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AUGUST 2020 • VOL. 44 NO. 2 • PAGES 13-24 aapgrandrounds.org

Incidence of Vitamin K Deficiency

Bleeding in Infants

Overuse of Continuous Pulse

Oximetry in Bronchiolitis

Health Services Use of Low-Income

Youths Who Died by Suicide

Etiologies of Encephalitis in
Children
 Table of Contents
NEONATOLOGY
Editorial Board Meghan Candee, Salt Lake City, UT
Esther K. Chung, Seattle, WA p15 
Incidence of Vitamin K Deficiency Bleeding in Infants
EDITOR Benjamin Doolittle, New Haven, CT
James A. Taylor, Seattle, WA Mike Dubik, Portsmouth, VA MEDICINE-PEDIATRICS
DEPUTY EDITOR Patricia Fechner, Seattle, WA p16 
Overuse of Continuous Pulse Oximetry in Bronchiolitis
Leslie L. Barton, Tucson, AZ William L. Hennrikus, Hershey, PA
Gloria Higgins, Columbus, OH GENERAL PEDIATRICS
ASSOCIATE EDITOR
Douglas J. Opel, Seattle, WA
Mary-Jane Staba Hogan, p17 
Health Services Use of Low-Income Youths Who Died
New Haven, CT
CME QUESTION EDITOR Daniel Lesser, San Diego, CA
by Suicide
Robert Wittler, Wichita, KS Jonathan Mintzer, Montclair, NJ
INFECTIOUS DISEASE
EDITORIAL BOARD Philip Rosenthal, San Francisco, CA
Cheryl Sanchez-Kazi, Loma Linda, CA p18 
Etiologies of Encephalitis in Children
Kirsten Bechtel, New Haven, CT
Rebecca Brady, Cincinnati, OH David Spar, Cincinnati, OH
ADOLESCENT MEDICINE
Susan L. Bratton, Salt Lake City, UT Jeffrey Winer, Memphis, TN
p19 
Liraglutide for Weight Reduction in Obese Adolescents
GASTROENTEROLOGY
Mission: To provide pediatricians with timely synopses and
p20 Slower Growth Exists Before Celiac Disease Diagnosis
critiques of important new studies relevant to pediatric practice,
reviewing methodology, significance, and practical impact, as part RHEUMATOLOGY
of ongoing CME activity.
p21 
Juvenile Idiopathic Arthritis Outcomes in the “Biologic Era”
HEMATOLOGY/ONCOLOGY
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Transplantation Outcomes in Diamond-Blackfan Anemia
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NEONATOLOGY

Incidence of Vitamin K Deficiency

Bleeding in Infants
Source: Zurynski Y, Grover CJ, Jalaludin B, et al. Vitamin K deficiency Families refuse birth vitamin K administration for a variety of
bleeding in Australian infants 1993-2017: an Australian Paediatric reported reasons. Factors affecting vitamin K administration
Surveillance Unit study. Arch Dis Child. 2020;105(5):433-438; doi: 10.1136/ decisions include perceived risks, a preference for a more “natu-
archdischild-2018-316424 ral” childbirth experience, potential mistrust in allopathic med-
Investigators from multiple Australian institutions conducted a ical practices, and/or reported unfavorable experiences with
prospective cohort study to assess the incidence of vitamin K defi- prior vitamin K therapy.1 Among families refusing intramuscular
ciency bleeding (VKDB) in infants <6 months old. Cases of VKDB vitamin K, a preference for oral vitamin K administration has
were identified through monthly solicitations of pediatricians been reported.2 However, oral vitamin K has been demonstrated
and other child health specialists participating in the Australian to be less efficacious than IM vitamin K preparations in prevent-
Pediatric Surveillance Unit, who report occurrences of several ing VKDB.3,4 Tellingly, in the current study, 7 (12%) of the reported
conditions of interest, including VKDB. Solicitations began in 1993 VKDB cases received oral vitamin K, of whom 6 (86%) did not
and continued through 2017. VKDB was defined as spontaneous complete the currently recommended 3-dose regimen.5
bruising, bleeding, or intracranial hemorrhage associated with The results of the current study demonstrate exceedingly
prolonged clotting times that was not due to disseminated intra- low rates of VKDB among the Australian newborn population.
vascular coagulation or an inherited coagulopathy. For each VKDB Importantly, previously elevated rates of VKDB in the early 1990s
case reported, pediatricians were asked to provide case demo- declined precipitously following a change in recommendations
graphics, clinical characteristics, lab results, type of vitamin K pro- from oral to IM vitamin K given its superior efficacy to oral prepa-
phylaxis received (intramuscular [IM], oral, or none), and outcome. rations. However, current trends demonstrate an increasing
Cases of VKDB were categorized as definite if there was a clini- occurrence of vitamin K refusal in the post-2006 data set. This is
cal history consistent with VKDB as well as complete coagulation especially concerning given that VKDB occurred most frequently
results. A case was probable if a clinical history was consistent, among neonates who received no vitamin K prophylaxis, with
but coagulation results were incomplete. VKDB cases also were withheld consent being by far the most common reason.
classified by age of onset of bleeding: early within 24 hours of Parental refusal of prophylactic therapies provided near the time
birth, classic between 1 and 7 days, and late between 1 week and of birth, including vitamin K administration, erythromycin ocular
6 months of age. Investigators calculated the annual incidence of ointment, and hepatitis B vaccination, is an increasingly common
VKDB between 1993 and 2017 per 100,000 live births using popu- occurrence in newborn medical practice.6 Frequently, hepatitis B
lation estimates published by the Australian Bureau of Statistics. vaccination is deferred to the family’s chosen pediatrician, and
There were 58 reported cases of VKDB (47 definite and 11 prob- erythromycin ointment administration is withheld with a plan to
able) during the study period, corresponding to an annual inci- closely monitor for clinical signs of disease.7 However, with refusal
dence of 0.84 per 100,000 live births (95% CI, 0.64-1.08). Most cases of vitamin K prophylaxis, newborns experience a heightened risk of
(72%) were classified as late VKDB. Vitamin K prophylaxis had been potentially lethal VKDB. It thus follows that educational campaigns
given to 43% (N=25), including IM to 14 and oral to 7 cases of VKDB. geared toward highlighting the favorable risk/benefit ratio of pro-
Among the 33 cases in which no vitamin K prophylaxis was given, phylactic vitamin K administration are warranted to mitigate this
85% (N=28) were due to parental refusal. There was a higher pro- unfortunate risk exposure. (See AAP Grand Rounds. 2017;37 [6]:67.8)
portion of parental refusal of vitamin K prophylaxis among VKDB Bottom Line: Though VKDB is a rare occurrence, ongoing increases
cases from 2006-2017 (63%) than 1993-2005 (32%). in vitamin K prophylaxis refusal are quite concerning and war-
Overall, the most common sites of bleeding among cases were rant urgent educational interventions to prevent this potentially
cutaneous (45%), gastrointestinal (34%), and intracranial (29%). lethal disorder.
There were 6 deaths, all from intracranial hemorrhage in infants References
with late VKDB. In 3 of these cases, parents had refused vitamin 1. Loyal J, et al. Acad Pediatr. 2019;19(7):793-800; doi: 10.1016/j.acap.2019.04.003
K; in the other 3, IM prophylaxis had been given. 2. Bernhardt H, et al. J Paediatr Child Health. 2015;51(9):889-894; doi: 10.1111/jpc.12887
3. Ng E, et al. Paediatr Child Health. 2018;23(6):394-402; doi: 10.1093/pch/pxy082
The investigators conclude that the overall incidence of VKDB is 4. Sankar MJ, et al. J Perinatol. 2016;36(Suppl 1):S29-35; doi: 10.1038/jp.2016.30
low, but cases of VKDB due to parental refusal of vitamin K pro- 5. National Health and Medical Research Council. Joint statement and recommendations
phylaxis are increasing. on vitamin K administration to newborn infants to prevent vitamin K deficiency
bleeding in infancy. Canberra: National health and medical Research Council, 2010.
COMMENTARY BY Available at www.nhmrc.gov.au/about-us/ publications/vitamin-k-administration-
Jonathan Mintzer, MD, FAAP, Neonatal-Perinatal Medicine, newborns-joint-statement#block-viewsblock-file-attachments-content-block-1.
Mountainside Medical Center, Montclair, NJ 6. Danziger P, et al. Hosp Pediatr. 2019;9(6):429-433; doi: 10.1542/hpeds.2019-0029
7. Burton T, et al. Adv Pediatr. 2018;65(1):89-104; doi: 10.1016/j.yapd.2018.04.006
Dr Mintzer has disclosed no financial relationship relevant to this commentary. This commentary
8. Loyal J, et al. Acad Pediatr. 2017;17(4):368-373; doi: 10.1016/j.acap.2016.10.012
does not contain a discussion of an unapproved/investigative use of a commercial product/device.

