From the Guidelines
For fever of unknown origin (FUO), I recommend a systematic diagnostic approach rather than empiric treatment, starting with a thorough history and physical examination, followed by basic laboratory tests and imaging studies, as outlined in the most recent guidelines 1. The diagnostic workup for FUO should begin with:
- A thorough history and physical examination to identify potential causes of fever
- Basic laboratory tests, including:
- Complete blood count
- Comprehensive metabolic panel
- Urinalysis
- Blood cultures
- Chest X-ray If these initial tests are unrevealing, second-tier testing should include:
- Inflammatory markers (ESR, CRP)
- Tuberculosis testing
- HIV serology
- CT scans of chest, abdomen, and pelvis Further specialized testing may be necessary, including:
- PET-CT scan, as recommended by the European Journal of Nuclear Medicine and Molecular Imaging 1
- Bone marrow biopsy
- Temporal artery biopsy in older patients
- Liver biopsy, depending on clinical suspicion The most common causes of FUO are:
- Infections (particularly endocarditis, tuberculosis, abscesses)
- Malignancies (lymphoma, leukemia)
- Autoimmune disorders (Still's disease, vasculitis)
- Miscellaneous conditions (drug fever, factitious fever) Empiric antibiotics should generally be avoided unless the patient is critically ill, as they may mask the underlying diagnosis 1. Antipyretics like acetaminophen or NSAIDs can be used for symptomatic relief while the diagnostic workup continues. The key to managing FUO is patience and persistence in the diagnostic process, rather than rushing to treatment without a clear diagnosis. It is essential to note that the diagnostic approach may vary depending on the patient's specific clinical presentation and the results of initial tests. In critically ill patients, the use of 18F-fluorodeoxyglucose positron emission tomography/CT (18F-FDG PET/CT) may be considered if other diagnostic tests have failed to establish an etiology, as suggested by the Society of Critical Care Medicine and the Infectious Diseases Society of America 1.
From the Research
Causes of Pyrexia (Fever) of Unknown Origin (FUO)
- Infections, malignancies, and noninfectious inflammatory diseases are the three major categories that account for most FUOs 2
- Over 200 malignant/neoplastic, infectious, rheumatic/inflammatory, and miscellaneous disorders can cause FUO 3
- Hematological malignant diseases, infectious diseases, systemic mastocytosis, and disseminated granulomatosis are some of the specific diseases that can cause FUO 4
Diagnostic Approaches for FUO
- A methodical approach to FUO involves categorizing it into classic FUO, nosocomial FUO, neutropenic FUO, and HIV-associated FUO based on the clinical setting and patient's underlying immune status 5
- Evaluation starts with the identification of potential diagnostic clues (PDCs), which should guide further investigations 6
- A standardized diagnostic protocol should be followed in the absence of PDCs, with PET-CT as the imaging technique of first choice 6
- Repeated physical investigations and thorough history-taking combined with standardized laboratory tests and simple imaging procedures are part of the diagnostic approach 2
- Bone marrow biopsy (BMB) is a useful technique for the diagnosis of prolonged fever in immunocompetent patients, especially in those with thrombocytopenia and anemia 4
- (18)F-FDG PET has the potential to play a central role as a second-line procedure in the management of patients with FUO, contributing to the final diagnosis in 25%-69% of patients 2