruses (rhinoviruses, parainfluenza viruses, influenza
mo viruses, human metapneumovirus, adenovirus), S. pneumoniae, H. influenzae (type b,* nontypeable); if
patient is afebrile, consider Chlamydia trachomatis
 4 mo-4 Respiratory syncytial virus, other respiratory viruses (rhinoviruses, parainfluenza viruses, influenza
yr viruses, human metapneumovirus, adenovirus), S. pneumoniae, H. influenzae (type b,* nontypeable),
Mycoplasma pneumoniae, group A streptococcus
≥5 yr M. pneumoniae, S. pneumoniae, Chlamydophila pneumoniae, H. influenzae (type b,* nontypeable),
influenza viruses, adenovirus, other respiratory viruses, Legionella pneumophila
* H. influenzae type b is uncommon with routine immunization.

Adapted from Kliegman RM, Marcdante KJ, Jenson HJ, et al: Nelson essentials of pediatrics , ed
5, Philadelphia, 2006, Elsevier, p. 507.

Table 428.4
Pneumonia: Etiology Suggested by Exposure History

EXPOSURE HISTORY INFECTIOUS AGENT

Exposure to concurrent illness in school dormitory or household setting Neisseria meningitidis,
Mycoplasma pneumoniae
ENVIRONMENTAL EXPOSURES
Exposure to contaminated aerosols (e.g., air coolers, hospital water supply) Legionnaires' disease
Exposure to goat hair, raw wool, animal hides Anthrax
Ingestion of unpasteurized milk Brucellosis
Exposure to bat droppings (caving) or dust from soil enriched with bird Histoplasmosis
droppings
Exposure to water contaminated with animal urine Leptospirosis
Exposure to rodent droppings, urine, saliva Hantavirus
Potential bioterrorism exposure Anthrax, plague, tularemia
ZOONOTIC EXPOSURES
Employment as abattoir work or veterinarian Brucellosis
Exposure to cattle, goats, pigs Anthrax, brucellosis
Exposure to ground squirrels, chipmunks, rabbits, prairie dogs, rats in Africa or Plague
southwestern United States
Hunting or exposure to rabbits, foxes, squirrels Tularemia
Bites from flies or ticks Tularemia
Exposure to birds (parrots, budgerigars, cockatoos, pigeons, turkeys) Psittacosis
Exposure to infected dogs and cats Pasteurella multocida, Q fever
(Coxiella burnetii)
Exposure to infected goats, cattle, sheep, domestic animals, and their secretions Q fever (C. burnetii)
(milk, amniotic fluid, placenta, feces)
TRAVEL EXPOSURES
Residence in or travel to San Joaquin Valley, southern California, southwestern Coccidioidomycosis
Texas, southern Arizona, New Mexico
Residence in or travel to Mississippi or Ohio river valleys, Great Lakes States, Histoplasmosis, blastomycosis
Caribbean, Central America, or Africa
Residence in or travel to southern China SARS, avian influenza
Residence in or travel to Arabian peninsula MERS-CoV
Residence in or travel to Southeast Asia Paragonimiasis, melioidosis
Residence in or travel to West Indies, Australia, or Guam Melioidosis
MERS-CoV, Middle East respiratory syndrome coronavirus; SARS, severe acute respiratory
syndrome.
From Ellison RT III, Donowitz GR: Acute pneumonia, In Bennett JE, Dolin R, Blaser MJ, editors:
progresses, sloughed cellular debris, inflammatory cells, and mucus cause
airway obstruction, with spread of infection occurring along the bronchial tree,
as is seen in viral pneumonia. S. pneumoniae produces local edema that aids in
the proliferation of organisms and their spread into adjacent portions of lung,
often resulting in the characteristic focal lobar involvement. Group A
streptococcus lower respiratory tract infection typically results in more diffuse
lung involvement with interstitial pneumonia. The pathology includes necrosis
of tracheobronchial mucosa; formation of large amounts of exudate, edema, and
local hemorrhage, with extension into the interalveolar septa; and involvement
of lymphatic vessels with frequent pleural involvement. S. aureus pneumonia
manifests as confluent bronchopneumonia, which is often unilateral and
characterized by the presence of extensive areas of hemorrhagic necrosis and
irregular areas of cavitation of the lung parenchyma, resulting in pneumatoceles,
empyema, and, at times, bronchopulmonary fistulas.
Recurrent pneumonia is defined as 2 or more episodes in a single year or 3
or more episodes ever, with radiographic clearing between occurrences. An
underlying disorder should be considered if a child experiences recurrent
pneumonia (Table 428.5 ).

Table 428.5
Differential Diagnosis of Recurrent Pneumonia
HEREDITARY DISORDERS
Cystic fibrosis
Sickle cell disease
DISORDERS OF IMMUNITY
HIV/AIDS
Bruton agammaglobulinemia
Selective immunoglobulin G subclass deficiencies
Common variable immunodeficiency syndrome
Severe combined immunodeficiency syndrome
Chronic granulomatous disease
Hyperimmunoglobulin E syndromes
Leukocyte adhesion defect
DISORDERS OF CILIA
Primary ciliary dyskinesia
Kartagener syndrome
ANATOMIC DISORDERS
Pulmonary sequestration
Lobar emphysema
Congenital cystic adenomatoid malformation
Gastroesophageal reflux
Foreign body
 Tracheoesophageal fistula (H type)
Bronchiectasis
Aspiration (oropharyngeal incoordination)
Aberrant bronchus
Adapted from Kliegman RM, Marcdante KJ, Jenson HJ, et al: Nelson essentials of pediatrics , ed
5, Philadelphia, 2006, Elsevier, p. 507.

Clinical Manifestations
Pneumonia is frequently preceded by several days of symptoms of an upper
respiratory tract infection, typically rhinitis and cough. In viral pneumonia, fever
is usually present but temperatures are generally lower than in bacterial
pneumonia. Tachypnea is the most consistent clinical manifestation of
pneumonia. Increased work of breathing accompanied by intercostal, subcostal,
and suprasternal retractions, nasal flaring, and use of accessory muscles is
common. Severe infection may be accompanied by cyanosis and lethargy,
especially in infants. Auscultation of the chest may reveal crackles and
wheezing, but it is often difficult to localize the source of these adventitious
sounds in very young children with hyperresonant chests. It is often not possible
to distinguish viral pneumonia (especially adenovirus) clinically from disease
caused by Mycoplasma and other bacterial pathogens.
Bacterial pneumonia in adults and older children typically begins suddenly
with high fever, cough, and chest pain. Other symptoms that may be seen include
drowsiness with intermittent periods of restlessness; rapid respirations; anxiety;
and, occasionally, delirium. In many children, splinting on the affected side to
minimize pleuritic pain and improve ventilation is noted; such children may lie
on one side with the knees drawn up to the chest.
Physical findings depend on the stage of pneumonia. Early in the course of
illness, diminished breath sounds, scattered crackles, and rhonchi are commonly
heard over the affected lung field. With the development of increasing
consolidation or complications of pneumonia such as pleural effusion or
empyema, dullness on percussion is noted and breath sounds may be diminished.
A lag in respiratory excursion often occurs on the affected side. Abdominal
distention may be prominent because of gastric dilation from swallowed air or
ileus. Abdominal pain is common in lower-lobe pneumonia. The liver may seem
enlarged because of downward displacement of the diaphragm secondary to
hyperinflation of the lungs or superimposed congestive heart failure.
Symptoms described in adults with pneumococcal pneumonia may be noted in

FIG. 428.3 Radiographic findings characteristic of pneumococcal pneumonia in a 14 yr
old boy with cough and fever. Posteroanterior (A) and lateral (B) chest radiographs
reveal consolidation in the right lower lobe, strongly suggesting bacterial pneumonia.

Point-of-care use of portable or handheld ultrasonography is highly sensitive

and specific in diagnosing pneumonia in children by determining lung
consolidations and air bronchograms or effusions (Fig. 428.4 ). However, the
reliability of this imaging modality for pneumonia diagnosis is highly user-
dependent, which has limited its widespread use.
radiographic and laboratory findings; although pneumococcal pneumonia is
associated with a higher WBC count, erythrocyte sedimentation rate,
procalcitonin, and C-reactive protein level, there is considerable overlap.
The definitive diagnosis of a viral infection rests on the detection of the viral
genome or antigen in respiratory tract secretions. Reliable PCR assays are
widely available for the rapid detection of many respiratory viruses, including
RSV, parainfluenza, influenza, human metapneumovirus, adenovirus,
enterovirus, and rhinovirus. Serologic techniques can also be used to diagnose a
recent respiratory viral infection but generally require testing of acute and
convalescent serum samples for a rise in antibodies to a specific virus. This
diagnostic technique is laborious, slow, and not generally clinically useful
because the infection usually has resolved by the time it is confirmed
serologically. Serologic testing may be valuable as an epidemiologic tool to
define the incidence and prevalence of the various respiratory viral pathogens.
The definitive diagnosis of a typical bacterial infection requires isolation of an
organism from the blood, pleural fluid, or lung. Culture of sputum is of little
value in the diagnosis of pneumonia in young children, while percutaneous lung
aspiration is invasive and not routinely performed. Blood culture is positive in
only 10% of children with pneumococcal pneumonia and is not recommended
for nontoxic-appearing children treated as outpatients. Blood cultures are
recommended for children who fail to improve or have clinical deterioration,
have complicated pneumonia (Table 428.6 ), or require hospitalization. Urinary
antigen tests should not be used to diagnose pneumonia caused by S.
pneumoniae in children because of a high rate of false positives resulting from
nasopharyngeal carriage. Pertussis infection can be diagnosed by PCR or culture
of a nasopharyngeal specimen; although culture is considered the gold standard
for pertussis diagnosis, it is less sensitive than the available PCR assays. Acute
infection caused by M. pneumoniae can be diagnosed on the basis of a PCR test
result from a respiratory specimen or seroconversion in an immunoglobulin G
assay. Cold agglutinins at titers > 1 : 64 are also found in the blood of roughly
half of patients with M. pneumoniae infections; however, cold agglutinins are
nonspecific because other pathogens such as influenza viruses may also cause
increases. Serologic evidence, such as antistreptolysin O and anti-DNase B
titers, may also be useful in the diagnosis of group A streptococcal pneumonia.

Table 428.6
Factors Suggesting Need for Hospitalization of Children
With Pneumonia
Age <6 mo
Immunocompromised state
Toxic appearance
Moderate to severe respiratory distress
Hypoxemia (oxygen saturation <90% breathing room air, sea level)
Complicated pneumonia*
Sickle cell anemia with acute chest syndrome
Vomiting or inability to tolerate oral fluids or medications
Severe dehydration
No response to appropriate oral antibiotic therapy
Social factors (e.g., inability of caregivers to administer medications at home or follow-up appropriately)
* Pleural effusion, empyema, abscess, bronchopleural fistula, necrotizing pneumonia, acute

respiratory distress syndrome, extrapulmonary infection (meningitis, arthritis, pericarditis,

osteomyelitis, endocarditis), hemolytic uremic syndrome, or sepsis.
Adapted from Baltimore RS: Pneumonia. In Jenson HB, Baltimore RS, editors: Pediatric infectious
diseases: principles and practice, Philadelphia, 2002, WB Saunders, p. 801.

There is a great deal of interest in developing a non-invasive diagnostic test

that can accurately differentiate children with bacterial versus viral causes of
pneumonia. Various biomarkers, including C-reactive protein, procalcitonin,
lipocalin-2, and tumor necrosis factor-related apoptosis-inducing ligand, have
been evaluated for their ability to differentiate these pneumonia etiologies. For
many of these biomarkers, values differ in children with bacterial compared with
viral causes of pneumonia, but the reliability of these tests is not sufficiently
high to justify routine use. Studies of these biomarkers have also been hampered
by the lack of a gold standard for determining pneumonia etiology and the
relatively frequent occurrence of viral–bacterial co-infections. Patient peripheral
cell gene expression patterns determined by microarray reverse transcription
PCR is an emerging technology that may help differentiate bacterial from viral
causes of pneumonia, although further study is needed.

Treatment
Treatment of suspected bacterial pneumonia is based on the presumptive cause
and the age and clinical appearance of the child. For mildly ill children who do
not require hospitalization, amoxicillin is recommended. With the emergence of
penicillin-resistant pneumococci, high doses of amoxicillin (90 mg/kg/day orally
divided twice daily) should be prescribed unless local data indicate a low
prevalence of resistance (Table 428.7 ). Therapeutic alternatives include
cefuroxime and amoxicillin/clavulanate. For school-aged children and
adolescents or when infection with M. pneumoniae or C. pneumoniae is
suspected, a macrolide antibiotic is an appropriate choice for outpatient
management. Azithromycin is generally preferred, while clarithromycin or
doxycycline (for children 8 yr or older) are alternatives. For adolescents, a
respiratory fluoroquinolone (levofloxacin, moxifloxacin) may also be considered
as an alternative if there are contraindications to other agents.

Table 428.7

Selection of Antimicrobial Therapy for Specific Pathogens

ORAL THERAPY (STEP-DOWN
PATHOGEN PARENTERAL THERAPY
THERAPY OR MILD INFECTION)
Streptococcus Preferred: ampicillin (150-200 mg/kg/day Preferred: amoxicillin (90 mg/kg/day in
pneumoniae every 6 hr) or penicillin (200,000-250,000 2 doses or 45 mg/kg/day in 3 doses);
with MICs for U/kg/day every 4-6 hr); Alternatives: second- or third-
penicillin ≤ 2.0 Alternatives: ceftriaxone (50-100 mg/kg/day generation cephalosporin
µg/mL every 12-24 hr) (preferred for parenteral (cefpodoxime, cefixime, cefprozil); oral
outpatient therapy); may also be effective: levofloxacin, if susceptible (16-20
clindamycin (40 mg/kg/day every 6-8 hr) or mg/kg/day in 2 doses for children 6 mo
vancomycin (40-60 mg/kg/day every 6-8 hr) to 5 yr old and 8-10 mg/kg/day once
daily for children 5-16 yr old;
maximum daily dose, 750 mg) or oral
linezolid (30 mg/kg/day in 3 doses for
children <12 yr old and 20 mg/kg/day
in 2 doses for children ≥12 yr old)
S. pneumoniae Preferred: ceftriaxone (100 mg/kg/day every Preferred: oral levofloxacin (16-20
resistant to 12-24 hr); mg/kg/day in 2 doses for children 6 mo
penicillin, with Alternatives: ampicillin (300-400 mg/kg/day to 5 yr and 8-10 mg/kg/day once daily
MICs ≥ 4.0 every 6 hr), levofloxacin (16-20 mg/kg/day for children 5-16 yr, maximum daily
µg/mL every 12 hr for children 6 mo to 5 yr old and dose, 750 mg), if susceptible, or oral
8-10 mg/kg/day once daily for children 5-16 linezolid (30 mg/kg/day in 3 doses for
yr old; maximum daily dose, 750 mg), or children <12 yr and 20 mg/kg/day in 2
linezolid (30 mg/kg/day every 8 hr for doses for children ≥12 yr);
children <12 yr old and 20 mg/kg/day every Alternative: oral clindamycin (30-40
12 hr for children ≥12 yr old); may also be mg/kg/day in 3 doses)
effective: clindamycin (40 mg/kg/day every 6-
8 hr) or vancomycin (40-60 mg/kg/day every
6-8 hr)
Group A Preferred: intravenous penicillin (100,000– Preferred: amoxicillin (50-75
streptococcus 250,000 U/kg/day every 4-6 hr) or ampicillin mg/kg/day in 2 doses), or penicillin V
(200 mg/kg/day every 6 hr); (50-75 mg/kg/day in 3 or 4 doses);
Alternatives: ceftriaxone (50-100 mg/kg/day Alternative: oral clindamycin (40
every 12-24 hr); may also be effective: mg/kg/day in 3 doses)
clindamycin, if susceptible (40 mg/kg/day
every 6-8 hr) or vancomycin (40-60
mg/kg/day every 6-8 hr)
Staphylococcus Preferred: cefazolin (150 mg/kg/day every 8 Preferred: oral cephalexin (75-100
aureus , hr) or semisynthetic penicillin, e.g., oxacillin mg/kg/day in 3 or 4 doses);
 methicillin (150-200 mg/kg/day every 6-8 hr); Alternative: oral clindamycin (30-40
susceptible Alternatives: clindamycin (40 mg/kg/day mg/kg/day in 3 or 4 doses)
(combination every 6-8 hr) or vancomycin (40-60
therapy not mg/kg/day every 6-8 hr)
well studied)
S. aureus , Preferred: vancomycin (40-60 mg/kg/day Preferred: oral clindamycin (30-40
methicillin every 6-8 hr or dosing to achieve an mg/kg/day in 3 or 4 doses);
resistant, AUC/MIC ratio of >400) or clindamycin (40 Alternatives: oral linezolid (30
susceptible to mg/kg/day every 6-8 hr); mg/kg/day in 3 doses for children <12
clindamycin Alternatives: linezolid (30 mg/kg/day every 8 yr and 20 mg/kg/day in 2 doses for
(combination hr for children <12 yr old and 20 mg/kg/day children ≥12 yr)
therapy not every 12 hr for children ≥ 12 yr old)
well-studied)
S. aureus, Preferred: vancomycin (40-60 mg/kg/day Preferred: oral linezolid (30 mg/kg/day
methicillin every 6-8 hr or dosing to achieve an in 3 doses for children <12 yr and 20
resistant, AUC/MIC ratio of >400); mg/kg/day in 2 doses for children ≥12
resistant to Alternatives: linezolid (30 mg/kg/day every 8 yr old);
clindamycin hr for children <12 yr old and 20 mg/kg/day Alternatives: none; entire treatment
(combination every 12 hr for children ≥12 yr old) course with parenteral therapy may be
therapy not required
well studied)
Haemophilus Preferred: intravenous ampicillin (150-200 Preferred: amoxicillin (75-100
influenza, mg/kg/day every 6 hr) if β-lactamase negative, mg/kg/day in 3 doses) if β-lactamase
typeable (A-F) ceftriaxone (50-100 mg/kg/day every 12-24 negative, or amoxicillin clavulanate
or nontypeable hr) if β-lactamase producing (amoxicillin component, 45 mg/kg/day
Alternatives: intravenous ciprofloxacin (30 in 3 doses or 90 mg/kg/day in 2 doses)
mg/kg/day every 12 hr) or intravenous if β-lactamase producing;
levofloxacin (16-20 mg/kg/day every 12 hr for Alternatives: cefdinir, cefixime,
children 6 mo to 5 yr old and 8-10 mg/kg/day cefpodoxime, or ceftibuten
once daily for children 5-16 yr old; maximum
daily dose, 750 mg)
Mycoplasma Preferred: intravenous azithromycin (10 Preferred: azithromycin (10 mg/kg on
pneumoniae mg/kg on days 1 and 2 of therapy; transition to day 1, followed by 5 mg/kg/day once
oral therapy if possible); daily on days 2-5);
Alternatives: intravenous erythromycin Alternatives: clarithromycin (15
lactobionate (20 mg/kg/day every 6 hr) or mg/kg/day in 2 doses) or oral
levofloxacin (16-20 mg/kg/day every 12 hr; erythromycin (40 mg/kg/day in 4
maximum daily dose, 750 mg) doses); for children >7 yr old,
doxycycline (2-4 mg/kg/day in 2 doses;
for adolescents with skeletal maturity,
levofloxacin (500 mg once daily) or
moxifloxacin (400 mg once daily)
Chlamydia Preferred: intravenous azithromycin (10 Preferred: azithromycin (10 mg/kg on
trachomatis or mg/kg on days 1 and 2 of therapy; transition to day 1, followed by 5 mg/kg/day once
Chlamydophila oral therapy if possible); daily days 2-5);
pneumoniae Alternatives: intravenous erythromycin Alternatives: clarithromycin (15
lactobionate (20 mg/kg/day every 6 hr) or mg/kg/day in 2 doses) or oral
levofloxacin (16-20 mg/kg/day in 2 doses for erythromycin (40 mg/kg/day in 4
children 6 mo to 5 yr old and 8-10 mg/kg/day doses); for children >7 yr old,
once daily for children 5-16 yr old; maximum doxycycline (2-4 mg/kg/day in 2
daily dose, 750 mg) doses); for adolescents with skeletal
maturity, levofloxacin (500 mg once
daily) or moxifloxacin (400 mg once
daily)
Doses for oral therapy should not exceed adult doses.
 editors: Caffrey's pediatric diagnostic imaging, ed 10, Philadelphia, 2004,
Mosby, p. 1002.)

S. aureus, S. pneumoniae, and S. pyogenes are the most common causes of

parapneumonic effusions and empyema. Nonetheless many effusions that
complicate bacterial pneumonia are sterile. Analysis of pleural fluid parameters,
including pH, glucose, protein, and lactate dehydrogenase, can differentiate
transudative from exudative effusions (Table 428.8 ). However, current PIDS–
IDSA guidelines do not recommend that these tests be performed because this
distinction rarely changes management. Pleural fluid should be sent for Gram
stain, and bacterial culture as this may identify the bacterial cause of pneumonia.
Molecular methods, including bacterial species-specific PCR assays or
sequencing of the bacterial 16S ribosomal RNA gene, detect bacterial DNA and
can often determine the bacterial etiology of the effusion if the culture is
negative, particularly if the pleural fluid sample was obtained after initiation of
antibiotics. A pleural fluid WBC count with differential may be helpful if there is
suspicion for pulmonary tuberculosis or a noninfectious etiology for the pleural
effusion, such as malignancy.

Table 428.8

Features Differentiating Exudative From Transudative Pleural Effusion

FEATURE TRANSUDATE EXUDATE
Appearance Serous Cloudy
Leukocyte count <10,000/mm3 >50,000/mm3
pH >7.2 <7.2
Protein <3.0 g/dL >3.0 g/dL
Ratio of pleural fluid protein to serum <0.5 >0.5
LDH <200 IU/L >200 IU/L
Ratio of pleural fluid LDH to serum <0.6 >0.6
Glucose ≥60 mg/dL <60 mg/dL
LDH, lactate dehydrogenase.
From Septimus EJ: Pleural effusion and empyema, In Bennett JE, Dolin R, Blaser MJ, editors:
Mandell, Douglas, and Bennett's principles and practice of infectious diseases , ed 8, vol 1,
Philadelphia, 2015, Elsevier, Table 70-1, p. 851.

Small (<1 cm on lateral decubitus radiograph), free-flowing parapneumonic

effusions often do not require drainage but respond to appropriate antibiotic
therapy. Larger effusions should typically be drained, particularly if the effusion
is purulent (empyema) or associated with respiratory distress. Chest ultrasound,
or alternatively CT, may be helpful in determining whether loculations are
CHAPTER 432

Cystic Fibrosis
Marie E. Egan, Michael S. Schechter, Judith A. Voynow

Cystic fibrosis (CF) is an inherited multisystem disorder of children and adults;

it is the most common life-limiting recessive genetic trait among whites.
Dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR)
protein, the primary defect, leads to a wide and variable array of presenting
manifestations and complications.
CF is responsible for most cases of exocrine pancreatic insufficiency in early
life and is the major cause of severe chronic lung disease in children. It is also
responsible for many cases of hyponatremic salt depletion, nasal polyposis,
pansinusitis, rectal prolapse, pancreatitis, cholelithiasis, and nonautoimmune
insulin-dependent hyperglycemia. Because CF may manifest as failure to thrive
and hepatic dysfunction, including cirrhosis, this disorder enters into the
differential diagnosis of many pediatric conditions (Table 432.1 ).