• August 2020 15
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MEDICINE-PEDIATRICS

Overuse of Continuous Pulse

Oximetry in Bronchiolitis
Source: Bonafide CP, Xiao R, Brady PW, et al. Prevalence of continuous The current provocative study addresses a vexing issue in the man-
pulse oximetry monitoring in hospitalized children with bronchiolitis not agement of bronchiolitis among patients on room air. Why do we
requiring supplemental oxygen. JAMA. 2020;323(15):1467-1477; doi: 10.1001/ persist with cSpO2 when several treatment algorithms—including
jama.2020.2998 the Choosing Wisely campaign and the AAP—recommend against
Investigators from multiple institutions conducted a multicenter, its use?1 Several compelling forces promote the use of cSpO2,
cross-sectional study to assess the use of continuous pulse oxim- despite guidelines. Perhaps the most persuasive is parental per-
etry (cSpO2) in children hospitalized for bronchiolitis but not need- ception. One important study showed that parents believed cSpO2
ing supplemental oxygen. Patients were eligible if they were (a) 8 was protective, even if they knew it might delay discharge.2 Also,
weeks through 23 months old, (b) admitted with bronchiolitis from physicians still struggle with uncertainty about recommendations.
December 2018 to March 2019 to an acute (nonintensive) care ward at (See AAP Grand Rounds. 2014;32[6]:61.3) Since our therapeutic
a hospital that belongs to the Pediatric Research in Inpatient Settings options—supplemental oxygen and nasal suctioning—are mostly
(PRIS) network, and (c) not receiving any supplemental oxygen at the supportive, cSpO2 has become an all too common mainstay. How
time of data collection. Patients were excluded if they were born at else will we know if a patient needs a higher level of care?
<28 weeks’ gestation or had cyanotic congenital heart disease, pul- However, cSpO2 is not a benign intervention. Several studies
monary hypertension, a home oxygen requirement, or tracheos- show that it prolongs hospitalization, increases health care costs,
tomy. Demographics and clinical characteristics of participants were and may cause patient harm.4-6 Bronchiolitis is the most com-
obtained from the medical record, including age (categorized as 8 mon cause of hospitalization among children <2 years of age and
weeks-5 months, 6-11 months, 12-17 months, and 18-23 months), race, costs more than $734 million per year.7 We need to get this right.
gestational age, time since weaning supplemental oxygen (catego-
rized as never received oxygen and <1, 1-<2, 2-<4, 4-<6, 6-<12, 12-<24, Interestingly, the current investigators found a broad range of
and ≥24 hours), history of apnea or cyanosis during present illness, oximetry use—from 6% to 82% of observations—with no cor-
hospital type (categorized as freestanding children’s hospital, chil- relation between the type of hospital and the use of cSpO2.
dren’s hospital within hospital, and community hospital), and comor- Freestanding children’s hospitals and children’s hospitals within
bid conditions associated with neurologic impairment. a hospital were just as likely as community hospitals to use cSpO2.
Overall, 27% of the variability was associated with unmeasured
The primary outcome was use of cSpO2, determined via visual hospital-level variables. Those patients perceived to be higher
confirmation by study staff. Staff conducted observations during risk, such as younger infants, those with a history of apnea, or
daytime hours as well as at night. Investigators calculated the those who recently weaned off oxygen, also received cSpO2. Also,
cSpO2 use percentage by dividing the number of observations in cSpO2 was more common at night. The results of this study com-
which use of cSpO2 was confirmed by the total number of obser- pel us toward the logical next step: de-implementation trials to
vations. Investigators used multivariable logistic regression to demonstrate either noninferiority or even beneficial outcomes.
identify factors that were independently associated with cSpO2
use after adjusting for potential confounders. Bottom Line: Despite guidelines, cSpO2 is common among hospital-
ized children with bronchiolitis not receiving supplemental oxygen.
There were 3,525 patient observations at 49 PRIS hospitals included
in analysis. The overall percentage of cSpO2 use was 46% (95% CI, EDITOR’S NOTE
40%-53%). In multivariable analyses, several variables were asso- Prior studies of previously healthy infants with bronchiolitis
ciated with cSpO2 use, including age (8-week to 5-month-olds had cared for at home demonstrated that transient oxygen desatura-
a 1.51 [95% CI, 1.12-2.03] increased odds of cSpO2 use compared to tion detected by cSpO2 is common and does not affect outcome.
18- to 23-month-olds), time since weaning supplemental oxygen (See AAP Grand Rounds 2106;35[6]:64.8) Oximeter use in both
(those weaned within 2-<4 hours had the highest odds of cSpO2 inpatients and outpatients requires reexamination.
use compared to those who never had received oxygen [adjusted References
odds ratio, aOR, 5.55; 95% CI, 3.91-7.89]), history of apnea or cyano- 1. Ralston SL, et al. Pediatrics. 2014;134(5):e1474-e1502; doi: 10.1542/peds.2014-2742
2. Hendaus MA, et al. Patient Prefer Adherence. 2018;12:483-487; doi: 10.2147/PPA.S152880
sis during present illness (aOR, 1.40; 95% CI, 1.01-1.93), and night-
3. Schuh S, et al. JAMA. 2014;312(7):712-718; doi: 10.1001/jama.2014.8637
time observation (aOR, 2.07; 95% CI, 1.76-2.43). 4. Schroeder AR, et al. Arch Pediatr Adolesc Med. 2004;158(6):527-530; doi: 10.1001/
archpedi.158.6.527
The investigators conclude that cSpO2 use in children admitted for
5. Cunningham S, et al. Health Technol Assess. 2015;19(71):i-xxiii, 1-172; doi: 10.3310/
bronchiolitis who do not need supplemental oxygen is frequent. hta19710
COMMENTARY BY 6. McBride SC, et al. Pediatrics. 2005;116(3):603-608; doi: 10.1542/peds.2004-2387
7. Fujiogi M, et al. Pediatrics. 2019;144(6):e20192614; doi: 10.1542/peds.2019-2614
Benjamin R. Doolittle, MD, M Div, FAAP, FACP, Internal Medicine &
8. Principi T, et al. JAMA Pediatr. 2016;170(6):602-608; doi: 10.1001/
Pediatrics, Yale University School of Medicine, New Haven, CT jamapediatrics.2016.0114
Dr Doolittle has disclosed no financial relationship relevant to this commentary. This commentary
does not contain a discussion of an unapproved/investigative use of a commercial product/device.

