Initial Workup and Treatment for Fever of Unknown Origin (FUO)
The initial workup for fever of unknown origin should begin with a chest radiograph, blood cultures (at least 2 sets, ideally 60 mL total), complete blood count with manual differential, acute phase reactants (C-reactive protein, erythrocyte sedimentation rate), and liver function tests. 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
FUO is categorized into four subcategories:
- Classical
- Nosocomial
- Neutropenic
- HIV-related 1
Initial Diagnostic Approach
Step 1: Directed Physical Examination
- Look for adenopathy
- Check for hepatosplenomegaly
- Examine for skin rashes
- Identify any signs of infection 1
Step 2: Initial Laboratory Tests
- Complete blood count with manual differential
- Acute phase reactants (CRP, ESR)
- Liver function tests
- Blood cultures (at least 2 sets, ideally 60 mL total)
- Urinalysis and culture
- Electrolyte panel 1, 2
Step 3: Additional Initial Testing
- Lactate dehydrogenase
- Creatine kinase
- Rheumatoid factor
- Antinuclear antibodies
- HIV testing
- Region-specific serologic testing (e.g., CMV, EBV, tuberculosis) 2, 3
Step 4: Initial Imaging
Advanced Diagnostic Workup
If the diagnosis remains elusive after standard evaluation:
Advanced Imaging
- 18F-FDG PET/CT should be considered, with a high diagnostic yield in FUO cases (56%) and sensitivity of 84-86% 1, 4
- Should be performed within 3 days of starting oral glucocorticoid therapy
- More diagnostically useful than anatomic imaging like ultrasound and CT 4
Specialized Testing Based on Clinical Clues
- If abnormal chest radiograph: Consider thoracic bedside ultrasound
- If abdominal symptoms or abnormal liver function tests: Perform formal bedside diagnostic ultrasound of abdomen
- If suspected pneumonia or respiratory symptoms: Test for viral pathogens using nucleic acid amplification test panels
- If recent abdominal/thoracic/pelvic surgery: Perform CT in collaboration with surgical service 1
Invasive Testing
- If noninvasive tests are unrevealing, tissue biopsy may be necessary (liver, lymph node, temporal artery, skin, skin-muscle, or bone marrow) based on clinical indications 3
Management Recommendations
- Avoid routine use of antipyretic medications solely for reducing temperature in critically ill patients with fever 1
- Avoid empiric antibiotics except in patients who are neutropenic, immunocompromised, or critically ill 1, 3
- Avoid routine abdominal imaging for patients without abdominal symptoms or liver function abnormalities 1
Special Considerations
Etiology to Consider
- Infections (pneumonia, catheter-associated infections, tuberculosis, endocarditis)
- Neoplasms (lymphomas, leukemias, solid tumors)
- Inflammatory diseases (adult-onset Still's disease, vasculitis, connective tissue diseases)
- Miscellaneous causes (venous thromboembolism, thyroiditis) 1, 3
Special Populations
- 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 1
Helpful Diagnostic Markers
- Ferritin levels >5000 ng/mL suggest adult-onset Still's disease
- Glycosylated ferritin <20% is highly specific for adult-onset Still's disease
- Procalcitonin may be useful in diagnosing bacterial infections 1
Common Pitfalls to Avoid
- Rushing to empiric antibiotics or steroids without a diagnosis 2, 3
- Overlooking that FUO is more often an atypical presentation of a common disease rather than an unusual disease 2
- Failing to recognize that up to 75% of cases will resolve spontaneously without reaching a definitive diagnosis 3
- Delaying 18F-FDG PET/CT, which should be performed earlier rather than later in the diagnostic evaluation 4