Table 432.1
Complications of Cystic Fibrosis
RESPIRATORY
Bronchiectasis, bronchitis, bronchiolitis, pneumonia
Atelectasis
Hemoptysis
Pneumothorax
Nasal polyps
Sinusitis
Reactive airway disease
Mucoid impaction of the bronchi
Allergic bronchopulmonary aspergillosis
Cor pulmonale
Respiratory failure
GASTROINTESTINAL
Meconium ileus, meconium plug (neonate)
Meconium peritonitis (neonate)
 Distal intestinal obstruction syndrome (non-neonatal obstruction)
Rectal prolapse
Intussusception
Volvulus
Fibrosing colonopathy (strictures)
Appendicitis
Intestinal atresia
Pancreatitis
Biliary cirrhosis (portal hypertension: esophageal varices, hypersplenism)
Neonatal obstructive jaundice
Hepatic steatosis
Gastroesophageal reflux
Cholelithiasis
Inguinal hernia
Growth failure (malabsorption)
Vitamin deficiency states (vitamins A, K, E, D)
Insulin deficiency, symptomatic hyperglycemia, diabetes
Malignancy (rare)
OTHER
Infertility
Delayed puberty
Edema-hypoproteinemia
Dehydration–heat exhaustion
Hypertrophic osteoarthropathy-arthritis
Clubbing
Amyloidosis
Diabetes mellitus
Aquagenic palmoplantar keratoderma (skin wrinkling)
Adapted from Silverman FN, Kuhn JP: Essentials of Caffey's pediatric x-ray diagnosis, Chicago,
1990, Year Book, p. 649.

Genetics
CF occurs most frequently in white populations of northern Europe, North
America, and Australia/New Zealand. The prevalence in these populations varies
but approximates 1 in 3,500 live births (1 in 9,200 individuals of Hispanic
descent and 1 in 15,000 African Americans). Although less frequent in African,
Hispanic, Middle Eastern, South Asian, and eastern Asian populations, the
disorder does exist in these populations as well (Fig. 432.1 ).
CFTR is the deletion of a single phenylalanine residue at amino acid 508
(F508del). This mutation is responsible for the high incidence of CF in northern
European populations and is considerably less frequent in other populations,
such as those of southern Europe and Israel. Nearly 50% of individuals with CF
in the United States Cystic Fibrosis Foundation (CFF) Patient Registry are
homozygous for F508del, and approximately 87% carry at least 1 F508del gene.
Remaining patients have an extensive array of mutations, none of which has a
prevalence of more than several percentage points, except in certain populations;
for example, the W1282X mutation occurs in 60% of Ashkenazi Jews with CF.
Through the use of probes for 40 of the most common mutations, the genotype
of 80–90% of Americans with CF can be ascertained. Genotyping using a
discreet panel of mutation probes is quick and less costly than more
comprehensive sequencing and is the approach typically used in state newborn
screening programs. In remaining patients, sequencing the entire CFTR gene and
looking for deletions and duplications are necessary to establish the genotype.
As sequencing technologies evolve and costs decrease, sequencing the entire
CFTR gene may become mainstream for all patients.

Table 432.2
One Proposed Classification of Cystic Fibrosis
Transmembrane Conductance Regulator (CFTR) Mutations

FUNCTIONAL
CLASS EFFECT ON CFTR CFTR SAMPLE MUTATIONS
PRESENT?
I Lack of protein production No Stop codons (designation in X; e.g., Trp1282X,
Gly542X); splicing defects with no protein
production (e.g., 711+1G→T, 1717-1G→A)
II Defect in protein trafficking withNo/substantially Phe508del, Asn1303Lys, Gly85Gly,
ubiquitination and degradation in reduced leu1065Pro, Asp507, Ser549Arg
endoplasmic reticulum/Golgi body
III Defective regulation; CFTR not No (nonfunction Gly551Asp, Ser492Phe, Val520Phe,
activated by adenosine triphosphate CFTR present in Arg553Gly, Arg560Thr, Arg560Ser
or cyclic adenosine monophosphate apical
membrane)
IV Reduced chloride transport through Yes Ala455Glu, Arg117Cys, Asp1152His,
CFTR at the apical membrane Leu227Arg, Arg334Trp, Arg117His*
V Splicing defect with reduced Yes 3849+10kbC→T, 1811+16kbA→G, IVS8-5T,
production of CFTR 2789+5G→A
* Function of Arg117His depends on the length of the polythymidine track on the same
chromosome in intron 8 (IVS8): 5T, 7T, or 9T. There is more normal CFTR function with a longer
polythymidine track.
Excessive loss of salt in the sweat predisposes young children to salt depletion
episodes, especially during episodes of gastroenteritis and during warm weather.
These children may present with hypochloremic alkalosis. Hyponatremia is a
risk particularly in warm climates. Frequently, parents notice salt frosting of the
skin or a salty taste when they kiss the child. A few genotypes are associated
with normal sweat chloride values.

Diagnosis and Assessment

The diagnosis of CF has been based on a positive quantitative sweat test (Cl− ≥
60 mEq/L) in conjunction with one or more of the following features:
identification of 2 CFTR mutations, typical chronic obstructive pulmonary
disease, documented exocrine pancreatic insufficiency, and a positive family
history. With newborn screening, diagnosis is often made prior to obvious
clinical manifestations such as failure to thrive and chronic cough. Diagnostic
criteria have been recommended to include additional testing procedures (Table
432.3 ).

Table 432.3

Diagnostic Criteria for Cystic Fibrosis (CF)

Presence of typical clinical features (respiratory, gastrointestinal, or genitourinary)

or
A history of CF in a sibling
or
A positive newborn screening test
plus
Laboratory evidence for CFTR (CF transmembrane regulator) dysfunction:
Two elevated sweat chloride concentrations obtained on separate days
or
Identification of two CF mutations
or
An abnormal nasal potential difference measurement

Sweat Testing
The sweat test, which involves using pilocarpine iontophoresis to collect sweat
and performing chemical analysis of its chloride content, is the standard
approach to diagnosis of CF. The procedure requires care and accuracy. An
electric current is used to carry pilocarpine into the skin of the forearm and
locally stimulate the sweat glands. If an adequate amount of sweat is collected,
the specimens are analyzed for chloride concentration. Infants with a positive
newborn screen for CF should have the sweat chloride testing performed after
36-wk corrected gestational age and at a weight greater than 2 kg and at age
greater than 10 days to increase the likelihood of sufficient sweat collection for
an accurate study. Positive results should be confirmed; for a negative result, the
test should be repeated if suspicion of the diagnosis remains.
More than 60 mmol/L of chloride in sweat is diagnostic of CF when one or
more other criteria are present. In individuals with a positive newborn screen, a
sweat chloride level less than 30 mmol/L indicates that CF is unlikely.
Borderline (or intermediate) values of 30-59 mmol/L have been reported in
patients of all ages who have CF with atypical involvement and require further
testing. Table 432.4 lists the conditions associated with false-negative and false-
positive sweat test results.

Table 432.4
Conditions Associated With False-Positive and False-
Negative Sweat Test Results
WITH FALSE-POSITIVE RESULTS
Eczema (atopic dermatitis)
Ectodermal dysplasia
Malnutrition/failure to thrive/deprivation
Anorexia nervosa
Congenital adrenal hyperplasia
Adrenal insufficiency
Glucose-6-phosphatase deficiency
Mauriac syndrome
Fucosidosis
Familial hypoparathyroidism
Hypothyroidism
Nephrogenic diabetes insipidus
Pseudohypoaldosteronism
Klinefelter syndrome
Familial cholestasis syndrome
Autonomic dysfunction
Prostaglandin E infusions
Munchausen syndrome by proxy
WITH FALSE-NEGATIVE RESULTS
 Dilution
Malnutrition
Edema
Insufficient sweat quantity
Hyponatremia
Cystic fibrosis transmembrane conductance regulator mutations with preserved sweat duct function

DNA Testing
Several commercial laboratories test for 30-96 of the most common CFTR
mutations. This testing identifies ≥90% of individuals who carry 2 CF mutations.
Some children with typical CF manifestations are found to have 1 or no
detectable mutations by this methodology. Some laboratories perform
comprehensive mutation analysis screening for all the >1,900 identified
mutations.

Other Diagnostic Tests

The finding of increased potential differences across nasal epithelium (nasal
potential difference) that is the increased voltage response to topical amiloride
application, followed by the absence of a voltage response to a β-adrenergic
agonist, has been used to confirm the diagnosis of CF in patients with equivocal
or frankly normal sweat chloride values. This testing is primarily used in
research applications and has never undergone extensive validation as a clinical
tool.

Pancreatic Function
The diagnosis of pancreatic malabsorption can be made by the quantification of
elastase-1 activity in a fresh stool sample by an enzyme-linked immunosorbent
assay specific for human elastase. The quantification of fat malabsorption with a
72-hr stool collection is rarely necessary in the clinical setting. CF-related
diabetes affects approximately 20% of adolescents and 40–50% of adults, and
clinical guidelines recommend yearly oral glucose tolerance testing (OGTT)
after age 10. OGTT may sometimes be clinically indicated at an earlier age. Spot
testing of blood and urine glucose levels and glycosylated hemoglobin levels are
not sufficiently sensitive.
that is not available, a lower pharyngeal swab taken during or after a forced
cough is obtained for culture and antibiotic susceptibility studies. Because
irreversible loss of pulmonary function from low-grade infection can occur
gradually and without acute symptoms, emphasis is placed on a thorough
pulmonary history and physical exam and routine pulmonary function testing.
Table 432.5 lists symptoms and signs that suggest the need for more intensive
antibiotic and physical therapy (PT). Protection against exposure to methicillin-
resistant S. aureus, P. aeruginosa, B. cepacia, and other resistant Gram-negative
organisms is essential, including contact isolation procedures and careful
attention to cleaning of inhalation therapy equipment. A nurse, physical
therapist, respiratory therapist, social worker, and dietitian, as members of the
multidisciplinary care team, should evaluate children regularly and contribute to
the development of a comprehensive daily care plan. Considerable education and
programs to empower families and older children to take responsibility for care
are likely to result in the best adherence to daily care programs. Screening
patients and caregivers for anxiety and depression annually is expected to
identify issues that can interfere with adherence to daily care. Standardization of
practice, on the part of both caregivers and families, as well as close monitoring
and early intervention for new or increasing symptoms appears to result in the
best long-term outcomes.

Table 432.5
Symptoms and Signs Associated With Exacerbation of
Pulmonary Infection in Patients With Cystic Fibrosis
SYMPTOMS
Increased frequency and duration of cough
Increased sputum production
Change in appearance of sputum
Increased shortness of breath
Decreased exercise tolerance
Decreased appetite
Feeling of increased congestion in the chest
SIGNS
Increased respiratory rate
Use of accessory muscles for breathing
Intercostal retractions
Change in results of auscultatory examination of chest
Decline in measures of pulmonary function consistent with the presence of obstructive airway disease
Fever and leukocytosis
Weight loss
New infiltrate on chest radiograph
aspects of the patient's history and examination, including anorexia, weight loss,
and diminished activity, must be used to guide the frequency and duration of
therapy. Antibiotic treatment varies from intermittent short courses of 1
antibiotic to nearly continuous treatment with 1 or more antibiotics. Dosages for
some antibiotics are often 2-3 times the amount recommended for minor
infections because patients with CF have proportionately more lean body mass
and higher clearance rates for many antibiotics than other individuals. In
addition, it is difficult to achieve effective drug levels of many antimicrobials in
respiratory tract secretions.

Oral Antibiotic Therapy

Indications for oral antibiotic therapy in a patient with CF include the presence
of respiratory tract symptoms, physical signs, or changes in pulmonary function
testing or chest x-ray. Treatment is guided by identification of pathogenic
organisms in respiratory tract cultures and in vitro sensitivity testing. Common
organisms, including S. aureus (MRSA or MSSA), nontypeable H. influenzae, P.
aeruginosa; B. cepacia and other Gram-negative rods, are encountered with
increasing frequency. The usual course of therapy is 2 wk, and maximal doses
are recommended. Table 432.6 lists useful oral antibiotics. The quinolones are
the only broadly effective oral antibiotics for Pseudomonas infection, but
resistance against these agents may emerge. Macrolides may reduce the
virulence properties of P. aeruginosa, such as biofilm production, and contribute
antiinflammatory effects. Long-term therapy with azithromycin 3 times a week
improves lung function in patients with chronic P. aeruginosa infection.

Table 432.6
Antimicrobial Agents for Cystic Fibrosis Lung Infection

DOSAGE (mg/kg/24 NO. DOSES/24

ROUTE ORGANISMS AGENTS
hr) hr
Oral Staphylococcus aureus Dicloxacillin 25-50 4
Linezolid 20 2
Cephalexin 50 4
Clindamycin 10-30 3-4
Amoxicillin-clavulanate 25-45 2-3
Haemophilus Amoxicillin 50-100 2-3
influenzae
Pseudomonas Ciprofloxacin 20-30 2-3
aeruginosa
Burkholderia cepacia Trimethoprim- 8-10* 2-4
 sulfamethoxazole
Empirical Azithromycin 10, day 1; 5, days 2-5 1
Erythromycin 30-50 3-4
Intravenous S. aureus Nafcillin 100-200 4-6
Vancomycin 40 3-4
P. aeruginosa Tobramycin 8-12 1-3
Amikacin 15-30 2-3
Ticarcillin 400 4
Piperacillin 300-400 4
Ticarcillin-clavulanate 400 † 4
Piperacillin-tazobactam 240-400 ‡ 3
Meropenem 60-120 3
Imipenem-cilastatin 45-100 3-4
Ceftazidime 150 3
Aztreonam 150-200 4
B. cepacia Chloramphenicol 50-100 4
Meropenem 60-120 3
Aerosol Tobramycin (inhaled) 300 § 2
Aztreonam (inhaled) 75 3
* Quantity of trimethoprim.

† Quantity of ticarcillin.

‡
Quantity of piperacillin.
§ In mg per dose.

Aerosolized Antibiotic Therapy

Aerosolized antibiotics are often used as part of daily therapy when the airways
are infected with P. aeruginosa . Aerosolized tobramycin inhalation solution or
powder, or aztreonam inhalation solution used as a suppressive therapy (on 1
mo, off 1 mo), may reduce symptoms, improve pulmonary function, and
decrease the occurrence of pulmonary exacerbations. Although these therapies
are sometimes used in acute pulmonary exacerbations, the evidence to support
this application is limited.
Another important indication for aerosolized antibiotic therapy is to eradicate
P. aeruginosa in the airways after initial detection. Early infection may be
cleared for mo to several yr in this way, although eventual reinfection is
common. Other antibiotics have been used via inhalation, including liposomal
amikacin and levofloxacin for P. aeruginosa , and there was no inferiority of
efficacy compared with inhaled tobramycin.

Intravenous Antibiotic Therapy

 FIG. 432.11 Cystic fibrosis transmembrane conductance regulator (CFTR)
pharmacologic modulators have different modes of action. A, Read-through
compounds which include aminoglycoside antibiotics (e.g., gentamicin,
tobramycin) act by suppressing premature termination codons (PTCs), thus
permitting translation to continue to the normal termination of the transcript
and thus increasing the total amount of complete CFTR being produced in
the cell. B, Correctors (e.g., VX-809 also known as lumacaftor; VX-661)
potentially promote folding of mutant CFTR protein, allowing it to escape
ER degradation and reach the cell surface, thus increasing the number of
channels present at the plasma membrane. C, Stabilizers include
compounds (e.g., hepatocyte growth factor) that enhance CFTR
retention/anchoring at the cell surface, thus also contributing to increase
the number of channels present at the cell surface. D, Potentiators (e.g.,
VX-770 also known as ivacaftor) activate CFTR, that is, increase the open
probability (Po ) of the channel by regulating its gating and possibly also the
conductance. (From Bell SC, De Boeck K, Amaral MD: New
pharmacological approaches for cystic fibrosis: promises, progress, pitfalls,
Pharmacol Therapeu 145:19–34, 2015 [Fig. 4, p. 26].)

The combination of ivacaftor with lumacaftor, a corrector that stabilizes

misfolded F508del and enables trafficking of the mutant molecule to the apical
cell membrane where it is potentiated by ivacaftor, is available for patients older
than 6 yr of age who are homozygous for the F508del mutation (see Fig. 432.11
). This medication is associated with smaller increments in pulmonary and
nutritional outcomes but is an important proof-of-concept treatment.
Tezacaftor and ivacaftor is another combination indicated for patients ≥ 12 yr
with 1 or 2 Phe508del alleles. This combination improves predicted FEV1 and
overall well-being (Table 432.7 ). VX-445 combined with tezacaftor-ivacaftor
adds another CFTR correction agent; the triple combination improves predicted
FEV1 and reduces sweat chloride levels.

Table 432.7
Cystic Fibrosis Transmembrane Regulator Modulators for
Cystic Fibrosis
 DRUG FDA-APPROVED INDICATION FORMULATIONS USUAL DOSAGE
Ivacaftor ≥ 12 mo with a responsive mutation 150 mg tabs; 50, 75 mg ≥ 6 years: 150 mg q12
1 granule packets 2 hr 3
Lumacaftor/ivacaftor ≥ 2 yr, F508del-homozygous 100/125, 200/125 mg tabs; 6-11 yr: 200/250
100/125, 150/188 mg mg q12 hr
granule packets 2 ≥ 12 yr: 400/250
mg q12 hr 4
Tezacaftor/ivacaftor ≥ 12 yr, F508del-homozygous or 100/150 mg tabs co- ≥ 12 yr: 100/150 mg
F508del-heterozygous with another packaged with ivacaftor tab qAM, then 150 mg
responsive mutation 1 150 mg tabs ivacaftor qPM
1 Responsive mutations are those in which chloride transport is expected to increase to at least

10% of untreated normal over baseline with drug therapy, based on clinical or in vitro data.
2 The granules should be mixed with 5 mL of room-temperature or cold soft food or liquid and
consumed within 1 hr.
3 In patients 12 mo to 6 yr old, the recommended dosage is 50 mg every 12 hr for those weighing
<14 kg, and 75 mg every 12 hr for those weighing ≥ 14 kg.
4 In patients 2-5 yr old, the recommended dosage is 100/125 mg every 12 hr for those weighing

<14 kg, and 150/188 mg every 12 hr for those weighing ≥ 14 kg.

Modified from The Medical Letter on Drugs and Therapeutics: Tezacaftor/Ivacaftor (Symdeko) for
cystic fibrosis; Med Lett 60(1558):174–176, 2018 (Table 3, p. 175).

Other Therapies
Attempts to clear recalcitrant atelectasis and airway plugging with
bronchopulmonary lavage and direct installation of various medications are
sometimes used in exceptional cases; there is no evidence for sustained benefit
from repeated procedures. Expectorants such as iodides and guaifenesin do not
effectively assist with the removal of secretions from the respiratory tract.
Inspiratory muscle training can enhance maximum oxygen consumption during
exercise, as well as FEV1 .

Treatment of Pulmonary Complications

Atelectasis
Lobar atelectasis occurs relatively infrequently; it may be asymptomatic and
noted only at the time of a routine chest radiograph. Aggressive intravenous
therapy with antibiotics and increased chest PT directed at the affected lobe may
be effective. If there is no improvement in 5-7 days, bronchoscopic examination
of the airways may be indicated. If the atelectasis does not resolve, continued
 FIG. 433.3 Classification of genes mutated in primary ciliary dyskinesia
based on ultrastructural findings.

The genetic bases of ciliopathies have yielded greater understanding of

genotype-phenotype relationships in PCD. Mutations in nexin-dynein regulatory
complex proteins create inconsistent ultrastructural abnormalities characterized
by absent inner dynein arms in all axonemes, but misplaced radial spokes and
microtubular disorganization in only some cilia. A cross-sectional study showed
that children who had microtubular disorganization, primarily due to biallelic
mutations in CCDC39 or CCDC40 , had more severe lung disease. In contrast,
patients with mutations in RSPH1 appear to have milder respiratory phenotypes.

Clinical Manifestations of Primary Ciliary

Dyskinesia
See Table 433.1 .

Table 433.1
Clinical Manifestations of Primary Ciliary Dyskinesia
RESPIRATORY
• Unexplained respiratory distress in term neonate
• Daily productive (wet) cough since early infancy
• Daily, nonseasonal rhinosinusitis since early infancy
• Chronic otitis media and persistent middle ear effusions
• Digital clubbing (rare in children)
• Atypical asthma unresponsive to therapy
• Recurrent pneumonias
• Bronchiectasis
LEFT-RIGHT LATERALITY DEFECTS
• Situs inversus totalis
• Heterotaxy with or without complex congenital heart disease
MISCELLANEOUS
• Male infertility, immotile sperm
• Female subfertility, ectopic pregnancy
• Hydrocephalus (rare)

PCD has several characteristic clinical features. Neonatal respiratory distress

(NRD) is a common feature, and most affected term newborns develop increased
work of breathing, tachypnea, and upper and middle lobe atelectasis on chest
radiographs. The association of respiratory distress in term neonates with PCD
respiratory infections in families with RPGR gene mutations. Intraflagellar
transport proteins are essential for photoreceptor assembly and, when mutated,
lead to apoptosis of the retinal pigment epithelium (see Chapter 648 ).

Diagnosis of Primary Ciliary Dyskinesia

The diagnosis of PCD should be suspected in children with chronic or recurring
upper and lower respiratory tract symptoms that begin in early infancy and is
currently based on the presence of characteristic clinical phenotype and
ultrastructural defects of cilia, though this approach will miss affected
individuals (Table 433.2 ). The diagnosis is often delayed, even in children who
have classic clinical features, such as situs inversus totalis . A high index of
suspicion is necessary. The diagnosis should be entertained in infants and
children with unexplained NRD in term newborns, daily year-round productive
(wet) cough that begins in infancy, persistent rhinosinusitis, and left-right
laterality defects.

Table 433.2
New Consensus-Based Primary Ciliary Dyskinesia (PCD)
Diagnostic Criteria by Age
NEWBORNS (0–1 MO OF AGE)
Situs inversus totalis and unexplained neonatal respiratory distress (NRD) at term birth, plus at least one of the
following:
• Diagnostic ciliary ultrastructure on electron micrographs or 2 mutations in PCD-associated gene
CHILDREN (1 MO TO 5 YR)
2 or more major PCD clinical criteria (NRD,* daily wet cough, persistent nasal congestion, laterality defect), plus
at least one of the following (nasal nitric oxide not included in this age group because it is not yet sufficiently
tested):
• Diagnostic ciliary ultrastructure on electron micrographs
• 2 mutations in 1 PCD-associated gene
• Persistent and diagnostic ciliary waveform abnormalities on high-speed videomicroscopy, on multiple occasions
CHILDREN (5–18 YR OF AGE) AND ADULTS
2 or more PCD clinical criteria (NRD,* daily productive cough or bronchiectasis, persistent nasal congestion,
laterality defect), plus at least one of the following:
• Nasal nitric oxide during plateau <77 nL/min on 2 occasions, >2 mo apart (with CF excluded)
• Diagnostic ciliary ultrastructure on electron micrographs
• Two mutations in 1 PCD-associated gene
• Persistent and diagnostic ciliary waveform abnormalities on high-speed videomicroscopy, on multiple occasions
* In term neonates.