16 aapgrandrounds.org
GENERAL PEDIATRICS

Health Services Use of Low-Income

Youths Who Died by Suicide
Source: Fontanella CA, Warner LA, Steelesmith D, et al. Clinical profiles and Suicide is the 10th-leading cause of death in the United States,
health services patterns of Medicaid-enrolled youths who died by suicide. claiming the lives of >47,000 people annually.1 Approximately 14%
JAMA Pediatr. 2020;174(5):470-477; doi: 10.1001/jamapediatrics.2020.0002 of suicide deaths occur among youths and young adults, ages
Investigators from multiple institutions conducted a case-con- 10-24 years.1 The Joint Commission requires that hospitals screen
trol study to compare clinical conditions and health care ser- all patients being evaluated and treated for behavioral health
vices among children 10-18 years old who died by suicide to conditions for suicidal ideation, starting at age 12 years, using a
those of living controls. Cases were children and adolescents validated screening tool.2,3 The AAP recommends that all adoles-
from 16 US states who were enrolled in Medicaid and died by cents aged 12 years and older be screened for depression annu-
suicide between 2009 and 2013. Review of death certificates was ally using a formal screening tool.4
used to identify these cases. Up to 10 controls were matched The current investigators’ findings that youths who died from
to each case on sex, race, ethnicity, state of residence, and age. suicide were more likely to have an MH or PH visit in the pre-
Medicaid databases were reviewed, and information on all men- ceding 1 and 6 months suggests that there may be opportunities
tal health (MH) and physical health (PH) visits in the 6-month for clinicians to screen for suicidal ideation and provide support
period before the date of death (index date) were abstracted for and treatment. The odds of suicide decreased by approximately
cases and their matching controls. Visits were categorized as MH 22% for every 5 MH visits that occurred in the 30 days prior to
or PH visits using ICD-9 and/or mental health procedure codes. suicide, suggesting that frequent contact with a mental health
Conditional logistic regression was used to identify psychiatric provider may be beneficial. The authors did not address emer-
conditions associated with death by suicide and to assess the gency visit diagnoses, medications, sexuality, bullying, and other
impact of number of mental health visits within 30 days of the important factors related to suicide risk.5,6
index date on the risk of suicide. Chi-square tests were used to
To address the lack of available MH providers, a number of
compare numbers and types of visits in cases and controls.
regions have established telephone-based MH consult services,
Data were analyzed on 910 youths who died by suicide and 6,346 whereby primary care providers consult with child psychiatrists
controls. Overall, 72.9% of the sample was male, and the mean to discuss treatment and follow-up.7 One innovative approach
age at the index date was 15.7 + 2.0 years. Among cases, 41.3% to address screening youth is the use of a suicide risk screen-
had a mental health diagnosis compared to 17.5% of controls (P < ing clinical pathway in pediatric EDs.2 A number of resources are
.001). In the 1 month before the index date, 22.4% of cases had an available online that target youth suicide prevention.8
MH visit versus 10.1% of controls, and 32.1% had a PH visit versus
17.2% of controls (odds ratio [OR], 3.21; 95% CI, 2.65-3.89; and OR, Bottom Line: Among Medicaid-enrolled youths who died by sui-
2.38; 95% CI, 2.03-2.79, respectively). In the final 6 months before cide, the majority had accessed health services in the preceding
the index date, cases were significantly more likely than controls 6 months.
to have an MH or PH visit than controls (40.3% and 66.3%, respec- EDITOR’S NOTE
tively, vs 18.8% and 52%, respectively). Among those with any vis- ED visits for pediatric MH disorders have risen by 60% and those
its, 24.5% of cases had ≥4 MH visits in the 1 month before the for deliberate self-harm by 329% during the last decade.9 The
index case, compared to 18.3% of controls (P < .001), and 26.7% data underscore the need for MH services—both emergent and
had ≥2 PH visits versus 19.0% of controls (P < .001). For every 5 nonemergent—in children of all economic strata.
MH visits in the month before the index date, the risk of suicide References
decreased (OR, 0.78; 95% CI, 0.65-0.92). Psychiatric conditions 1. National Institutes of Mental Health. Suicide. Available at: https://www.nimh.nih.gov/
associated with a significantly increased risk for suicide included health/statistics/suicide.shtml
2. Brahmbhatt K, et al. Psychosomatics. 2019;60(1):1-9; doi: 10.1016/j.psym.2018.09.003
depression (OR, 3.19), bipolar or mood diagnosis (OR, 2.09), and
3. The Joint Commission. R3 report. 2018;18:1-5. Updated 2019. Available
substance use disorder (OR, 2.65).
at: https://www.jointcommission.org/en/standards/r3-report/
The authors conclude that use of health care services among r3-report-issue-18-national-patient-safety-goal-for-suicide-prevention/
4. Zuckerbrot RA, et al. Pediatrics. 2018;141:e20174081; doi: 10.1542/peds.2017-4081
youths who die by suicide were distinct from those of living
5. Carbone JT, et al. J Pediatr. 2019;206:225-232; doi: 10.1016/j.jpeds.2018.10.017
controls. 6. Mueller AS, et al. Am J Public Health. 2015;105:980-985; doi: 10.2105/AJPH.2014.302391
COMMENTARY BY 7. Hilt RJ, et al. JAMA Pediatr. 2013;167(2):162-168; doi: 10.1001/2013.jamapediatrics.47
8. Interagency Working Group on Youth Programs. Preventing youth suicide. Available at:
Esther K. Chung, General Pediatrics, MD, MPH, FAAP, University of
https://youth.gov/youth-topics/youth-suicide-prevention/preventing-youth-suicide
Washington School of Medicine and Seattle Children’s Hospital, 9. Lo CB, et al. Pediatrics. 2020;145(6)e20191536; doi: 10.1542/peds.2019-1536
Seattle, WA
Dr Chung has disclosed no financial relationship relevant to this commentary. This commentary
does not contain a discussion of an unapproved/investigative use of a commercial product/device.

• August 2020 17
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INFECTIOUS DISEASES

