Fever of Unknown Origin, or FUO, is a medical classification used when a prolonged elevation in body temperature resists diagnosis despite standard initial testing. It is a category of exclusion, meaning it describes a medical mystery rather than a specific disease itself. Physicians use the FUO classification to signal the need for a systematic, comprehensive investigation beyond routine screenings. This designation helps distinguish truly complicated cases from common, self-limiting fevers. The underlying causes can range across many different medical fields, necessitating a thorough diagnostic approach.
Defining the Clinical Criteria for FUO
The standard definition for classifying a patient’s condition as FUO was first proposed in 1961 and has since been modified to reflect modern outpatient care. For a fever to be categorized as classic FUO, it must meet three specific quantitative criteria. The first requirement is that the body temperature must exceed 101°F (38.3°C) on several separate occasions.
The second condition is that the fever must have persisted for a minimum of three weeks. This duration threshold helps exclude the majority of common, acute infections that generally resolve within that timeframe. Finally, a diagnosis must remain uncertain even after three full days of inpatient investigation or three comprehensive outpatient visits.
These parameters ensure that the FUO classification is reserved for cases where an underlying condition is genuinely difficult to uncover. The criteria prompt the medical team to transition from routine testing to a more expansive, focused, and potentially invasive diagnostic strategy.
Primary Categories of Underlying Causes
The causes of FUO are traditionally grouped into four broad categories, which guides the differential diagnosis process. Although the frequency of these categories has shifted due to advances in diagnostic technology, the framework remains useful for organizing the investigation. Infections historically represent one of the largest categories, though they often present atypically in FUO cases.
Infectious causes frequently include localized or chronic issues such as subacute bacterial endocarditis, an infection of the heart valves. Other examples involve hidden pockets of infection, like intra-abdominal or pelvic abscesses, or systemic diseases such as miliary tuberculosis. Viral syndromes, including HIV, cytomegalovirus (CMV), and Epstein-Barr virus (EBV), are also known to cause prolonged fevers.
Non-infectious inflammatory disorders constitute another major grouping, often involving systemic autoimmune conditions. These include diseases where the body’s immune system mistakenly attacks its own tissues, such as Systemic Lupus Erythematosus (SLE) or various forms of vasculitis. Adult Still’s disease, a form of inflammatory arthritis, also frequently presents with high, spiking fevers.
Malignancies, or cancers, form a third category, with certain types being more commonly associated with FUO. Lymphoma and leukemia are frequently cited examples, as these blood cancers can cause fever due to the production of inflammatory signaling molecules. Renal cell carcinoma, a type of kidney cancer, is also known to cause fever without other overt symptoms.
The final category is the miscellaneous group, which includes a wide range of less common conditions and cases that remain truly undiagnosed. Examples include drug-induced fevers, which resolve once the offending medication is stopped, and fevers resulting from recurrent pulmonary emboli. A portion of FUO cases will remain undiagnosed, though most of these patients experience spontaneous resolution of the fever.
Navigating the Diagnostic Workup
The diagnostic workup for FUO is a methodical, multi-stage process that begins with a comprehensive review of the patient’s history and a detailed physical examination. Initial laboratory screening includes a complete blood count, liver function tests, and inflammatory markers such as the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). Obtaining multiple sets of blood cultures from different sites is a mandatory early step to detect circulating bacteria.
The investigation then progresses to imaging studies designed to locate hidden sources of inflammation or infection. A chest X-ray is standard, and if initial labs suggest internal inflammation, computed tomography (CT) scans of the chest, abdomen, and pelvis are commonly employed. These cross-sectional images are useful for identifying abscesses or enlarged lymph nodes that might point to a specific disease.
More advanced imaging techniques, such as positron emission tomography (PET) scans, are frequently used when initial tests are inconclusive. A specialized PET scan using a radioactive glucose tracer highlights areas of increased metabolic activity, which is characteristic of both infection and inflammation. This technique can often localize a potential site for further, targeted investigation.
When non-invasive tests fail to yield a diagnosis, the workup advances to invasive procedures involving obtaining tissue samples for analysis. Biopsies may be taken from sites like the bone marrow, liver, or lymph nodes based on clues gathered from imaging studies. Specialized procedures, such as an echocardiogram or a temporal artery biopsy, are performed only when specific symptoms or lab results suggest those conditions. The diagnostic process is iterative and time-consuming, often requiring consultation with specialists in infectious diseases or rheumatology.