Imaging studies show extensive involvement of the paranasal sinuses. Chest

radiographs frequently demonstrate bilateral lung overinflation, peribronchial
infiltrates, and lobar atelectasis. Computed x-ray tomography of the chest often
reveals bronchiectasis, often involving the anatomic right middle lobe or lingula,
even in young children. Situs inversus totalis in a child who has chronic
respiratory tract symptoms is highly suggestive of PCD, but this configuration
occurs in only half of patients with PCD. Pulmonary function tests may be
normal early but demonstrate obstructive airway disease as the disease
progresses. Typical findings include decreased expiratory flow rates and
increased residual volume. Bronchodilator responsiveness is variable.
Longitudinal analyses of children with PCD show wide variation in intrathoracic
airway obstruction.
Transmission electron microscopy is the current gold standard to assess
structural defects within the cilium. These ultrastructural defects are found in
cilia throughout the upper and lower airways and oviduct, as well as in sperm
flagella. Curettage from the nasal epithelium or endobronchial brushing can
provide an adequate specimen for review. Identification of a discrete, consistent
defect in any aspect of the ciliary structure with concurrent phenotypic features
is sufficient to make the diagnosis. There are several characteristic ciliary
abnormalities: outer dynein arm defects, combined inner and outer dynein arm
defects, central apparatus defects, and inner dynein arm defects with
microtubular disorganization. Inner dynein arm defects alone are uncommon.
Ultrastructural examination of cilia as a diagnostic test for PCD has limitations.
First, the absence of axonemal defects does not exclude PCD; nearly 30% of all
affected individuals have normal ciliary ultrastructure. Other patients with
symptoms consistent with PCD have been found to have ciliary aplasia or few
motor cilia on the epithelial surface (Table 433.3 ).

Table 433.3
Electron Microscopic Findings in Primary Ciliary
Dyskinesia
DYNEIN ARM DEFECTS
• Total or partial absence of outer dynein arms
• Total or partial absence of inner and outer dynein arms
• Total or partial absence of inner dynein arms alone (rare)
RADIAL SPOKE DEFECTS
• Total absence of radial spokes
• Absence of radial spoke heads
MICROTUBULAR TRANSPOSITION DEFECTS
 • Inner dynein arm defect with microtubular derangement (in some axonemes)
• Absent central pair of tubules with outer doublet transposition
OTHER
• Central microtubular agenesis
• Ciliary aplasia or reduced cilia numbers
• Normal ultrastructure

Careful interpretation of the ultrastructural findings is necessary because

nonspecific changes may be seen in relation to exposure to environmental
pollutants or infection. Ciliary defects can be acquired. Acute airway infection or
inflammation can result in structural changes (e.g., compound cilia or blebs).
Ciliary disorientation has been proposed as a form of PCD, but this phenomenon
is the result of airway injury. Frequently, the diagnosis of PCD can be delayed or
missed because of inadequate tissue collection or sample processing, or
misinterpretation of ciliary defects. Some investigators have advocated culturing
of airway epithelial cells and allowing the secondary changes to resolve.
Qualitative tests to assess ciliary function have been used to screen for PCD.
Ciliary beat frequency measurements that use conventional microscopic
techniques have been used as a screen, but this method alone will miss cases of
PCD. Cilia inspection using standard light microscopy is insufficient to support
or exclude the diagnosis. High-resolution, high-speed, digital imaging of ciliary
motion in multiple planes permits comprehensive analysis of cilia beating, which
has shown that certain beat patterns are associated with specific ultrastructural
defects. This approach is available only at a limited number of clinical centers,
primarily in Europe, and requires sophisticated software and expertise.
Immunofluorescent staining for ciliary proteins is a newer approach that holds
promise and may address some limitations of transmission electron microscopy.
This approach is currently a research tool and not widely available.
Another promising approach has exploited the observation that nasal nitric
oxide concentrations are reduced in subjects with PCD. Because nasal nitric
oxide measurements are relatively easy to perform and noninvasive, this method
is a promising screen and potentially a diagnostic test for PCD, provided that
cystic fibrosis has been excluded (see Chapter 432 ). Few studies in children <5
yr have been reported, and the accuracy of nasal nitric oxide measurements in
infants has not been established.
PCD is highly heterogenic owing to the large number of proteins involved in
cilia assembly and function. Recent advances in gene sequencing techniques
have led to the identification of a growing number of PCD-associated genes.
Biallelic, disease-causing mutations have been found in more than 70% of
chromosome 10, whereas single genes encode SP-B (SFTPB), SP-C (SFTPC),
TTF-1 (NKX2-1), and ABCA3 (ABCA3), which are located on human
chromosomes 2, 8, 14, and 16, respectively. Inherited disorders of SP-B, SP-C,
ABCA3, and TTF-1 have been recognized in humans and are collectively termed
surfactant dysfunction disorders (Table 434.1 ).

Table 434.1
Comparison of Surfactant Dysfunction Disorders

SP-B TTF-1
SP-C DISEASE ABCA3 DEFICIENCY
DEFICIENCY DISORDERS
Gene name SFTPB SFTPC ABCA3 NKX2-1
Age of onset Birth Birth–adulthood Birth–childhood; rarely adult Birth–childhood
Inheritance Recessive Dominant/sporadic Recessive Sporadic/dominant
Mechanism Loss of function Gain of toxic Loss of function Loss of
function or function
dominant negative Gain of
function
Natural Lethal Variable Generally lethal, may be chronic Variable
history
DIAGNOSIS
Biochemical Absence of SP-B None None None
(tracheal and presence of
aspirate) incompletely
processed proSP-C
Genetic Sequence SFTPB Sequence SFTPC Sequence ABCA3 Sequence NKX2-
(DNA) 1; deletion
analysis
Ultrastructural Disorganized Not specific; may Small dense lamellar bodies with Variable
(lung biopsy– lamellar bodies have dense eccentrically placed dense cores
electron aggregates
microscopy)
Treatment Lung Supportive care, Lung transplantation or Supportive care;
transplantation or lung compassionate care for infants with treat coexisting
compassionate transplantation if biallelic null mutations; lung conditions
care progressing transplantation for other mutations (hypothyroidism)
if progressing
SP , Surfactant protein.

Pathology
Histopathologically, these disorders share a unique constellation of features,
including AEC2 hyperplasia, alveolar macrophage accumulation, interstitial
thickening and inflammation, and alveolar proteinosis. A number of different
 Wambach J, Wegner D, DePass K, et al. Single ABCA3
mutations and risk for neonatal respiratory distress syndrome.
Pediatrics . 2012;130:e1575–e1582.
Wang Y, Kuan PJ, Xing C, et al. Genetic defects in surfactant
protein A2 are associated with pulmonary fibrosis and lung
cancer. Am J Hum Genet . 2009;84:52–59.

434.2
Pulmonary Alveolar Proteinosis
Jennifer A. Wambach, Lawrence M. Nogee, F. Sessions Cole III, Aaron Hamvas

Pulmonary alveolar proteinosis (PAP) is a rare syndrome characterized by the

intra-alveolar and terminal airway accumulation of surfactant leading to
progressive hypoxemic respiratory failure. PAP can result from abnormalities in
surfactant production or surfactant clearance. Histopathologic examination
shows distal air spaces are filled with a granular, eosinophilic material that stains
positively with periodic acid–Schiff reagent and is diastase resistant. This
material contains large amounts of surfactant proteins and lipids and the primary
mechanism for its accumulation is impaired catabolism by alveolar
macrophages. PAP is classified as either primary due to disruption of
granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling or
secondary due to several different diseases that reduce alveolar macrophage
number or function (Table 434.2 ). A fulminant, usually lethal form of PAP
manifesting shortly after birth has been termed congenital alveolar proteinosis ,
but because this condition is caused by disrupted surfactant metabolism or
surfactant dysfunction within alveolar type II cells, the disease is included under
“Inherited Disorders of Surfactant Metabolism,” above (see Chapter 434.1 ).

Table 434.2
Comparison of Pulmonary Alveolar Proteinosis Syndromes
 GM-CSF LYSINURIC
MARS GATA2
AUTOIMMUNE RECEPTOR PROTEIN
DEFICIENCY DEFICIENCY
DEFICIENCY INTOLERANCE
Gene(s) CSFR2A, CSFR2B SLC7A7 MARS GATA2
Age of onset Adult > child Childhood to adult Childhood Childhood to adult Childhood to adult
Inheritance N.A. Recessive Recessive Recessive Sporadic/dominant
Mechanism Neutralizing Loss of function Loss of function Loss of function Loss of function;
antibodies to haploinsufficiency
GM-CSF
Other Emesis; failure to Liver disease; Immune deficiency;
manifestations thrive hypothyroidism myelodysplasia
DIAGNOSIS
Biochemical Detection of Elevated serum Increased cationic None None
serum GM-CSF GM-CSF levels amino acids in urine,
autoantibody especially lysine
Genetic (DNA N.A. Sequence CSFR2A, Sequence SLC7A7 Sequence MARS Sequence GATA2
) CSFR2B
Treatment Whole lung Whole lung lavage; Whole lung lavage, Whole lung lavage Whole lung lavage;
lavage; inhaled bone marrow dietary protein bone marrow
GM-CSF transplantation restriction, transplantation
administration of
citrulline and nitrogen
scavenging drugs
GM-CSF , Granulocyte-macrophage colony-stimulating factor.

Etiology and Pathophysiology

Primary Alveolar Proteinosis
Disordered signaling of GM-CSF leading to impaired alveolar macrophage
maturation is the major underlying cause of primary PAP in children and adults.
Most cases of primary PAP in older children and adults are mediated by
neutralizing autoantibodies directed against GM-CSF, which can be detected in
serum and bronchoalveolar lavage (BAL) fluid. These autoantibodies block
binding of GM-CSF to its receptor, thereby inhibiting alveolar macrophage
maturation and function and surfactant clearance. Mutations in the genes
encoding both the α and β subunits of the GM-CSF receptor (CSF2RA, CSFR2B)
in children with primary alveolar proteinosis account for a genetic basis for some
cases of primary PAP in childhood.

Secondary Alveolar Proteinosis

Alveolar proteinosis has also been reported in children, including young infants,
erythematosus (SLE; see Chapter 183 ), drug-induced capillaritis,
granulomatosis with polyangiitis (previously Wegener granulomatosis),
Goodpasture syndrome, and Henoch-Schönlein purpura (see Chapter 192 ). The
finding of DAH in patients with granulomatosis with polyangiitis and
microscopic polyangiitis (MPA; see Chapter 192 ) is frequently associated with
pathologic evidence of pulmonary capillaritis. In patients with Goodpasture
syndrome or SLE, DAH has been reported both with and without the associated
finding of capillaritis. A number of systemic autoimmune and inflammatory
disorders may predispose a host to DAH with pulmonary capillaritis. Similarly, a
variety of drugs have been associated with the finding of pulmonary capillaritis
but mechanisms of cellular derangement are as yet unidentified.
These disorders are distinguished from those without pulmonary capillaritis.
Those disorders in which the pathologic finding of capillary network disruption
is absent are further divided into cardiac (pulmonary hypertension, mitral
stenosis) and noncardiac (immunodeficiency, Heiner syndrome, coagulopathies,
IPH) etiologies. Table 435.1 provides a summary and classification of the
diagnoses that may manifest as recurrent or chronic pulmonary bleeding.

Table 435.1
Diffuse Alveolar Hemorrhage Syndromes

CLASSIFICATION SYNDROME
DISORDERS WITH PULMONARY CAPILLARITIS
Idiopathic (isolated) pulmonary capillaritis (ANCA positive or negative)
Granulomatosis with polyangiitis (Wegener granulomatosis)
Microscopic polyangiitis
Systemic lupus erythematosus (SLE)
Scleroderma
Polymyositis
Goodpasture syndrome
Antiphospholipid antibody syndrome
Henoch-Schönlein purpura
Immunoglobulin A nephropathy
Behçet syndrome
Cryoglobulinemia
Drug-induced capillaritis (phenytoin, retinoic acid, propylthiouracil)
Idiopathic pulmonary-renal syndrome
Acute lung transplant rejection
Eosinophilic granulomatosis angiitis (Churg-Strauss syndrome)
Idiopathic pulmonary fibrosis
Disorders without pulmonary capillaritis
Noncardiovascular causes Idiopathic pulmonary hemosiderosis
Heiner syndrome
Acute idiopathic pulmonary hemorrhage of infancy
 Bone marrow transplantation
Immunodeficiency
Coagulation disorders
Hemolytic uremic syndromes
Celiac disease (Lane-Hamilton syndrome)
SLE
Non-accidental trauma
Radiation therapy
Infection (HIV, cryptococcosis, Legionnaires disease)
Drugs—toxins
Cardiovascular causes Mitral stenosis
Pulmonary venoocclusive disease
Arteriovenous malformations
Pulmonary lymphangioleiomyomatosis
Pulmonary hypertension
Pulmonary capillary hemangiomatosis
Chronic heart failure
Vascular thrombosis with infarction
Endocarditis
Modified from Susarla SC, Fan LL: Diffuse alveolar hemorrhage syndromes in children, Curr Opin
Pediatr 19:314–320, 2007.

Epidemiology
Disorders that present as DAH are highly variable in their severity, as well as in
their associated symptomatology and identifiable abnormalities in laboratory
testing; the diagnosis may be significantly delayed, making frequency estimates
unreliable. Similarly, the prevalence of IPH is largely unknown. Of the children
and young adults diagnosed with IPH in the past, it has been postulated that the
etiology of the hemorrhage might have been discovered if they had been studied
with the newer and more advanced diagnostics available today; specific
serologic testing has vastly improved our ability to appreciate immune mediated
disease. Estimates of prevalence obtained from Swedish and Japanese
retrospective case analyses vary from 0.24 to 1.23 cases per million. Children
and adolescents account for 30% of cases. The ratio of affected males:females is
1 : 1 in the childhood diagnosis group, and men are only slightly more affected
in the group diagnosed as young adults.

Pathology
In pulmonary capillaritis, key histologic features include (1) fibrin thrombi,
which occlude capillaries, (2) fibrin clots adherent to interalveolar septae, (3)
source of morbidity and mortality and may only be recognized on postmortem
examination. A high level of clinical suspicion and appropriate identification of
at-risk individuals is therefore recommended.

Table 436.1
Risk Factors for Pulmonary Embolism
ENVIRONMENTAL
Long-haul air travel (>4 hr)
Obesity
Cigarette smoking
Hypertension
Immobility
WOMEN'S HEALTH
Oral contraceptives, including progesterone-only and, especially, third-generation pills
Pregnancy or puerperium
Hormone replacement therapy
Septic abortion
MEDICAL ILLNESS
Personal or family history of prior pulmonary embolism or deep venous thrombosis
Cancer
Heart failure
Chronic obstructive pulmonary disease
Diabetes mellitus
Inflammatory bowel disease
Antipsychotic drug use
Long-term indwelling central venous catheter
Permanent pacemaker
Internal cardiac defibrillator
Stroke with limb paresis
Spinal cord injury
Nursing home confinement or current or repeated hospital admission
SURGICAL
Trauma
Orthopedic surgery
General surgery
Neurosurgery, especially craniotomy for brain tumor
Vascular anomalies
May-Turner syndrome
THROMBOPHILIA
Factor V Leiden mutation
Prothrombin gene (20210G A) mutation
Hyperhomocysteinemia (including mutation in methylenetetrahydrofolate reductase)
Antiphospholipid antibody syndrome
Deficiency of antithrombin III, protein C, or protein S
High concentrations of factor VIII or XI
Increased lipoprotein (a)
NONTHROMBOTIC
Air
Foreign particles (e.g., hair, talc, as a consequence of intravenous drug misuse)
Amniotic fluid
 Bone fragments, bone marrow
Fat
Tumors (Wilms tumor)
Modified from Goldhaber SZ: Pulmonary embolism, Lancet 363:1295–1305, 2004.

Etiology
A number of risk factors may be identified in children and adolescents; the
presence of immobility, malignancy, pregnancy, infection, indwelling central
venous catheters, and a number of inherited and acquired thrombophilic
conditions have all been identified as placing an individual at risk. In children, a
significantly greater percentage of VTEs are risk associated as compared with
their adult counterparts. Children with deep venous thrombosis (DVT) and
pulmonary embolism (PE) are much more likely to have one or more
identifiable conditions or circumstances placing them at risk. In contrast to
adults, idiopathic thrombosis is a rare occurrence in the pediatric population. In a
retrospective cohort of patients with VTE in U.S. children's hospitals from 2001
to 2007, the majority (63%) of affected children were found to have one or more
chronic medical comorbidities. In a large Canadian registry, 96% of pediatric
patients were found to have one risk factor and 90% had two or more risk
factors. In contrast, approximately 60% of adults with this disorder have an
identifiable risk factor (see Table 436.1 ). The most common identified risk
factors in children include infection, congenital heart disease, and the presence
of an indwelling central venous catheter.
Embolic disease in children is varied in its origin. An embolus can contain
thrombus, air, amniotic fluid, septic material, or metastatic neoplastic tissue.
Thromboemboli are the type most commonly encountered. A commonly
encountered risk factor for DVT and PE in the pediatric population is the
presence of a central venous catheter. More than 50% of DVTs in children and
more than 80% in newborns are found in patients with indwelling central venous
lines. The presence of a catheter in a vessel lumen, as well as instilled
medications, can induce endothelial damage and favor thrombus formation.
Children with malignancies are also at considerable risk. Although PE has
been described in children with leukemia, the risk of PE is more significant in
children with solid rather than hematologic malignancies. A child with
malignancy may have numerous risk factors related to the primary disease
process and the therapeutic interventions. Infection from chronic
nephrotic syndrome (see Chapter 545 ) and antiphospholipid antibody syndrome.
From one-quarter to one-half of children with systemic lupus erythematosus (see
Chapter 183 ) have thromboembolic disease. There is a significant association
with VTE onset in children for each inherited thrombophilic trait evaluated,
thereby illuminating the importance of screening for thrombophilic conditions
for those at risk for VTE. Septic emboli are rare in children but may be caused
by osteomyelitis, jugular vein or umbilical thrombophlebitis, cellulitis, urinary
tract infection, and right-sided endocarditis.
Other risk factors include infection, cardiac disease, recent surgery, and
trauma. Surgical risk is thought to be more significant when immobility will be a
prominent feature of the recovery. Use of oral contraceptives confers additional
risk, although the level of risk in patients taking these medications appears to be
decreasing, perhaps because of the lower amounts of estrogen in current
formulations. In a previously healthy adolescent patient, the risk factors are often
unknown or are similar to adults (see Tables 436.1 and 436.2 ).

Table 436.2
Clinical Decision Rules for Deep Vein Thrombosis and
Pulmonary Embolism
WELLS' SCORE FOR DEEP VEIN THROMBOSIS *
Active cancer +1 NA
Paralysis, paresis, or recent plaster cast on lower extremities +1 NA
Recent immobilization >3 days or major surgery within the past 4 wk +1 NA
Localized tenderness of deep venous system +1 NA
Swelling of entire leg +1 NA
Calf swelling >3 cm compared to asymptomatic side +1 NA
Unilateral pitting edema +1 NA
Collateral superficial veins +1 NA
Previously documented deep vein thrombosis +1 NA
Alternative diagnosis at least as likely as deep vein thrombosis −2 NA
WELLS' SCORE FOR PULMONARY EMBOLISM † , ‡
Alternative diagnosis less likely than pulmonary embolism +3 +1
Clinical signs and symptoms of deep vein thrombosis +3 +1
Heart rate >100 beats/min +1⋅5 +1
Previous deep vein thrombosis or pulmonary embolism +1⋅5 +1
Immobilization or surgery within the past 4 wk +1⋅5 +1
Active cancer +1 +1
Hemoptysis +1 +1
REVISED GENEVA SCORE FOR PULMONARY EMBOLISM § , ||
Heart rate ≥95 beats/min +5 +2
Heart rate 75–94 beats/min +3 +1
Pain on lower-limb deep venous palpation and unilateral edema +4 +1
 Unilateral lower-limb pain +3 +1
Previous deep vein thrombosis or pulmonary embolism +3 +1
Active cancer +2 +1
Hemoptysis +2 +1
Surgery or fracture within the past 4 wk +2 +1
Age >65 yr +1 +1
*
Classification for original Wells' score for deep vein thrombosis: deep vein thrombosis unlikely if
score ≤2; deep vein thrombosis likely if score >2.
†
Classification for original Wells' score for pulmonary embolism: pulmonary embolism unlikely if
score ≤4; pulmonary embolism likely if score >4.
‡
Classification for simplified Wells' score for pulmonary embolism: pulmonary embolism unlikely if
score ≤1; pulmonary embolism likely if score >1.
§ Classification for original revised Geneva score for pulmonary embolism: non-high probability of
pulmonary embolism if score ≤10; high probability of pulmonary embolism if score >10.
|| Classification for simplified revised Geneva score for pulmonary embolism: non-high probability
of pulmonary embolism if score ≤4; high probability of pulmonary embolism if score >4.
From Di Nisio M, van Es N, Büller HR: Deep vein thrombosis and pulmonary embolism, Lancet
388:3060–3069, 2016 (Table 1, p. 3062).

Epidemiology
A retrospective cohort study was performed with patients younger than 18 yr of
age, discharged from 35 to 40 children's hospitals across the United States from
2001 to 2007. During this time, a dramatic increase was noted in the incidence of
VTE; the annual rate of VTE increased by 70% from 34 to 58 cases per 10,000
hospital admissions. Although this increased incidence was noted in all age
groups, a bimodal distribution of patient ages was found, consistent with prior
studies; infants younger than 1 yr of age and adolescents made up the majority of
admissions with VTE, but neonates continue to be at greatest risk. The peak
incidence for VTE in childhood appears to occur in the 1st mo of life. It is in this
neonatal period that thromboembolic events are more problematic, likely as a
result of an imbalance between procoagulant factors and fibrinolysis. The yearly
incidence of venous events was estimated at 5.3/10,000 hospital admissions in
children and 24/10,000 in the neonatal intensive care.
Pediatric autopsy reviews have estimated the incidence of thromboembolic
disease in children as between 1% and 4%, although not all were clinically
significant. Thromboembolic pulmonary disease is often unrecognized, and
antemortem studies may underestimate the true incidence. Pediatric deaths from
etc.) may become an alternate therapy for both acute PE and long-term treatment
(Table 436.3 ).

