Diagnostic Approach to Pediatric Fever of Unknown Origin

Definition and Risk Stratification

The American Academy of Pediatrics defines fever of unknown origin (FUO) as a fever greater than 38.3°C (100.9°F) lasting for more than 3 weeks without a diagnosis, and recommends immediate stratification by age due to differing management approaches between young infants and older children 1, 2
Infants under 3 months are at the highest risk, with an 8-13% rate of invasive bacterial infections, predominantly urinary tract infections, requiring aggressive evaluation and empiric antibiotics due to increased morbidity and mortality from delayed diagnosis 3, 4, 5
Infants under 28 days are at an even higher risk, warranting the most aggressive approach 6
Children over 3 months have a lower risk of serious bacterial infection, with approximately 75% having self-limited viral infections 4

All children with FUO require a complete blood count with differential, inflammatory markers (ESR/CRP), urinalysis with culture, and at least 3 sets of blood cultures obtained before any antibiotic administration, as recommended by the American College of Radiology 1, 2, 5
The American College of Radiology suggests that infants under 3 months require hospitalization, lumbar puncture (if high-risk features are present), and empiric antibiotic therapy immediately while awaiting culture results 6, 5
Infants under 3 months should undergo urinalysis with leukocyte esterase, nitrites, leukocyte count, or Gram stain, as well as blood culture and inflammatory markers, with lumbar puncture based on risk stratification 5, 3, 6

The American College of Radiology recommends FDG-PET/CT whole body as the highest-yield advanced diagnostic tool, with 84-86% sensitivity and 56% diagnostic yield, identifying the source in 48% of pediatric FUO cases 8, 9, 10, 1, 2
The most common diagnoses on PET/CT include endocarditis (11%), systemic juvenile idiopathic arthritis (5%), and inflammatory bowel disease (5%), with treatment modifications made in 53% of patients after PET/CT 8, 9, 10

The American Academy of Pediatrics advises against diagnosing FUO prematurely in resource-limited settings, and recommends assuming and treating infection when fever cannot be explained 1
The American College of Radiology warns against using high-dose steroids empirically, as this can increase hospital-acquired infections, hyperglycemia, GI bleeding, and delirium without improving mortality, and can mask inflammatory findings on subsequent imaging 1
Recent antipyretic use can mask fever severity, as noted by the American College of Radiology 5