What is the treatment for pyrexia of unknown origin?

Treatment of Pyrexia of Unknown Origin (PUO)

The management of pyrexia of unknown origin should follow a systematic diagnostic approach before initiating targeted therapy, as there is no standard empiric treatment for PUO itself.

Diagnostic Approach

Initial Evaluation

• Obtain at least 2 sets of blood cultures if fever is present 1
• Complete blood count with differential to identify neutrophilia (band neutrophils >6% or band neutrophil count ≥1500/mm³) 1
• Chest radiography or CT scans to identify potential infectious sources 1
• Respiratory virus testing for patients with upper respiratory symptoms 1

Risk Assessment

• Apply the MASCC risk index for patients with neutrophilia and fever:
  • MASCC score <21 indicates high risk of complications 1
  • Factors include disease burden, blood pressure, pulmonary status, hydration, and age

Advanced Diagnostics

• PET-CT has improved diagnostic capability and should be considered early in the evaluation 2
• Molecular and serological tests for infection should be utilized based on clinical suspicion 2

Treatment Strategy

For Neutropenic PUO

1. Empiric Antibiotic Therapy

   • For neutropenic patients with fever: vancomycin plus antipseudomonal antibiotics (cefepime, carbapenems, or piperacillin-tazobactam) 1
   • Continue antibiotics until neutrophil recovery (ANC ≥ 500/mm³) 1

2. Antifungal Therapy

   • Consider empiric antifungal therapy (caspofungin or liposomal amphotericin B) if fever persists >96 hours in neutropenic patients 1
   • Prophylaxis with fluconazole 400 mg orally daily until ANC recovers to >1000/mm³ 1

3. Antiviral Therapy

   • For influenza: neuraminidase inhibitors (oseltamivir or zanamivir) 1
   • Prophylaxis with acyclovir 400 mg or valacyclovir 500 mg orally twice daily for at least 3 months 1

4. Supportive Care

   • G-CSF (filgrastim) at 5 μg/kg/day subcutaneously to reduce myelosuppression in high-risk patients 1
   • Implement infection prevention measures including hand hygiene 1
   • Daily assessment of fever trends and clinical status 1

For Non-Neutropenic PUO

• Treatment should be directed at the underlying cause once identified 3
• Avoid multiple courses of empiric antimicrobials in stable patients without a clear diagnosis 3
• For patients with progressive disease despite extensive investigations, judicious use of narrow-spectrum antimicrobial therapy may be warranted 3

Special Considerations

Tuberculosis

• Consider tuberculosis as a cause of PUO, especially with symptoms of fever, malaise, and weight loss 4
• For confirmed tuberculosis (including isolated splenic TB), a 12-month course of combination anti-tuberculous therapy is appropriate 4
• Fever may persist for up to 6 weeks after initiating anti-tuberculous therapy 4

Monitoring and Follow-up

• Monitor complete blood count every 2-3 days during active fever 1
• Continue close monitoring until resolution of symptoms and recovery of neutrophil count 1
• Patients should seek medical attention immediately for temperature greater than 38.3°C 1

Common Pitfalls

• Up to 50% of PUO cases remain undiagnosed despite adequate investigations 2
• Diagnostic testing should be guided by clinical findings rather than following a "routine" set of investigations 3
• For stable patients with undiagnosed PUO, careful clinical observation is preferred over empiric antimicrobial therapy 3
• The undiagnosed cohort generally has a good prognosis, so aggressive empiric treatment is not always necessary 2