Table 436.3
Anticoagulant Therapies for Deep Vein Thrombosis and
Pulmonary Embolism

RENAL INITIAL MAINTENANCE EXTENDED

ROUTE OF
CLEARANCE HALF-LIFE TREATMENT TREATMENT TREATMENT
ADMINISTRATION
(%) DOSING DOSING DOSING
Unfractionated Intravenous ∼30 ∼1.5 hr Maintain aPTT
heparin (UFH) 1.5-times upper
limit of normal
Low Subcutaneous ∼80 3-4 hr Weight-based Weight-based
molecular dosing dosing*
weight heparin
(LMWH)
Fondaparinux Subcutaneous 100 17-21 hr Weight-based Weight-based
dosing dosing
Vitamin K Oral Negligible Acenocoumarol Target at INR Maintain INR at Maintain INR
antagonists 8-11 hr; at 2.0-3.0 and 2.0-3.0 at 2.0-3.0
warfarin 36 hr; give parallel
phenprocoumon heparin
160 hr treatment for at
least 5 days
Dabigatran Oral ∼80 † 14-17 hr Requires at 150 mg twice a 150 mg twice a
least 5 days day day
heparin lead-in
Rivaroxaban Oral ∼33 ‡ 7-11 hr 15 mg twice a 20 mg once a day 20 mg once a
day for 3 wk day
Apixaban Oral ∼25 ‡ 8-12 hr 10 mg twice a 5 mg twice a day 2.5 mg twice a
day for 1 wk day
Edoxaban Oral ∼35 ‡ 6-11 hr Requires at 60 mg once a day § 60 mg once a
least 5 days day
heparin lead-in
Aspirin Oral ∼10 15 min 80–100 mg
once a day
* Treatment with low molecular weight heparin is recommended for patients with active cancer
and pregnant women.
† Dabigatran is contraindicated in patients with a creatinine clearance below 30 mL/min.

‡ Apixaban, edoxaban, and rivaroxaban are contraindicated in patients with a creatinine clearance
below 15 mL/min.
§ The recommended edoxaban dose is 30 mg once a day for patients with a creatinine clearance
of 30–50 mL/min, a bodyweight less than or equal to 60 kg, or for those on certain strong P-
glycoprotein inhibitors.
Medication dosing may vary with regard to primary diagnosis, age, comorbidities, and other
436.2
Pulmonary Hemorrhage and
Hemoptysis
Mary A. Nevin

Pulmonary hemorrhage is relatively uncommon but a potentially fatal

occurrence in children. The patient with suspected hemoptysis may present
acutely or subacutely and to a variety of different practitioners with distinct areas
of specialty. Diffuse, slow bleeding in the lower airways may become severe and
manifest as anemia, fatigue, or respiratory compromise without the patient ever
experiencing episodes of hemoptysis. Hemoptysis must also be separated from
episodes of hematemesis or epistaxis, each of which may have indistinguishable
presentations in the young patient.

Etiology
Table 436.4 and Table 435.1 (in Chapter 435 ) present conditions that can
manifest as pulmonary hemorrhage or hemoptysis in children. The chronic
(opposed to an acute) presence of a foreign body can lead to inflammation
and/or infection, thereby inducing hemorrhage. Bleeding is more likely to occur
in association with a chronically retained foreign body of vegetable origin.

Table 436.4
Etiology of Pulmonary Hemorrhage (Hemoptysis)
FOCAL HEMORRHAGE
Bronchitis and bronchiectasis (especially cystic fibrosis–related)
Infection (acute or chronic), pneumonia, abscess
Tuberculosis
Trauma
Pulmonary arteriovenous malformation (with or without hereditary hemorrhagic telangiectasia)
Foreign body (chronic)
 Neoplasm including hemangioma
Pulmonary embolus with or without infarction
Bronchogenic cysts
DIFFUSE HEMORRHAGE
Idiopathic of infancy
Congenital heart disease (including pulmonary hypertension, venoocclusive disease, congestive heart failure)
Prematurity
Cow's milk hyperreactivity (Heiner syndrome)
Goodpasture syndrome
Collagen vascular diseases (systemic lupus erythematosus, rheumatoid arthritis)
Henoch-Schönlein purpura and vasculitic disorders
Granulomatous disease (granulomatosis with polyangiitis)
Celiac disease
Coagulopathy (congenital or acquired)
Malignancy
Immunodeficiency
Exogenous toxins, especially inhaled
Hyperammonemia
Pulmonary hypertension
Pulmonary alveolar proteinosis
Idiopathic pulmonary hemosiderosis
Tuberous sclerosis
Lymphangiomyomatosis or lymphangioleiomyomatosis
Physical injury or abuse
Catamenial
See also Table 435.1 .

Hemorrhage most commonly reflects chronic inflammation and infection such

as that seen with bronchiectasis due to cystic fibrosis or with cavitary disease in
association with infectious tuberculosis. Hemoptysis may occasionally reflect an
acute and intense infectious condition such as bronchitis or bronchopneumonia.
Other relatively common etiologies are congenital heart disease and trauma.
Pulmonary hypertension secondary to cardiac disease is a prominent etiology for
hemoptysis in those patients without cystic fibrosis. Traumatic irritation or
damage in the airway may be accidental in nature. Traumatic injury to the airway
and pulmonary contusion may result from motor vehicle crashes or other direct
force injuries. Bleeding can also be related to instrumentation or iatrogenic
irritation of the airway as is commonly seen in a child with a tracheostomy or a
child with repeated suction trauma to the upper airway. Children who have been
victims of nonaccidental trauma or deliberate suffocation can also be found to
have blood in the mouth or airway (see Chapter 16 ). Factitious hemoptysis may
rarely be encountered in the setting of Factitious Disorder by Proxy (formerly
Munchausen's by proxy; see Chapter 16.2 ).
Rare causes for hemoptysis include tumors and vascular anomalies such as
arteriovenous malformations (Fig. 436.2 ). Congenital vascular malformations in
CHAPTER 437

Atelectasis
Ranna A. Rozenfeld

Atelectasis is the incomplete expansion or complete collapse of air-bearing

tissue, resulting from obstruction of air intake into the alveolar sacs. Segmental,
lobar, or whole lung collapse is associated with the absorption of air contained in
the alveoli, which are no longer ventilated.

Pathophysiology
The causes of atelectasis can be divided into 5 groups (Table 437.1 ). Respiratory
syncytial virus (see Chapter 287 ) and other viral infections, including influenza
viruses in young children can cause multiple areas of atelectasis. Mucous plugs
are a common predisposing factor to atelectasis. Massive collapse of one or both
lungs is most often a postoperative complication but occasionally results from
other causes, such as trauma, asthma, pneumonia, tension pneumothorax (see
Chapter 439 ), aspiration of foreign material (see Chapters 414 and 425 ),
paralysis, or after extubation. Massive atelectasis is usually produced by a
combination of factors, including immobilization or decreased use of the
diaphragm and the respiratory muscles, obstruction of the bronchial tree, and
abolition of the cough reflex.

Table 437.1

Anatomic Causes of Atelectasis

CAUSE CLINICAL EXAMPLES
External compression on the Pleural effusion, pneumothorax, intrathoracic tumors, diaphragmatic hernia
pulmonary parenchyma
Endobronchial obstruction Enlarged lymph node, tumor, cardiac enlargement, foreign body, mucoid plug,
completely obstructing the broncholithiasis
 ingress of air
Intraluminal obstruction of a Foreign body, asthma, granulomatous tissue, tumor, secretions including mucous
bronchus plugs, bronchiectasis, pulmonary abscess, chronic bronchitis, acute
laryngotracheobronchitis, plastic bronchitis
Intrabronchiolar obstruction Bronchiolitis, interstitial pneumonitis, asthma
Respiratory compromise or Neuromuscular abnormalities, osseous deformities, overly restrictive casts and
paralysis surgical dressings, defective movement of the diaphragm, or restriction of
respiratory effort

Clinical Manifestations
Symptoms vary with the cause and extent of the atelectasis. A small area is
likely to be asymptomatic. When a large area of previously normal lung becomes
atelectatic, especially when it does so suddenly, dyspnea accompanied by rapid
shallow respirations, tachycardia, cough, and often cyanosis occurs. If the
obstruction is removed, the symptoms disappear rapidly. Although it was once
believed that atelectasis alone can cause fever, studies have shown no association
between atelectasis and fever. Physical findings include limitation of chest
excursion, decreased breath sound intensity, and coarse crackles. Breath sounds
are decreased or absent over extensive atelectatic areas.
Massive pulmonary atelectasis usually presents with dyspnea, cyanosis, and
tachycardia. An affected child is extremely anxious and, if old enough,
complains of chest pain. The chest appears flat on the affected side, where
decreased respiratory excursion, dullness to percussion, and feeble or absent
breath sounds are also noted. Postoperative atelectasis usually manifests within
24 hr of operation but may not occur for several days.
Acute lobar collapse is a frequent occurrence in patients receiving intensive
care. If undetected, it can lead to impaired gas exchange, secondary infection,
and subsequent pulmonary fibrosis. Initially, hypoxemia may result from
ventilation-perfusion mismatch. In contrast to atelectasis in adult patients, in
whom the lower lobes and, in particular, the left lower lobe are most often
involved, 90% of cases in children involve the upper lobes and 63% involve the
right upper lobe. There is also a high incidence of upper lobe atelectasis and,
especially, right upper lobe collapse in patients with atelectasis being treated in
neonatal intensive care units. This high incidence may be a result of movement
of the endotracheal tube into the right mainstem bronchus, where it obstructs or
causes inflammation of the bronchus to the right upper lobe.
 bronchoscopic removal of a mucous plug from the right mainstem
bronchus.

Treatment
Treatment depends on the cause of the collapse (Table 437.2 ). If effusion or
pneumothorax is responsible, the external compression must first be removed.
Often vigorous efforts at cough, deep breathing, and percussion will facilitate
expansion. Aspiration with sterile tracheal catheters may facilitate removal of
mucous plugs. Continuous positive airway pressure may improve atelectasis.

Table 437.2

Treatment for Atelectasis

CAUSE OF ATELECTASIS TREATMENT
Pleural effusion or pneumothorax Relieve compression
Mucus plug Tracheal or bronchoscopic aspiration
Continuous positive airway pressure
Foreign body Bronchoscopic examination
Asthma Bronchodilator and corticosteroid treatment
Recombinant human deoxyribonuclease (off label use)
Hypertonic saline with or without bronchodilator
Neuromuscular diseases Intermittent positive pressure breathing
Mechanical insufflator–exsufflator
Noninvasive bi-level positive pressure ventilation
Cystic fibrosis Airway clearance therapies
Hypertonic saline with or without bronchodilator

Bronchoscopic examination is immediately indicated if atelectasis is the result

of a foreign body or any other bronchial obstruction that can be relieved. For
bilateral atelectasis, bronchoscopic aspiration should also be performed
immediately. It is also indicated when an isolated area of atelectasis persists for
several weeks. If no anatomic basis for atelectasis is found and no material can
be obtained by suctioning, the introduction of a small amount of saline followed
by suctioning allows recovery of bronchial secretions for culture and, possibly,
for cytologic examination. Frequent changes in the child's position, deep
breathing, and chest physiotherapy may be beneficial. Intrapulmonary percussive
ventilation is a chest physiotherapy technique that is safe and effective. Oxygen
therapy is indicated when there is dyspnea or desaturation. Intermittent positive-
pressure breathing and incentive spirometry are recommended when atelectasis
CHAPTER 439

Pneumothorax
Glenna B. Winnie, Suraiya K. Haider, Aarthi P. Vemana, Steven V. Lossef

Pneumothorax is the accumulation of extrapulmonary air within the chest, most

commonly from leakage of air from within the lung. Air leaks can be primary or
secondary and can be spontaneous, traumatic, iatrogenic, or catamenial (Table
439.1 ). Pneumothorax in the neonatal period is also discussed in Chapter 122.1 .

Table 439.1
Causes of Pneumothorax in Children
SPONTANEOUS
Primary Idiopathic (no underlying lung disease)
Spontaneous rupture of subpleural blebs
Secondary (underlying lung disease)
Congenital lung disease
• Congenital cystic adenomatoid malformation
• Bronchogenic cysts
• Pulmonary hypoplasia
• Birt-Hogg-Dube syndrome
Conditions associated with increased intrathoracic pressure
• Asthma
• Bronchiolitis
• Cystic fibrosis
• Airway foreign body
• Smoking (cigarettes, marijuana, crack cocaine)
Infection
• Tuberculosis
• Pneumocystis carinii (jirovecii)
• Echinococcosis
• Pneumatocele
• Lung abscess
• Bronchopleural fistula
Lung disease
• Langerhans cell histiocytosis
• Tuberous sclerosis
• Marfan syndrome
• Ehlers-Danlos syndrome
 • Pulmonary fibrosis
• Sarcoidosis
• Rheumatoid arthritis, scleroderma, ankylosing spondylitis
• Metastatic neoplasm—usually osteosarcoma (rare)
• Pulmonary blastoma
TRAUMATIC
Non-iatrogenic
• Penetrating trauma
• Blunt trauma
Iatrogenic
• Thoracotomy
• Thoracoscopy, thoracentesis
• Tracheostomy
• Tube or needle puncture
• Mechanical ventilation
• High-flow therapy (moved from non-iatrogenic)
Adapted from Noppen M. Spontaneous pneumothorax:epidemiology, pathophysiology and cause.
Eur Respir Rev 19:117, 217–219, 2010 (Table 1, 2, p 218).

Etiology and Epidemiology

A primary spontaneous pneumothorax occurs without trauma or underlying
lung disease. Spontaneous pneumothorax with or without exertion occurs
occasionally in teenagers and young adults, most frequently in males who are
tall, thin, and thought to have subpleural blebs. Smoking and asthma are also risk
factors for developing pneumothorax. Familial cases of spontaneous
pneumothorax occur and have been associated with mutations in the folliculin
gene (FCLN) . Over 150 unique FCLN mutations have been associated in the
Birt-Hogg-Dube syndrome (skin fibrofolliculomas, multiple basal lung cysts,
renal malignancies) or in patients with familial or recurrent spontaneous
pneumothoraces. Individuals with other inherited disorders such as α1 -
antitrypsin (see Chapter 421 ) and homocystinuria are also predisposed to
pneumothorax. Patients with collagen synthesis defects such as Ehlers-Danlos
disease (see Chapter 678 ) and Marfan syndrome (see Chapter 722 ) are at
increased risk for the development of pneumothorax.
A pneumothorax arising as a complication of an underlying lung disorder but
without trauma is a secondary spontaneous pneumothorax. Pneumothorax can
occur in pneumonia, usually with empyema; it can also be secondary to
pulmonary abscess, gangrene, infarct, rupture of a cyst or an emphysematous
bleb (in asthma), or foreign bodies in the lung. In infants with staphylococcal
pneumonia, the incidence of pneumothorax is relatively high. It can be found in
CHAPTER 444

Bronchopulmonary Dysplasia
Sharon A. McGrath-Morrow, J. Michael Collaco

Bronchopulmonary Dysplasia
Bronchopulmonary dysplasia (BPD) is a chronic lung disease of infancy and
childhood that occurs primarily in preterm infants born at less than 32 wk
gestation. BPD is characterized by alveolar hypoplasia, often with concomitant
small airway dysfunction and impaired pulmonary vascular growth. Contributing
factors to the development of BPD may include early gestational age, low birth
weight, lung barotrauma, exposure to hyperoxia, lung inflammation, and pre-
and postnatal infections, as well as potential modifier genes and epigenetic
factors. The currently accepted definition includes an oxygen requirement for 28
days postnatally, and the disorder is graded as mild, moderate, or severe on the
basis of supplemental oxygen and ventilation requirements at specific timepoints
(Table 444.1 ). For initial inpatient presentation and management, see Chapter
122 .

Table 444.1
Definitions of Bronchopulmonary Dysplasia

ADDITIONAL ADDITIONAL
FEATURES ADDITIONAL FEATURES OF
FEATURES OF MILD FEATURES OF
OF ALL BPD SEVERE BPD
BPD MODERATE BPD
<32 wk Breathing room air at 36 <30% supplemental oxygen >30% supplemental oxygen and/or
gestational wk PMA or at at 36 wk PMA or at positive pressure ventilation at 36 wk
age at birthdischarge, whichever discharge, whichever PMA or at discharge, whichever comes
Oxygen comes first comes first first
requirement
for at least
28 days
>32 wk Breathing room air at 56 <30% supplemental oxygen >30% supplemental oxygen and/or
 gestational days of life or at at 56 days of life or at positive pressure ventilation at 56 days
age at birth discharge, whichever discharge, whichever of life or at discharge, whichever comes
Oxygen comes first comes first first
requirement
for at least
28 days
BPD , bronchopulmonary dysplasia; PMA , postmenstrual age.

Clinical Manifestations
Physical findings of the pulmonary exam vary with the severity of disease and
with respiratory illnesses. Although some patients may appear to be comfortably
breathing when well, they can experience significant deterioration when ill or
with periods of stress due to decreased pulmonary reserve secondary to alveolar
hypoplasia and small airway disease. Children with BPD may exhibit tachypnea,
head bobbing, and retractions when ill or at baseline depending on the severity
of disease. Although breath sounds may be clear, many patients have baseline
wheeze or coarse crackles. A persistent fixed wheeze or stridor suggests
subglottic stenosis (see Chapter 415 ) or large airway malacia. Fine crackles may
be present in patients prone to fluid overload. Chest radiographs may
demonstrate air trapping, focal atelectasis, interstitial changes, and/or
peribronchial thickening.
The most severely affected patients may require respiratory support to achieve
adequate gas exchange. Supplemental oxygen may be required to maintain
acceptable oxygen saturations and often is needed to minimize the work of
breathing. Chronic respiratory insufficiency may be evidenced as elevation of
serum bicarbonate, elevated carbon dioxide on blood gas analysis, hypoxemia,
or polycythemia; the most severe cases may require tracheostomy and
ventilation to achieve long-term respiratory stability. Patients must be monitored
for the development of pulmonary hypertension, especially if they require
supplemental oxygen and have chronic respiratory insufficiency.
Aspiration from dysphagia and/or gastroesophageal reflux (GERD) (see
Chapter 349 ) can compromise pulmonary status. The risk of aspiration may
increase during periods of illness due to worsening tachypnea and air trapping.
Other comorbidities resulting from premature birth that complicate the
management of BPD include fixed and functional upper airway obstruction,
CNS injuries leading to abnormal control of breathing, abnormal airway tone,
increased aspiration risk, gastrointestinal dysmotility, systemic hypertension, and
noninvasive long-term ventilation. The conditions leading to the need for home
ventilation are diverse. Most literature focuses on single-center experience, but
broad themes emerge. About two-thirds of children have a primary neurologic
indication, including neuromuscular weakness or abnormal ventilatory control,
and about one-third have chronic lung disease (Table 446.1 ).

Table 446.1
Indications for Long-Term Mechanical Ventilation
PULMONARY/ALVEOLAR
BRONCHOPULMONARY DYSPLASIA (BPD)
PARDS (Severe acquired lung disease, such as after pediatric acute respiratory distress syndrome)
Pulmonary fibrosis syndromes
AIRWAY
Severe tracheomalacia
Severe bronchomalacia
Obstructive sleep apnea
Storage diseases
CHEST (SEE CHAPTER 445 )
Kyphoscoliosis
Skeletal dysplasias
Obesity
NEUROMUSCULAR
Spinal muscular atrophy
Spinal cord injury
Diaphragmatic dysfunction
Mitochondrial diseases
CNS
Congenital central hypoventilation syndrome (CCHS)
Rapid-onset obesity with hypothalamic dysregulation, hypoventilation, and autonomic dysfunction (ROHHAD)
Severe ischemic brain injury
Myelomeningocele with Arnold-Chiari type II malformation
Acquired hypoventilation syndromes

Patients with primarily pulmonary indications have a greater likelihood of

ultimately being weaned from the need for ventilation than do those with
neuromuscular or central nervous system disease. Mortality for patients
requiring chronic ventilation is reported to be approximately 12–34% depending
on underlying disease. The lower mortality range is for children with neonatal
lung disease, with the higher value for children with congenital heart disease. An
overall mortality rate of 20% is common. Approximately 12–40% of children are
eventually weaned from ventilation and decannulated, again reflecting the
underlying cause for which ventilation is required. This can usually be
accomplished within the first 5 yr of life. Nonetheless, the care of these children
can be challenging. One study reported that up to 40% of chronically ventilated
Debra E. Weese-Mayer, Casey M. Rand, Amy Zhou, Michael S. Carroll

Keywords
congenital central hypoventilation syndrome
Hirschsprung disease
neuroblastoma neural crest tumors
ganglioneuroblastoma
ganglioneuroma
diaphragm pacing
autonomic dysregulation
control of breathing

CCHS is a clinically complex neurocristopathy that includes a variable severity

of respiratory and autonomic dysregulation, as well as Hirschsprung disease and
neural crest tumors in a subset of patients. In the classic CCHS presentation,
symptoms of alveolar hypoventilation manifest in the newborn period and during
sleep only—with diminished tidal volume and a typically monotonous
respiratory rate leading to cyanosis and hypercarbia. In more severe cases of
CCHS, the hypoventilation manifests during wakefulness and sleep. In the later-
onset cases of CCHS (LO-CCHS), symptoms appear after 1 mo of age and older
(often into childhood and adulthood). Hypoventilation is typically during sleep
only and usually milder in later-onset cases than in patients who present in the
neonatal period. CCHS and LO-CCHS are further characterized by partial to
complete peripheral and central chemoreceptor failure to properly respond to
hypercarbia and hypoxemia during wakefulness and sleep, coupled with
physiologic and/or anatomic autonomic nervous system (ANS) dysregulation
(ANSD). Physiologic dysregulation may include all organ systems affected by
the ANS, specifically the respiratory, cardiac, sudomotor, vasomotor,
ophthalmologic, neurologic, and enteric systems (Table 446.2 ). The anatomic or
structural ANSD includes Hirschsprung disease and tumors of neural crest origin
(neuroblastoma, ganglioneuroma, or ganglioneuroblastoma).

Table 446.2
Congenital Central Hypoventilation Syndrome-Related
Symptoms
THE SYMPTOMS EMERGE FROM DIFFERENT ORGAN SYSTEMS AND COULD BE
OVERLOOKED BY THE CLINICIANS
Respiratory symptoms Nocturnal hypoventilation and possible daytime hypoventilation
Ability to hold breath for a long period of time and absence of air hunger
afterwards
Cardiovascular Arrhythmias
symptoms Reduced heart rate variability
Vasovagal syncope
Syncope
Cold extremities
Postural hypotension
Neurologic symptoms Developmental delay
Seizures (primarily during infancy)
Motor and speech delay
Learning disabilities
Altered perception of pain
Gastrointestinal Hirschsprung disease-related symptoms: dysphagia, constipation, and gastroesophageal
symptoms reflux
Ophthalmologic Nonreactive/sluggish pupils
symptoms Altered lacrimation and near response
Anisocoria, miosis, and ptosis
Strabismus
Temperature instability Altered perspiring
Absence of fever with infections
Malignancies Tumors of neural crest origin
Psychological Decreased anxiety
From Lijubić K, Fister I Jr, Fister I: Congenital central hypoventilation syndrome: a comprehensive
review and future challenges, J Respir Med 856149:1–8, 2014 (Table 1, p. 3).

