What is the approach to managing Pyrexia of Unknown Origin (PUO)?

Approach to Managing Pyrexia of Unknown Origin (PUO)

A systematic, stepwise diagnostic approach with thorough clinical evaluation followed by targeted investigations is essential for managing Pyrexia of Unknown Origin, with early consideration of infectious, inflammatory, neoplastic, and miscellaneous causes.

Definition and Classification

PUO is defined as:

• Fever ≥38.3°C (101°F) lasting ≥3 weeks
• No identified cause after 3 days of investigation in hospital or after 3+ outpatient visits 1

PUO can be classified into different subgroups:

• Classical PUO
• Nosocomial PUO
• Neutropenic PUO
• HIV-related PUO
• Elderly PUO 1

Etiological Categories

The main causes of PUO include:

1. Infections (40%)
2. Neoplasms (20%)
3. Inflammatory/collagen vascular diseases (15%)
4. Miscellaneous causes (25%) 2

Initial Evaluation

History and Physical Examination

• Detailed travel history, occupational exposures, animal contacts
• Medication history (drug fever)
• Family history of inflammatory conditions
• Comprehensive systems review
• Meticulous physical examination with special attention to:
  • Skin lesions
  • Lymphadenopathy
  • Heart murmurs
  • Abdominal masses
  • Joint abnormalities

First-line Investigations

• Complete blood count with differential
• Comprehensive metabolic panel
• Blood cultures (at least 2 sets)
• Urinalysis and urine culture
• Chest radiograph
• Inflammatory markers (ESR, CRP)
• Liver function tests
• Autoimmune screen (ANA, RF)
• HIV testing 3, 1

Second-line Investigations

Investigations should be guided by clinical findings rather than following a rigid protocol 4:

Imaging Studies

• CT scan of chest, abdomen, and pelvis
• Echocardiography (if suspecting endocarditis)
• PET-CT scan (increasingly used early in evaluation) 1

Microbiological Testing

• Blood cultures for fastidious organisms
• Serological testing for specific infections
• Molecular diagnostic tests (PCR)

Tissue Sampling

• Bone marrow aspiration and biopsy
• Lymph node biopsy
• Liver biopsy (if abnormal liver function)
• Temporal artery biopsy (in elderly patients)

Special Considerations for Neutropenic PUO

For neutropenic patients with fever:

1. Immediate Action:

   • Prompt initiation of broad-spectrum antibiotics within 2 hours 3
   • Anti-pseudomonal β-lactam (cefepime, meropenem, or piperacillin-tazobactam)

2. Risk Stratification:

   • Use MASCC risk index to categorize as high or low risk 3
   • Low risk: Score ≥21 (6% complication rate)
   • High risk: Score <21 (higher complication rate)

3. Monitoring:

   • Daily assessment of fever trends, bone marrow and renal function
   • Monitor until patient is apyrexial and ANC ≥0.5×10^9/L 5

4. Antifungal Consideration:

   • If fever persists >4-6 days, consider antifungal therapy
   • High-resolution chest CT if invasive aspergillosis suspected 5, 3

Management Algorithm

1. Initial Assessment:

   • Confirm true fever pattern (continuous, remittent, intermittent)
   • Rule out factitious fever
   • Complete first-line investigations

2. Early Management:

   • Avoid empiric antibiotics unless neutropenic or critically ill
   • Avoid antipyretics if possible to preserve fever pattern

3. Targeted Investigation:

   • Direct second-line tests based on abnormalities found
   • Consider PET-CT if initial investigations inconclusive

4. Therapeutic Trials:

   • Consider empiric therapy only if:
     • Disease is clearly progressive
     • Patient is deteriorating clinically
     • Diagnostic testing has been exhaustive 4

5. Follow-up:

   • Regular clinical reassessment for new symptoms/signs
   • Repeat key investigations if clinical status changes
   • Consider watchful waiting in stable patients with undiagnosed PUO

Common Pitfalls

• Premature use of antibiotics obscuring diagnosis
• Inadequate history and physical examination
• Failure to review all previous data and investigations
• Overlooking non-infectious causes
• Excessive, unfocused testing
• Failure to repeat examinations over time

Prognosis

Reassuringly, patients with undiagnosed PUO after thorough investigation (up to 50% of cases) generally have a good prognosis 1.