Etiologies of Encephalitis in Children

Source: Erickson TA, Muscal E, Munoz FM, et al. Infectious and autoim- Encephalitis is a rare, but serious, neurologic condition that
mune causes of encephalitis in children. Pediatrics. 2020;145(6):e20192543; often requires ICU management.1 Similar to previous investiga-
doi: 10.1542/peds.2019-2543 tors,2,3 the authors identified an etiology in about half of the
Investigators from several Texas institutions conducted a ret- 231 cases. Identifying an etiology may allow initiation of effec-
rospective cohort study to assess the etiology and characteris- tive therapy.1 Herpes simplex virus (HSV) encephalitis is treated
tics of pediatric patients diagnosed with encephalitis. Children with IV acyclovir and, therefore, polymerase chain reaction (PCR)
were eligible if they had an ICD-9 or ICD-10 code associated with testing of CSF for HSV is recommended.4 Enterovirus is another
encephalitis or meningoencephalitis from an admission at Texas etiology that can be identified by PCR testing of CSF.5 No specific
Children’s Hospital from 2010-2017 and were >90 days old and antiviral therapy is available, but its identification provides prog-
<18 years old. Investigators reviewed the medical records of eli- nostic information and can avoid unnecessary diagnostic testing
gible children to identify cases of encephalitis using the 2013 or empiric therapies.1
International Encephalitis Consortium definition for encephali- The authors identified 2 additional infectious etiologies that are
tis, which required altered mental status lasting ≥24 hours with relatively common. Arboviruses (arthropod-borne viruses) are
no other explainable cause and ≥2 of the following: fever ≥38°C transmitted to humans by the bites of infected mosquitoes and
within 3 days of presentation, new onset seizures, new onset of ticks and, hence, occur from late spring through early fall.6 Their
focal neurologic findings, cerebrospinal fluid (CSF) white blood distribution varies by geographic location, so eliciting a travel his-
cell count of ≥5/mm3, new onset neuroimaging abnormality, or tory is important. Arbovirus diagnosis is established by virus-spe-
EEG abnormality. Data on demographics, lab, clinical character- cific antibody testing of the serum (probable case) and CSF
istics, and season of admission of identified encephalitis cases (confirmed case).1 There are no specific therapies, so management
were abstracted from the medical record. is supportive. The second etiology is B. henselae, the bacteria that
Cases were categorized as having an identified or unknown eti- cause cat-scratch disease. Clues to this diagnosis include contact
ology. Identified etiologies included infectious etiologies, which with a cat and a history of a papule at a cat scratch with ipsilateral
were further categorized as viral, bacterial, or other, and nonin- regional lymphadenopathy.7 Serology and PCR are the diagnostic
fectious etiologies, which included autoimmune or immune-me- tests of choice. The disease usually has an excellent prognosis;
diated etiologies. To meet criteria for autoimmune encephalitis, antibiotics can be used but may not be needed.
cases needed to have altered mental status or neuropsychiatric NMDAR encephalitis was first defined in 2005 and increasingly
deficits and ≥1 objective central nervous system abnormality. is being recognized as a treatable autoimmune encephalitis in
Cases also were considered to have autoimmune encephalitis if children.8 Definitive diagnosis is made by detecting anti-NMDAR
the CSF antibody test was present in an abnormal range in the antibodies in the CSF. Some cases are associated with ovarian
absence of any other identified case of encephalitis. tumors that require resection. Immunosuppressive therapy
There were 231 identified cases of encephalitis during the study improves outcomes.
period, with 58% (N=133) having an identified etiology. Among Bottom Line: Herpesviruses, arboviruses (including West Nile
cases with identified etiologies, most (N=73) had infectious etiolo- virus), B. henselae, and NMDAR are common causes of encepha-
gies. The predominant infectious etiology was viral (N=51), with the litis in children. Testing for these etiologies can guide manage-
most common viral etiologies being herpesvirus (N=20) and arbo- ment decisions and may improve long-term outcomes.
virus (N=13, with West Nile virus causing 12 of these cases). The
EDITOR’S NOTE
most common bacterial etiology was Bartonella henselae (N=7).
The results of the current study are sobering. Despite the num-
Among the 60 cases of noninfectious etiology, the most frequently
ber (>100) of etiologies associated with encephalitis, the per-
identified cause was anti-N-methyl-D-aspartate receptor (NMDAR)
centage of patients with an identified etiology has remained
encephalitis (N=31). Infectious (vs autoimmune) causes of enceph-
static.1 Further delineation of noninfectious and novel infectious
alitis were significantly more common in males and those who
were immunocompromised. There were no observed associations etiologies is clearly necessary.
between etiologies of encephalitis and season of admission. References
1. Messacar K, et al. Infect Dis Clin N Am. 2018;32(1):145-162; doi: 10.1016/j.idc.2017.10.007
The investigators conclude that arbovirus, Bartonella, and 2. George BP, et al. PloS One. 2014;9(9):e104169; doi: 10.1371/journal.pone.0104169
NMDAR testing should be considered in the etiologic diagnosis 3. Iro MA, et al. Lancet Infect Dis. 2017;17:422-430; doi: 10.1016/S1473-3099(17)30114-7
of encephalitis in children. 4. Weil AA, et al. Clin Infect Dis. 2002;34:1154-1157; doi: 10.1086/339550
5. Rudolph H, et al. Pediatr Infect Dis J. 2016;35:567-569; doi: 10.1097/
COMMENTARY BY INF.0000000000001090
Rebecca Brady, MD, FAAP, Pediatric Infectious Diseases, 6. AAP. Arboviruses. In: Kimberlin DW, Brady MT, Jackson MA, Long SS, eds. Red Book:
Cincinnati Children’s Hospital, Cincinnati, OH 2018 Report of the Committee on Infectious Diseases. 31st ed. Itasca, IL: American
Academy of Pediatrics; 2018:220-227
Dr Brady has disclosed no financial relationship relevant to this commentary. This commentary does
7. Cherinet Y, et al. Emerg Med J. 2008;25:703-704; doi: 10.1136/emj.2008.060616
not contain a discussion of an unapproved/investigative use of a commercial product/device.
8. Scheer S, et al. J Pediatr Health Care. 2016;30:347-358; doi: 10.1016/j.pedhc.2015.09.004

18 aapgrandrounds.org
ADOLESCENT MEDICINE

Liraglutide for Weight Reduction

in Obese Adolescents
Source: Kelly AS, Auerbach P, Barrientos-Perez M, et al. A randomized, COMMENTARY BY
controlled trial of liraglutide for adolescents with obesity. N Engl J Med. Charlene Wong, MD, MSHP, FAAP, Adolescent Medicine, Duke
2020;382(22):2117-2128; doi: 10.1056/NEJMoa1916038 Clinical Research Institute, Margolis Center for Health Policy, Duke
Investigators from multiple institutions conducted a randomized, University, Durham, NC
double blind, placebo-controlled trial to assess the efficacy and Sarah Armstrong, MD, FAAP, Pediatrics, Population Health
safety of liraglutide, a glucagon-like peptide analogue that increases Sciences, Duke Clinical Research Institute, Duke University School
postprandial insulin, reduces glucagon secretion, and delays gastric of Medicine, Durham, NC
emptying, in adolescents with obesity. Children aged 12-17 years were Drs Wong and Armstrong have disclosed no financial relationship relevant to this commentary.
This commentary does not contain a discussion of an unapproved/investigative use of a com-
enrolled at 32 sites in 5 countries (Belgium, Mexico, Russia, Sweden, mercial product/device.
and the United States). Children were eligible if they had a BMI ≥30, a
weight change of <5 kg in the previous 90 days, and a poor response Despite decades of research and public health advocacy to
to lifestyle therapy alone. Participants were randomly assigned in a 1:1 reduce pediatric obesity, prevalence continues to increase.1 In
ratio to the intervention or placebo group. Intervention participants adults, pharmacologic options have expanded in the last sev-
received 12 weeks of lifestyle therapy followed by 56 weeks of liraglu- eral years but remain limited to 4 FDA-approved drugs (orlistat,
tide subcutaneously at a dose of 0.6 mg once daily for 1 week, which phentermine-topiramate, naltrexone-bupropion, and liraglu-
was increased weekly until the maximum tolerated dose or the high- tide). For children and teens, the options remain even more lim-
est dose allowed of 3.0 mg. Placebo participants received 12 weeks of ited. Orlistat, an intestinal lipase inhibitor, is the only medication
lifestyle therapy followed by 56 weeks of a volume-matched placebo currently approved for long-term use in children >12 years old,
administered subcutaneously once daily. but it is infrequently prescribed because of modest efficacy and
intolerable side effects, including flatus and steatorrhea.2
The primary outcome was the change from baseline at week 56
in the BMI standard deviation score, a measure of the number In adults, liraglutide leads to clinically meaningful weight loss3
of standard deviations from the population mean BMI, matched and improvements in cardiovascular4 outcomes in patients with
for age and sex. Secondary outcomes included a change from type 2 diabetes. In children, we have evidence of safety and
baseline in BMI and adverse events during the treatment period. tolerability in children aged 7-185 years and improved glycemic
Investigators assessed the effect of allocation group on out- control6 among children with type 2 diabetes. The results of the
comes according to the intention-to-treat principle. present study may be practice-changing; for children aged 12-17
years with obesity receiving lifestyle therapy, liraglutide reduced
There were 125 participants in the intervention group and 126 in the BMI nearly 5 kg/m2 more than placebo.
placebo group; 80.8% and 79.4% intervention and placebo partici-
pants, respectively, completed treatment through week 56. Among The limitations of translating this evidence into practice are not
intervention participants, 82.4% reached the maximal 3.0 mg dose. insignificant. How do physicians define having “failed” lifestyle treat-
ment? Will parents and teens be accepting of an injectable weight
The change from baseline in BMI standard deviation score was loss medication? How will patients comply with the daily regimen?
greater in the intervention group than placebo group (treatment Limitations of the current study include lower proportions of par-
difference, -0.22; 95% CI, -0.37, -0.08). There also was a greater ticipants from minority backgrounds despite growing racial/ethnic
relative change in BMI among intervention participants than and income disparities in childhood obesity.1 If liraglutide becomes
placebo participants (treatment difference, -4.64; 95% CI, -7.14, more widely available for children, monitoring is needed on its use
-2.14). There was no difference in the proportion of participants and impact among adolescents in poor or minority households who
who reported adverse events in the intervention (88.8%) and experience lower access to health-promoting food, physical activity
placebo (84.9%) groups. However, gastrointestinal events (nau- opportunities, and other obesity treatment programs.7
sea, vomiting, and diarrhea) were reported by more interven-
tion than placebo participants (64.8% vs 36.5%, respectively; P < We are in urgent need of obesity treatments to augment lifestyle
.001). Discontinuation of the trial because of adverse events also modifications, especially for adolescents. Engaging adolescents
occurred in more intervention than placebo participants (13 vs 0 in comprehensive obesity-intensive lifestyle therapy is very chal-
participants, respectively; P < .001). lenging. Incorporating liraglutide into a chronic disease manage-
ment model of care for adolescents with obesity in addition to
The authors conclude that liraglutide plus lifestyle therapy is self-management support and delivery systems, policies, and
superior to placebo plus lifestyle therapy in reduction of BMI in communities to support young people can maximize the lifelong
adolescents with obesity. benefits of reducing obesity in adolescents.
Bottom Line: When combined with lifestyle changes, daily sub-
cutaneous liraglutide results in greater BMI reduction in adoles-
cents with obesity than placebo.
See Liraglutide on page 20

