Pediatrics

By: Z. Dolezel and Marco Alves

6th year
Individual Project
Introduction
Fever without a discernible cause is always difficult for
clinicians because fever suggests disease. The inability to
identify the cause of the fever can undermine the
physician's credibility and can affect rapport with patients.
The longer the fever persists, the more concern is raised
by the parents. A fever of only a few days' duration that is
not associated with any localizing signs or symptoms
frequently does not even come to a physician's attention
unless the child also appears ill. Fever that continues
beyond 5 to 7 days, or one that occurs repeatedly, usually
alarms parents enough to prompt a medical consultation.
This presentation focus on these prolonged fevers and on
how to evaluate them.
 Definition
Fever of unknown origin (FUO) also called febris e causa
ignota(febris E.C.I.) was defined in 1961 by Petersdorf and
Beeson as the following:
 (1) a temperature greater than 38.3°C on several occasions
(2) more than 3 weeks' duration of illness
(3) failure to reach a diagnosis despite 1 week of inpatient investigation
It is now generally accepted that unexplained fever that persists longer
than 1 week in a child warrants preliminary investigations as fever
from viral infections generally resolves within that time frame.
Therefore, most recent case series of pediatric FUO require persistence
of fever for only 1 or 2 weeks with negative preliminary investigations.
General Principles
Most children with FUO do not have rare or exotic diseases,
which as been shown to be true even in series from major
pediatric referral centers. For example, in a series of 100 children
evaluated at the children’s hospital medical center in Boston,
only three patients had diseases that would be considered
rare(undefined vasculitis, Behçet syndrome, and Ichtyosis).
Although in different frequencies, the three causes for FUO most
commonly identified in children are the same as for adults:
Infectious diseases, rheumatologic disorders, and malignancies.
The prognosis in children is somewhat better than adults, but
FUO often presents as a serious condition in children with
studies showing mortality rates of 9%(Series of Pizzo and
colleagues) and 17%(Lohr and Hendley).
In many cases of FUO in children, a specific diagnosis is never
established and the condition eventually resolves spontaneously.
Causes of FUO
Bacterial Infectious Diseases
 Bacterial endocarditis Viral Infectious
 Bartonellosis
 Brucellosis Diseases
 Chlamydia
 Lymphogranuloma venereum
Cytomegalovirus
 Psittacosis
 Leptospirosis
Epstein-Barr virus
 Liver abscess (infectious mononucleosis)
 Mastoiditis (chronic)
 Osteomyelitis
Hepatitis viruses
 Pelvic abscess Q fever
 Perinephric abscess
 Pyelonephritis Rickettsial diseases
 Salmonellosis
 Sinusitis  Q fever
 Subdiaphragmatic abscess  Rocky Mountain spotted
 Tuberculosis
 Tularemia fever
Causes cont.
Fungal Infectious
Diseases Autoimmune Diseases
Blastomycosis Polyarteritis nodosa
(nonpulmonary)
Histoplasmosis Systemic idiopathic
(disseminated) juvenile arthritis
Systemic lupus
Parasitic Infectious
Diseases
erythematosus
Malaria
Sarcoidosis
Toxoplasmosis
Visceral larva migrans
Visceral leishmaniasis
Causes cont.
 Malignancies  Miscellaneous Causes
 Hodgkin disease  Central diabetes insipidus
 Leukemia or lymphoma  Drug fever
 Neuroblastoma  Ectodermal dysplasia
 Familial dysautonomia
 Periodic Fever Syndromes  Granulomatous colitis
 Cyclic neutropenia  Infantile cortical hyperostosis
 Familial Mediterranean fever  Münchausen by proxy
 Hyperimmunoglobulinemia D  Nephrogenic diabetes insipidus
and periodic fever syndrome  Pancreatitis
(HIDS)  Pseudo-fever
 Periodic fever, aphthous
 Sarcoidosis
stomatitis, pharyngitis, and
cervical adenopathy (PFAPA)  Serum sickness
 Tumor necrosis factor receptor–  Thyrotoxicosis
associated periodic syndrome  Ulcerative colitis
(TRAPS)
 Other periodic fever syndromes
 Age

