What is the treatment for Pyrexia of Unknown Origin (PUO)?

Management of Pyrexia of Unknown Origin (PUO)

The management of pyrexia of unknown origin (PUO) requires a systematic diagnostic approach followed by targeted therapy based on identified causes, with empiric treatment reserved for specific scenarios when the diagnosis remains elusive despite thorough investigation.

Definition and Classification

PUO is defined as:

• Fever ≥38.3°C (101°F) lasting ≥3 weeks
• Diagnosis remains uncertain after initial investigations

PUO can be classified into several categories:

• Classical PUO
• Nosocomial PUO
• Neutropenic PUO
• HIV-associated PUO
• Elderly PUO

Diagnostic Approach

Initial Evaluation

1. Detailed history and targeted physical examination:

   • Travel history
   • Occupational exposures
   • Animal contacts
   • Medication history
   • Family history of inflammatory conditions

2. First-line investigations:

   • Complete blood count with differential
   • Blood cultures (at least 2 sets)
   • Comprehensive metabolic panel
   • Chest radiograph
   • Urinalysis and culture

Second-line Investigations

Based on clinical suspicion and initial results:

• Advanced imaging (CT, MRI, PET-CT)
• Serological tests for specific infections
• Tissue biopsies
• Molecular diagnostic tests

Treatment Approach

Empiric Therapy for Neutropenic PUO

For neutropenic patients with PUO, prompt initiation of broad-spectrum antibiotics is essential 1:

1. Initial antibiotic therapy:

   • Anti-pseudomonal β-lactam (cefepime, ceftazidime, meropenem, or piperacillin-tazobactam)
   • Start within 2 hours of fever onset

2. If fever persists after 3-5 days:

   • Reassess with physical examination, repeat cultures, and imaging
   • Consider continuing initial antibiotics or changing regimen

3. If fever persists beyond 5-7 days:

   • Add empiric antifungal therapy (amphotericin B)
   • Continue until neutrophil recovery or for at least 14 days if fungal infection is confirmed

4. Discontinuation criteria:

   • If neutrophil count ≥0.5 × 10^9/L and patient becomes afebrile for 48 hours with negative cultures
   • If neutrophil count remains low, continue antibiotics for 5-7 days if patient becomes afebrile with no complications

Management of Non-Neutropenic PUO

For patients with classical PUO without neutropenia, the approach differs 2, 3:

1. Targeted therapy when diagnosis is established:

   • Antimicrobials for identified infections
   • Anti-inflammatory agents for autoimmune/inflammatory conditions
   • Appropriate therapy for malignancies

2. When diagnosis remains unclear:

   • For clinically deteriorating patients: Consider judicious use of narrow-spectrum antimicrobial therapy
   • For stable patients: Careful clinical observation rather than empiric antimicrobials

Special Considerations

HIV-Associated PUO

For HIV-positive patients with PUO 4, 5:

• Consider opportunistic infections, particularly mycobacterial disease
• Lymphadenitis should be treated as tuberculosis until proven otherwise
• Restoration of immunocompetence with antiretroviral therapy is crucial

Tuberculosis as a Cause of PUO

When tuberculosis is identified as the cause 6:

• Standard anti-tuberculosis therapy for 6-12 months depending on site of infection
• For splenic tuberculosis, a 12-month course of anti-tuberculous treatment is appropriate

Prognosis

• Up to 50% of PUO cases may remain undiagnosed despite adequate investigations
• The cohort of undiagnosed patients generally has a good prognosis
• Mortality is low (approximately 1.1%) in most PUO cases 7

Key Points

• PUO management should be guided by clinical findings rather than routine investigations
• Diagnostic testing should be individualized based on abnormalities found on clinical examination
• Empiric antimicrobial therapy is warranted only in neutropenic patients or when disease is clearly progressive
• In stable patients with undiagnosed PUO, observation is preferred over multiple courses of empiric antimicrobials