Genetics
The paired-like homeobox 2B (PHOX2B) gene is the disease-defining gene for
CCHS. PHOX2B encodes a highly conserved homeodomain transcription factor,
is essential to the embryologic development of the ANS from the neural crest,
and is expressed in key regions and systems that explain much of the CCHS
phenotype. Individuals with CCHS are heterozygous for either a polyalanine
repeat expansion mutation (PARM) in exon 3 of the PHOX2B gene (normal
number of alanines is 20 with normal genotype 20/20), such that individuals
with CCHS have 24-33 alanines on the affected allele (genotype range is 20/24-
20/33), or a non-polyalanine repeat expansion mutation (NPARM) resulting from
a missense, nonsense, frameshift, stop codon, or splice site mutation.
hypercarbia without respiratory distress during sleep will quickly lead the
clinician to consider the diagnosis of CCHS or LO-CCHS.

Table 446.3
Differential Diagnoses of Congenital Central
Hypoventilation Syndrome
METABOLIC
Mitochondrial defects, e.g., Leigh disease
Pyruvate dehydrogenase deficiency
Hypothyroidism
NEUROLOGIC
Structural central nervous system abnormalities, e.g., Arnold Chiari malformation, Moebius syndrome
Vascular injury, e.g., central nervous system (CNS) hemorrhage, infarct
Trauma
Tumor
PULMONARY
Primary lung disease
Respiratory muscle weakness, e.g., diaphragm paralysis, congenital myopathy
GENETIC
Prader Willi syndrome
Familial dysautonomia
SEDATIVE DRUGS
OTHER
Rapid-onset obesity, hypothalamic dysregulation hypoventilation, autonomic dysregulation (ROHHAD)
Modified from Healy F, Marcus CL: Congenital central hypoventilation syndrome in children,
Pediatr Respir Rev 12:253–263, 2011 (Table 1, p. 258).

Management
Supported Ventilation—Diaphragm Pacing
Depending on the severity of the hypoventilation, the individual with CCHS can
have various options for artificial ventilation: positive pressure ventilation
(noninvasive via mask or via tracheostomy) or negative pressure ventilation
(pneumosuit, chest cuirass, or diaphragm pacing). Chronic mechanical
ventilation is addressed in Chapters 446.1 and 446.4 . Diaphragm pacing offers
another mode of supported ventilation, involving bilateral surgical implantation
of electrodes beneath the phrenic nerves, with connecting wires to
subcutaneously implanted receivers. The external transmitter, which is much
smaller and lighter in weight than a ventilator, sends a signal to flat donut-shaped
antennae that are placed on the skin over the subcutaneously implanted
 Takotsubo cardiomyopathy (primary or secondary)

Idiopathic (Common)

Anxiety, hyperventilation
Panic disorder

Other (Less Common)

Spinal cord or nerve root compression

Breast-related pathologic condition (mastalgia)
Castleman disease (lymph node neoplasm)

Cardiac disease may be a manifestation of a known congenital malformation

syndrome with typical physical findings (Table 449.2 ) or a manifestation of a
generalized disorder affecting the heart and other organ systems (Table 449.3 ).
Extracardiac malformations may be noted in 20–45% of infants with CHD.
Between 5% and 10% of patients have a known chromosomal abnormality; the
importance of genetic evaluation will increase as our knowledge of specific gene
defects linked to CHD increases (Fig. 449.1 ).

Table 449.2
Congenital Malformation Syndromes Associated With
Congenital Heart Disease

SYNDROME FEATURES
CHROMOSOMAL DISORDERS
Trisomy 21 (Down syndrome) Endocardial cushion defect, VSD, ASD
Trisomy 21p (cat-eye syndrome) Miscellaneous, total anomalous pulmonary venous return
Trisomy 18 VSD, ASD, PDA, TOF, coarctation of aorta, bicuspid aortic or
pulmonary valve
Trisomy 13 VSD, ASD, PDA, coarctation of aorta, bicuspid aortic or
pulmonary valve
Trisomy 9 Miscellaneous, VSD
XXXXY PDA, ASD
Penta X PDA, VSD
Triploidy VSD, ASD, PDA
XO (Turner syndrome) Bicuspid aortic valve, coarctation of aorta
Fragile X Mitral valve prolapse, aortic root dilatation
Duplication 3q2 Miscellaneous
Deletion 4p VSD, PDA, aortic stenosis
Deletion 9p Miscellaneous
Deletion 5p (cri du chat syndrome) VSD, PDA, ASD, TOF
Deletion 10q VSD, TOF, conotruncal lesions*
Deletion 13q VSD
Deletion 18q VSD
Deletion 1p36 ASD, VSD, PDA, TOF, cardiomyopathy
Deletion/duplication 1q21.1 ASD, VSD, PS
Deletion 17q11 (William syndrome) Supravalvar AS, branch PS
Deletion 11q 24-25 (Jacobsen syndrome) VSD, left sided lesions
SYNDROME COMPLEXES
CHARGE association (c oloboma, h eart, a VSD, ASD, PDA, TOF, endocardial cushion defect
tresia choanae, r etardation, g enital, and e ar
anomalies)
DiGeorge sequence, CATCH 22 (c ardiac Aortic arch anomalies, conotruncal anomalies
defects, a bnormal facies, t hymic aplasia, c left
palate, h ypocalcemia, and deletion 22q11)
Alagille syndrome (arteriohepatic dysplasia) Peripheral pulmonic stenosis, PS, TOF
VATER association (v ertebral, a nal, t racheoe VSD, TOF, ASD, PDA
sophageal, r adial, and r enal anomalies)
FAVS (f acioa uriculov ertebral s pectrum) TOF, VSD
CHILD (c ongenital h emidysplasia with i Miscellaneous
chthyosiform erythroderma, l imb d efects)
Mulibrey nanism (muscle, liver, brain, eye) Pericardial thickening, constrictive pericarditis
Asplenia syndrome Complex cyanotic heart lesions with decreased pulmonary blood
flow, transposition of great arteries, anomalous pulmonary
venous return, dextrocardia, single ventricle, single
atrioventricular valve
Polysplenia syndrome Acyanotic lesions with increased pulmonary blood flow, azygos
continuation of inferior vena cava, partial anomalous pulmonary
venous return, dextrocardia, single ventricle, common
atrioventricular valve
PHACE syndrome (p osterior brain fossa VSD, PDA, coarctation of aorta, arterial aneurysms
anomalies, facial h emangiomas, a rterial
anomalies, c ardiac anomalies and aortic
coarctation, e ye anomalies)
TERATOGENIC AGENTS
Congenital rubella PDA, peripheral pulmonic stenosis
Fetal hydantoin syndrome VSD, ASD, coarctation of aorta, PDA
Fetal alcohol syndrome ASD, VSD
Fetal valproate effects Coarctation of aorta, hypoplastic left side of heart, aortic
stenosis, pulmonary atresia, VSD
Maternal phenylketonuria VSD, ASD, PDA, coarctation of aorta
Retinoic acid embryopathy Conotruncal anomalies
OTHERS
Apert syndrome VSD
Autosomal dominant polycystic kidney disease Mitral valve prolapse
Carpenter syndrome PDA
Conradi syndrome VSD, PDA
Crouzon disease PDA, coarctation of aorta
Cutis laxa Pulmonary hypertension, pulmonic stenosis
De Lange syndrome VSD
Ellis–van Creveld syndrome Single atrium, VSD
 Holt-Oram syndrome ASD, VSD, 1st-degree heart block
Infant of diabetic mother Hypertrophic cardiomyopathy, VSD, conotruncal anomalies
Kartagener syndrome Dextrocardia
Meckel-Gruber syndrome ASD, VSD
Noonan syndrome Pulmonic stenosis, ASD, cardiomyopathy
Pallister-Hall syndrome Endocardial cushion defect
Primary ciliary dyskinesia Heterotaxia disorders
Rubinstein-Taybi syndrome VSD
Scimitar syndrome Hypoplasia of right lung, anomalous pulmonary venous return to
inferior vena cava
Smith-Lemli-Opitz syndrome VSD, PDA
TAR syndrome (thrombocytopenia and absent ASD, TOF
radius)
Treacher Collins syndrome VSD, ASD, PDA
* Conotruncal includes TOF, pulmonary atresia, truncus arteriosus, and transposition of great

arteries.
ASD, Atrial septal defect; AV, aortic valve; PDA, patent ductus arteriosus; PS, pulmonary stenosis;
TOF, tetralogy of Fallot; VSD, ventricular septal defect.

Table 449.3
Cardiac Manifestations of Systemic Diseases

SYSTEMIC DISEASE CARDIAC COMPLICATIONS

INFLAMMATORY DISORDERS
Sepsis Hypotension, myocardial dysfunction, pericardial effusion, pulmonary
hypertension
Juvenile idiopathic arthritis Pericarditis, rarely myocarditis
Systemic lupus erythematosus Pericarditis, Libman-Sacks endocarditis, coronary arteritis, coronary
atherosclerosis (with steroids), congenital heart block
Scleroderma Pulmonary hypertension, myocardial fibrosis, cardiomyopathy
Dermatomyositis Cardiomyopathy, arrhythmias, heart block
Kawasaki disease Coronary artery aneurysm and thrombosis, myocardial infarction,
myocarditis, valvular insufficiency
Sarcoidosis Granuloma, fibrosis, amyloidosis, biventricular hypertrophy, arrhythmias
Lyme disease Arrhythmias, myocarditis
Löffler hypereosinophilic syndrome Endomyocardial disease
INBORN ERRORS OF METABOLISM
Refsum disease Arrhythmia, sudden death
Hunter or Hurler syndrome Valvular insufficiency, heart failure, hypertension
Fabry disease Mitral insufficiency, coronary artery disease with myocardial infarction
Glycogen storage disease IIa Short P-R interval, cardiomegaly, heart failure, arrhythmias
(Pompe disease)
Carnitine deficiency Heart failure, cardiomyopathy
Gaucher disease Pericarditis
Homocystinuria Coronary thrombosis
Alkaptonuria Atherosclerosis, valvular disease
Morquio-Ullrich syndrome Aortic incompetence
Scheie syndrome Aortic incompetence
 CONNECTIVE TISSUE DISORDERS
Arterial calcification of infancy Calcinosis of coronary arteries, aorta, heart failure, hypertension
Marfan syndrome Aortic and mitral insufficiency, dissecting aortic aneurysm, mitral valve
prolapse
Congenital contractural Mitral insufficiency or prolapse
arachnodactyly
Ehlers-Danlos syndrome Mitral valve prolapse, dilatated aortic root
Osteogenesis imperfecta Aortic incompetence
Pseudoxanthoma elasticum Peripheral arterial disease
NEUROMUSCULAR DISORDERS
Friedreich ataxia Cardiomyopathy
Duchenne dystrophy Cardiomyopathy, heart failure
Tuberous sclerosis Cardiac rhabdomyoma
Familial deafness Occasionally arrhythmia, sudden death
Neurofibromatosis Pulmonic stenosis, pheochromocytoma, coarctation of aorta
Riley-Day syndrome Episodic hypertension, postural hypotension
Von Hippel–Lindau disease Hemangiomas, pheochromocytomas
ENDOCRINE-METABOLIC DISORDERS
Graves' disease Tachycardia, arrhythmias, heart failure
Hypothyroidism Bradycardia, pericardial effusion, cardiomyopathy, low-voltage
electrocardiogram
Pheochromocytoma Hypertension, myocardial ischemia, myocardial fibrosis, cardiomyopathy
Carcinoid Right-sided endocardial fibrosis
HEMATOLOGIC DISORDERS
Sickle cell anemia High-output heart failure, cardiomyopathy, pulmonary hypertension
Thalassemia major High-output heart failure, hemochromatosis
Hemochromatosis (1st or 2nd Cardiomyopathy
degree)
OTHERS
Appetite suppressants (fenfluramine Cardiac valvulopathy, pulmonary hypertension
and dexfenfluramine)
Cockayne syndrome Atherosclerosis
Familial dwarfism and nevi Cardiomyopathy
Jervell and Lange-Nielsen Prolonged Q-T interval, sudden death
syndrome
Kearns-Sayre syndrome Heart block
LEOPARD syndrome (lentiginosis) Pulmonic stenosis, prolonged Q-T interval
Progeria Accelerated atherosclerosis
Osler-Weber-Rendu disease Arteriovenous fistula (lung, liver, mucous membrane)
Romano-Ward syndrome Prolonged Q-T interval, sudden death
Weill-Marchesani syndrome Patent ductus arteriosus
Werner syndrome Vascular sclerosis, cardiomyopathy
LEOPARD, Multiple l entigines, e lectrocardiographic conduction abnormalities, o cular
hypertelorism, p ulmonary stenosis, a bnormal genitals, r etardation of growth, sensorineural d
eafness.
 FIG. 449.1 Genetics screening algorithm for congenital heart disease
(CHD) patients. FISH, Fluorescence in situ hybridization; WES, whole
exome sequencing. (From Simmons MA, Brueckner M: The genetics of
congenital heart disease… understanding and improving long-term
outcomes in congenital heart disease: a review for the general cardiologist
and primary care physician, Curr Opin Pediatr 29:520–528, 2017, Fig 2, p
526.)

A careful family history may also reveal early (at age <50 yr) coronary artery
disease or stroke (suggestive of familial hypercholesterolemia or thrombophilia),
sudden death (suggestive of cardiomyopathy or familial arrhythmic disorder),
generalized muscle disease (suggestive of one of the muscular dystrophies,
dermatomyositis, or familial or metabolic cardiomyopathy), or first-degree
relatives with congenital heart disease.

General Physical Examination

In the evaluation of a child with a heart murmur, a general physical examination
is always performed, with specific attention directed toward the presence of
cyanosis, abnormalities in growth, chest wall abnormalities, and any evidence of
respiratory distress. Although the murmur may be the most prominent part of the
overall examination, any murmur must be placed in context of other physical
findings. Associated findings such as quality of the pulses, presence of a
ventricular heave or thrill , or splitting of the second heart sound provide
important clues to a specific cardiac diagnosis.
 Accurate measurement of height and weight and plotting on a standard growth
chart are important because both cardiac failure and chronic cyanosis can result
in failure to thrive . Growth failure is manifested predominantly by poor weight
gain; if length or head circumference is also affected, additional congenital
malformations or metabolic disorders should be suspected.
Mild cyanosis may be too subtle for early detection, and clubbing of the
fingers and toes is not usually manifested until late in the 1st year of life, even in
the presence of severe arterial oxygen desaturation. Cyanosis is best observed
over the nail beds, lips, tongue, and mucous membranes. Differential cyanosis ,
manifested as blue lower extremities and pink upper extremities (usually the
right arm), is seen with right-to-left shunting across a ductus arteriosus in the
presence of coarctation or an interrupted aortic arch. Circumoral cyanosis or
blueness around the forehead may be the result of prominent venous plexuses in
these areas, rather than decreased arterial oxygen saturation. The extremities of
infants often turn blue when the infant is unwrapped and cold (acrocyanosis),
and this condition can be distinguished from central cyanosis by examination of
the tongue and mucous membranes.
Heart failure in infants and children usually results in some degree of
hepatomegaly and occasionally splenomegaly. The sites of peripheral edema
are age dependent. In infants, edema is usually seen around the eyes and over the
flanks, especially on initially waking. Older children and teenagers manifest both
periorbital edema and pedal edema. An initial complaint in these older patients
may be that their clothes no longer fit.
The heart rate of newborn infants is rapid and subject to wide fluctuations
(Table 449.4 ). The average rate ranges from 120-140 beats/min and may
increase to 170+ beats/min during crying and activity or drop to 70-90 beats/min
during sleep. As the child grows older, the average pulse rate decreases and may
be as low as 40 beats/min at rest in athletic adolescents. Persistent tachycardia
(>200 beats/min in neonates, 150 beats/min in infants, or 120 beats/min in older
children), bradycardia, or an irregular heartbeat other than sinus arrhythmia
requires investigation to exclude pathologic arrhythmias (see Chapter 462 ).
Sinus arrhythmia can usually be distinguished by the rhythmic nature of the
heart rate variations, occurring in concert with the respiratory cycle, and with a P
wave before every QRS complex.

Table 449.4
Pulse Rates at Rest
 LOWER LIMITS OF NORMAL AVERAGE UPPER LIMITS OF NORMAL
AGE
(beats/min) (beats/min) (beats/min)
Newborn 70 125 190
1–11 mo 80 120 160
2 yr 80 110 130
4 yr 80 100 120
6 yr 75 100 115
8 yr 70 90 110
10 yr 70 90 110
GIRLS BOYS GIRLS BOYS GIRLS BOYS
12 yr 70 65 90 85 110 105
14 yr 65 60 85 80 105 100
16 yr 60 55 80 75 100 95
18 yr 55 50 75 70 95 90

Careful evaluation of the character of the pulses is an important early step in

the physical diagnosis of CHD. A wide pulse pressure with bounding pulses may
suggest an aortic runoff lesion such as patent ductus arteriosus (PDA), aortic
insufficiency, an arteriovenous communication, or increased cardiac output
secondary to anemia, anxiety, or conditions associated with increased
catecholamine or thyroid hormone secretion. The presence of diminished pulses
in all extremities is associated with pericardial tamponade, left ventricular
outflow obstruction, or cardiomyopathy. The radial and femoral pulses should
always be palpated simultaneously. Normally, the femoral pulse should be
appreciated immediately before the radial pulse. In infants with coarctation of
the aorta, the femoral pulses may be decreased. However, in older children with
coarctation of the aorta, blood flow to the descending aorta may channel through
collateral vessels and results in the femoral pulse being palpable but delayed
until after the radial pulse (radial-femoral delay).
Blood pressure (BP) should be measured in the legs as well as in the arms to
be certain that coarctation of the aorta is not overlooked. Palpation of the
femoral or dorsalis pedis pulse, or both, is not reliable alone to exclude
coarctation. In older children, a mercury sphygmomanometer with a cuff that
covers approximately two thirds of the upper part of the arm or leg may be used
for BP measurement. A cuff that is too small results in falsely high readings,
whereas a cuff that is too large records slightly decreased BP. Pediatric clinical
facilities should be equipped with 3, 5, 7, 12, and 18 cm cuffs to accommodate
the large spectrum of pediatric patient sizes. The first Korotkoff sounds indicate
systolic pressure. As cuff pressure is slowly decreased, the sounds usually
become muffled before they disappear. Diastolic pressure may be recorded when
the sounds become muffled (preferred) or when they disappear altogether; the
CHAPTER 451

Epidemiology and Genetic Basis of

Congenital Heart Disease
Daniel Bernstein

Prevalence
Congenital heart disease (CHD) occurs in approximately 0.8% of live births. The
incidence is higher in stillborns (3–4%), spontaneous abortuses (10–25%), and
premature infants (approximately 2% excluding patent ductus arteriosus [PDA]).
This overall incidence does not include mitral valve prolapse, PDA of preterm
infants, and bicuspid aortic valves (present in 1–2% of adults). Congenital
cardiac defects have a wide spectrum of severity in infants: approximately 2-3 in
1,000 newborn infants will be symptomatic with heart disease in the 1st yr of
life. The diagnosis is established by 1 wk of age in 40–50% of patients with
CHD and by 1 mo of age in 50–60%. With advances in both corrective and
palliative surgery, the number of children with CHD surviving to adulthood has
increased dramatically. Despite these advances, CHD remains the leading cause
of death in children with congenital malformations. Table 451.1 summarizes the
relative frequency of the most common congenital cardiac lesions.

Table 451.1

Relative Frequency of Major Congenital Heart Lesions*

LESION % OF ALL LESIONS
Ventricular septal defect 35-30
Atrial septal defect (secundum) 6-8
Patent ductus arteriosus 6-8
Coarctation of aorta 5-7
Tetralogy of Fallot 5-7
Pulmonary valve stenosis 5-7
Aortic valve stenosis 4-7
 D -Transposition of great arteries 3-5
Hypoplastic left ventricle 1-3
Hypoplastic right ventricle 1-3
Truncus arteriosus 1-2
Total anomalous pulmonary venous return 1-2
Tricuspid atresia 1-2
Single ventricle 1-2
Double-outlet right ventricle 1-2
Others 5-10
* Excluding patent ductus arteriosus in preterm neonates, bicuspid aortic valve, physiologic

peripheral pulmonic stenosis, and mitral valve prolapse.

Most congenital defects are well tolerated in the fetus because of the parallel
nature of the fetal circulation. Even the most severe cardiac defects, such as
hypoplastic left heart syndrome (HLHS) , can usually be well compensated
for by the fetal circulation. In HLHS the entire fetal cardiac output would be
ejected by the right ventricle via the ductus arteriosus into both the descending
and ascending aortae (the latter filling in a retrograde fashion), so that fetal organ
blood flow would be minimally perturbed. Because the placenta provides for gas
exchange and the normal fetal circulation has mixing between more highly and
more poorly oxygenated blood, fetal organ oxygen delivery is also not
dramatically affected. It is only after birth when the fetal pathways (ductus
arteriosus and foramen ovale) begin to close that the full hemodynamic impact
of an anatomic abnormality becomes apparent. One notable exception is the case
of severe regurgitant lesions, most frequently of the tricuspid valve. In these
lesions, such as Ebstein anomaly of the tricuspid valve or severe right
ventricular outflow obstruction (see Chapter 457.7 ), the parallel fetal circulation
cannot compensate for the volume load imposed on the right side of the heart. In
utero heart failure, often with fetal pleural and pericardial effusions, and
generalized ascites (nonimmune hydrops fetalis) may occur.
Although the most significant transitions in circulation occur in the immediate
perinatal period, the circulation continues to undergo changes after birth, and
these later changes may also have a hemodynamic impact on cardiac lesions and
their apparent incidence. As pulmonary vascular resistance (PVR) falls in the 1st
several wk of life, left-to-right shunting through intracardiac defects increases
and symptoms become more apparent. Thus, in patients with a ventricular
septal defect (VSD) , heart failure is often first noticed between 1 and 3 mo of
age (see Chapter 453.6 ). The severity of various defects can also change
dramatically with growth; some VSDs may become smaller and even close as
the child ages. Alternatively, stenosis of the aortic or pulmonary valve, which
syndrome or the Shprintzen (velocardiofacial) syndrome. The acronym
CATCH 22 has been used to summarize the major components of these
syndromes: cardiac defects, abnormal facies, thymic aplasia, cleft palate, and
hypocalcemia. The specific cardiac anomalies are conotruncal defects (tetralogy
of Fallot, truncus arteriosus, double-outlet right ventricle, subarterial VSD) and
branchial arch defects (coarctation of the aorta, interrupted aortic arch, right
aortic arch). Congenital airway anomalies such as tracheomalacia and
bronchomalacia are sometimes present. Although the risk of recurrence is
extremely low in the absence of a parental 22q11.2 deletion, it is 50% if 1 parent
carries the deletion. More than 90% of patients with the clinical features of
DiGeorge syndrome have a deletion at 22q11.2. A 2nd genetic locus on the short
arm of chromosome 10 (10p13p14) has also been identified, the deletion of
which shares some, but not all, phenotypic characteristics with the 22q11.2
deletion; patients with del(10p) have an increased incidence of sensorineural
hearing loss.
Other structural heart lesions associated with specific chromosomal
abnormalities include familial secundum atrial septal defect (ASD) associated
with heart block (the transcription factor Nkx2.5 on chromosome 5q35),
familial ASD without heart block (the transcription factor GATA4), Alagille
syndrome (Jagged1 on chromosome 20p12), and Williams syndrome (elastin
on chromosome 7q11). Of interest, patients with VSDs and atrioventricular
septal defects have been found to have multiple Nkx2.5 mutations in cells
isolated from diseased heart tissues, but not from normal heart tissues or from
circulating lymphocytes, indicating a potential role for somatic mutations
leading to mosaicism in the pathogenesis of congenital heart defects. Tables
451.2 and 451.3 are a compilation of known genetic causes of CHD.

