What is the diagnostic workup and treatment approach for a pediatric patient with recurrent fevers?

Diagnostic Workup and Treatment Approach for Pediatric Patients with Recurrent Fevers

The diagnostic workup for pediatric patients with recurrent fevers should follow a systematic approach that includes targeted laboratory testing, imaging when indicated, and consideration of both common and rare causes, with particular attention to autoinflammatory disorders when common infectious causes have been ruled out. 1, 2

Initial Assessment and Risk Stratification

• Determine fever pattern (prolonged, recurrent, or periodic) to help narrow the differential diagnosis 3, 2
• Document fever characteristics with a meticulous fever diary including frequency, duration, peak temperatures, and associated symptoms 2
• Assess for accompanying symptoms that may suggest specific diagnoses:
  • Mucocutaneous findings (rash, conjunctivitis, oral ulcers) 4
  • Gastrointestinal symptoms (abdominal pain, vomiting, diarrhea) 5
  • Respiratory symptoms (cough, respiratory distress) 4
  • Lymphadenopathy or adenitis 4
  • Neurologic symptoms (headache, altered mental status) 4

Laboratory Evaluation

First-tier Testing (All Patients)

• Complete blood count with manual differential 4
• Complete metabolic panel 4
• Inflammatory markers: C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) 4
• Blood cultures during febrile episodes 4
• Urinalysis and urine culture (especially in children <5 years) 4

Second-tier Testing (Based on First-tier Results)

• If elevated inflammatory markers and one or more abnormal findings (lymphopenia, neutrophilia, thrombocytopenia, hyponatremia, or hypoalbuminemia), proceed with:
  • Additional infectious workup including viral studies 4
  • Immunologic testing if recurrent infections are suspected 6
  • Genetic testing for autoinflammatory disorders if clinical picture is suggestive 1, 6

Imaging Studies

• Chest radiograph should be obtained in:
  • Febrile children <3 months with evidence of acute respiratory illness (Level B recommendation) 4
  • Children >3 months with temperature >39°C (>102.2°F) and WBC count >20,000/mm³ (Level C recommendation) 4
• Chest radiograph is usually not indicated in febrile children >3 months with temperature <39°C without clinical evidence of pulmonary disease 4
• MRI is not indicated in the workup of a child with simple febrile seizures 4
• Consider CT imaging of sinuses in children >2 years with persistent fever and neutropenia to evaluate for invasive fungal disease 4

Specific Clinical Scenarios

Recurrent Fevers in Oncology Patients/Neutropenic Fever

• Risk stratification into low-risk and high-risk categories is essential 4
• For neutropenic patients with fever:
  • Obtain blood cultures before starting antibiotics 4
  • Initiate empiric broad-spectrum antibiotics 4
  • In high-risk patients with persistent fever >96 hours, consider empiric antifungal therapy with either caspofungin or liposomal amphotericin B 4
  • Discontinue empiric antibiotics when blood cultures are negative at 48 hours, patient has been afebrile for at least 24 hours, and there is evidence of marrow recovery 4

Suspected Autoinflammatory Disorders

• Consider autoinflammatory disorders in children with:

  • Stereotypical recurrent fever episodes 1, 2
  • Family history of similar symptoms 1
  • Lack of response to antimicrobial therapy 6, 2
  • Elevated inflammatory markers during and between episodes 1, 6

• Common autoinflammatory syndromes to consider:

  • PFAPA (Periodic Fever, Aphthous stomatitis, Pharyngitis, Adenitis) - most common periodic fever syndrome in children 2, 5
  • Hereditary recurrent fevers (Familial Mediterranean Fever, TRAPS, etc.) 1
  • SURF (Syndrome of Undifferentiated Recurrent Fever) - patients with recurrent fevers who don't meet PFAPA criteria 5

Treatment Approaches

• For infectious causes: targeted antimicrobial therapy based on identified pathogen 7

• For neutropenic fever:

  • Consider outpatient management for low-risk patients if infrastructure exists for careful monitoring 4
  • Consider oral antibiotic administration if the child can tolerate it reliably 4
  • Do not modify initial empiric antibacterial regimen based solely on persistent fever in clinically stable children 4

• For suspected autoinflammatory disorders:

  • PFAPA: on-demand corticosteroids during fever episodes; tonsillectomy may be considered 2, 5
  • Hereditary recurrent fevers: targeted biologic therapies based on specific diagnosis 1
  • SURF: individualized approach may include on-demand steroids or tonsillectomy 5

Common Pitfalls and Caveats

• Not all reported "fevers" are true fevers - verify with reliable measurement 2
• Avoid cognitive bias of anchoring on specific diagnoses (e.g., MIS-C during COVID-19 pandemic) without thorough evaluation 4
• Remember that most children with recurrent fevers have self-limited viral illnesses 3, 2
• Irregular, intermittent fevers in well-appearing children are likely sequential viral illnesses 2
• Cyclic neutropenia should be considered in children with fever cycles of approximately 21 days 2
• Avoid unnecessary antibiotic use for viral or non-infectious causes of fever 7