• August 2020 19
TM
GASTROENTEROLOGY

Slower Growth Exists Before

Celiac Disease Diagnosis
Source: Auricchio R, Stellato P, Bruzzese D, et al. Growth rate of coe- are evident. Already at 4 months, before gluten introduction, infants
liac children is compromised before the onset of the disease. Arch Dis who eventually will develop CD were about 0.5 cm shorter and 100
Child. 2020 30 April [published online ahead of print]; doi: 10.1136/ g lighter than their peers who did not develop CD by 6 years. The
archdischild-2019-317976 differences in growth increments between the cases and controls
Investigators from multiple institutions conducted a case-con- were based on mean values, not those of specific individuals. The
trol study to assess growth in children with celiac disease variability between individuals was too large to allow for individual
(CD). Children were eligible if they were a newborn and had a differences to be seen. The investigators’ findings are interesting in
first-degree relative with CD. Participants had their length and terms of CD etiology, but they are unlikely to be useful clinically for
height measured about once a month from birth to age 6 years. prediction of CD since only aggregate data showed the differences
Participants also periodically were monitored for serum mark- in growth. What is the likely reason for this difference observed even
ers of CD, including serum antigliadin and anti-transglutami- before gluten introduction into the diet? The authors hypothesize
nase-IgA antibodies. Participants who were diagnosed during that genetic variants associated with increased risk for CD may be
the study period with CD per European Society for Paediatric responsible. The CD-associated HLA haplotype also has been asso-
Gastroenterology, Hepatology, and Nutrition criteria were con- ciated with slower growth in the first 24 months of life.3 The effect of
sidered cases; those who were not were considered controls. HLA haplotype could not be evaluated in this study since all new-
borns were HLA DQ-positive. Other CD-predisposing factors may be
The primary outcomes were length and height, standardized
present before gluten introduction and could contribute to growth
for age and sex by transforming to z-scores based on the WHO
impairment. Infections may be the result of one of these factors.
growth standards. Investigators characterized cases and con-
trols using descriptive statistics. They also compared outcomes However, neither infections nor any other clinical events
between case and control participants at birth, 1, 4, 12, and 24 were found to be related to the outcome in the whole cohort.
months of age using t-tests, as well as over the first year of life Modifiable and nonmodifiable maternal and perinatal factors,
and from birth to age 6 years using linear mixed-effect models. including elective caesarian delivery and maternal UTI, are epi-
demiologically associated with increased risk of CD in childhood.
There were 944 participants included in analysis, 113 (11.9%) of whom
(See AAP Grand Rounds. 2016;36[4]:46.4)
developed CD by age 6 years. The median age at CD diagnosis was 40
months. None of the cases developed CD before 12 months of age. Bottom Line: Slower growth is present in CD patients even before
introduction of gluten in the diet.
In comparison of outcomes at birth, 1, 4, 12, and 24 months, cases had
significantly lower length and weight mean z-scores than controls at EDITOR’S NOTE
12 and 24 months of age but no significant difference in length and We repeatedly have cautioned prudence when considering the
weight z-scores prior to 12 months of age. In linear models, however, increasingly common and expensive elimination of dietary glu-
cases had a significantly lower growth rate in weight (-0.027 z-score/ ten by those without gluten allergy or CD.4 The findings of the
month; 95% CI, -0.038, -0.017) and length (-0.018 z-score/month; 95% current investigators suggest that growth impairment in the truly
CI, -0.031, -0.005) during the first year of life. The growth of cases gluten sensitive may be inherent in those who subsequently
from birth to age 6 years also was significantly different from con- develop CD before gluten introduction, absolving gluten of the
trols (weight, -0.006 z-score/month; 95% CI, -0.009, -0.004; length, culpability for early compromised growth.
-0.007 z-score/month; 95% CI, -0.010, -0.005). References
1. Lohi S, et al. Aliment Pharmacol Ther. 2007;26(9):1217-1225; doi:
Investigators conclude that growth was significantly slower in
10.1111/j.1365-2036.2007.03502.x
children with CD, and this slow growth was apparent before CD 2. Almallouhi E, et al. J Pediatr Gastroenterol Nutr. 2017;65(4):432-437; doi: 10.1097.
diagnosis. MPG.0000000000001532
3. Peet A, et al. Diabetes Metab Res Rev. 2014;30:60-68; doi: 10.1002/dmrr.2449
COMMENTARY BY
4. Namatovu F, et al. BMC Pediatr. 2016;16(1):77; doi: 10.1186/s12887-016-0613-y
Philip Rosenthal, MD, FAAP, Pediatric Gastroenterology, University
of California, San Francisco, San Francisco, CA
Dr Rosenthal has disclosed no financial relationship relevant to this commentary. This commentary Liraglutide continued from page 19
does not contain a discussion of an unapproved/investigative use of a commercial product/device.
References
The results of the current study suggest that growth is affected 1. Skinner AC, et al. Pediatrics. 2018;141(3):e20173459; doi: 10.1542/peds.2017-3459
2. Chanoine JP, et al. Int J Pediatr Obes. 2011;6(2):95-101; doi: 10.3109/17477166.2010.519387
long before symptoms and diagnosis are apparent in CD. CD has
3. Pi-Sunyer X, et al. N Engl J Med. 2015;373(1):11-22; doi: 10.1056/NEJMoa1411892
been increasingly diagnosed in the past few years.1 (See AAP Grand 4. Marso SP, et al. N Engl J Med. 2016;375(4):311-322; doi: 10.1056/NEJMoa1603827
Rounds. 2018;39[1];9.2) The cause of this increase has not been eluci- 5. Mastrandrea LD, et al. Pediatr Obes. 2019;14(5):e12495; doi: 10.1111/ijpo.12495
dated. In the current study, investigators found that altered growth 6. Tamborlane WV, et al. N Engl J Med. 2019;381(7):637-646; doi: 10.1056/NEJMoa1903822
may already be manifested before any clinical or serologic signs 7. Byrd AS, et al. Curr Obes Rep. 2018;7(2):130-138; doi: 10.1007/s13679-018-0301-3

