What is the recommended treatment for pyrexia of unknown origin in children?

Management of Pyrexia of Unknown Origin in Children

The treatment of pyrexia of unknown origin (PUO) in children requires a systematic diagnostic workup before initiating empiric therapy, with immediate broad-spectrum antibiotics reserved only for high-risk patients (severe neutropenia, hemodynamic instability, or suspected severe bacterial infection), while stable children should undergo structured investigation to identify the underlying cause rather than receiving blind antimicrobial therapy. 1, 2

Initial Assessment and Risk Stratification

The first critical step is determining whether the child requires immediate empiric treatment or can safely undergo diagnostic evaluation:

High-Risk Features Requiring Immediate Treatment:

• Severe neutropenia (ANC <0.5 × 10⁹/L) constitutes a medical emergency requiring same-day broad-spectrum antibacterial therapy without waiting for culture results 2
• Hemodynamic instability with signs of sepsis 2
• Clinical features suggesting severe bacterial pneumonia: fever >38.5°C with chest recession and respiratory rate >50/min in children under 3 years 2
• Suspected malaria in returned travelers (requires up to three daily blood films) 2

Stable Patients:

Most children with PUO who are hemodynamically stable, non-neutropenic, and without severe respiratory distress should not receive empiric antibiotics initially, as this reduces diagnostic yield and may mask serious underlying conditions 2, 3

Diagnostic Workup Algorithm

First-Line Evaluation (0-72 hours):

Mandatory laboratory testing includes: 1

• Complete blood count with differential (assess for neutropenia, leukemia, or inflammatory patterns)
• Blood cultures (minimum 3 sets before any antibiotics)
• Inflammatory markers (CRP, ESR)
• Urinalysis and urine culture
• Liver function tests
• Chest radiography (25% of young children with PUO and no obvious source have pneumonia) 2

Critical history elements to elicit: 1, 2

• Travel history (malaria, viral hemorrhagic fevers)
• Animal exposures
• Immunization status
• Sick contacts
• Medication history
• Family history of autoinflammatory diseases

Second-Line Evaluation (72-96 hours if fever persists):

Advanced imaging should be pursued based on clinical suspicion: 1

• CT abdomen/pelvis with IV contrast for abdominal symptoms or hepatosplenomegaly
• Echocardiography if cardiac murmur or stigmata of endocarditis present
• Targeted imaging based on localizing symptoms

Specialized testing guided by exposure history: 1

• Serologies for specific infections (EBV, CMV, toxoplasma, Bartonella)
• Autoimmune markers if inflammatory pattern suggests rheumatologic disease
• Tuberculosis testing if risk factors present

Third-Line Evaluation (>96 hours without diagnosis):

FDG-PET/CT is the preferred advanced imaging modality for children with persistent unexplained fever after initial workup 4, 1:

• Sensitivity of 80-100% and specificity of 66.7-79.2% in pediatric PUO 4
• Identifies fever source in 48% of cases 4
• Leads to treatment modifications in 53% of patients 4
• Most commonly identifies: endocarditis (11%), systemic juvenile idiopathic arthritis (5%), inflammatory bowel disease (5%) 4
• Should be performed ideally within 3 days of glucocorticoid initiation if steroids are being considered 4
• Higher diagnostic yield in patients with elevated inflammatory markers 4

Patient preparation for PET/CT: Fast 4-6 hours before FDG injection, maintain adequate hydration, ensure blood glucose <150-180 mg/dL 4

Whole-body MRI can be considered as an alternative, especially in pediatric patients where radiation exposure is a concern 1

Treatment Approach Based on Findings

When Specific Diagnosis is Made:

Bacterial pneumonia: 5

• Amoxicillin is first-choice oral therapy for children under 5 years (effective, well-tolerated, inexpensive)
• Alternatives: co-amoxiclav, cefaclor, erythromycin, clarithromycin, azithromycin
• Intravenous antibiotics (co-amoxiclav, cefuroxime, cefotaxime) for severe disease or inability to tolerate oral medications
• Switch to oral therapy when clear clinical improvement occurs

Pleural infection/empyema: 5

• All cases require intravenous antibiotics covering S. pneumoniae, S. pyogenes, and S. aureus
• Broader spectrum coverage (including anaerobes) if aspiration suspected
• Consider ceftriaxone 100 mg/kg/day for empiric broad-spectrum coverage 5
• Drainage procedures if effusion enlarging or compromising respiratory function

Severe malaria (if travel history positive): 5

• Parenteral quinine: loading dose 20 mg salt/kg over 4 hours, then 10 mg/kg every 8 hours
• Correct hypoglycemia with 5 ml/kg of 10% dextrose if blood glucose <3 mmol/L
• Treat hyperpyrexia with antipyretics (ibuprofen superior to paracetamol)

When No Diagnosis After Extensive Workup:

Watchful waiting is appropriate for stable patients with negative comprehensive evaluation: 2, 3

• A negative FDG-PET/CT predicts favorable prognosis through spontaneous remission 1
• Up to 50% of adequately investigated PUO cases remain undiagnosed, but this cohort has good prognosis 6
• Avoid multiple courses of empiric antimicrobials in stable patients without progressive disease 3

Narrow-spectrum antimicrobial trial may be warranted only if: 3

• Disease process is clearly progressive
• Patient is deteriorating clinically
• Strong clinical suspicion for specific treatable infection despite negative workup

Critical Re-evaluation Points

If child remains pyrexial or unwell 48 hours after admission, systematically reassess: 5

• Is antibiotic dosing adequate and appropriate for suspected pathogen?
• Are there complications: pleural effusion, empyema, lung abscess?
• Is there underlying immunosuppression or coexistent disease (cystic fibrosis)?
• Should imaging be repeated or advanced imaging pursued?

Common Pitfalls to Avoid

• Do not give empiric antibiotics to stable children before obtaining blood cultures - this dramatically reduces diagnostic yield 2
• Do not assume penicillin resistance means treatment failure - standard IV penicillin/ampicillin dosages achieve serum concentrations exceeding MIC for most resistant strains 5
• Do not delay PET/CT if considering steroids - perform within 3 days of glucocorticoid initiation to prevent suppression of inflammatory activity 4
• Do not perform repeated needle thoracocentesis - insert proper drain if second tap required 5
• Do not use steroids for raised intracranial pressure in severe malaria - may adversely affect outcome 5