What is the initial workup and treatment for a patient with fever of unknown origin?

Fever of Unknown Origin Workup

The initial workup for fever of unknown origin (FUO) should begin with chest radiography, blood cultures, complete blood count with manual differential, acute phase reactants (CRP, ESR), liver function tests, and urinalysis, followed by 18F-FDG PET/CT if the diagnosis remains elusive after standard evaluation. 1

Definition and Classification

FUO 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 1

FUO is categorized into four distinct subcategories:

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

Initial Diagnostic Approach

First-Line Investigations

1. Laboratory studies:

   • Complete blood count with manual differential
   • Acute phase reactants (C-reactive protein, erythrocyte sedimentation rate)
   • Liver function tests
   • Blood cultures (at least 2 sets, ideally 60 mL total)
   • Urinalysis and culture 1, 3, 2

2. Imaging:

   • Chest radiography 1, 3
   • Abdominal and pelvic ultrasonography or CT (if abdominal symptoms or abnormal liver function tests) 1, 3

Second-Line Investigations

If the diagnosis remains unclear after initial workup:

1. Additional laboratory tests:

   • Lactate dehydrogenase
   • Creatine kinase
   • Rheumatoid factor
   • Antinuclear antibodies
   • HIV testing
   • Region-specific serologic testing (e.g., cytomegalovirus, Epstein-Barr virus, tuberculosis) 1, 3

2. Advanced imaging:

   • 18F-FDG PET/CT - should be performed if diagnosis remains elusive (high diagnostic yield of 56%, sensitivity 84-86%, specificity 52-63%) 1, 2
   • Note: 18F-FDG PET/CT should be performed within 3 days of starting oral glucocorticoid therapy 1

3. Invasive procedures:

   • If noninvasive tests are unrevealing, tissue biopsy has a relatively high diagnostic yield
   • Options include liver, lymph node, temporal artery, skin, skin-muscle, or bone marrow biopsy based on clinical indications 2

Etiology Considerations

The major categories of FUO causes include:

1. Infections (30-40%):

   • Tuberculosis
   • Endocarditis
   • Abscesses
   • Complicated UTIs
   • Osteomyelitis 1, 3, 2

2. Malignancies (20-30%):

   • Lymphomas
   • Leukemias
   • Solid tumors 1, 2

3. Non-infectious inflammatory diseases (10-30%):

   • Adult-onset Still's disease
   • Vasculitis
   • Connective tissue diseases 1, 2
   • Consider ferritin levels (>5000 ng/mL suggests adult-onset Still's disease) 1
   • Glycosylated ferritin <20% is highly specific for adult-onset Still's disease 1

4. Miscellaneous causes (10-20%):

   • Drug fever
   • Venous thromboembolism
   • Thyroiditis 1, 2

Special Considerations

• Neutropenic patients: Require urgent evaluation with CT scans and bronchoscopy if they have pulmonary infiltrates 1
• Travelers: Evaluate for infectious diseases such as malaria, dengue, and typhoid fever 1
• Patients with central venous catheters: Evaluate catheter and peripheral blood cultures for differential time to positivity 1
• Procalcitonin: May be useful in diagnosing bacterial infections, particularly in patients with low to intermediate probability of infection 1

Treatment Considerations

• Avoid empiric antibiotics in immunocompetent patients with FUO as they have not been shown to be effective and may obscure the diagnosis 2
• Exception: Empiric antibiotics should be considered in patients who are neutropenic, immunocompromised, or critically ill 2
• Avoid routine use of antipyretic medications solely for the purpose of reducing temperature in critically ill patients with fever 1

Common Pitfalls to Avoid

1. Ordering non-clue-based imaging and specific testing early in the FUO workup, which may be inefficient or misleading 4
2. Routine abdominal imaging for patients without abdominal symptoms or liver function abnormalities 1
3. Starting empiric antibiotics or steroids, which can mask symptoms and complicate diagnosis 3, 2
4. Failing to recognize that FUO is more often an atypical presentation of a common disease rather than an unusual disease 3

Remember that up to 75% of FUO cases will resolve spontaneously without reaching a definitive diagnosis 2, but a systematic approach is essential to rule out serious underlying conditions.