How to manage a patient with fever of unknown origin, negative for malaria and dengue, and up-to-date on all vaccinations?

Management of Fever of Unknown Origin with Negative Malaria and Dengue Tests in a Fully Vaccinated Patient

For patients with fever of unknown origin who have negative malaria and dengue tests and are up-to-date on vaccinations, a systematic diagnostic approach with empiric broad-spectrum antibiotics is recommended while pursuing further investigations.

Initial Assessment and Diagnostic Approach

Key Clinical Considerations:

• Travel history: Essential to determine potential exposures 1
• Duration of fever: Classify as acute (<1 week), subacute (1-3 weeks), or chronic (>3 weeks) 2
• Associated symptoms: Look for specific patterns that might suggest etiology
• Laboratory abnormalities: Pay particular attention to thrombocytopenia and hyperbilirubinemia which have high likelihood ratios for certain infections 1

First-line Investigations:

• Complete blood count with differential
• Comprehensive metabolic panel
• Blood cultures (at least two sets)
• Urinalysis and urine culture
• Chest X-ray
• Liver function tests

Empiric Treatment Strategy

Initial Antibiotic Therapy:

• Start with a broad-spectrum β-lactam with antipseudomonal activity such as:
  • Piperacillin-tazobactam
  • Cefepime
  • Meropenem 3

Consider Adding Vancomycin If:

• Hemodynamic instability
• Suspected catheter-related infection
• Skin/soft tissue infection
• Known MRSA colonization 3

For β-lactam Allergic Patients:

• Use ciprofloxacin plus clindamycin or
• Aztreonam plus vancomycin 3

Monitoring and Reassessment

Reassess after 2-4 days of empiric therapy:

• If improving: Continue current regimen
• If persistent fever but stable: Maintain regimen and pursue further diagnostics
• If worsening: Broaden coverage and intensify diagnostic efforts 1

Important monitoring parameters:

• Daily physical examination
• Review of systems for new symptoms
• Cultures from suspicious sites
• Directed imaging studies based on clinical findings 1

Further Diagnostic Workup

If Initial Tests Are Negative:

• Consider specific infectious causes based on geographic exposures:
  • Leptospirosis: CSF + blood cultures (within 5 days of symptom onset)
  • Brucellosis: Extended blood cultures, serology (if livestock exposure)
  • Rickettsial diseases: Acute and convalescent serology (if tick exposure)
  • Viral hepatitis: Anti-HAV IgM, HBsAg, anti-HEV IgM 1

If Fever Persists with Hepatomegaly/Splenomegaly:

• Consider:
  • Amoebic liver abscess: Serology and abdominal ultrasound
  • Visceral leishmaniasis: Serology, bone marrow examination
  • Tuberculosis: Particularly important in endemic areas 1, 4

Special Considerations

For Persistent Fever Despite Antibiotics:

• If fever persists >4-7 days in high-risk patients, consider adding antifungal therapy 3
• Consider non-infectious causes: drug-related fever, thrombophlebitis, underlying malignancy 1

Important Cautions:

• Persistent fever alone in a stable patient is rarely an indication to alter the antibiotic regimen 1
• Avoid adding vancomycin empirically for persistent fever if the patient is otherwise stable 1
• Avoid unnecessary antibiotic changes based solely on fever pattern 3

Duration of Therapy

• Continue appropriate antibiotics until clear etiology is identified or clinical improvement occurs
• For most bacterial infections, 10-14 days of therapy is recommended 3
• If no source is identified but patient improves clinically with resolution of fever, antibiotics can be discontinued 1

Prognosis

For patients with non-diagnostic but overall reassuring workup, the prognosis is typically favorable with self-limiting illness 2. However, continued monitoring is essential as some causes of FUO (particularly tuberculosis in endemic areas) may require specific treatment 4.