What is the appropriate work‑up and management for a child with fever persisting more than 14 days or daily recurrent fever for ≥14 days?

Prolonged Fever in Children: Diagnostic Work-Up and Management

Initial Risk Stratification

For children with fever persisting >14 days, immediately assess clinical stability and perform systematic risk stratification to guide the diagnostic approach and determine whether empiric antibiotics are needed. 1

Low-Risk Features

• Normal vital signs, no dehydration, well-appearing clinical status, and absence of respiratory distress 1
• Normal hepatic and renal function tests 2
• Ability of caregivers to monitor continuously and return for follow-up 3

High-Risk Features

• Clinical instability, hypotension, severe respiratory distress, or multiorgan dysfunction 1
• Documented neutropenia (absolute neutrophil count <500 cells/mm³) 4
• Temperature ≥39°C with WBC ≥15,000/mm³ in children <3 years 1

Mandatory Initial Diagnostic Evaluation

All children with prolonged fever require a standardized first-tier laboratory assessment regardless of clinical appearance. 1

Essential Laboratory Tests

• Complete blood count with manual differential 1, 2
• Complete metabolic panel (including sodium, potassium, creatinine, glucose, liver enzymes, albumin, bilirubin) 4
• Inflammatory markers: C-reactive protein and erythrocyte sedimentation rate 1, 2
• Blood cultures during febrile episodes (from all lumens if central venous catheter present) 2
• Urinalysis and urine culture if clean-catch specimen readily available 2

Targeted Imaging

• Chest radiography only if respiratory symptoms are present 1, 2
• Do not obtain routine chest x-rays in asymptomatic children 4

Critical Differential Diagnoses to Exclude First

Kawasaki Disease (Priority #1)

For any child with fever ≥5 days, Kawasaki disease must be excluded first, as delayed treatment beyond 10 days significantly increases coronary artery aneurysm risk from 1% to 15-25%. 4, 3

Diagnostic Criteria

• Fever ≥5 days plus ≥4 of the following: 4
  • Bilateral non-exudative conjunctivitis
  • Oral mucous membrane changes (red/cracked lips, strawberry tongue, oropharyngeal erythema)
  • Polymorphous rash (not vesicular)
  • Extremity changes (erythema, edema, desquamation)
  • Cervical lymphadenopathy (≥1.5 cm, usually unilateral)

Features That Exclude Kawasaki Disease

• Exudative conjunctivitis or pharyngitis 4
• Discrete intraoral lesions 4
• Bullous or vesicular rash 4
• Generalized lymphadenopathy 4

Management if Suspected

• Obtain echocardiography if clinical features compatible with Kawasaki disease 4
• Initiate treatment with IVIG 2 g/kg plus high-dose aspirin (80-100 mg/kg/day divided into 4 doses) within 10 days of fever onset 4
• Children presenting after 10 days should still be treated if fever or elevated inflammatory markers persist 4

Multisystem Inflammatory Syndrome in Children (MIS-C)

Consider MIS-C in any child with prolonged fever and history of COVID-19 exposure or positive SARS-CoV-2 testing within the past 4 weeks. 4

Key Clinical Features

• Fever ≥3 days 4
• ≥2 of the following: rash, conjunctivitis, mucocutaneous inflammation, hypotension/shock, cardiac involvement, coagulopathy, acute GI symptoms 4
• Elevated inflammatory markers (ESR, CRP, procalcitonin, D-dimer, ferritin, LDH, IL-6) 4
• Evidence of SARS-CoV-2 infection by PCR, antigen test, serology, or exposure 4

First-Line Treatment

• IVIG 2 g/kg plus methylprednisolone 1-2 mg/kg/day 4
• Assess cardiac function before IVIG administration; may divide dose (1 g/kg daily over 2 days) if cardiac dysfunction present 4

Management Algorithm Based on Clinical Stability

For Clinically Stable, Well-Appearing Children

Close observation with careful follow-up is appropriate; avoid empiric broad-spectrum antibiotics. 1

Outpatient Management Criteria

• Meets all low-risk criteria 1, 2
• Reliable caregivers who can monitor continuously 3
• Ability to return within 24 hours if clinical status changes 3

