What is the definition of fever of unknown origin?

Definition of Fever of Unknown Origin (FUO)

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

Classification of FUO

FUO is divided into four distinct subcategories:

1. Classical FUO - The standard definition as described above
2. Nosocomial FUO - Hospital-acquired fever without clear source
3. Neutropenic FUO - Fever in patients with neutropenia
4. HIV-related FUO - Fever in patients with HIV infection

Etiology of FUO

The causes of FUO can be categorized into four main groups:

• Infections: Tuberculosis, endocarditis, abscesses, complicated UTIs
• Malignancies: Lymphomas, leukemias, solid tumors
• Non-infectious inflammatory diseases: Adult-onset Still's disease, vasculitis, connective tissue diseases
• Miscellaneous causes: Drug fever, factitious fever

Diagnostic Approach

Initial Evaluation

1. Laboratory tests:

   • 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)

2. Imaging:

   • Chest radiography
   • Abdominal and pelvic ultrasonography or CT (if indicated by symptoms)

Advanced Diagnostic Testing

When initial evaluation is non-diagnostic:

• 18F-FDG PET/CT should be performed with a high diagnostic yield (56%) in FUO cases 1, 2
  • Sensitivity: 84-86%
  • Specificity: 52-63%
  • Should be performed within 3 days of starting oral glucocorticoid therapy

Special Considerations

• Neutropenic patients require urgent evaluation with CT scans and bronchoscopy if they have pulmonary infiltrates 2
• Travelers should be evaluated for infectious diseases such as malaria, dengue, and typhoid fever 2
• Patients with central venous catheters should have catheter and peripheral blood cultures evaluated for differential time to positivity 2

Common Pitfalls to Avoid

1. Diagnosing "fever of unknown origin" prematurely: FUO is a diagnosis of exclusion that requires meeting specific criteria and thorough investigation 1

2. Empiric use of antibiotics or steroids: These can mask underlying conditions and should generally be avoided unless there is a clear indication 3

3. Overlooking atypical presentations: FUO is more often an atypical presentation of a common disease rather than an unusual disease 3

4. Neglecting the value of 18F-FDG PET/CT: This imaging modality has become crucial in the evaluation of FUO when diagnostic clues are absent 4

5. Insufficient evaluation of patients with normal inflammatory markers: Current guidelines note insufficient evidence for evaluation of patients with FUO and normal inflammatory markers (CRP, ESR) 1

Key Points for Clinical Practice

• The definition of FUO has evolved since its original characterization in 1961 by Petersdorf and Beeson 5
• Although there are more than 200 diseases in the differential diagnosis, most cases in adults are limited to several dozen possible causes 3
• FDG-PET/CT appears to be a cost-effective routine imaging technique in FUO by avoiding unnecessary investigations and reducing the duration of hospitalization 4
• Inflammation of unknown origin (IUO), defined as unexplained and prolonged elevation of inflammatory markers without fever, shares similar etiologies with FUO 1

By following a systematic approach to diagnosis and utilizing appropriate advanced imaging techniques like 18F-FDG PET/CT, clinicians can effectively evaluate and manage patients with FUO to improve morbidity, mortality, and quality of life outcomes.