The acronym FUO stands for Fever of Unknown Origin, representing a formal medical diagnosis applied when a prolonged fever resists identification despite initial medical investigation. This classification signals a complex diagnostic challenge, requiring a systematic, often interdisciplinary, approach to uncover the underlying condition. Unlike a common viral illness, an FUO suggests an atypical presentation of a more serious disease or an uncommon disorder.
Defining Fever of Unknown Origin
A fever is only classified as FUO once it meets specific clinical criteria defining its duration and resistance to diagnosis. The minimum temperature required is a core body temperature of 101°F (38.3°C) or higher, documented on multiple occasions. This elevated temperature must persist for an extended period, typically three weeks or longer.
The diagnosis of FUO is assigned only after a thorough initial diagnostic workup fails to identify the cause. This preliminary evaluation usually involves basic blood tests, cultures, and imaging studies. Modern definitions require three days of hospital evaluation or three comprehensive outpatient visits without a diagnosis being reached.
Primary Categories of Underlying Causes
The conditions leading to FUO are broadly grouped into three major categories, plus a smaller fourth group encompassing miscellaneous causes. These classifications guide the diagnostic process, allowing clinicians to focus their search on the most likely culprits.
Infections constitute a significant cause of FUO, often presenting as unusual manifestations of common pathogens or rare infections. Examples include localized abscesses, atypical presentations of tuberculosis, or chronic infections like endocarditis. These infections are challenging to detect because they lack typical localizing symptoms.
Malignancies, or cancers, are another major grouping. Lymphomas (such as Hodgkin’s disease and non-Hodgkin lymphoma), leukemias, and solid tumors like renal cell carcinoma are frequent offenders. The fever in these cases is often caused by the release of fever-producing substances, called pyrogens, by the cancer cells or by immune cells reacting to the tumor.
The third main category involves systemic rheumatic and inflammatory diseases, where the immune system mistakenly attacks the body’s own tissues. Prominent examples include Adult Still’s disease, systemic lupus erythematosus (SLE), and vasculitis. These disorders cause fever and systemic inflammation without clear localized symptoms, mimicking infection or malignancy.
A final, smaller group is categorized as miscellaneous. This includes entities like drug-induced fever, where a medication triggers an adverse reaction. Conditions such as deep vein thrombosis leading to pulmonary embolism or chronic thyroiditis can also manifest as an FUO. Many cases, up to 20% to 50% in some developed countries, ultimately remain undiagnosed, though the fever often resolves spontaneously.
The Systematic Diagnostic Process
The investigation of FUO is a methodical, multi-phase process designed to minimize unnecessary testing while increasing the diagnostic yield. Clinicians begin with a detailed review of the patient’s history, focusing on travel, medication use, animal exposure, and family history, to generate initial diagnostic clues.
The first phase involves basic laboratory tests, including complete blood counts, inflammatory markers (like C-reactive protein and ESR), and cultures of blood and urine. Elevated inflammatory markers confirm systemic inflammation, guiding the workup toward inflammatory or infectious causes. This initial screening aims to rule out easily detectable causes.
If the initial phase is unrevealing, the diagnostic process moves into a second phase utilizing advanced imaging. Computed Tomography (CT) scans of the chest, abdomen, and pelvis search for deep abscesses, enlarged lymph nodes, or tumors. Highly specialized nuclear medicine scans, such as Positron Emission Tomography (PET) combined with CT ([18F]FDG PET/CT), are valuable because they detect areas of increased metabolic activity, pinpointing sites of occult infection, inflammation, or malignancy.
When non-invasive methods fail, the third phase involves more invasive procedures, often guided by earlier imaging findings. Tissue biopsy of a suspicious lymph node, liver, or bone marrow is frequently performed to obtain a definitive histological diagnosis. These procedures are reserved for cases where clinical suspicion is high or when advanced imaging has identified a specific target area. The diagnostic process is collaborative, often requiring input from infectious disease specialists, rheumatologists, and oncologists.
Management Strategies and Prognosis
Management of FUO is guided by finding the underlying cause, as targeted treatment is the most effective strategy. Once a diagnosis is established, the care plan shifts to treating the specific infection, malignancy, or inflammatory condition identified. For instance, giant cell arteritis would be treated with high doses of corticosteroids.
If the fever persists and the cause remains elusive, empirical or symptomatic treatment may be considered, though this is avoided in stable patients. Empiric antibiotics or corticosteroids can mask the true diagnosis and are typically reserved for patients who are critically ill or immunocompromised. Symptomatic management focuses on patient comfort, such as using non-steroidal anti-inflammatory drugs (NSAIDs) to control the temperature.
The long-term outlook for a patient with FUO is generally favorable, especially in otherwise healthy individuals. In a significant percentage of cases (43% to 75%), the fever resolves spontaneously without a definitive diagnosis ever being made. Undiagnosed FUO in adults often carries a low mortality risk, and the prognosis is better than for cases where a serious underlying disease like malignancy is eventually found.