Table 451.2
Genetics of Congenital Heart Disease: Defects Associated
With Syndromes

COMMON
CARDIOVASCULAR CHROMOSOMAL
GENE(S) IMPLICATED* CARDIAC
DISEASE LOCATION
DEFECTS
DiGeorge syndrome, 22q11.2, 11p13p14 TBX1 TOF, IAA, TA,
velocardiofacial syndrome VSD
Familial ASD with heart 5q35 NKX2.5 ASD, heart block
block
Familial ASD without 8p22-23 GATA4 ASD
heart block
Alagille syndrome (bile 20p12, 1p12 JAGGED1, NOTCH2 Peripheral
duct hypoplasia, right- pulmonary
sided cardiac lesions) hypoplasia, PS,
TOF
Holt-Oram syndrome 12q24 TBX5 ASD, VSD, PDA
(limb defects, ASD)
Trisomy 21 (Down 21q22 Not known AVSD
syndrome)
Isolated familial AV septal 1p31-p21, 3p25 CRELD1 AVSD
defect (without trisomy
21)
Familial TAPVR 4p13-q12 Not known TAPVR
Noonan syndrome (PS, 12q24, 12p1.21, 2p212, 3p25.2, PTPN11, KRAS, SOS1, SOS2, PS, ASD, VSD,
ASD, hypertrophic 7q34, 15q22.31, 11p15.5, 1p13.2, RAF1, BRAF, MEK1, HRAS, PDA,
cardiomyopathy) 10q25.2, 11q23.3,17q11.2 NRAS, SHOC2, CBL, NF1 cardiomyopathy
Ellis–van Creveld 4p16 EVC, EVC2 ASD, common
syndrome (polydactyly, atrium
ASD)
Char syndrome 6p12-21.1 TFAP2B PDA
(craniofacial, limb defects,
PDA)
Williams-Beuren 7q11.23 ELN (Elastin) Supravalvular
syndrome (supravalvular AS, peripheral
AS, branch PS, PS
hypercalcemia)
Marfan syndrome 15q21 Fibrillin Aortic aneurysm,
(connective tissue mitral valve
weakness, aortic root disease
dilation)
Familial laterality Xq24-2q7, 1q42, 9p13-21 ZIC3, DNAI1 Situs inversus,
abnormalities complex
congenital heart
disease
Turner syndrome X Not known Coarctation of
the aorta, aortic
stenosis
Trisomy 13 (Patau 13 Not known ASD, VSD,
syndrome) PDA, valve
abnormalities
Trisomy 18 (Edwards 18 Not known ASD, VSD,
syndrome) PDA, valve
abnormalities
Cri du chat syndrome 5p15.2 CTNND2 ASD, VSD,
PDA, TOF
Cat-eye syndrome 22q11 Not known TAPVR, TOF
Jacobsen 11q23 JAM3 HLHS
Costello 11p15.5 HRAS PS, hypertrophic
cardiomyopathy,
arrhythmias
CHARGE 8p12, 7q21.11 CHD7, SEMA3E ASD, VSD, TOF
Kabuki syndrome 12q13.12 MLL2 ASD, VSD,
TOF, coarctation,
TGA
 Carney syndrome 2p16 PRKAR1A Atrial and
ventricular
myxomas
*
In many cases, mutation of a single gene has been closely linked to a specific cardiovascular
disease, for example, by finding a high incidence of mutations or deletions of that gene in a large
group of patients. These findings are often confirmed by studies in mice in which deletion or
alteration of the gene induces a similar cardiac phenotype to the human disease. In others,
mutation of a gene may increase the risk of cardiovascular disease, but with decreased
penetrance, suggesting that modifier genes or environmental factors play a role. Finally, in some
cases, gene mutations have only been identified in a small number of pedigrees, and confirmation
awaits screening of larger numbers of patients.
AS, aortic stenosis; ASD, atrial septal defect; AV, atrioventricular; AVSD, atrioventricular septal
defect; HLHS, hypoplastic left heart syndrome; IAA, interrupted aortic arch; PDA, patent ductus
arteriosus; PS, pulmonic stenosis; TA, truncus arteriosus; TAPVR, total anomalous pulmonary
venous return; TGA, transposition of great arteries; TOF, tetralogy of Fallot; VSD, ventricular
septal defect.

Table 451.3
Genetics of Isolated Congenital Heart Disease
(Nonsyndromic)

GENE
PROTEIN ENCODED CARDIAC DEFECTS
IMPLICATED*
GENES ENCODING TRANSCRIPTION FACTORS
ANKRD1 Ankyrin repeat domain TAPVR
CITED2 cAMP responsive element-binding ASD, VSD
protein
FOG2/ZFPM2 Friend of GATA TOF
GATA6 GATA6 transcription factor ASD, VSD, TOF, PS, AVSD, PDA
HAND2 Helix-loop-helix transcription factor TOF
IRX4 Iroquois homeobox 4 VSD
MED13L Mediator complex subunit 13-like TGA
NKX2-5/NKX2.5 Homeobox containing transcription factor ASD, VSD, TOF, HLHS, CoA, TGA, IAA
TBX20 T-Box 20 transcription factor ASD, VSD, mitral stenosis
ZIC3 Zinc finger transcription factor TGA, PS, TAPVR, HLHS, ASD, VSD
GENES ENCODING RECEPTORS AND SIGNALING MOLECULES
ACVR1/ALK2 BMP receptor AVSD
ACVR2B Activin receptor PS, DORV, TGA
ALDH1A2 Retinaldehyde dehydrogenase TOF
CFC1/CRYPTIC Cryptic protein TOF, TGA, AVSD, ASD, VSD, IAA,
DORV
CRELD1 Epidermal growth factor–related proteins ASD; AVSD
FOXH1 Forkhead activin signal transducer TOF, TGA
GDF1 Growth differentiation factor-1 TOF, TGA, DORV, heterotaxy
GJA1 Connexin 43 ASD, HLHS, TAPVR
LEFTY2 Left-right determination factor TGA, AVSD, IAA, CoA
 NODAL Nodal homolog (TGF-β superfamily) TGA, PA, TOF, DORV, TAPVR, AVSD
NOTCH1 NOTCH1 (Ligand of JAG1) Bicuspid aortic valve, AS, CoA, HLHS
PDGFRA Platelet-derived growth factor receptor α TAPVR
SMAD6 MAD-related protein Bicuspid aortic valve, CoA, AS
TAB2 TGF-β–activated kinase Outflow tract defects
TDGF1 Teratocarcinoma-derived growth factor 1 TOF, VSD
VEGF Vascular endothelial growth factor CoA, outflow tract defects
GENES ENCODING STRUCTURAL PROTEINS
ACTC α Cardiac actin ASD
MYH11 Myosin heavy chain 11 PDA, aortic aneurysm
MYH6 α-Myosin heavy chain ASD, TA, AS, TGA
MYH7 β-Myosin heavy chain Ebstein anomaly, ASD
* In many cases, mutation of a single gene has been closely linked to a specific cardiovascular

disease, for example, by finding a high incidence of mutations or deletions of that gene in a large
group of patients. These findings are often confirmed by studies in mice in which deletion or
alteration of the gene induces a similar cardiac phenotype to the human disease. In others,
mutation of a gene may increase the risk of cardiovascular disease, but with decreased
penetrance, suggesting that modifier genes or environmental factors play a role. Finally, in some
cases, gene mutations have only been identified in a small number of pedigrees, and confirmation
awaits screening of larger numbers of patients.
AS, Aortic stenosis; ASD, atrial septal defect; AVSD, atrioventricular septal defect; cAMP, cyclic
adenosine monophosphate; CoA, coarctation of the aorta; DORV, double-outlet right ventricle;
HLHS, hypoplastic left heart syndrome; IAA, interrupted aortic arch; PA, pulmonary artery; PDA,
patent ductus arteriosus; PS, pulmonic stenosis; TA, truncus arteriosus; TAPVR, total anomalous
pulmonary venous return; TGA, transposition of the great arteries; TGF, transforming growth
factor; TOF, tetralogy of Fallot; VSD, ventricular septal defect.
Partially adapted from Fahed AC, Gelb BD, Seidman JG, Seidman CE: Genetics of congenital
heart disease: the glass half empty. Circ Res 112:707–720, 2013.

The most progress in identifying the genetic origin of cardiovascular disease

has been made in the genetic cardiomyopathies , and in particular,
hypertrophic cardiomyopathy. Mutations in about a dozen genes have been
implicated, most of which encode protein components of the cardiac sarcomere,
either components of the thick filaments (myosin) or associated regulatory
subunits, although mutations in mitochondrial genes are increasingly recognized
and play a larger role in those presenting with hypertrophic cardiomyopathy as
young infants than in older children and adults. Mutations of the cardiac β-
myosin heavy-chain gene MYH7 (chromosome 14q1) and the myosin-binding
protein C gene (chromosome 11q11) are the most common (see Table 451.4 ),
with less common mutations including the cardiac troponin T and I genes, α-
tropomyosin, regulatory and essential myosin light chains, titin, and the α-
myosin heavy chain. Several hundred mutations have been identified in these
genes, and some patients (up to 15% in one study) may carry mutations in more
than one gene. Routine clinical laboratory tests are now available for most of
these mutations, however, not all mutations causing hypertrophic
cardiomyopathy have been identified, so a negative test does not eliminate a
genetic cause.

Table 451.4
Genetics of Cardiomyopathies

CHROMOSOMAL
CARDIOMYOPATHY GENE
LOCATION
Hypertrophic cardiomyopathy 14q1 β-Myosin heavy chain
15q2 α-Tropomyosin
1q31 Troponin T
19p13.2-19q13.2 Troponin I
11p13-q13 Myosin-binding protein C
12q23 Cardiac slow myosin regulatory light chain
13p21 Ventricular slow myosin essential light chain
2q31 Titin
3p25 Caveolin-3
Mitochondrial DNA tRNA-glycine
Mitochondrial DNA tRNA-isoleucine
Hypertrophic cardiomyopathy 7q36.1 AMP-activated protein kinase
with Wolff-Parkinson-White
syndrome
Other Genetic Diseases Causing Cardiac Hypertrophy
Familial amyloid disease 18q12.1 Transthyretin (TTR)
Noonan syndrome 12q24.1, 2p22.1, Protein tyrosine phosphatase 11 (PTPN11), son of
3p25, 12p12.1 sevenless homolog 1 (SOS1), RAF1 protooncogene,
GTPase KRAS
Fabry disease Xq22 α-Galactoside A (GLA)
Danon disease Xq24 Lysosomal-associated membrane protein 2 (LAMP2)
Hereditary hemochromatosis 6p21.3 Hereditary hemochromatosis protein (HFE)
Pompe disease 17q25 Acid α-glucosidase (GAA)
Dilated cardiomyopathy
X-linked Xp21 Dystrophin
Xp28 Tafazzin
Autosomal recessive 19p13.2-19q13.2 Troponin I
Autosomal dominant : Genes encoding multiple proteins have been identified, including cardiac
actin; desmin; δ-sarcoglycan; β-myosin heavy chain; cardiac troponin C and T; α-tropomyosin;
titin; metavinculin; myosin-binding protein C; muscle LIM protein; α-actinin-2; phospholamban;
Cypher/LIM binding domain 3; α-myosin heavy chain; SUR2A (regulatory subunit of KATP
channel); and lamin A/C.
Isolated noncompaction of the left ventricle : Autosomal dominant, autosomal recessive, X-
linked, and mitochondrial inheritance patterns have been reported. Genes that have been
implicated include those for α-dystrobrevin, Cypher/ZASP, lamin A/C, Tafazzin, MIB1, and LIM
domain-binding protein 3 (LDB3).
Partially adapted from Dunn KE, Caleshu C, Cirino AL, et al: A clinical approach to inherited
hypertrophy: the use of family history in diagnosis, risk assessment, and management, Circ
Cardiovasc Genet 6:118–131, 2013.

Progress has also been made in identifying the genetic basis of dilated
cardiomyopathy, which is familial in 20–50% of cases. Autosomal dominant
inheritance is most often encountered, and similar to hypertrophic
cardiomyopathy, multiple genes have been identified (see Table 451.2 ). X-
linked inheritance accounts for 5–10% of cases of familial dilated
cardiomyopathy. Mutations in the dystrophin gene (chromosome Xp21) are the
most common in this group, causing Duchene or Becker muscular dystrophy .
Mutations in the gene encoding tafazzin are associated with Barth syndrome
and some cases of isolated noncompaction of the left ventricle (LVNC).
Autosomal recessive inheritance is associated with a mutation in cardiac
troponin I. Mitochondrial myopathies may be caused by mutations of enzymes
of the electron transport chain encoded by nuclear DNA (in which inheritance
will follow mendelian genetic patterns) or enzymes of fatty acid oxidation
encoded by mitochondrial DNA (which is inherited solely from the mother).
Table 451.4 is a compilation of the most common genetic causes of
cardiomyopathy.
The genetic basis of heritable arrhythmias , most notably the long QT
syndromes , has been linked to mutations of genes coding for subunits of
cardiac potassium and sodium channels (see Table 451.2 ). Other heritable
arrhythmias include arrhythmogenic right ventricular dysplasia , familial
atrial fibrillation, familial complete heart block, and Brugada syndrome . Table
451.5 is a compilation of the most common genetic causes of arrhythmias.

Table 451.5
Genetics of Arrhythmias

CHROMOSOMAL
ARRHYTHMIA GENE(S) IMPLICATED
LOCATION
Complete heart block 19q13 Not known
Long QT syndrome
LQT1 (autosomal dominant) 11p15.5 KVLQT1 (K+ channel)
LQT2 (autosomal dominant) 7q35 HERG (K+ channel)
LQT3 (autosomal dominant) 3p21 SCN5A (Na+ channel)
LQT4 (autosomal dominant) 4q25-27 Not known
LQT5 (autosomal dominant) 21q22-q22 KCNE1 (K+ channel)
LQT6 21q22.1 KCNE2 (K+ channel)
Jervell and Lange-Nielsen syndrome (autosomal recessive, 11p15.5 KVLQT1 (K+ channel)
congenital deafness)
 LQT8-13 Unknown Private mutations (rare)
Arrhythmogenic right ventricular dysplasia (ARVD): 11 genes are now associated with ARVD (ARVD1 through
ARVD11 ) usually with autosomal dominant inheritance, but with variable penetrance. These genes include TGF
β3 (transforming growth factor β), RYR2 (ryanodine receptor), LAMR1 (laminin receptor-1), PTPLA (protein
tyrosine phosphatase), DSP (desmoplakin), PKP2 (plakophilin-2), DSG2 (desmoglein), and DSC2 (desmocollin).
Familial atrial fibrillation (autosomal dominant) 10q22-q24, 6q14-16 Not known
11p15.5 KVLQT1 (K+ channel)
11p15.5 KCNQ1 (K+ channel)
21q22 KCNE2 (K+ channel)
17q23.1-q24.2 KCNJ2 (K+ channel)
7q35-q36 KCNH2 (K+ channel)
Brugada syndrome (right bundle branch block, ST segment 3p21-p24 SCN5A (Na+ channel)
elevation, unexpected sudden death) 3p22-p24 GPD-1L (glycerol-3-
phosphate dehydrogenase)
Catecholaminergic polymorphic ventricular tachycardia — RYR2 (autosomal dominant)
— CASQ2 (autosomal recessive)

Of all cases of congenital heart disease, 2–4% are associated with known
environmental or adverse maternal conditions and teratogenic influences,
including maternal diabetes mellitus, maternal phenylketonuria, or systemic
lupus erythematosus; congenital rubella syndrome; and maternal ingestion of
drugs (lithium, ethanol, warfarin, thalidomide, antimetabolites, vitamin A
derivatives, anticonvulsant agents) (see Table 449.2 ). Associated noncardiac
malformations noted in identifiable syndromes may be seen in as many as 25%
of patients with CHD.
Gender differences in the occurrence of specific cardiac lesions have been
identified. Transposition of the great arteries and left-sided obstructive lesions
are slightly more common in boys (65%), whereas ASD, VSD, PDA, and
pulmonic stenosis are more common in girls. No racial differences in the
occurrence of congenital heart lesions as a whole have been noted; for specific
lesions such as transposition of the great arteries, a higher occurrence is seen in
white infants.

Next-Generation Genome Sequencing

and Congenital Heart Disease
The US National Institutes of Health (NIH) launched the Pediatric Cardiac
Genomics Consortium (PCGC) in 2009 with the aim of performing genome
sequencing on 10,000 children with CHD and both parents (known as a trio ), to
identify de novo gene variants associated with congenital heart defects. In one
study, in >300 trios, de novo mutations in several hundred genes were found to
Table 455.1
Causes and Mechanisms of Mitral Regurgitation

ORGANIC FUNCTIONAL
Type I* /TYPE
Type I* Type II † Type IIIa ‡
IIIb ‡
Nonischemic Endocarditis Degenerative Rheumatic (chronic RF); Cardiomyopathy;
(perforation); (billowing/flail leaflets); iatrogenic (radiation/drug); myocarditis; left-
degenerative endocarditis (ruptured inflammatory ventricular
(annular chordae); traumatic (lupus/anticardiolipin), dysfunction (any
calcification); (ruptured chord/PM); eosinophilic (endocardial cause)
congenital (cleft rheumatic (acute RF) disease, endomyocardial
leaflet) fibrosis)
Ischemic — Ruptured PM — Functional
ischemic
* Mechanism involves normal leaflet movement.

†
Mechanism involves excessive valve movement.
‡ Restricted valve movement, IIIa in diastole, IIIb in systole.

PM, Papillary muscle; RF, rheumatic fever.

Adapted from Sarano ME, Akins CW, Vahanian A: Mitral regurgitation, Lancet 373:1382–1394,
2009, Table 1.

In isolated mitral insufficiency, the mitral valve annulus is usually dilated, the
chordae tendineae are short and may insert anomalously, and the valve leaflets
are deformed. When mitral insufficiency is severe enough to cause clinical
symptoms, the left atrium enlarges as a result of the regurgitant flow, and the left
ventricle becomes hypertrophied and dilated. Pulmonary venous pressure is
increased, and the increased pressure ultimately results in pulmonary
hypertension and RV hypertrophy and dilation. Mild lesions produce no
symptoms; the only abnormal sign is the apical holosystolic murmur of mitral
regurgitation. Severe regurgitation results in symptoms that can appear at any
age, including poor physical development, frequent respiratory infections,
fatigue on exertion, and episodes of pulmonary edema or congestive heart
failure. Often, a diagnosis of reactive airways disease will have been made
because of the similarity in pulmonary symptoms, including wheezing, which
may be a dominant finding in infants and young children.
The typical murmur of mitral insufficiency is a moderately high-pitched,
apical blowing holosystolic murmur. If the insufficiency is moderate to severe, it
is usually associated with a low-pitched, apical mid-diastolic rumbling murmur
indicative of increased diastolic flow across the mitral valve. The pulmonic
 direction of flow in the vertical vein that differentiates it from a left superior
vena cava. C, Total anomalous pulmonary venous drainage below the
diaphragm. The specimen shows the pulmonary veins as they enter the
confluence, whereas the echocardiogram demonstrates the descending
veins as they enter the liver. Note that the direction of flow is away from the
heart. AO, Aorta; CS, coronary sinus; DA, descending aorta; DV,
descending vein; LVV, left vertical vein; PA, pulmonary artery; PV,
pulmonary vein; PVC, pulmonary venous confluence; RA, right atrium.
(From Webb GD, Smallhorn, JF, Therrien J, Redington, AN: Congenital
heart disease in the adult and pediatric patient. In Braunwald's heart
disease: a textbook of cardiovascular medicine, ed 11, Philadelphia, 2018,
Elsevier, Fig 75-32, p 1553).

All forms of TAPVR involve mixing of oxygenated and deoxygenated blood

before or at the level of the right atrium (total mixing lesion ). This mixed right
atrial blood either passes into the right ventricle and pulmonary artery or passes
through an atrial septal defect (ASD) or patent foramen ovale into the left
atrium, which will be the only source of systemic blood flow. The right atrium
and ventricle and the pulmonary artery are generally enlarged, whereas the left
atrium and ventricle may be normal or small. The clinical manifestations of
TAPVR depend on the presence or absence of obstruction of the venous
channels (Table 458.1 ). If pulmonary venous return is obstructed, severe
pulmonary congestion and pulmonary hypertension develop; rapid deterioration
occurs without surgical intervention. Obstructed TAPVR is a pediatric cardiac
surgical emergency because prostaglandin therapy is usually not effective.

Table 458.1
Total Anomalous Pulmonary Venous Return

SITE OF CONNECTION (% OF CASES) % WITH SIGNIFICANT OBSTRUCTION

Supracardiac (50)
Left superior vena cava (40) 40
Right superior vena cava (10) 75
Cardiac (25)
Coronary sinus (20) 10
Right atrium (5) 5
Infracardiac (20) 95-100
Mixed (5)

Clinical Manifestations
Two major clinical patterns of TAPVR are seen, depending on the presence or

FIG. 458.16 A, Coronal T1-weighted MR image of a patient with
heterotaxy syndrome (polysplenia) demonstrates a bilateral hyparterial
bronchial branching pattern (arrows) and left upper quadrant spleens. B,
More posterior coronal T1-weighted MR image shows left azygos-
hemiazygos continuation to the left superior vena cava and right thoracic
aorta. (From Applegate KE, Goske MJ, Pierce G, Murphy D: Situs revisited:
imaging of the heterotaxy syndrome, Radiographics 19:837–852, 1999, Fig
4.)

