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

Diagnostic Workup for Pyrexia of Unknown Origin (PUO)

The most effective diagnostic approach for Pyrexia of Unknown Origin (PUO) should begin with standard laboratory testing and proceed to 18F-FDG PET/CT if the diagnosis remains elusive after initial evaluation, as PET/CT has a high diagnostic yield of 56% with sensitivity of 84-86% and specificity of 52-63%. 1

Definition and Classification

• PUO is defined as fever higher than 38.3°C (100.9°F) persisting for at least 3 weeks, with no diagnosis despite 3 outpatient visits or in-patient days 2
• Four distinct subcategories:
  • Classical PUO
  • Nosocomial PUO
  • Neutropenic PUO
  • HIV-related PUO 2, 1

Initial Diagnostic Workup

1. First-line investigations:

   • Complete blood count with manual differential
   • Acute phase reactants (C-reactive protein, erythrocyte sedimentation rate)
   • Liver function tests
   • Blood cultures (at least 2 sets, ideally 60 mL total)
   • Chest radiograph 1

2. Targeted physical examination:

   • Evaluate for adenopathy
   • Assess for hepatosplenomegaly
   • Look for skin rashes
   • Check for signs of infection 1

3. Additional first-line investigations based on clinical findings:

   • If abnormal chest radiograph: thoracic bedside ultrasound
   • If abdominal symptoms or abnormal liver function: abdominal ultrasound
   • If respiratory symptoms: viral pathogen testing
   • If recent surgery: CT of relevant area 1

Second-line Investigations

1. 18F-FDG PET/CT:

   • Should be performed if diagnosis remains unclear after standard workup
   • Ideally within 3 days of starting oral glucocorticoid therapy
   • Has high diagnostic yield (56%) in PUO cases 2, 1

2. Specialized testing based on suspected etiology:

   • Infectious causes:

     • Extended blood cultures for slow-growing organisms
     • Serological testing for specific pathogens
     • Tuberculosis testing (including cultures from appropriate sites) 2, 1

   • Inflammatory/rheumatologic causes:

     • Autoimmune panels
     • Ferritin levels (>5000 ng/mL suggests adult-onset Still's disease)
     • Glycosylated ferritin (<20% highly specific for adult-onset Still's disease) 1

   • Malignant causes:

     • Tumor markers
     • Lymph node biopsy if adenopathy present 1

3. Invasive procedures when indicated:

   • Liver biopsy: useful for diagnosing infections such as tuberculosis, storage disorders, and in investigation of PUO 2
   • Bone marrow biopsy: particularly if blood count abnormalities or suspected hematologic malignancy 3
   • Lymph node biopsy: if adenopathy present

Special Considerations

• Neutropenic patients: Require urgent evaluation with CT scans and bronchoscopy if pulmonary infiltrates are present 1

• Travelers: Evaluate for infectious diseases such as malaria, dengue, and typhoid fever 1

• Patients with central venous catheters: Evaluate catheter and peripheral blood cultures for differential time to positivity 1

• Patients with lymphadenitis: Should be treated as tuberculosis until confirmed otherwise 2

Management Pearls

• Avoid routine use of antipyretic medications solely for reducing temperature in critically ill patients with fever 1

• Avoid routine abdominal imaging for patients without abdominal symptoms or liver function abnormalities 1

• In patients with progressive disease despite extensive investigations, judicious use of narrow-spectrum antimicrobial therapy may be warranted 4

• For stable patients with no diagnosis after thorough evaluation, careful clinical observation for new symptoms and signs is recommended rather than multiple courses of antimicrobials 4

• Up to 50% of PUO cases may remain undiagnosed despite adequate investigations, but this undiagnosed cohort generally has a good prognosis 5

Pitfalls to Avoid

• Performing 18F-FDG PET/CT in patients with normal inflammatory markers (CRP, ESR) as evidence is insufficient for this approach 2

• Delaying 18F-FDG PET/CT until late in the diagnostic process, as early use has been shown to improve outcomes 2

• Initiating glucocorticoid therapy without obtaining appropriate imaging, as this may mask findings on subsequent studies 2

• Overlooking rare causes of PUO such as hepatic hemangioma, which should be considered after standard algorithmic approach fails to reveal other causes 6