What are the causes of Pyrexia of Unknown Origin (PUO)?

Causes of Pyrexia of Unknown Origin (PUO)

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, and can be classified into four distinct subcategories: Classical PUO, Nosocomial PUO, Neutropenic PUO, and HIV-related PUO. 1

Major Categories of PUO Causes

1. Infectious Causes

• Tuberculosis - Most common cause in many regions, especially extrapulmonary forms 1, 2
• Endocarditis
• Intra-abdominal abscesses
• Brucellosis
• Q fever
• Enteric fever
• Malaria
• Visceral leishmaniasis
• Dengue
• Catheter-associated infections
• Slow-growing organisms requiring extended blood cultures

2. Neoplastic Causes

• Lymphomas (Hodgkin and non-Hodgkin) - Second most common cause in many studies 2
• Leukemias
• Solid tumors

3. Non-Infectious Inflammatory Diseases

• Adult-onset Still's disease - Particularly common in adults ≤40 years 2
• Vasculitis
• Connective tissue diseases
• Sarcoidosis
• Autoimmune disorders

4. Miscellaneous Causes

• Drug fever
• Factitious fever
• Thermoregulatory disorders
• Heart failure
• Pruritus of elderly skin
• Psychological and emotional factors

5. Undiagnosed

• Approximately 12.5% of cases remain undiagnosed despite thorough evaluation 2
• Fever may resolve spontaneously in many undiagnosed cases

Geographic Variations in PUO Etiology

• Western countries: Higher rates of endocarditis, Q fever, and intra-abdominal abscesses 1
• India and developing regions: Higher rates of tuberculosis (particularly extrapulmonary), enteric fever, malaria, and visceral leishmaniasis 1, 2

Diagnostic Approach to PUO

The diagnostic approach should be guided by potential diagnostic clues from:

1. Initial laboratory workup:

   • Complete blood count with differential
   • Acute phase reactants (CRP, ESR)
   • Liver function tests
   • Blood cultures (at least 2 sets)
   • Chest radiograph

2. Advanced imaging:

   • 18F-FDG PET/CT has high diagnostic yield (56%) with sensitivity of 84-86% 1
   • Consider early in the diagnostic process rather than as a last resort

3. Specialized testing based on suspected etiology:

   • Extended blood cultures for slow-growing organisms
   • Serological testing for specific pathogens
   • Tuberculosis testing
   • Ferritin levels (>5000 ng/mL may suggest adult-onset Still's disease)
   • Glycosylated ferritin (<20% highly specific for adult-onset Still's disease)
   • Procalcitonin for bacterial infections

Special Considerations

• Travel history: Essential to evaluate for endemic infections like malaria, dengue, and typhoid fever
• Immunocompromised status: Changes the differential diagnosis significantly
• Central venous catheters: Evaluate for catheter-related infections
• Neutropenic patients: Require urgent evaluation with CT scans and bronchoscopy for pulmonary infiltrates

The relative frequency of different causes varies significantly by geographic region, with tuberculosis remaining the predominant cause in India (28.3% of cases), followed by lymphoma (12.5%) and adult-onset Still's disease (7.9%) 2. In contrast, Western countries show higher rates of endocarditis and other infections.

Rather than subjecting patients to a standard battery of tests, the diagnostic approach should be individualized based on clinical clues from history, physical examination, and initial laboratory results 3, 4.