Table 458.2

Comparison of Cardiosplenic Heterotaxy Syndromes

ASPLENIA (RIGHT
FEATURE POLYSPLENIA (LEFT ISOMERISM)
ISOMERISM)
Spleen Absent Multiple
Sidedness (isomerism) Bilateral right Bilateral left
Lungs Bilateral trilobar with Bilateral bilobar with hyparterial bronchi
eparterial bronchi
Sex Male (65%) Female ≥ male
Right-sided stomach Yes Less common
Symmetric liver Yes Yes
Partial intestinal rotation or Yes Yes
malrotation
Risk for midgut volvulus Yes Yes
Dextrocardia (%) 30-40 30-40
Pulmonary blood flow Decreased (usually) Increased (usually)
Severe cyanosis Yes No
Transposition of great arteries 60-75 15
(%)
Total anomalous pulmonary 70-80 Rare
venous return (%)
Common atrioventricular 80-90 20-40
valve (%)
Single ventricle (%) 40-50 10-15
Absent inferior vena cava No Characteristic
 with azygos continuation
Bilateral superior venae cavae Yes Yes
Other common defects PA, PS, right-sided Partial anomalous pulmonary venous return, ventricular
aortic arch septal defect, double-outlet right ventricle
Risk of pneumococcal sepsis Yes Yes
Howell-Jolly and Heinz Yes No
bodies, pitted erythrocytes
Risk of nosocomial infection Yes Yes
Absent gallbladder; biliary No Yes
atresia
PA, Pulmonary atresia; PS, pulmonary stenosis.

Human heterotaxia syndromes may be related to disorders in cilia and in utero

left-right axis development. Genes involved in the Nodal signaling pathway,
including NODAL (known asymmetric gene), as well as those influenced by
Nodal such as the transforming growth factor (TGF)-β superfamily (LEFTYA,
LEFTYB ) and Pitx2, may be implicated in the development of heterotaxia
syndromes (Fig. 458.17 ). Diagnostic gene panels are available to identify a
possible genetic basis.

FIG. 458.17 Pathway of left-right (LR) development in the mouse embryo, list of genes
associated with human LR asymmetry disorders, and corresponding phenotypes in
humans. LRD-containing monocilia generate leftward nodal flow, and polycystin 2–
containing cilia sense nodal flow and initiate an asymmetric calcium signal, which
induces Nodal expression around the node. Nodal signaling is involved in asymmetric
morphogenesis by inducing expression of the Nodal-responsive genes (NODAL,
appreciated by reviewing the embryology of the aortic arch (see Chapter 447 ,
Fig. 447.1 ). The most common anomalies include (1) double aortic arch (Fig.
459.1A ), (2) right aortic arch with a left ligamentum arteriosum, (3) anomalous
innominate artery arising farther to the left on the arch than usual, (4) anomalous
left carotid artery arising farther to the right than usual and passing anterior to
the trachea, and (5) anomalous left pulmonary artery (vascular sling ). In the
latter anomaly, the abnormal vessel arises from an elongated main pulmonary
artery or from the right pulmonary artery. It courses between and compresses the
trachea and the esophagus. Associated congenital heart disease may be present in
5–50% of patients, depending on the vascular anomaly.

Table 459.1
Vascular Rings

BARIUM
LESION SYMPTOMS PLAIN FILM BRONCHOSCOPY
SWALLOW
DOUBLE ARCH
Stridor AP—wider base of Bilateral Bilateral tracheal
Respiratory heart indentation compression—both
distress Lat.—narrowed of esophagus pulsatile
Swallowing trachea displaced
dysfunction forward at C3-C4
Reflex
apnea

RIGHT ARCH AND LIGAMENTUM/DUCTUS

Respiratory AP—tracheal deviation to Bilateral Bilateral tracheal
distress left (right arch) indentation compression—r.
Swallowing of esophagus pulsatile
dysfunction R > L

ANOMALOUS INNOMINATE
Cough AP—normal Normal Pulsatile anterior
Stridor Lat.—anterior tracheal tracheal compression
Reflex compression
apnea

ABERRANT RIGHT SUBCLAVIAN

Occasional Normal AP— Usually normal
swallowing oblique
 dysfunction defect
upward
to right
Lat.—
small
defect
on right
posterior
wall
PULMONARY SLING
Expiratory AP—low l. hilum, r. ±Anterior Tracheal
stridor emphysema/atelectasis indentation displacement to
Respiratory Lat.—anterior bowing above carina left
distress of right bronchus and between Compression of
trachea esophagus right main
and trachea bronchus

AP, Anteroposterior; L and l., left; Lat., lateral; MRI, magnetic resonance imaging; R and r., right.
From Kliegman RM, Greenbaum LA, Lye PS: Practical strategies in pediatric diagnosis and
therapy, ed 2, Philadelphia, 2004, Elsevier, p 88.

FIG. 459.1 Double aortic arch. A, Small anterior segment of the double aortic arch
(most common type). B, Operative procedure for release of the vascular ring. L., Left; a.
and art., artery; ant., anterior; innom., innominate; duct. arterios., ductus arteriosus;
pulm., pulmonary.

Clinical Manifestations
Fallot, transposition of the great arteries, congenitally corrected transposition of
the great arteries, single ventricle, tricuspid atresia, truncus arteriosus,
quadricuspid or bicuspid aortic valves, double-outlet ventricle). In addition,
acquired lesions of the coronary arteries caused by existing congenital heart
disease may develop as a consequence of hypertension or alterations in blood
flow; congenital heart lesions include coarctation of the aorta, supravalvular
aortic stenosis, aortic regurgitation, pulmonary atresia with intact ventricular
septum, hypoplastic left heart syndrome, and coronary ectasia secondary to
cyanotic heart disease.
Table 459.2
Congenital Anomalies of Coronary Arteries
Unassociated With Congenital Heart Disease
Anomalous Aortic Origin

• Eccentric ostium within an aortic sinus

• Ectopic ostium above an aortic sinus
• Conus artery from the right aortic sinus
• Circumflex coronary artery from the right aortic sinus or from the right
coronary artery
• Origin of left anterior descending and circumflex coronary arteries from
separate ostia in the left aortic sinus (absence of left main coronary artery)
• Atresia of the left main coronary artery
• Origin of the left anterior descending coronary artery from the right aortic
sinus or from the right coronary artery
• Origin of the right coronary artery from the left aortic sinus, from posterior
aortic sinus, or from left coronary artery
• Origin of a single coronary artery from the right or left aortic sinus
• Anomalous origin from a noncardiac systemic artery

Anomalous Aortic Origin With Anomalous Proximal Course

• Acute proximal angulation

• Ectopic right coronary artery passing between aorta and pulmonary trunk
 • Ectopic left main coronary artery
• Between aorta and pulmonary trunk
• Anterior to the pulmonary trunk
• Posterior to the aorta
• Within the ventricular septum (intramyocardial)
• Ectopic left anterior descending coronary artery that is anterior, posterior, or
between the aorta and pulmonary trunk

Anomalous Origin of a Coronary Artery From the Pulmonary

Trunk

• Left main coronary artery

• Left anterior descending coronary artery
• Right coronary artery
• Both right and left coronary arteries
• Circumflex coronary artery
• Accessory coronary artery

From Perloff JK, Marelli J: Perloff's clinical recognition of congenital heart

disease, ed 6, Philadelphia, 2012, Elsevier Saunders (Table 32-3, p 532).

Anomalous Origin of Left Coronary

Artery From Pulmonary Artery
In anomalous origin of the left coronary artery from the pulmonary artery
(ALCAPA ), the blood supply to the left ventricular (LV) myocardium is
severely compromised. Soon after birth, as pulmonary artery pressure falls,
perfusion pressure to the left coronary artery (LCA) becomes inadequate;
myocardial ischemia, infarction, and fibrosis result. In some cases, interarterial
collateral anastomoses develop between the right coronary artery (RCA) and
LCA. Blood flow in the LCA is then reversed, and it empties into the pulmonary
artery, a condition known as the “myocardial steal” syndrome. The left ventricle
becomes dilated, and its performance is decreased. Mitral insufficiency is a
frequent complication secondary to a dilated valve ring or infarction of a
vessels. Angina and sudden death can occur in adolescence or adulthood. When
recognized, this anomaly should be repaired by reanastomosis of the RCA to the
aorta.

Ectopic Origin of a Coronary Artery From

the Aorta With Aberrant Proximal Course
In ectopic origin of the coronary artery from the aorta with an aberrant proximal
course, the aberrant artery may be a left, right, or major branch coronary artery.
The site of origin may be the wrong sinus of Valsalva (anomalous origin of a
coronary artery from the opposite sinus, ACAOS ) or a proximal coronary
artery. The ostium may be hypoplastic, slit-like, or of normal caliber. The
aberrant vessel may pass anteriorly, posteriorly, or between the aorta and right
ventricular outflow tract (RVOT); it may tunnel in the conal or interventricular
septal tissue. Obstruction resulting from hypoplasia of the ostia, tunneling
between the aorta and RVOT or interventricular septum, and acute angulation
produces myocardial infarction. Unobstructed vessels produce no symptoms
(Table 459.3 ). Patients with this rare abnormality are often initially seen with
severe myocardial infarction, ventricular arrhythmias, angina pectoris, or
syncope; sudden death may occur, especially in young athletes.

Table 459.3

Classification of Coronary Anomalies Based on Ischemia

ISCHEMIA CLASSIFICATION
Absence of Most anomalies (split RCA, ectopic RCA from right cusp; ectopic RCA from left cusp)
ischemia
Episodic Anomalous origin of a coronary artery from the opposite sinus (ACAOS); coronary artery
ischemia fistulas; myocardial bridge
Typical Anomalous left coronary artery from the pulmonary artery (ALCAPA); coronary ostial atresia
ischemia or severe stenosis
RCA, Right coronary artery.
From Mehran R, Dangas GD: Coronary angiography and intravascular imaging. In Braunwald's
heart disease: a textbook of cardiovascular medicine, ed 11, Philadelphia, 2018, Elsevier (Fig
20.8, p 385).

Diagnostic modalities include ECG, stress testing, 2D echocardiography, CT

or MRI, radionuclide perfusion scan, and cardiac catheterization with selective
coronary angiography.
Updated Classification of Pulmonary
Hypertension (PH)*
1. Pulmonary arterial hypertension (PAH)
1.1 Idiopathic PAH
1.2 Heritable PAH
1.2.1 BMPR2
1.2.2 ALK1, ENG, SMAD9 , CAV1 , KCNK3
1.2.3 Unknown
1.3 Drug and toxin induced
1.4 Associated with:
1.4.1 Connective tissue disease
1.4.2 HIV infection
1.4.3 Portal hypertension
1.4.4 Congenital heart disease
1.4.5 Schistosomiasis
1′. Pulmonary venoocclusive disease and/or pulmonary capillary
hemangiomatosis
1″. Persistent pulmonary hypertension of the newborn (PPHN)
2. Pulmonary hypertension due to left heart disease
2.1 Left ventricular systolic dysfunction
2.2 Left ventricular diastolic dysfunction
2.3 Valvular disease
2.4 Congenital/acquired left heart inflow/outflow tract obstruction
and congenital cardiomyopathies
3. Pulmonary hypertension due to lung diseases and/or hypoxia
3.1 Chronic obstructive pulmonary disease
3.2 Interstitial lung disease
3.3 Other pulmonary diseases with mixed restrictive and obstructive
pattern
3.4 Sleep-disordered breathing
3.5 Alveolar hypoventilation disorders
3.6 Chronic exposure to high altitude
3.7 Developmental lung diseases
4. Chronic thromboembolic pulmonary hypertension (CTEPH)
 5. Pulmonary hypertension with unclear multifactorial mechanisms
5.1 Hematologic disorders: chronic hemolytic anemia ,
myeloproliferative disorders, splenectomy
5.2 Systemic disorders: sarcoidosis, pulmonary histiocytosis,
lymphangioleiomyomatosis
5.3 Metabolic disorders: glycogen storage disease, Gaucher disease,
thyroid disorders
5.4 Others: tumoral obstruction, fibrosing mediastinitis, chronic
renal failure, segmental PH

BMPR2, Bone morphogenetic protein receptor type II; CAV1, caveolin 1;

ENG, endoglin; KCNK3, potassium channel K3.

* Modified as compared with the Dana Point classification.

From Simonneau G, Gatzoulis MA, Adatia I: Updated clinical classification of

pulmonary hypertension, J Am Coll Cardiol 62:D34–D41, 2013.
Table 460.2
Developmental Lung Diseases Associated With
Pulmonary Hypertension
Congenital diaphragmatic hernia
Bronchopulmonary dysplasia
Alveolar capillary dysplasia (ACD)
ACD with misalignment of veins
Lung hypoplasia (“primary” or “secondary”)
Surfactant protein abnormalities
Surfactant protein B (SPB) deficiency
SPC deficiency
ATP-binding cassette A3 mutation
Thyroid transcription factor 1/Nkx2.1 homeobox mutation
Pulmonary interstitial glycogenosis
Pulmonary alveolar proteinosis
Pulmonary lymphangiectasia
Table 460.3

Summary of Drugs Used to Treat Pulmonary Hypertension*

DRUG AND
MECHANISM OF DOSES USED IN PEDIATRIC STUDIES COMMON SIDE EFFECTS
ACTION
Epoprostenol 1 ng/kg/min initially. Increase based on clinical Flushing, headache, nausea, diarrhea,
(prostacyclin [PGI2 ], course and tolerance to 5-50 ng/kg/min. Some hypotension, chest pain, jaw pain
a potent vasodilator; patients may require even higher doses. Must be
also inhibits platelet given by continuous infusion that is not
aggregation) interrupted.
Iloprost (synthetic 2.5-5.0 µg 6-9 times daily (not more frequently Flushing, headache, diarrhea,
analog of PGI2 ) than every 2 hr) via inhalation hypotension, jaw pain, exacerbation of
pulmonary symptoms (cough,
wheezing)
Treprostinil (synthetic 1 ng/kg/min initially. Target dose ranges from Flushing, headache, diarrhea,
analog of PGI2 ) 20-80 ng/kg/min. Given either IV or SC via hypotension, jaw pain. Pain at infusion
continuous infusion. Longer half-life than site when given SC.
epoprostenol.
Ambrisentan Target dose ranges from 1.25-10 mg. Use Flushing, headache, hypotension, fluid
(selective endothelin retention/edema, nasopharyngitis,
dose for 1st mo.
EtA receptor sinusitis, anemia, fluid retention,
antagonist) exacerbation of heart failure, anemia,
palpitations
Bosentan 2 mg/kg/dose bid. Use dose for 1st mo and Flushing, headache, nasopharyngitis,
(nonselective fluid retention, exacerbation of heart
check for LFT abnormalities before up-titrating.
endothelin receptor failure, anemia, elevated LFTs,
EtA and EtB palpitations
antagonist)
Macitentan — Flushing, headache, fluid retention,
(nonselective exacerbation of heart failure, anemia,
endothelin receptor nasopharyngitis, bronchitis, influenza,
EtA and EtB urinary tract infections
antagonist)
Sildenafil (inhibitor 1 mg/kg/dose given 3-4 times daily. Initial dosing Flushing, headache, diarrhea, myalgia,
of cGMP-specific should be final target dose to evaluate for hypotension, priapism, visual
phosphodiesterase 5) disturbance (blue coloration), tinnitus
hypotension
Tadalafil, a 1 mg/kg/dose given daily. Initial dosing should Flushing, headache, diarrhea, myalgia,
phosphodiesterase be final target dose to evaluate for hypotension, priapism, visual
type 5 inhibitor disturbance (blue coloration), tinnitus
hypotension.
Calcium channel Previously widely used. Now indicated only for Flushing, headache, edema,
blockers (amlodipine, patients who show a strong response to nitric arrhythmia, headache, hypotension,
diltiazem, nifedipine) oxide during cardiac catheterization. rash, nausea, constipation, elevated
LFTs
* These medications should only be administered under the direction of a specialist in pulmonary
hypertension.
cGMP, Cyclic guanosine monophosphate; IV, Intravenously; LFT, liver function test; SC,
 Routine immunizations should be given, with the inclusion of influenza
vaccine during the appropriate season. Prophylaxis against the respiratory
syncytial virus (RSV) is recommended during RSV season in young infants with
unrepaired CHD and significant hemodynamic abnormalities. Careful
consideration of the timing of administration of live-virus vaccination is required
in patients who are potential candidates for heart or heart-lung transplantation,
and these patients cannot receive live-virus vaccines after they have received
their transplant.
Bacterial infections should be treated vigorously, but the presence of CHD is
not a reason to use antibiotics indiscriminately. Prophylaxis against bacterial
endocarditis should be carried out during dental procedures for appropriate
patients. The American Heart Association (AHA) over time has significantly
revised these recommendations, with most patients no longer requiring routine
prophylaxis (see Chapter 464 ). Even for patients who do require endocarditis
prophylaxis, it is generally recommended only for dental or oral surgical
procedures and no longer recommended for gastrointestinal or genitourinary
procedures.
Cyanotic patients need to be monitored for noncardiac manifestations of
oxygen deficiency (Table 461.1 ). With modern surgical procedures, it is rare
today for a patient to remain significantly cyanotic beyond the 1st few years of
life, although mild degrees of cyanosis may be seen in patients with a single
ventricle (e.g. hypoplastic left heart) who have a fenestration in their Fontan
conduits allowing right-to-left shunting. These patients should also be carefully
observed for excessive polycythemia . Cyanotic patients should avoid situations
where dehydration may occur, which leads to increased viscosity and increases
the risk of stroke. Diuretics may need to be decreased or temporarily
discontinued during episodes of acute gastroenteritis. High altitudes and sudden
changes in the thermal environment should also be avoided. Treatment of iron-
deficiency anemia is important in cyanotic patients, who may have a low mean
corpuscular hemoglobin concentration despite polycythemia. These patients will
show improved exercise tolerance and general well-being with restoration of
normal hemoglobin levels, and their risk of stroke may be reduced if the red
blood cells are not microcytic. Phlebotomy with partial exchange transfusion is
carried out only in symptomatic patients with severe polycythemia (usually those
with hematocrit >65%).

Table 461.1
Extracardiac Complications of Cyanotic Congenital Heart
Disease and Eisenmenger Physiology
PROBLEM ETIOLOGY THERAPY
Polycythemia Persistent hypoxia Phlebotomy if symptomatic
Relative anemia Nutritional deficiency Iron replacement
CNS abscess Right-to-left shunting Antibiotics, drainage
CNS thromboembolic stroke Right-to-left shunting or Anticoagulation, phlebotomy
polycythemia
Low-grade DIC, thrombocytopenia Polycythemia None for DIC unless
bleeding, then phlebotomy
Hemoptysis Pulmonary infarct, thrombosis, or Embolization
rupture of pulmonary artery
plexiform lesion
Plastic bronchitis Fontan procedure Bronchoscopy, vascular
coiling, lymphatic ablation
Gum disease Polycythemia, gingivitis, bleeding Dental hygiene
Gout Polycythemia, diuretic agent Allopurinol
Arthritis, clubbing Hypoxic osteoarthropathy None
Pregnancy complications: miscarriage, fetal Poor placental perfusion, poor Pregnancy prevention
growth retardation, prematurity increase, ability to increase cardiac output counseling, high-risk
maternal illness obstetric management
Infections Associated asplenia, DiGeorge Antibiotics
syndrome, endocarditis
Fatal RSV pneumonia with Ribavirin; RSV
pulmonary hypertension immunoglobulin (prevention)
Failure to thrive Increased oxygen consumption, Treat heart failure; correct
decreased nutrient intake defect early; increase caloric
intake
Protein-losing enteropathy s/p Fontan; high right-sided Oral budesonide or sildenafil
pressures
Chylothorax Injury to thoracic duct Medium-chain
triglyceride diet
Octreotide
Surgical ligation of
thoracic duct
Neurodevelopmental disabilities Chronic hypoxia, cardiac surgery, Early school-based
genetic evaluation and intervention
Psychosocial adjustment Limited activity, cyanotic Counseling
appearance, chronic disease,
multiple hospitalizations
CNS, Central nervous system; DIC, disseminated intravascular coagulation; RSV, respiratory
syncytial virus; s/p, status post (after).

Patients with moderate to severe forms of CHD or a history of rhythm

disturbance should be carefully monitored during anesthesia for even routine
surgical or dental procedures. Consultation with an anesthesiologist experienced
in the care of children with CHD is recommended even if the surgical procedure
is not cardiac related.
with a 5% increase every year. In the last decade, 35% of hospitalizations for
CHD were patients older than 18 yr (mean age: 55 yr).

Long-Term Medical Considerations

Approximately 25% of adults with CHD have a mild form that has allowed them
to survive into adulthood without surgical or interventional cardiac
catheterization. The most common lesions in this category include mild aortic
valve stenosis (usually in setting of bicuspid aortic valve), small restrictive
ventricular septal defects (VSDs), mild pulmonary valve stenosis, and mitral
valve prolapse (Table 461.2 ). These patients need less frequent follow-up to
assess for progression of disease and to identify associated complications. Many
adults with CHD living in the United States are patients who have had previous
intervention (Table 461.3 ). Although most children who undergo surgical
intervention will survive to adulthood, with few exceptions, total correction is
not the rule. The few exceptions include PDA, VSDs, and atrial septal defects
(ASDs); this is true only if they are closed early, before the development of
irreversible pulmonary vascular changes, and if no residual lesions exist.
Table 461.2
Congenital Heart Defects Associated With
Survival Into Adulthood Without Surgery or
Interventional Cardiac Catheterization

Mild pulmonary valve stenosis

Bicuspid aortic valve
Small to moderate-size atrial septal defect
Small ventricular septal defect
Small patent ductus arteriosus
Mitral valve prolapse
Partial atrioventricular canal (ostium primum atrial septal defect and cleft
mitral valve)
Marfan syndrome
Ebstein anomaly
Congenitally corrected transposition (atrioventricular and ventriculoarterial
discordance)
Table 461.3
Most Common Congenital Heart Defects in
Patients Surviving to Adulthood After
Surgery or Interventional Catheterization
Aortic valve disease following balloon valvuloplasty or surgical valvotomy
Pulmonary valve stenosis following balloon valvuloplasty or surgical
valvotomy
Tetralogy of Fallot
Ventricular septal defect
Complete atrioventricular canal defect
Transposition of the great arteries
Coarctation of the aorta
Complex single ventricles after the modified Fontan procedure

It has become apparent that even the simplest congenital heart lesions can be
associated with long-term complications, including both cardiac and noncardiac
problems (Tables 461.4 and 461.5 and Fig. 461.2 ). Cardiac complications
include arrhythmias and conduction defects, ventricular dysfunction, residual
shunts, valvular lesions (regurgitation and stenosis), hypertension, and
aneurysms. Noncardiac sequelae (comorbidities ) include pulmonary, renal, and
hepatic dysfunction that is caused either directly or indirectly by the underlying
CHD. Abnormal pulmonary function most often presents as restrictive lung
physiology and likely results from prior sternotomy or thoracotomy, scoliosis,
diaphragmatic dysfunction, or parenchymal lung disease. Reduced pulmonary
function contributes to reduced exercise tolerance and is a risk factor for
mortality in adults with CHD. Renal dysfunction may result from chronic
cyanosis, multiple surgeries requiring CPB, or from other comorbid conditions,
such as hypertension and diabetes mellitus. Hepatic injury from chronic liver
congestion in patients with elevated central venous pressures, particularly
patients palliated with the Fontan procedure, can result in hepatic fibrosis,
cirrhosis, hepatic dysfunction, and rarely hepatocellular carcinoma. Adults with
CHD are at risk for developmental abnormalities such as intellectual
impairment, somatic abnormalities such as facial dysmorphism (cleft palate/lip),
CNS abnormalities such as seizure disorders from previous thromboembolic
events or cerebrovascular accidents, and impairments of hearing or vision loss.
Psychosocial problems involving employment, life and health insurance,
participation in sports, sexual activity, and contraception are common. As a
result of these long-term complications, the majority of adults with CHD need
lifelong follow-up. When adults with CHD are hospitalized, it is usually for
heart failure or an arrhythmia; others may require catheterization or another
cardiac surgical procedure.
Table 461.4
Risks in Adults Who Have Congenital Heart
Disease
Rhythm Disorders

Supraventricular tachycardia
Right bundle branch block
Heart block
Ventricular tachycardia
Sudden death

Coarctation of Aorta

Essential hypertension
Recoarctation
Aneurysm formation

Residual Lesions (Shunts)

Ventral septal defect

Atrial septal defect
Patent ductus arteriosus

Acquired Lesions

Subacute bacterial endocarditis

Subvalvular stenosis
 Supravalvular stenosis
Valvular insufficiency
Valvular restenosis
Eisenmenger complex

Pregnancy Risk (See Table 461.5 )

Table 461.5

Lesion-Specific Risks of Maternal and Neonatal Complications of Pregnancy

RISK LESION/COMPLICATION
No additional risk Small septal defects
Surgically closed ASD, VSD, PDA
Mild to moderate aortic regurgitation
Mild to moderate pulmonary stenosis
Slightly increased risk Postoperative repair of tetralogy of Fallot
Transposition of the great arteries, s/p arterial switch procedure
Moderate risk Transposition of the great arteries, s/p atrial switch procedure
Congenitally corrected transposition of the great arteries
Single ventricle physiology, s/p Fontan procedure
Severe risk Cyanotic congenital heart disease, unoperated or palliated
Marfan syndrome
Prosthetic valves
Obstructive lesions including coarctation
Pregnancy contraindicated Severe pulmonary hypertension
Severe obstructive lesions
Marfan syndrome, aortic root >40 mm
ASD, Atrial septal defect; PDA, patent ductus arteriosus; s/p, status post (after); VSD, ventricular
septal defect.
the primary care provider and the pediatric cardiologist, who must identify an
appropriate adult CHD program to which transition and transfer will be made at
an appropriate time (Table 461.6 ).
Table 461.6
Adolescent Transition Issues Requiring
Coordination of Patient Care Between
Cardiologist and Primary Care Physician
Antibiotic prophylaxis for endocarditis
Medications and drug interactions
Anticoagulation with prosthetic valves
Exercise and sports participation
Educational and vocational planning
Contraception and pregnancy
Drug, alcohol, and tobacco use
Noncardiac surgical planning
Anesthetic issues
New symptoms or acute illnesses
Comorbid conditions
Travel

A successful transition program includes the following elements:

◆ Development of a written transition plan that

should begin by age 14 yr
◆ Because adolescents and young adults are
frequently unaware of the details of their cardiac
diagnosis and history, a complete, concise, portable
medical record, including all pertinent aspects of
cardiac care, should be shared with adolescents and
their family and prepared for transmittal to the
with malignant ventricular arrhythmias and an increased risk of sudden death.

