What is the current definition of Pyrexia of Unknown Origin (PUO) according to Harrison's Internal Medicine?

Definition of Pyrexia of Unknown Origin (PUO) According to Harrison's Internal Medicine

According to Harrison's Internal Medicine, pyrexia of unknown origin (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. 1

Classification of PUO

PUO is divided into four distinct subcategories:

1. Classical PUO - The standard definition as described above
2. Nosocomial PUO - Hospital-acquired fever without clear cause
3. Neutropenic PUO - Fever in patients with neutropenia
4. HIV-related PUO - Fever in HIV-positive individuals

Etiology of PUO

The causes of PUO can be broadly categorized into:

• Infectious causes (30-40%): Tuberculosis, endocarditis, abscesses, complicated UTIs
• Inflammatory/rheumatologic causes (15-30%): Adult-onset Still's disease, vasculitis, connective tissue diseases
• Malignant causes (10-20%): Lymphomas, leukemias, solid tumors with metastasis
• Miscellaneous causes (10-20%): Drug fever, factitious fever, thromboembolism
• Undiagnosed (up to 50% of cases): Despite thorough investigation

Diagnostic Approach

Initial Evaluation

• Complete history and physical examination focusing on:

  • Travel history
  • Medication use
  • Occupational exposures
  • Risk factors for HIV
  • Subtle signs of infection or malignancy

• Laboratory tests:

  • Complete blood count with differential
  • Comprehensive metabolic panel
  • Urinalysis and urine culture
  • Blood cultures (at least 2 sets)
  • Erythrocyte sedimentation rate (ESR)
  • C-reactive protein (CRP)
  • HIV testing

Advanced Imaging

• 18F-FDG PET/CT has high diagnostic yield (56%) in FUO cases, with sensitivity of 84-86% and specificity of 52-63% 1
• PET/CT should ideally be performed within 3 days of initiation of oral glucocorticoid therapy 1
• CT scans of chest, abdomen, and pelvis if PET/CT is not available

Invasive Procedures

• Biopsy of abnormal tissue (lymph nodes, liver, bone marrow) based on clinical suspicion
• Temporal artery biopsy in elderly patients with elevated ESR

Special Considerations

• Inflammation of unknown origin (IUO) is defined as unexplained and prolonged elevation of inflammatory markers without fever, and shares similar etiologies with PUO 1

• PET/CT has insufficient evidence for evaluation of patients with FUO and normal inflammatory markers (CRP, ESR) 1, 2

• In patients with prolonged fever lasting more than 3 weeks who have no identifiable source, the diagnosis of FUO should be considered 1

• Empiric antimicrobial therapy has not been shown to be effective in the treatment of FUO and should be avoided except in patients who are neutropenic, immunocompromised, or critically ill 3

• Up to 75% of cases will resolve spontaneously without reaching a definitive diagnosis 3

Common Pitfalls

• Premature closure: Accepting an early diagnosis without adequate investigation
• Empiric antibiotics: Administering antibiotics before obtaining adequate cultures
• Inadequate follow-up: Failing to reassess patients with persistent fever
• Over-reliance on laboratory tests: Missing diagnoses that require careful physical examination
• Failure to consider rare presentations of common diseases: Most cases of PUO are atypical presentations of common conditions rather than rare diseases

By following this structured approach to PUO diagnosis and management, clinicians can systematically evaluate patients with prolonged unexplained fever and improve diagnostic yield while minimizing unnecessary testing.