Diagnosis <6 Years >6 Years Total

Infection

Viral 14 (27%) 7 (15%) 21

Nonviral 20 (38%) 11 (23%) 31

Other

Collagen 4 (8%) 16 (33%) 20

Malignancy 4 (8%) 2 (4%) 6

Miscellaneous 7 (13%) 3 (6%) 10

No diagnosis 3 (6%) 9 (19%) 12

Total 52 49 100

Table 182-1: Diagnoses of Prolonged Fever in Children

From Pizzo PA, Lovejoy FH, Smith DH. Prolonged fever in children: review of 100
cases. Pediatrics. 1975;55(4):468-473.
Evaluation
 HISTORY
 Whether the child has a true FUO or a pseudo-FUO cannot be determined
without a precise history and thorough physical examination, with the
physician paying close attention to behavioral, social, familial, and
environmental factors. Information regarding travel, patient place of residence
if outside Europe, animal exposure, frequency of exposure to other persons
who have common febrile illnesses, previous illness, hospitalizations,
medications, family history of disease, race and ethnicity, and the precise
course of the exhibiting symptoms must be obtained methodically and
efficiently. Meticulous documentation of dates is especially important. To this
end, having the family record on a calendar, both the daily time and height of
the fever along with associated symptoms, is usually helpful.
For children older than 11 to 12 years, a separate interview should be
conducted alone with the child to obtain the child's perspective on the illness
and to elicit information that may be difficult to express in the presence of
parents. School, peer relationships, family functioning, and sexual identity and
activity should be explored.
Evaluation
PHYSICAL EXAMINATION

A full physical examination must be performed. Rectal

temperature, respiratory rate, heart rate, and blood
pressure measurements should be obtained. Any
discrepancy between heart rate and temperature implies
factitious fever. A thorough examination of the respiratory
tract is indicated. Inspection of the pharynx for hyperemia
and exudate, of the tympanic membranes for chronic otitis
media, transillumination of the sinuses for sinusitis, a
search for a purulent nasal discharge, and auscultation of
the chest for localized wheezing are all important. In the
older child, an examination of the teeth to exclude dental
caries and periodontal disease should be included.
Evaluation
Physical Examination Cont.

A new cardiac murmur may be a clue to rheumatic fever or infective

endocarditis. Lymphadenopathy, especially if generalized, may
suggest a viral infection, such as infectious mononucleosis,
cytomegalovirus infection, toxoplasmosis, or HIV infection. Joints
must be examined meticulously for swelling, restricted range of
motion, and tenderness. Skin rashes may suggest a viral disease or an
autoimmune disease such as juvenile idiopathic arthritis. The absence
of sweating and the presence of a smooth tongue are consistent with
familial dysautonomia, a rare genetic disorder of thermoregulation.
Finally, a rectal examination in the older child and a stool guaiac test
are imperative; finding pararectal lymphadenopathy may suggest a
pelvic infection, and a positive stool guaiac test may be consistent
with inflammatory bowel disease.
Evaluation
Physical Examination review
Careful physical exam which should be performed while the
patient is febrile
Special attention to the following areas:
General appearance and vital signs
Skin and scalp
Eyes
Sinuses
Oropharynx
Lymph nodes
Abdomen
Musculoskeletal
Genitourinary
Evaluation
Diagnostic Studies

Directed toward likely cause of fever based on

information gained from the history and physical
Timing of labs and studies is based on severity of
illness, ie, patients who are more ill should be
evaluated with laboratory studies at a faster pace than
those who appear well.
Initial Tests: CBC and peripheral smear, ESR, CRP,
Aerobic blood cultures, UA, urine culture, CXR,
tuberculin skin test, electrolytes, BUN, creatinine,
hepatic enzymes, HIV serology
Evaluation
Diagnostic Studies cont.

CBC:
Anemia: may be suggestive of malaria, infective endocarditis,
IBD, SLE or tuberculosis
Thrombocytosis: Kawaskai disease
WBC: atypical lymphocytes may suggest a viral infection,
immature forms may suggest
leukemia and eosinophilia is suggestive of parasitic, fungal,
neoplastic, allergic or
immunodeficiency disorders
ESR and CRP: non-specific acute phase reactants and general
indicators of inflammation
Evaluation
Diagnostic Studies cont.

