What is the approach to managing pyrexia of unknown origin?

Approach to Managing Pyrexia of Unknown Origin

FDG-PET/CT is the most effective diagnostic tool for identifying the source of pyrexia of unknown origin (PUO), particularly in cases where conventional investigations have failed to reveal a cause. 1, 2

Definition and Classification

PUO is defined as:

• Fever ≥38.3°C (101°F) lasting ≥3 weeks
• No identified cause after 3 days of hospital investigation or 3+ outpatient visits 2

PUO can be classified into five subgroups:

• Classical PUO
• Nosocomial PUO
• Neutropenic PUO
• HIV-related PUO
• Elderly PUO 2

Initial Evaluation

Laboratory Investigations

• Complete blood count with differential (look for band neutrophils >6% or band neutrophil count ≥1500/mm³, strongly suggesting bacterial infection) 3
• At least 2 sets of blood cultures 3
• Basic metabolic panel
• Liver function tests
• Inflammatory markers (ESR, CRP)
• Urinalysis and urine culture

Initial Imaging

• Chest radiography 3
• Consider abdominal imaging based on symptoms

Etiological Categories

The main causes of PUO fall into four categories:

1. Infectious (decreasing in frequency over time) 4
2. Inflammatory/autoimmune (increasing in frequency) 4
3. Neoplastic (increasing in frequency) 4
4. Miscellaneous (including drug fever, factitious fever)

Advanced Diagnostic Approach

For Persistent PUO After Initial Workup:

1. Advanced Imaging:

   • FDG-PET/CT is highly recommended, with demonstrated high clinical impact (79% in pediatric patients with neutropenic fever) 1
   • FDG-PET/CT correctly identified fever sources in 88% of immunosuppressed children with PUO 1

2. For Neutropenic Patients:

   • Implement the MASCC risk index to stratify patients into low-risk (score ≥21) or high-risk (score <21) 3
   • High-risk patients require hospitalization and IV empirical antibiotic therapy 3
   • Consider monotherapy with anti-pseudomonal β-lactam (e.g., piperacillin-tazobactam) 3

3. For Prolonged Neutropenic Fever:

   • Consider empiric antifungal therapy if fever persists >96 hours 3
   • Options include caspofungin or liposomal amphotericin B 3
   • CT imaging of sinuses is not routinely recommended for prolonged febrile neutropenia without localizing symptoms 1

Management Strategies

For Neutropenic Fever:

• Initiate G-CSF (filgrastim) at 5 μg/kg/day subcutaneously until ANC recovers to >500/mm³ 3
• Continue antibiotics until neutrophil recovery (ANC ≥500/mm³) 3
• Consider prophylaxis:
  • Antibacterial: Levofloxacin or ciprofloxacin 500 mg daily 3
  • Antiviral: Acyclovir 400 mg or valacyclovir 500 mg twice daily 3
  • Antifungal: Fluconazole 400 mg daily 3

For Non-Neutropenic PUO:

• Avoid multiple courses of empiric antimicrobials in stable patients 5
• For progressive disease without diagnosis, consider judicious use of narrow-spectrum antimicrobials 5
• For stable patients without diagnosis, careful clinical observation is preferred over empiric therapy 5

Special Considerations

• Up to 50% of PUO cases remain undiagnosed despite adequate investigations 2
• The undiagnosed cohort generally has a good prognosis 2
• Diagnostic testing should be guided by clinical findings rather than following a rigid protocol 5
• Laparotomy may be considered in select cases where diagnosis remains elusive 4

Infection Prevention

• Implement hand hygiene and dietary restrictions for severe neutropenia 3
• Educate patients to seek immediate medical attention for temperature >38.3°C 3

Monitoring

• Daily assessment of fever trends and clinical status
• Monitor complete blood count every 2-3 days until resolution of symptoms and recovery of neutrophil count 3