20 aapgrandrounds.org
RHEUMATOLOGY

Juvenile Idiopathic Arthritis

Outcomes in the “Biologic Era”
Source: Chhabra A, Robinson C, Houghton K, et al. Long-term outcomes and with rheumatoid factor-positive polyarthritis and ≥70% of
disease course of children with juvenile idiopathic arthritis in the ReACCh- patients with other types of JIA achieved inactive disease within 2
Out cohort: a two-centre experience. Rheumatology (Oxford). 2020 13 May years.3 The current report provides longer-term follow-up of 247
[published online ahead of print]; doi: 10.1093/rheumatology/keaa118 of these JIA patients from 2 of the centers involved in the origi-
Investigators from the University of British Columbia, Vancouver, nal study, followed until 2018, discharge from clinic, or transfer
Canada, and McMaster University, Hamilton, Canada, conducted a to adult care. Though not separated by subtype in the current
retrospective cohort study to assess long-term outcomes in chil- report, outcomes remained similarly favorable, with 72% having
dren diagnosed with juvenile idiopathic arthritis (JIA) during the inactive disease at study end. Children with a large burden of
era when biologic treatments were available. Study participants residual arthritis at the end of this period were a low percentage
had been enrolled in the Research in Arthritis in Canadian Children of the initial cohort (28% with residual active disease x 35% with
Emphasizing Outcomes (ReACCh-Out) study that was designed to >1 active joint = 10%). An important omission in this report is the
assess clinical outcomes in patients diagnosed with JIA between percentage of patients in each outcome group who had taken or
2005 and 2010. Medical records of children in this cohort were still were taking biologic therapy.
reviewed in 2018, and data on disease activity, current treatment, Factors in addition to the use of powerful and expensive medica-
and joint damage at their last visit were abstracted. Disease activity tions likely contribute to improved outcomes in developed coun-
was classified as active or inactive based on the Wallace criteria; tries. One such example is a shift in the JIA care paradigm toward
participants were classified as being in remission off medications if early aggressive treatment, demonstrated to be important in the
they had ≥12 continuous months with inactive disease while being Trial of Early Aggressive Treatment of Polyarticular JIA (TREAT).1
off medications and in remission on medication if they had ≥6 con- Early prescribing of methotrexate for most categories of JIA is
tinuous months with inactive disease while receiving medications.1 now the norm.4 Other factors contributing to overall improved
The rate of inactive disease among the patients in the study was outcomes likely include an increased number of pediatric rheu-
informally compared to that of a historical cohort of children diag- matologists and an increased awareness of JIA among primary
nosed with JIA between 1974 and 1994 at 1 of 3 Canadian centers. In care providers leading to more timely referrals.
this cohort, 41% had active disease at a median age of 18.8 years.2
In a growing child, prompt reduction or elimination of joint
Data were analyzed on 247 participants. The median age at last visit inflammation without long-term use of corticosteroids translates
for these patients was 16.9 years with a median length of follow-up into less damage (eg, less overall growth retardation, osteopenia,
of 5.6 years after diagnosis; 58% were female. Overall, 180 study limb length discrepancy, micrognathia, limitation of joint motion,
patients (73%; 95% CI, 67%-78%) met criteria for inactive disease; 61 and uveitis-induced vision deficit) and better function. Research
(25%; 95% CI, 20%-30%) were in remission on medications, and 116 is ongoing to define phenotypic and genetic markers that should
(47%; 95% CI, 41%-53%) were in remission off medications. Among help predict prognosis and guide treatment.5,6
different types of JIA, those with systemic JIA had the highest remis-
sion rate (70%), and those with rheumatoid factor-positive polyar- The Bottom Line: Children with JIA diagnosed in the biologic era
thritis had the lowest (18%). For patients with active disease, 22% experience increased frequency of remission and decreased per-
had no active joints at the last visit, and 43% had one active joint. manent joint damage than historical controls. There is, however,
Overall, joint damage (erosion or joint space narrowing on x-ray or still room for improvement in the treatment of the different sub-
MRI) was seen in 45 participants (18%), 2 had avascular necrosis, and types of JIA.
5 (2%) required joint surgery. At their last visit 51% of study partici- EDITOR’S NOTE
pants were on at least one antirheumatic medication, including 10% Although biologic therapy is “revolutionizing the outcome” of JIA,
on nonsteroidal anti-inflammatory drugs, 19% on disease-modify- it is, as demonstrated by the results of the current study, a rev-
ing antirheumatic drugs, and 22% on biologics. olution still in progress. (See AAP Grand Rounds. 2019;41[6]:67.7)
The authors conclude that, in the era of biologic therapy, chil- References
dren with JIA have a more favorable prognosis compared to his- 1. Wallace C, et al. Arthritis Rheum. 2012;64:2012-21; doi: 10.1002/art.34343
2. Oen K, et al. J Rheumatol. 2002;29(9):1989-1999
torical cohorts.
3.  Guzman J, et al. Ann Rheum Dis. 2015;74:1854-1860; doi: 10.1136/
COMMENTARY BY annrheumdis-2014-205372

Gloria Higgins, PhD, MD, FAAP, FACR, Pediatric Rheumatology, The 4.  Giancane G, et al. Curr Opin Rheumatol. 2019;31:428-435; doi: 10.1097/
BOR.0000000000000632
Ohio State University, Columbus, OH 5.  Guzman J, et al. Curr Opin Rheumatol. 2019;31:436-439; doi: 10.1097/
Dr Higgins has disclosed no financial relationship relevant to this commentary. This commentary BOR.0000000000000620
does not contain a discussion of an unapproved/investigative use of a commercial product/device.
6. Nigrovic PA, et al. Curr Opin Rheumatol. 2019;31:402-410; doi: 10.1097/
In the original multicenter ReACCh-Out cohort, composed of 1,104 BOR.0000000000000637
7. Baris HE, et al. Clin Rheumatol. 2018;37(12):3263-3273; doi: 10.1007/s10067-018-4297-6
Canadian JIA patients followed from 2005-2010, 48% of patients

• August 2020 21
TM
HEMATOLOGY/ONCOLOGY

Transplantation Outcomes in
Diamond-Blackfan Anemia
Source: Strahm B, Loewecke F, Niemeyer CM, et al. Favorable outcomes of craniofacial, thumb, renal, or cardiac anomalies found in 50% of
hematopoietic stem cell transplantation in children and adolescents with cases. In young adulthood, affected individuals have an increased
Diamond-Blackfan anemia. Blood Adv. 2020;4(8):1760-1769; doi: 10.1182/ risk of malignancies, including myelodysplastic syndrome,
bloodadvances.2019001210 acute myelogenous leukemia, colon cancer, and osteosarcoma.
Investigators from multiple international institutions conducted Diagnosis is supported by elevated serum erythrocyte adenos-
a retrospective cohort study to assess outcomes in children <18 ine deaminase activity, fetal hemoglobin, and erythropoietin,
years old with Diamond-Blackfan anemia (DBA) who received an with deficient marrow red cell precursors.1 Approximately 60% of
allogeneic hematologic stem cell transplantation (HSCT) between cases have been associated with 7 of 79 known genes encoding
1985 and 2017. Children were identified using German and French ribosomal proteins or related gene mutations in GATA1 and TSR2.
DBA and HSCT registries. Patient characteristics, HSCT informa- Inheritance is autosomal dominant with varying expressivity and
tion (including donor type, categorized as matched sibling donor incomplete penetrance.2
[MSD], matched unrelated donor [MUD], or unrelated donor [UD]), Supportive treatment for infants is red blood cell (RBC) transfu-
and clinical outcomes were obtained from registry data. sions every 3-5 weeks to maintain growth. Daily corticosteroid
The primary outcomes were (a) the cumulative incidence of therapy started after 1 year of age, with a slow taper to the low-
acute graft-versus-host disease (aGVHD) and chronic GVHD est effective dose, initially is effective in 80% of cases, with an
(cGVHD), defined using established criteria, and (b) the proba- overall success rate of 50% being maintained at minimum weekly
bility of cGVHD-free survival (cGFS), defined as the time between doses with rare RBC transfusion needs. Factors related to spon-
HSCT and treatment failure, including cGVHD, death, or last fol- taneous remission observed in 20% of affected individuals are
low-up, whichever came first. A secondary outcome included the currently unknown. Adverse treatment effects include iron over-
probability of overall survival, defined as the time between HSCT, load, RBC alloimmunization, growth deficits, osteoporosis, cata-
death, or last follow-up, whichever came first. Investigators used racts, avascular necrosis, diabetes, hypothyroidism, and pubertal
Kaplan-Meier curves to estimate survival rates and multivariable delay. HSCT indications include transfusion dependency due to
models to identify factors that predicted cGFS. corticosteroid failure or cessation due to significant toxicity.3
There were 70 children included in analysis. The median age at Although retrospective, the current report includes the largest
HSCT was 5.5 years (range, 0.9-17.3 years) with a median follow-up cohort to date with lengthy follow-up, confirming results of pre-
of 4.5 years (0.2-22.2 years). Most (64%) received HSCT from an vious studies documenting least toxicities from HSCT in chil-
MSD; 17% received a HSCT from an MUD and 19% from a UD. dren <10 years old, performed after the year 2000 with human
leukocyte antigen (HLA)-matched sibling donors.1-3 The results
The cumulative incidence of aGVHD was 24% (95% CI, 16%-37%).
of the current study add that HLA-matched unrelated donors,
There was no difference in aGVHD in participants who received
cord blood grafts, and children transplanted at 10-18 years of
an MSD (vs UD) HSCT, though aGVHD was significantly lower in
age potentially have noninferior outcomes. Limitations include
participants who received an HSCT from an MSD (vs UD) in HSCTs
missing data on 15%-27% of subjects for physical anomalies,
performed after 1999. The cumulative incidence of cGVHD was
molecular genetics, total corticosteroids and transfusions, iron
11% (95% CI, 5%-22%).
overload and chelation status, and other comorbidities prior
The probability of overall survival was 91% (95% CI, 84%-98%). to HSCT. Future HSCT considerations include the impact of the
The probability of cGFS was 87% (95% CI, 79%-95%). In multivari- development of DNA- and RNA-based therapies, drugs targeting
able models, HSCT performed after the year 2000, MSD type, and RBC production, and overall malignancy risks.1-3
lower occurrence of aGVHD predicted higher cGFS.
Bottom Line: For children with DBA who fail or have toxicities to
The investigators conclude that HSCT is a relatively safe and corticosteroids and RBC transfusions, HSCT is safe and results in
effective treatment option for transfusion-dependent children an excellent probability of overall survival.
with DBA.
References
COMMENTARY BY 1. Bartels M, et al. Br J Haematol. 2019;184(2):123-133; doi: 10.1111/bjh.15701