Blood cultures: obtain several sets if infective endocarditis

is a consideration
Urinalysis and urine culture: UTI is a common source of
FUO, sterile pyuria is suggestive of Kawaski disease or
genitourinary tuberculosis
Chest X Ray: evaluate for infiltrates or lymphadenopathy
PPD for tuberculosis
Serum electrolytes, BUN, creatinine and hepatic enzymes
HIV: significant variability in manifestations of primary
HIV infection
Evaluation
Additional Tests: Guided by information obtained with history,
physical exam and results of initial testing

 Stool studies: culture, ova and parasites in patients with loose stools or recent
travel
 Bone marrow: most useful in diagnosing malignancy, histiocytic disorders and
hemophagocytic disease, not helpful in diagnosing infection
 Serologies: targeted approach is indicated
 HIV serology for all children with FUO
 Syphilis is recommended for neonates, young infants and adolescents
 Consider evaluation for EBV, CMV, toxoplasmosis, bartonellosis, brucellosis,
tularemia as well as parasitic infections such as strongyloidiasis
 Serum anti-nuclear antibody: obtain in children over age 5 with family history
of rheumatologic disease
Evaluation
 Additional tests

 Immunoglobulins: serum IgG, IgA and IgM in children with evidence of recurrent or
persistent infections and in those with persistent fever and a negative initial evaluation
 Molecular testing: (ie PCR) may be useful in specific cases

Imaging and other evaluations

 Abdominal imaging
 Indicated if inflammatory bowel disease is suspected
 Consider if fever may be due to psoas abscess or cat scratch disease
 Imaging of the nasal sinuses or mastoid is recommended if sinusitis is a possible
etiology for FUO
 ECG/Echocardiography should be performed if there is concern for infective
endocarditis
 Ophthalmologic exam can be helpful to evaluate uveitis or leukemic infiltration
 Biopsy is recommended only when there is evidence of specific organ involvement
Empiric Treatment
Generally avoid empiric treatment with anti-inflammatory
medications or antibiotics as an effort to diagnose the
patient’s condition.
Empiric antibiotics can mask or delay diagnosis of
infections such as meningitis, infectious endocarditis or
osteomyelitis
Exceptions:
 Nonsteroidal agents in children with presumed Juvenile
idiopathic arthritis
 Antituberculosis drugs in critically ill children with
possible disseminated TB
 Patients who are clinically deteriorating and in whom
bacteremia or sepsis is strongly suspected
 Patients who are immunocompromised
Summary
The evaluation of the child who has FUO must be
individualized to accommodate the history, the physical
examination, and the particular social environment in which
the child and family live. An intensive examination of all these
factors is the physician's responsibility and is the first stage of
managing the patient. Whether hospitalization is part of this
approach ultimately depends on the amount of parental
anxiety, the necessity to document fever, and the performance
of diagnostic tests that cannot be done on an outpatient basis.
The health care professional must continue to assess these
children frequently to detect new findings early and to maintain
the confidence of the family while the fever continues.
However, children with FUO generally do well, even though the
fever may last for weeks or months.
Thank you for your attention
References
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 Bleeker-Rovers CP, Vos FJ, de Kleijn EM, Mudde AH, Dofferhoff TS, Richter C, et
al. A prospective multicenter study on fever of unknown origin: the yield of a
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 Gaeta GB, Fusco FM, Nardiello S. Fever of unknown origin: a systematic review of
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Practice variations in the treatment of febrile infants among pediatric emergency
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 Wagner AD, Andresen J, Raum E, et al. Standardised work-up programme for
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diagnosis of hidden systemic vasculitis. Ann Rheum Dis. Jan 2005;64(1):105-10.
Bleeker-Rovers CP, van der Meer JW, Oyen WJ.
 Tolan, R.W. Fever of Unknown Origin: A Diagnostic Approach to This Vexing
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 2010 49:207.
 Palazzi, D.L. Etiologies of fever of unknown origin in children. UpToDate.
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 Fever of unknown origin. Semin Nucl Med. Mar 2009;39(2):81-7. Ozaras R,
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 World J Pediatr, Vol 7 No 1 . February 15, 2011 10 . www.wjpch.com
 Modified from Feigin RD, Cherry JD. Textbook of Pediatric Infectious
Diseases. 5th ed. Philadelphia, PA: WB Saunders; 2004. Copyright © 2004,
Elsevier
 Oski's Pediatrics: Principles And Practice.By Julia A. McMillan, Ralph
David Feigin.Chapter 133 page 911
 http://www.nursetogether.com/Portals/0/PublishThumbnails/pediatrics
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