Table 462.1
Antiarrhythmic Drugs Commonly Used in Pediatric
Patients, by Class

DRUG DRUG
DRUG INDICATIONS DOSING SIDE EFFECTS
INTERACTIONS LEVEL
CLASS IA: INHIBITS Na+ FAST CHANNEL, PROLONGS REPOLARIZATION
Quinidine SVT, atrial Oral: 30-60 Nausea, vomiting, Enhances digoxin, 2-6 µg/mL
fibrillation, atrial mg/kg/24 hr diarrhea, fever, may increase PTT
flutter, VT. In divided q6h cinchonism, QRS and when given with
atrial flutter, an (sulfate) or q8h QT prolongation, AV warfarin
AV node– (gluconate) nodal block, asystole
blocking drug In adults, 10 syncope,
(digoxin, mg/kg/day thrombocytopenia,
verapamil, divided q6h hemolytic anemia,
propranolol) must Max dose: 2.4 SLE, blurred vision,
be given first to g/24 hr convulsions, allergic
prevent 1 : 1 reactions, exacerbation
conduction of periodic paralysis
Procainamide SVT, atrial Oral: 15-50 PR, QRS, QT interval Toxicity increased 4-8
fibrillation, atrial mg/kg/24 hr prolongation, by amiodarone and µg/mL
flutter, VT divided q4h anorexia, nausea, cimetidine With
Max dose: 4 vomiting, rash, fever, NAPA
g/24 hr agranulocytosis, <40
IV: 10-15 thrombocytopenia, µg/mL
mg/kg over 30- Coombs-positive
45 min load hemolytic anemia,
followed by 20- SLE, hypotension,
80 µg/kg/min exacerbation of
Max dose: 2 periodic paralysis,
g/24 hr proarrhythmia
Disopyramide SVT, atrial Oral: <2 yr: 20- Anticholinergic 2-5 µg/ml
fibrillation, atrial 30 mg/kg/24 hr effects, urinary
flutter divided q6h or retention, blurred
q12h (long- vision, dry mouth, QT
acting form); 2- and QRS
10 yr: 9-24 prolongation, hepatic
mg/kg/24 hr toxicity, negative
divide q6h or inotropic effects,
q12h (long- agranulocytosis,
acting form); 11 psychosis,
yr: 5-13 hypoglycemia,
mg/kg/24 hr proarrhythmia
divided q6h or
q12h (long-
acting)
Max dose: 1.2
g/24 hr
CLASS IB: INHIBITS Na+ FAST CHANNEL, SHORTENS REPOLARIZATION

Lidocaine VT, VF IV: 1 mg/kg repeat qCNS effects, Propranolol, 1-5 µg/mL
5 min 2 times confusion, cimetidine,
followed by 20-50 convulsions, high- increases toxicity
µg/kg/min (max grade AV block,
dose: 3 mg/kg) asystole, coma,
paresthesias,
respiratory failure
Mexiletine VT Oral: 6-15 mg/kg/24 GI upset, skin rash, Cimetidine 0.8-2
hr divided q8h neurologic µg/mL
Phenytoin Digitalis Oral: 3-6 Rash, gingival Amiodarone, oral 10-20
intoxication mg/kg/24 hr hyperplasia, ataxia, anticoagulants, µg/mL
divided q12h lethargy, vertigo, cimetidine,
Max dose: 600 tremor, macrocytic nifedipine,
mg anemia, bradycardia disopyramide,
IV: 10-15 with rapid push increase toxicity
mg/kg over 1 hr
load
+
CLASS IC: INHIBITS Na CHANNEL
Flecainide SVT, atrial Oral: 6.7-9.5 Blurred vision, nausea, Amiodarone 0.2-1
tachycardia, VT mg/kg/24 hr decrease in increases toxicity µg/mL
divided q8h contractility,
In older proarrhythmia
children, 50-
200 mg/m2 /day
divided q12h
Propafenone SVT, atrial Oral: 150-300 Hypotension, Increases digoxin 0.2-1
tachycardia, atrial mg/m2 /24 hr decreased contractility, levels µg/mL
fibrillation, VT divided q6h hepatic toxicity,
paresthesia, headache,
proarrhythmia
CLASS II: β-BLOCKERS
Propranolol SVT, long QT Oral: 1-4 Bradycardia, loss of Co-administration
mg/kg/24 hr concentration, school with disopyramide,
divided q6h performance problems flecainide, or
Max dose 60 bronchospasm, verapamil may
mg/24 hr hypoglycemia, decrease
IV: 0.1-0.15 hypotension, heart ventricular
mg/kg over 5 block, CHF function.
min
Max IV dose:
10 mg
Atenolol SVT Oral: 0.5-1 Bradycardia, loss of Co-administration
mg/kg/24 hr once concentration, school with disopyramide,
daily or divided performance problems flecainide, or
q12h verapamil may
decrease
ventricular
function.
Nadolol SVT, long QT Oral: 1-2 mg/kg/24 Bradycardia, loss of Co-administration
 hr given once daily concentration, school with disopyramide,
performance problems flecainide, or
bronchospasm, verapamil may
hypoglycemia, decrease
hypotension, heart ventricular
block, CHF function.
CLASS III: PROLONGS REPOLARIZATION
Amiodarone SVT, JET, VT Oral: 10 Hypothyroidism or Digoxin (increases 0.5-2.5
mg/kg/24 hr in hyperthyroidism, levels), flecainide, mg/L
1-2 divided elevated triglycerides, procainamide,
doses for 4-14 hepatic toxicity, quinidine,
days; reduce to pulmonary fibrosis warfarin,
5 mg/kg/24 hr phenytoin
for several
weeks; if no
recurrence,
reduce to 2.5
mg/kg/24 hr
IV: 2.5-5 mg/kg
over 30-60 min,
may repeat 3
times, then 2-10
mg/kg/24 hr
continuous
infusion
CLASS IV AND MISCELLANEOUS MEDICATIONS
Digoxin SVT (not WPW), Oral/load PAC, PVC, Quinidine 1-2 mg/mL
atrial flutter, atrial instructions: bradycardia, AV Amiodarone,
fibrillation Premature: 20 block, nausea, verapamil,
µg/kg vomiting, anorexia, increase
Newborn: 30 prolongs PR interval digoxin levels
µg/kg
>6 mo: 40
µg/kg
Give total dose
followed by q8-
12h × 2 doses
Maintenance:
10 µg/kg/24 hr
divide q12h
Max dose: 0.5
mg
IV: PO dose
Max dose: 0.5
mg
Verapamil SVT (not WPW) Oral: 2-7 Bradycardia, asystole, Use with β-blocker
mg/kg/24 hr high degree AV block, or disopyramide
divided q8h PR prolongation, exacerbates CHF,
Max dose: 480 hypotension, CHF increases digoxin
mg level and toxicity
IV: 0.1-0.2
mg/kg q 20 min
× 2 doses
Max dose: 5-10
 mg

Adenosine SVT IV: 50-300 Chest pain, flushing,

µg/kg by need dyspnea,
rapid IV push bronchospasm, atrial
Begin with 50 fibrillation,
µg/kg and bradycardia, asystole
increase by 50-
100 µg/kg/dose
Max dose: 18
mg

AV, Atrioventricular; CHF, congestive heart failure; CNS, central nervous systems; GI,
gastrointestinal; IV, intravenous; JET, junctional ectopic tachycardia; NAPA, N -acetyl
procainamide; PAC, premature atrial contraction; PTT, partial thromboplastin time; PVC,
premature ventricular contraction; SLE, systemic lupus erythematosus–like illness; SVT,
supraventricular tachycardia; VF, ventricular fibrillation; VT, ventricular tachycardia; WPW, Wolff-
Parkinson-White syndrome.

462.1
Principles of Antiarrhythmic
Therapy
Aarti S. Dalal, George F. Van Hare

When considering drug therapy in the pediatric population, it is important to

recognize that there may be marked differences in pharmacokinetics by age and
comparison with adults. Infants may have slower absorption, slow gastric
emptying, and differing sizes of drug tissue compartments affecting the volume
of distribution. Hepatic metabolism and renal excretion may vary within the
pediatric age-group as well as in comparison to adults. Special consideration
must also be given to the frequency and diet of an infant when choosing specific
antiarrhythmics. When considering antiarrhythmic therapy, it is important to
recognize that the likely arrhythmia mechanism may be different for the
pediatric than the adult population.
Many antiarrhythmic agents are available for rhythm control. The majority are
deteriorate into ventricular fibrillation. In the neonatal period, VT may be
associated with an anomalous left coronary artery (see Chapter 459.2 ) or a
myocardial tumor.

FIG. 462.10 Ventricular arrhythmias. (From Park MY: Pediatric cardiology for
practitioners, ed 5, Philadelphia, 2008, Mosby Elsevier, Fig. 24-6, p 429.)

Table 462.2
Diagnosis of Tachyarrhythmias: Electrocardiographic
Findings

HEART RATE QRS

P WAVE REGULARITY
(BEATS/MIN) DURATION
Sinus <230 Always present, normal axis Normal Rate varies with respiration
tachycardia
Atrial 180-320 Present Normal or Usually regular but ventricular
tachycardia Abnormal P wave prolonged response may be variable because of
morphology and axis (with Wenckebach conduction
aberration)
Atrial 120-180 Fibrillatory waves Normal or Irregularly irregular (no 2 R-R
fibrillation prolonged intervals alike)
(with
aberration)
Atrial Atrial: 250- Saw-tooth flutter waves Normal or Regular ventricular response (e.g., 2
flutter 400 prolonged : 1, 3 : 1, 3 : 2, and so on)
Ventricular (with
response aberration)
variable:
100-320
Junctional 120-280 Atrioventricular dissociation Normal or Regular (except with capture beats)
tachycardia with no fusion, and normal prolonged
QRS capture beats (with
aberration)
Ventricular 120-300 Atrioventricular dissociation Prolonged for Regular (except with capture beats)
tachycardia with capture beats and fusion age
beats
Nielsen syndrome) is no longer made, because the latter recessive condition is
known to result from the homozygous state. Jervell-Lange-Nielsen syndrome
is associated with congenital sensorineural deafness. Asymptomatic but at-risk
patients carrying the gene mutation may not all have a prolonged QT duration.
QT interval prolongation may become apparent with exercise or during
catecholamine infusions.

Table 462.3
Updated Summary of Heritable Arrhythmia Syndrome
Susceptibility Genes
GENE LOCUS PROTEIN
LONG QT SYNDROME (LQTS)
Major LQTS Genes
KCNQ1 (LQT1) 11p15.5 IKs potassium channel alpha subunit (KVLQT1, Kv 7.1)
KCNH2 (LQT2) 7q35-36 IKr potassium channel alpha subunit (HERG, Kv 11.1)
SCN5A (LQT3) 3p21-p24 Cardiac sodium channel alpha subunit (Nav 1.5)
Minor LQTS Genes (Listed Alphabetically)
AKAP9 7q21-q22 Yotiao
CACNA1C 12p13.3 Voltage-gated L-type calcium channel (Cav 1.2)
CALM1 14q32.11 Calmodulin 1
CALM2 2p21 Calmodulin 2
CALM3 19q13.2-q13.3 Calmodulin 3
CAV3 3p25 Caveolin-3
KCNE1 21q22.1 Potassium channel beta subunit (MinK)
KCNE2 21q22.1 Potassium channel beta subunit (MiRP1)
KCNJ5 11q24.3 Kir3.4 subunit of IKACH channel
SCN4B 11q23.3 Sodium channel beta4 subunit
SNTA1 20q11.2 Syntrophin-alpha1
TRIADIN KNOCKOUT (TKO) SYNDROME
TRDN 6q22.31 Cardiac triadin
ANDERSEN-TAWIL SYNDROME (ATS)
KCNJ2 (ATS1) 17q23 IK1 potassium channel (Kir2.1)
TIMOTHY SYNDROME (TS)
CACNA1C 12p13.3 Voltage-gated L-type calcium channel (Cav 1.2)
Cardiac-Only TS (COTS)
CACNA1C 12p13.3 Voltage-gated L-type calcium channel (Cav 1.2)
SHORT QT SYNDROME (SQTS)
KCNH2 (SQT1) 7q35-36 IKr potassium channel alpha subunit (HERG, Kv 11.1)
KCNQ1 (SQT2) 11p15.5 IKs potassium channel alpha subunit (KVLQT1, Kv 7.1)
KCNJ2 (SQT3) 17q23 IK1 potassium channel (Kir2.1)
CACNA1C (SQT4) 12p13.3 Voltage-gated L-type calcium channel (Cav 1.2)
CACNB2 (SQT5) 10p12 Voltage-gated L-type calcium channel beta2 subunit
CACN2D1 (SQT6) 7q21-q22 Voltage-gated L-type calcium channel 2 delta1 subunit
CATECHOLAMINERGIC POLYMORPHIC VENTRICULAR TACHYCARDIA (CPVT)
RYR2 (CPVT1) 1q42.1-q43 Ryanodine receptor 2
CASQ2 (CPVT2) 1p13.3 Calsequestrin 2
KCNJ2 (CPVT3) 17q23 IK1 potassium channel (Kir2.1)
CALM1 14q32.11 Calmodulin 1
CALM3 19q13.2-q13.3 Calmodulin 3
TRDN 6q22.31 Cardiac triadin
BRUGADA SYNDROME (BrS)
SCN5A (BrS1) 3p21-p24 Cardiac sodium channel alpha subunit (Nav 1.5)
Minor Brs Genes (Listed Alphabetically)
ABCC9 12p12.1 ATP-binding cassette, subfamily C member 9
CACNA1C 2p13.3 Voltage-gated L-type calcium channel (Cav 1.2)
CACNA2D1 7q21-q22 Voltage-gated L-type calcium channel 2 delta1 subunit
CACNB2 10p12 Voltage-gated L-type calcium channel beta2 subunit
FGF12 3q28 Fibroblast growth factor 12
GPD1L 3p22.3 Glycerol-3-phosphate dehydrogenase 1–like
KCND3 1p13.2 Voltage-gated potassium channel (Ito ) subunit Kv 4.3
KCNE3 11q13.4 Potassium channel beta3 subunit (MiRP2)
KCNJ8 12p12.1 Inward rectifier K+ channel Kir6.1
HEY2 6q Hes-related family BHLH transcription factor with YRPW motif 2
PKP2 12p11 Plakophilin-2
RANGRF 17p13.1 RAN guanine nucleotide release factor 1
SCN1B 19q13 Sodium channel beta1
SCN2B 11q23 Sodium channel beta2
SCN3B 11q24.1 Sodium channel beta3
SCN10A 3p22.2 Sodium voltage-gated channel alpha10 subunit (Nav 1.8)
SLMAP 3p14.3 Sarcolemma-associated protein
EARLY REPOLARIZATION SYNDROME (ERS)
ABCC9 12p12.1 ATP-binding cassette, subfamily C member 9
CACNA1C 2p13.3 Voltage-gated L-type calcium channel (Cav 1.2)
CACNA2D1 7q21-q22 Voltage-gated L-type calcium channel 2 delta1 subunit
CACNB2 10p12 Voltage-gated L-type calcium channel beta2 subunit
KCNJ8 12p12.1 Inward rectifier K+ channel Kir6.1
SCN5A 3p21-p24 Cardiac sodium channel alpha subunit (Nav 1.5)
SCN10A 3p22.2 Sodium voltage-gated channel alpha10 subunit (Nav 1.8)
IDIOPATHIC VENTRICULAR FIBRILLATION (IVF)
ANK2 4q25-q27 Ankyrin B
CALM1 14q32.11 Calmodulin 1
DPP6 7q36 Dipeptidyl-peptidase-6
KCNJ8 12p12.1 Inward rectifier K+ channel Kir6.1
RYR2 1q42.1-q43 Ryanodine receptor 2
SCN3B 11q23 Sodium channel beta3 subunit
SCN5A 3p21-p24 Cardiac sodium channel alpha subunit (Nav 1.5)
PROGRESSIVE CARDIAC CONDUCTION DISEASE/DEFECT (PCCD)
SCN5A 3p21-p24 Cardiac sodium channel alpha subunit (Nav 1.5)
TRPM4 19q13.33 Transient receptor potential cation channel, subfamily M, member 4
SICK SINUS SYNDROME (SSS)
ANK2 4q25-q27 Ankyrin B
HCN4 15q24-q25 Hyperpolarization-activated cyclic nucleotide–gated channel 4
MYH6 14q11.2 Myosin, heavy chain 6, cardiac muscle, alpha
SCN5A 3p21-p24 Cardiac sodium channel alpha subunit (Nav 1.5)
 “ANKYRIN-B SYNDROME”
ANK2 4q25-q27 Ankyrin B
FAMILIAL ATRIAL FIBRILLATION (FAF)
ANK2 4q25-q27 Ankyrin B
GATA4 8p23.1-p22 GATA-binding protein 4
GATA5 20q13.33 GATA-binding protein 5
GJA5 1q21 Connexin 40
KCNA5 12p13 IKur potassium channel (Kv 1.5)
KCNE2 21q22.1 Potassium channel beta subunit (MiRP1)
KCNH2 7q35-36 IKr potassium channel alpha subunit (HERG, Kv 11.1)
KCNJ2 17q23 IK1 potassium channel (Kir2.1)
KCNQ1 11p15.5 IKs potassium channel alpha subunit (KVLQT1, Kv 7.1)
NPPA 1p36 Atrial natriuretic peptide precursor A
NUP155 5p13 Nucleoporin 155 kD
SCN5A 3p21-p24 Cardiac sodium channel alpha subunit (Nav 1.5)

From Tester DJ, Ackerman MJ: Genetics of cardiac arrhythmias. In Braunwald's heart disease, ed
11, Philadelphia, 2018, Elsevier (Table 33.1, p 605.)

FIG. 462.11 Genotype-phenotype correlations in long QT syndrome (LQTS). About 75%
of clinically strong LQTS is caused by mutations in 3 genes (35% KCNQ1 , 30% KCNH2
, and 10% SCN5A ) encoding for ion channels that are critically responsible for the
orchestration of the cardiac action potential. Observed genotype-phenotype
correlations include swimming/exertion/emotion and LQT1, auditory
triggers/postpartum period and LQT2, and sleep/rest and LQT3. (From Tester DJ,
Ackerman MJ: Genetics of cardiac arrhythmias. In Braunwald's heart disease, ed 11,
Philadelphia, 2018, Elsevier, Fig 33-3, p 607.)
 Genetic studies have identified mutations in cardiac potassium and sodium
channels (Table 462.3 ). Additional forms (up to 13 variants) of long QT
syndrome (LQTS) have been described, but these are much more uncommon.
Genotype may predict clinical manifestations; for example, LQTS type 1 (LQT1
) events are usually induced by stress or exertion, whereas events in LQT3 often
occur at rest, especially during sleep (Fig. 462.11 ). LQT2 events have an
intermediate pattern, often occurring in the postpartum period or with auditory
triggers. LQT3 has the highest probability for sudden death, followed by LQT2
and then LQT1. Drugs may prolong the QT interval directly but more often do
so when drugs such as erythromycin or ketoconazole inhibit their metabolism
(Table 462.4 ).
Table 462.4
Acquired Causes of QT Prolongation*
Drugs

Antibiotics—erythromycin, clarithromycin, azithromycin, telithromycin,

trimethoprim/sulfamethoxazole, fluoroquinolones †
Antifungal agents † —fluconazole, itraconazole, ketoconazole
Antiprotozoal agents—pentamidine isethionate
Antihistamines—astemizole, terfenadine (Seldane; Seldane has been
removed from the market for this reason)
Antidepressants—tricyclics such as imipramine (Tofranil), amitriptyline
(Elavil), desipramine (Norpramin), and doxepin (Sinequan)
Antipsychotics—haloperidol, risperidone, phenothiazines such as
thioridazine (Mellaril) and chlorpromazine (Thorazine), selective
serotonin uptake inhibitors
Antiarrhythmic agents
Class 1A (sodium channel blockers)—quinidine, procainamide,
disopyramide
Class III (prolong depolarization)—amiodarone (rare), bretylium,
dofetilide, N -acetyl-procainamide, sotalol
Lipid-lowering agen