What is the initial approach to managing a child with fever of unknown origin (FUO)?

Initial Approach to Pediatric Fever of Unknown Origin

Definition and Risk Stratification

Begin by confirming true FUO: fever >38.3°C (100.9°F) persisting ≥3 weeks without diagnosis despite thorough evaluation, and immediately stratify by age as management differs dramatically between young infants and older children. 1, 2

Age-Based Risk Categories

• Infants <3 months: Highest risk group with 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
• Infants <28 days: Even higher risk than older infants, warranting the most aggressive approach 3
• Children >3 months: Lower risk of serious bacterial infection; approximately 75% have self-limited viral infections 3

Initial Evaluation (0-72 Hours)

Mandatory First-Line Laboratory Tests

All children with FUO require 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. 1, 2, 4

Critical History Elements

• Travel history: Specific countries visited (malaria in Central/Western Africa, dengue/schistosomiasis in Eastern/Western Africa) 1
• Immigration status or visiting friends/relatives abroad: These patients less likely to seek pre-travel advice and have higher malaria rates 1
• Exposure history: Animal contacts, tick exposure, sick contacts, medication use 1, 2
• Duration and pattern: Continuous vs. intermittent fever, associated symptoms 5, 6

Physical Examination Focus

Perform serial, repeated physical examinations as this is paramount—clues are frequently missed on initial evaluation due to time constraints or evolving findings. 5, 7, 8

• Examine for lymphadenopathy, hepatosplenomegaly, cardiac murmurs, rashes, joint swelling 6
• Critical pitfall: Only 58% of infants with bacteremia/meningitis appear clinically ill, so never rely solely on clinical appearance 4

Age-Specific Management Protocols

Infants <3 Months

These infants require hospitalization, lumbar puncture (if high-risk features present), and empiric antibiotic therapy immediately while awaiting culture results. 3, 4

• Obtain urinalysis with leukocyte esterase, nitrites, leukocyte count, or Gram stain 4
• Blood culture and inflammatory markers mandatory 4
• Lumbar puncture based on risk stratification (clinical practice guidelines available to minimize unnecessary procedures) 3
• Chest radiography only if respiratory signs present or concern for occult pneumonia (prevalence only 1-3% in this age group) 3
• Do not assume viral infection excludes bacterial infection—they can coexist 4

Children >3 Months with Prolonged FUO

Avoid empiric antibiotics or steroids in stable patients, as they obscure diagnosis and may be harmful if malignancy or certain infections are present. 1

Advanced Imaging (If Initial Workup Negative at 72-96 Hours)

Second-Line Imaging

FDG-PET/CT whole body is the highest-yield advanced diagnostic tool with 84-86% sensitivity and 56% diagnostic yield, identifying the source in 48% of pediatric FUO cases. 3, 1, 2

• Most common diagnoses on PET/CT: endocarditis (11%), systemic juvenile idiopathic arthritis (5%), inflammatory bowel disease (5%) 3
• Timing critical: Perform within 3 days of initiating oral glucocorticoid therapy to avoid false negatives 1
• Treatment modifications made in 53% of patients after PET/CT 3
• Alternative: CT abdomen/pelvis with IV contrast as second-line if PET/CT unavailable 2

Third-Line Considerations

• Whole body MRI may be considered, especially in pediatric patients to minimize radiation 2
• Tissue biopsy of any suspicious lesions identified on imaging 2

Common Etiologies by Frequency

Infections remain the most common cause (34-38%), with uncommon presentations of common diseases more likely than rare diseases. 5, 8, 6

• Infectious: Bacterial meningitis (6.5%), urinary tract infection (11.4%), tuberculosis, Epstein-Barr virus, cat-scratch disease 8, 6
• Malignancy: 17.2% of cases 6
• Autoimmune/inflammatory: Kawasaki disease, collagen-vascular diseases (14-16%) 8, 6
• Miscellaneous: 16.1% 6
• Undiagnosed: Increasing trend due to earlier diagnosis with advanced techniques 8

Critical Pitfalls to Avoid

• Never diagnose FUO prematurely in resource-limited settings—always assume and treat infection when fever cannot be explained 1
• Do not use high-dose steroids empirically: Increases hospital-acquired infections, hyperglycemia, GI bleeding, and delirium without improving mortality, and masks inflammatory findings on subsequent imaging 1
• Failure to perform repeated examinations: Most common management error; continued observation is paramount for difficult cases 8
• Recent antipyretic use can mask fever severity 4

Exceptions Requiring Empiric Therapy

Consider empiric treatment only in specific high-risk scenarios while continuing diagnostic workup: 1

• Neutropenic patients (require prompt antimicrobial therapy) 2
• Suspected tickborne rickettsial diseases 1
• Critically ill/unstable patients 1
• Confirmed diagnoses (malaria, bacterial meningitis, adult-onset Still's disease) per established guidelines 1

Diagnostic Yield by Stage

Most diagnoses (45.6%) are identified in Stage 3 (advanced imaging/invasive procedures), with only 2.5% diagnosed in Stage 1 (basic labs), emphasizing the need for systematic progression through evaluation stages. 6