Mary-Jane Staba Hogan, MD, MPH, FAAP, Pediatric Hematology 2. Ulirsch JC, et al. Am J Hum Genet. 2018;103(6):930-947; doi: 10.1016/j.ajhg.2018.10.027
3. Aspesi A, et al. Curr Gene Ther. 2018;18(6):327-335; doi: 10.2174/1566523218666181109124
Oncology, Yale University School of Medicine, New Haven, CT
538
Dr Hogan has disclosed no financial relationship relevant to this commentary. This commentary
does not contain a discussion of an unapproved/investigative use of a commercial product/device.

Diamond-Blackfan anemia is a rare, congenital bone marrow

failure syndrome manifesting in infancy with transfusion-depen-
dent macrocytic anemia, reticulocytopenia, and a spectrum of

22 aapgrandrounds.org
HOSPITAL MEDICINE

Predicting Abnormal Renal

Ultrasound in Febrile UTI
Source: Wallace SS, Ban K, Singh A, et al. Clinical predictors for abnor- COMMENTARY BY
mal renal bladder ultrasound in hospitalized young children with a Jeffrey Winer, MD, MA, MSHS, FAAP, Pediatric Academic Hospital
first febrile urinary tract infection. Hosp Pediatr. 2020;10(5):392-400; doi: Medicine, Le Bonheur Children’s Hospital, University of Tennessee
10.1542/hpeds.2019-0240 Health Science Center, Memphis, TN
Investigators from multiple institutions conducted a prospective Dr Winer has disclosed no financial relationship relevant to this commentary. This commentary does
not contain a discussion of an unapproved/investigative use of a commercial product/device.
cohort study to identify predictors of abnormal renal bladder
ultrasounds (RBUS) in young children with a first febrile UTI. Over the last 10 years there has been a shift toward reducing
Study participants were patients 0 to 24 months old hospitalized unnecessary imaging in infants and toddlers presenting with
with a first febrile UTI at a quaternary care children’s hospital febrile UTIs.1 Based on evidence that medical treatment of low-
between October 2016 and December 2018. Eligible children were grade vesicoureteral reflux does not prevent subsequent UTIs
identified on an ongoing basis by review of the medical records or kidney damage, the 2011 clinical practice guidelines2 recom-
of hospitalized patients who had a urine culture performed. mend that voiding cystourethrography (VCUG) “should not be
Children were considered to have a febrile UTI if they had a tem- performed routinely after the first febrile UTI.” The authors of the
perature ≥100.4°F, a urine specimen was obtained by suprapubic present study sought to evaluate whether a similar narrowing of
aspiration or catheterization and grew ≥50,000 colony forming focus could be done safely for RBUS.
units (CFU) on culture, and pyuria was present on urinalysis (pos-
While this was a small, observational study, the authors brought
itive leukocyte esterase or ≥5 white blood cells per high power
up multiple factors that should be considered as this question
field); infants <2 months old were included if their urine culture
is investigated. It is unclear whether PNUS obviates the need
grew ≥10,000 CFU with pyuria or ≥50,000 CFU. Demographic and
for RBUS after a febrile UTI. Variability in technique and timing
clinical data were collected on study participants by interview
may also impact the management. There is some evidence that
with caregivers and review of the medical record. Information
comprehensive third-trimester PNUS may be sensitive enough to
collected included gestational age, family history of kidney dis-
serve in place of a RBUS at the time of a febrile UTI,3 but this is
ease, uropathogen (Escherichia coli vs others), presence of bac-
not certain enough to guide clinical decisions at this time.
teremia, sex, and, in males, history of circumcision. Information
regarding prenatal ultrasound (PNUS) was collected by caregiver While RBUS does not have the radiation exposure risk of VCUG,
interview and included number of PNUS, trimester of last PNUS, cost-effectiveness modeling has estimated a cost to the system
and results. of $11,200 per UTI prevented and led to an additional unneces-
sary VCUG in 1 out of every 7 infants with a febrile UTI.4 Further
The primary study outcome was abnormal RBUS during the hos-
studies are likely to use large populations to evaluate models,
pitalization for febrile UTI. A multidisciplinary team developed
not to identify patients at high risk for abnormal RBUS, but to
criteria for defining a clinically significant abnormal RBUS based
identify a subpopulation with sufficiently low risk of abnormal
on specific findings reported by the radiologist. Possible demo-
RBUS to forgo the test.
graphic or clinical predictors of an abnormal RBUS identified by
bivariate analyses were included in a multivariate logistic regres- Bottom Line: Currently, there is insufficient evidence to stop per-
sion model to identify independent predictors. forming routine RBUS in all children 2-24 months of age with a
first febrile UTI. (See AAP Grand Rounds. 2017;37[2]:20.5)
Data were analyzed on 211 children. Among these children, the
References
median age was 1.0 month (65% were <2 months old), and 60%
1. Lee T, et al. J Urol. 2017;197(4S):e801; doi: 10.1016/j.juro.2017.02.1865
were male, of whom 91% were uncircumcised. Urine cultures 2. American Academy of Pediatrics. Pediatrics. 2011;128(3):595-610; doi: 10.1542/
grew E coli in 85% of study patients, and 20% had bacteremia. All peds.2011-1330
study children had PNUS, 84% had ≥3, and 84% had a PNUS in the 3. De Grauw AM, et al. J Matern Fetal Neonatal Med. 2016;29(2):237-241; doi:
last trimester; the last PNUS in 10% of patients was reportedly 10.3109/14767058.2014.996125
4. Gaither TW, et al. J Pediatr. 2020;216:73-81.e1; doi: 10.1016/j.jpeds.2019.06.049
abnormal. With bivariate analysis, gestational age and abnor-
5. Chang PW, et al. Hosp Pediatr. 2016;6(11):647-652; doi: 10.1542/hpeds.2015-0229
mal PNUS were identified as possible predictors of an abnormal
RBUS; however, in the multivariate analysis neither of these was
independently associated with an abnormal RBUS.
The authors concluded that no independent predictors of an
abnormal RBUS were identified in this study.

