From the Guidelines
The workup of fever of unknown origin (FUO) should start with a thorough history and physical examination, followed by basic laboratory tests and imaging, with consideration of [18F]FDG PET/CT due to its high diagnostic yield in this clinical setting. The diagnostic approach to FUO, as defined by fever higher than 38.3°C (100.9°F) persisting for at least 3 weeks with no diagnosis despite extensive evaluation 1, requires a systematic and methodical strategy. This includes initial basic laboratory tests such as complete blood count, comprehensive metabolic panel, urinalysis, blood cultures, and inflammatory markers (ESR, CRP). Initial imaging should encompass chest X-ray and abdominal ultrasound or CT scan.
If these initial steps are unrevealing, more specialized tests should be pursued based on clinical suspicion, including:
- Tuberculin skin test
- HIV testing
- Autoimmune panels (ANA, RF)
- Specialized imaging such as CT scans of chest/abdomen/pelvis, MRI, or [18F]FDG PET/CT, which has been shown to have a high diagnostic yield in both FUO and inflammation of unknown origin (IUO) 1. Invasive procedures like bone marrow biopsy, lymph node biopsy, or liver biopsy may be necessary if non-invasive tests are inconclusive. It's crucial to guide the diagnostic approach by potential etiologies including infections, malignancies, autoimmune disorders, and miscellaneous causes. Throughout the workup, periodic reassessment of the patient is vital, as new symptoms or signs may develop that provide diagnostic clues. Empiric therapy is generally not recommended unless the patient is critically ill. The use of [18F]FDG PET/CT is particularly noteworthy due to its ability to help in diagnosing both infectious and inflammatory causes of FUO, as highlighted in the recent guideline for its use in infection and inflammation in adults 1.
From the Research
Definition and Classification of Fever of Unknown Origin
- Fever of unknown origin (FUO) is defined as a clinically documented temperature of 101°F or higher on several occasions, coupled with an unrevealing diagnostic workup 2
- FUO can be categorized into classic FUO, nosocomial FUO, neutropenic FUO, and HIV-associated FUO based on the clinical setting and patient's underlying immune status 3
Diagnostic Approach
- The workup should begin with a comprehensive history and physical examination to help narrow potential etiologies 2, 4
- Initial testing should include an evaluation for infectious etiologies, malignancies, inflammatory diseases, and miscellaneous causes such as venous thromboembolism and thyroiditis 2
- A minimum diagnostic workup should include a complete blood count, chest radiography, urinalysis and culture, electrolyte panel, liver enzymes, erythrocyte sedimentation rate, and C-reactive protein level testing 4
- Further testing may include blood cultures, lactate dehydrogenase, creatine kinase, rheumatoid factor, and antinuclear antibodies 4
Advanced Diagnostic Tests
- If erythrocyte sedimentation rate or C-reactive protein levels are elevated and a diagnosis has not been made after initial evaluation, 18F fluorodeoxyglucose positron emission tomography scan, with computed tomography, may be useful in reaching a diagnosis 2, 4
- Tissue biopsy may be necessary if noninvasive diagnostic tests are unrevealing, with a relatively high diagnostic yield 2
Treatment
- Empiric antimicrobial therapy has not been shown to be effective in the treatment of fever of unknown origin and therefore should be avoided except in patients who are neutropenic, immunocompromised, or critically ill 2, 4
- Empiric antibiotics or steroids are generally discouraged in patients with fever of unknown origin 4