What is the duration of fever persistence required for a diagnosis of fever of unknown origin?

Fever of Unknown Origin Definition and Diagnostic Criteria

Fever of unknown origin (FUO) is defined as a 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, 2

Classification of FUO

FUO is categorized into four distinct subcategories:

• Classical FUO
• Nosocomial FUO
• Neutropenic FUO
• HIV-related FUO 1, 2

Etiology

The causes of FUO can be broadly classified into:

1. Infectious causes: Including tuberculosis, endocarditis, intra-abdominal abscesses, and catheter-associated infections
2. Inflammatory/rheumatologic causes: Such as adult-onset Still's disease, vasculitis, and connective tissue diseases
3. Malignant causes: Including lymphomas, leukemias, and solid tumors
4. Miscellaneous causes: Various other conditions that don't fit into the above categories 2

Diagnostic Approach

Initial Evaluation

• Complete blood count with 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 2

Advanced Diagnostic Testing

When initial evaluation is non-diagnostic:

1. 18F-FDG PET/CT:

   • High diagnostic yield (56%) in FUO cases
   • Sensitivity of 84-86% and specificity of 52-63%
   • Should be performed within 3 days of starting oral glucocorticoid therapy 1, 2

2. Additional imaging based on symptoms:

   • Abdominal ultrasound if abdominal symptoms or abnormal liver function tests
   • CT scans for suspected thoracic or abdominal pathology
   • Thoracic ultrasound if abnormal chest radiograph 2

Special Considerations

• Travelers: Evaluate for malaria, dengue, and typhoid fever
• Patients with central venous catheters: Evaluate catheter and peripheral blood cultures for differential time to positivity
• Neutropenic patients: Require urgent evaluation with CT scans and bronchoscopy if pulmonary infiltrates are present 2

Management Principles

• Avoid routine use of antipyretic medications solely for reducing temperature in critically ill patients with fever
• Avoid routine abdominal imaging for patients without abdominal symptoms or liver function abnormalities
• Consider specialized referral for persistent FUO cases, as recent studies show that despite improved diagnostic procedures, the percentage of undiagnosed FUO cases has increased 2, 3

Diagnostic Pitfalls to Avoid

• Ordering non-clue-based imaging and specific testing early in the FUO work-up, which may be inefficient or misleading 4
• Failing to recognize characteristic fever patterns (e.g., double quotidian fever may suggest juvenile rheumatoid arthritis) 5
• Overlooking the value of FDG-PET/CT, which can be cost-effective by avoiding unnecessary investigations and reducing hospitalization duration 6

Despite advances in diagnostic technology, FUO remains a challenging clinical entity requiring a systematic approach and often specialized expertise for proper diagnosis and management.