From the Guidelines
Fever of unknown origin (FUO) is defined as 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. The diagnostic criteria for FUO include a prolonged period of fever, with no identified cause despite appropriate investigation, and can be divided into four subcategories: classical, nosocomial, neutropenic, and Human Immunodeficiency Virus (HIV) – related 1.
Key Diagnostic Considerations
- The etiology of FUO includes infectious, inflammatory, malignant, and miscellaneous causes, with the distribution varying according to the FUO subcategory and geographical location.
- Inflammation of unknown origin (IUO), defined as unexplained and prolonged elevation of inflammatory markers, without fever, shares similar etiologies to FUO.
- The diagnostic approach should include a thorough history and physical examination, followed by a systematic investigation including:
- Complete blood count
- Comprehensive metabolic panel
- Blood cultures
- Urinalysis
- Chest X-ray
- Appropriate serological tests
- Additional testing such as CT scans, MRI, echocardiography, and nuclear medicine studies like PET scans, as guided by clinical clues.
Diagnostic Yield of Imaging Studies
- [18F]FDG PET/CT has a high diagnostic yield in both FUO and IUO, and is usually preferred over sensitivity and specificity due to the high number of patients who never have a final causative diagnosis 1.
Clinical Approach
- The diagnostic approach should be guided by clinical clues from the history, physical examination, and initial laboratory findings, rather than pursuing exhaustive testing without direction.
- A methodical approach helps identify the underlying cause in approximately 85-90% of FUO cases.
From the Research
Diagnostic Criteria for Fever of Unknown Origin (FUO)
The diagnostic criteria for FUO are as follows:
- A fever of 38.3°C (101°F) or more lasting for at least three weeks for which no cause can be identified after three days of investigation in hospital or after three or more outpatient visits 2
- A febrile illness (temperature of 101°F [38.3°C] or higher) for three weeks or longer without an etiology despite a one-week inpatient evaluation 3
- A prolonged fever of more than 3 weeks duration and which resists a diagnosis after a week in hospital 4
- Fever of >38 °C on several occasions for greater than three weeks despite investigation in hospital (>3 days) or out of hospital (>2 visits) 5
Key Considerations
- The definition of FUO may vary depending on the geographic region, age structure of the population, and immune status of the patient 2, 5
- A comprehensive history and examination should be performed to look for potentially diagnostic clues to guide the initial evaluation 3
- A minimum diagnostic workup, including a complete blood count, chest radiography, urinalysis and culture, electrolyte panel, liver enzymes, erythrocyte sedimentation rate, and C-reactive protein level testing, should be performed if there are no potentially diagnostic clues 3