• August 2020 23
TM
CME QUESTIONS 5. A 15-year-old presents to your clinic for a follow-up appointment for child-
hood obesity. She and her mother report changes to her diet and increased
physical activity since her last visit 3 months ago. They would like to discuss
The following continuing medical education questions cover the content of the medication options for treating her obesity. Which of the following is the
August 2020 issue of AAP Grand Rounds. Please keep this issue. most accurate finding of the randomized placebo-controlled study by Kelly
Each year’s material is worth up to 18 AMA PRA Category 1 Credit(s)TM. et al concerning liraglutide for obesity treatment (all participants also
received lifestyle therapy) in adolescents?
Complete and claim credit online at www.aapgrandrounds.org.
Need username and password? Contact customer service at 866-843-2271. a. Adolescents receiving liraglutide compared to placebo had a greater reduc-
tion of BMI (treatment difference 4.65).
b. Headache was the most common adverse event for adolescents receiving
CME OBJECTIVES liraglutide.
1. Describe changes in the incidence of vitamin K refusal for newborns. c. Systolic blood pressure was significantly reduced in the adolescents receiv-
2. Understand the use of continuous pulse oximetry for hospitalized ing liraglutide compared to those in the placebo group.
d. Significantly greater BMI reductions were identified in adolescent girls than
children with bronchiolitis. boys receiving liraglutide.
3. Detail the most common etiologies of encephalitis in children. e. Adolescents in the placebo group had a greater increase in BMI in the
follow-up period (ie, after discontinuation of liraglutide in the intervention
group).
1. The parents of a newborn, full-term female infant express hesitation
regarding vitamin K administration during their baby’s birth hospital stay.
6. A white 9-month-old girl who is exclusively breastfed is brought to your
According to the article by Zurynski et al, which of the following statements
office for well-child care. Her mother tells you that her child appears to be
is most accurate concerning vitamin K deficiency bleeding (VKDB) in the
growing slower than her older siblings did. She is without any diarrhea or
newborn population?
other symptoms on a review of symptoms. The father has confirmed celiac
a. B abies for whom intramuscular vitamin K prophylaxis is withheld have an disease. Based on the study by Auricchio et al, which of the following actions
approximately 5% risk of developing early VKDB. should you take?
b. Oral and intramuscular vitamin K preparations have demonstrated similar
a. Reassure the mother that since the child is asymptomatic no further
efficacy profiles for prevention of VKDB.
workup is necessary.
c. As the incidence of VKDB is very low, withholding of vitamin K prophylaxis
b. A gluten-free diet should be initiated immediately.
is acceptable as long as coagulation parameters are checked within the
c. She should be closely followed for celiac disease over time as growth is
first 3 months of life.
affected before the onset of disease in children who subsequently are
d. T hough the incidence of VKDB remains low, there was a recent increase in
diagnosed with celiac disease.
the incidence of vitamin K prophylaxis refusal.
d. Serum markers of celiac disease, including serum antigliadin and
e. Since VKDB is significantly more common in male infants, withholding
anti-transglutaminase-IgA antibodies, should be obtained, as she is very
intramuscular vitamin K prophylaxis is an acceptable approach for female
likely to already have celiac disease.
babies.
e. She should be treated with suppressive corticosteroids for 6 months.
2. As a pediatric hospitalist, you sit on the guidelines committee of your
7. A 9-year-old girl presents to the office for a school physical. She recently
department in a community hospital. You notice that several children
was diagnosed with systemic juvenile idiopathic arthritis (JIA) and is being
admitted for bronchiolitis receive continuous pulse oximetry even though
followed and managed by a pediatric rheumatologist. Her mother has
they were on room air. As you begin the process of crafting a guideline for
talked to the pediatric rheumatologist about her prognosis but also would
bronchiolitis treatment, you recall the recent study by Bonafide et al con-
like your opinion. Based on the study by Chhabra et al, which of the follow-
cerning the use of continuous pulse oximetry in hospitalized children with
ing is most accurate concerning long-term outcomes and disease course
bronchiolitis not requiring supplemental oxygen. Which of the following is
with JIA?
the most accurate finding or conclusion from the study by Bonafide et al?
a. Patients with oligoarthritis had the lowest remission rate.
a. Community hospitals had a much higher use of continuous pulse oximetry
b. J oint damage (erosion or joint space narrowing on x-ray or MRI) was seen
in children not on supplemental oxygen.
in 36% of patients.
b. Continuous pulse oximetry was associated with improved clinical
c. Patients with systemic JIA had the highest remission rate.
outcomes.
d. Twelve percent of patients required joint surgery.
c. Continuous pulse oximetry was commonly used among all types of hospi-
e. At their last pediatric visit, 76% were on at least one antirheumatic
tals in children not requiring supplemental oxygen despite the recommen-
medication.
dations of clinical guidelines.
d. Parent expectation and nurse vigilance were the main reasons for the use
8. According to the retrospective study by Strahm et al, hematopoietic stem
of continuous pulse oximetry.
cell transplantation performed after the year 2000 for transfusion-de-
e. C ontinuous pulse oximetry should remain a mainstay in the management
pendent children with Diamond-Blackfan anemia resulted in which of the
of children with bronchiolitis, even when children have been weaned from
following?
supplemental oxygen to room air or never required supplemental oxygen.
a. Higher incidence of acute graft versus host disease (GVHD).
3. According to the study by Fontanella et al concerning low-income youths b. Higher probability of chronic GVHD-free survival.
who die by suicide, which of the following statements is the most accurate? c. Lower incidence of infection.
d. Lower probability of stem cell engraftment.
a. The study demonstrated that low-income youths are more at risk for sui-
e. Probability of overall survival <70%.
cide than their counterparts.
b. The study determined that Medicaid-enrolled youths who died from sui-
9. A 3-month-old, otherwise healthy female who was born at 40 weeks’ gesta-
cide were more likely to be prescribed antidepressant medications.
tion presents to a children’s hospital with fussiness and fever to 39.5°C. Her
c. Stigma associated with depression prevented youths from seeking health
family has no history of kidney or genitourinary abnormalities. She had a
services.
documented normal prenatal ultrasound performed at 21 weeks’ gestation.
d. Suicide decedents were more likely to have a mental or physical health
She has urine collected using a sterile catheter, which is significant for
encounter than controls in the 6 months prior to the index date.
150 white blood cells per high-powered field, 4+ leukocyte esterase, and
e. B ullying was found to be the greatest risk factor for suicide.
positive nitrites. She is administered ceftriaxone and is admitted to the
hospital for further monitoring. Her urine culture ultimately grows >100,000
4. A 14-year-old previously healthy girl presents in August with a fever of 39°C,
colony-forming units per microliter of pan-sensitive E coli. Based on the
confusion, and new onset generalized tonic-clonic seizures. Her CSF white
results presented in the recent article by Wallace et al and the 2011 American
blood cell count is 20/mm3, and no bacteria are identified on culture. PCR
Academy of Pediatrics’ clinical practice guidelines, which of the following is
testing of her CSF is negative for HSV and enteroviruses. Her brain MRI is
most accurate?
consistent with encephalitis. Based on the study by Erickson et al, which
of the following is most accurate concerning potential etiologies of her a. Due to E coli as a causative pathogen, renal bladder ultrasound is
encephalitis? unnecessary.
b. Due to the lack of family history, renal bladder ultrasound is unnecessary.
a. Autoimmune conditions were the most commonly identified causes of
c. Due to the normal prenatal and medical history, renal bladder ultrasound
pediatric encephalitis.
is unnecessary.
b. A utoimmune encephalitis was confirmed by detecting specific antibodies
d. Due to the normal prenatal ultrasound, renal bladder ultrasound is
in serum.
unnecessary.
c. The most common bacterial etiology was Mycoplasma pneumoniae.
e. The patient should receive a renal bladder ultrasound.
d. T he most common viral etiologies were herpesviruses and arboviruses.
e. W ith extensive testing, an etiology was identified for 80% of cases of
encephalitis in children.
8. b 6. c 2. c 4. d
9. e 7. c 5. a 1. d 3. d
Answers:

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