Follow-Up Requirements

• Repeat clinical evaluation within 24 hours 3
• Phone or telecommunication contact at appropriate intervals 3
• Meticulous fever diary documenting temperature, timing, and associated symptoms 5
• Serial clinical and laboratory evaluations to detect new signs 5

For Clinically Unstable or High-Risk Children

Initiate empiric broad-spectrum antibiotics immediately with an antipseudomonal β-lactam or carbapenem. 1, 2

Antibiotic Selection

• First-line: Antipseudomonal β-lactam (cefepime, piperacillin-tazobactam) or carbapenem (meropenem) 1
• Reserve addition of second gram-negative agent or glycopeptide for clinically unstable patients or suspected resistant infection 2
• Discontinue double coverage or empirical glycopeptide after 24-72 hours if no specific microbiologic indication 4

Antibiotic Discontinuation Criteria

• Low-risk patients: Discontinue at 48-72 hours if blood cultures negative, afebrile ≥24 hours, regardless of marrow recovery status with careful follow-up 4, 1
• All patients: Discontinue if blood cultures negative at 48 hours, afebrile ≥24 hours, and evidence of marrow recovery 4

Approach to Persistent Fever Beyond Initial Work-Up

If Fever Persists Despite Negative Initial Evaluation

Do not modify antibiotics based solely on persistent fever in clinically stable children. 4

Repeat Assessment at 7-10 Days

• Thorough repeat history and physical examination 1
• Assessment for new accompanying symptoms (arthritis, lymphadenopathy, rash) 6
• Consider subspecialty consultation (infectious disease, rheumatology, hematology-oncology) 1

Additional Diagnostic Considerations

• Infectious causes (most common, 19-47%): Unusual infections, occult abscesses, endocarditis, tuberculosis, fungal infections 5, 7, 6
• Connective tissue diseases (15-28% in fever >28 days): Juvenile idiopathic arthritis, systemic lupus erythematosus 7, 6
• Necrotizing lymphadenitis (8%): Kikuchi disease 6
• Malignancies (2-7%): Leukemia, lymphoma, neuroblastoma 7, 6
• Autoinflammatory diseases: Familial Mediterranean fever, PFAPA syndrome (periodic fever, aphthous stomatitis, pharyngitis, adenitis) 5, 8

Clinical Clues to Specific Diagnoses

• Arthritis: Strongly associated with connective tissue diseases 6
• Lymph node enlargement: Suggests necrotizing lymphadenitis 6
• Fever only without other symptoms: More likely to remain undiagnosed 6
• Clockwork periodicity (~21 days): Consider cyclic neutropenia 5
• Stereotypical recurrent fevers with pharyngitis/adenitis: Consider PFAPA syndrome 5, 8

If Clinical Deterioration Occurs

Escalate antibiotics to include coverage for resistant gram-negative, gram-positive, and anaerobic bacteria. 4

Common Pitfalls and Caveats

Critical Errors to Avoid

• Do not dismiss as "viral syndrome" without appropriate evaluation in children with persistent fever >14 days 2
• Do not delay Kawasaki disease evaluation beyond day 5 of fever, as coronary complications increase significantly after day 10 4, 3
• Do not obtain routine chest radiographs in asymptomatic children, as this leads to unnecessary radiation and false-positive findings 4, 1
• Do not continue empiric antibiotics indefinitely in stable children with negative cultures 4, 1

Important Considerations

• Approximately 50% of children with true fever of unknown origin will never have a specific diagnosis made and will have self-limited illness 5, 6
• The proportion of undiagnosed cases has increased due to improved diagnostic techniques for infectious diseases 6
• Age plays an important role: children <2 years more commonly have infectious causes, while those with fever >28 days have higher rates of connective tissue diseases 7, 6
• Some children referred for "prolonged fever" are not actually having elevated temperatures; careful history and correction of health misperceptions is essential 5

Symptomatic Management

• Acetaminophen as first-line antipyretic for comfort, not to normalize temperature 3
• Ensure adequate fluid intake and monitor urine output to prevent dehydration 3
• Avoid ibuprofen in children taking aspirin for Kawasaki disease, as it may antagonize antiplatelet effects 4