What is the evaluation algorithm for pyrexia (fever) of unknown origin?

Evaluation Algorithm for Pyrexia of Unknown Origin

The evaluation of pyrexia of unknown origin (PUO) requires a systematic approach starting with thorough clinical assessment followed by targeted investigations, with FDG-PET/CT being the most valuable second-line imaging modality when initial workup fails to identify the cause. 1, 2

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 3, 1
• PUO is classified into four subcategories: classical, nosocomial, neutropenic, and HIV-related 1, 4
• Inflammation of unknown origin (IUO), defined as unexplained and prolonged elevation of inflammatory markers without fever, shares similar etiologies 3, 1

Initial Diagnostic Approach

• First-line laboratory testing should include:
  • Complete blood count with differential 1, 5
  • Inflammatory markers (C-reactive protein, erythrocyte sedimentation rate) 1, 2
  • Blood cultures (at least 3 sets, before antibiotics) 5, 6
  • Urinalysis and urine culture 5, 7
  • Liver function tests 5, 7
  • Basic imaging: chest radiography 1, 2

Advanced Diagnostic Approach (If Initial Evaluation Inconclusive)

• Second-line investigations (after 72-96 hours of persistent fever):

  • Thoracic CT scan if respiratory symptoms present 2, 7
  • CT of abdomen and pelvis with IV contrast 3, 2
  • CT of paranasal sinuses (particularly in immunocompromised patients) 3
  • Blood tests for specific pathogens based on exposure history 2, 6
  • Serological testing for autoimmune conditions 1, 7

• Third-line investigations:

  • FDG-PET/CT is highly recommended when initial workup is non-diagnostic, with high sensitivity (84-86%) and diagnostic yield of approximately 56% 3, 1, 8
  • FDG-PET/CT should ideally be performed within 3 days of initiation of oral glucocorticoid therapy 3, 1
  • Consider myocardial suppression preparation when there is potential cardiac etiology 3, 1
  • Whole body MRI may be considered, especially in pediatric patients 3, 2
  • Tissue biopsy of suspicious lesions identified on imaging 7, 8

Special Considerations

Neutropenic Patients

• Require prompt evaluation and empiric antimicrobial therapy 1, 2
• Consider imaging tests to identify sources of infection, including chest radiography, CT of paranasal sinuses, chest CT, and CT of abdomen and pelvis with IV contrast 3, 2

Pediatric Patients

• Appropriate imaging tests include chest radiography, whole body MRI, and FDG-PET/CT 3, 2
• For febrile infants and young children without signs of respiratory infection, medical management without imaging is usually appropriate 3, 5

Returning Travelers

• All patients with relevant travel history should have an assessment for viral hemorrhagic fever risk 3
• Up to three daily blood films to exclude malaria 3
• Consider rapid diagnostic tests for dengue if malaria test is negative 3, 2

Common Pitfalls and Caveats

• Avoid premature closure on a diagnosis before adequate evaluation 2, 6
• Do not initiate empiric antimicrobial therapy before obtaining appropriate cultures, as this may mask the underlying cause 2, 6
• Early use of glucocorticoids may suppress inflammatory activity and lead to false negative results on imaging studies 3, 1
• Up to 50% of patients may have no cause found despite adequate investigations, but this cohort generally has a good prognosis 4, 9
• Avoid unnecessary imaging studies without specific clinical indications 5, 2

Diagnostic Algorithm Summary

1. Initial evaluation (0-72 hours):

   • Thorough history and physical examination
   • First-line laboratory tests and chest radiography
   • Empiric therapy only if critically ill

2. Secondary evaluation (72-96 hours if fever persists):

   • Targeted CT imaging based on clinical findings
   • Specialized blood tests based on exposure and risk factors
   • Consider infectious disease consultation

3. Tertiary evaluation (>96 hours if diagnosis remains elusive):

   • FDG-PET/CT as the preferred advanced imaging modality
   • Tissue biopsy of suspicious lesions
   • Consider multidisciplinary discussion for complex cases