Etiology of Pyrexia of Unknown Origin (PUO) in Western Countries vs. India
Extrapulmonary tuberculosis remains the predominant cause of PUO in India, while in Western countries, infections, malignancies, and inflammatory disorders occur in roughly equal proportions. 1, 2
Definition and Classification
PUO is defined as:
- Fever higher than 38.3°C (100.9°F)
- Persisting for at least 3 weeks
- No diagnosis despite 3 outpatient visits or in-patient days
PUO can be classified into four subcategories:
- Classical PUO
- Nosocomial PUO
- Neutropenic PUO
- HIV-related PUO 2
Etiology in Western Countries
Infectious Causes (20-30%)
- Endocarditis
- Intra-abdominal abscesses
- Tuberculosis (less common than in India)
- Q fever
- Brucellosis 3
- Viral infections including HIV seroconversion
Malignant Causes (20-30%)
- Lymphomas (both Hodgkin and non-Hodgkin)
- Leukemias
- Solid tumors with metastases 2
Inflammatory/Rheumatologic Causes (20-30%)
- Adult-onset Still's disease
- Vasculitis
- Connective tissue diseases
- Polymyalgia rheumatica 2
Miscellaneous Causes (10-20%)
- Drug fever
- Factitious fever
- Thromboembolic disease 4
Undiagnosed (10-30%)
- Despite extensive investigations, many cases remain undiagnosed
- These patients generally have a good prognosis 4
Etiology in India
Infectious Causes (40-50%)
- Tuberculosis (28-30%) - predominantly extrapulmonary (70% of TB cases), especially gastrointestinal 1
- Enteric fever
- Malaria
- Visceral leishmaniasis (Kala-azar)
- Brucellosis
- Dengue 3
Malignant Causes (20-25%)
- Lymphomas (Hodgkin and non-Hodgkin equally distributed)
- Leukemias
- Solid malignancies (less common than in Western countries) 1
Inflammatory/Rheumatologic Causes (15-20%)
- Adult-onset Still's disease (second most common cause in adults ≤40 years)
- Systemic lupus erythematosus
- Rheumatoid arthritis 1
Miscellaneous Causes (2-5%)
- Drug fever
- Factitious fever 1
Undiagnosed (10-15%)
- Fever resolves spontaneously in approximately 60-70% of undiagnosed cases 1
Key Differences Between Western and Indian PUO Etiology
Tuberculosis prevalence: Extrapulmonary TB is the leading cause in India (28-30%) but much less common in Western countries 1
Distribution of causes:
Specific infections:
- India: Higher rates of endemic infections like tuberculosis, enteric fever, malaria, and visceral leishmaniasis
- Western: Higher rates of endocarditis, Q fever, and intra-abdominal abscesses 3
Adult-onset Still's disease: Second most common cause in younger adults in India but less prominent in Western PUO cases 1
Diagnostic Approach
The diagnostic approach should be guided by epidemiological considerations:
Initial Workup (Both Regions)
- Chest radiograph
- Blood cultures (at least 2 sets)
- Complete blood count with differential
- Acute phase reactants (CRP, ESR)
- Liver function tests 2
Region-Specific Considerations
India:
- Higher index of suspicion for tuberculosis, especially extrapulmonary
- Testing for endemic infections (malaria, enteric fever, visceral leishmaniasis)
- Abdominal imaging to detect gastrointestinal tuberculosis 1
Western Countries:
- Higher suspicion for endocarditis, Q fever, and brucellosis
- Consider travel history to endemic regions
- More emphasis on autoimmune and malignant causes 3
Advanced Diagnostics
- 18F-FDG PET/CT has high diagnostic yield (56%) in both regions when diagnosis remains elusive 2, 5
- Specialized testing based on suspected etiology (extended blood cultures, serological testing)
- Invasive procedures like liver biopsy may be necessary 2
Conclusion
Understanding the regional differences in PUO etiology is crucial for efficient diagnosis and management. While the diagnostic approach follows similar principles worldwide, the pre-test probability of specific causes varies significantly between Western countries and India, necessitating tailored investigation strategies.