Fever Of Unknown Origin

Anthony Zeimet Key Points

• A comprehensive history and physical examination with laboratory and radiologic evaluation are important in the workup for fever of unknown origin (FUO).

• If routine information is unrevealing, more specific testing for FUO is undertaken based on the patient's age, travel history, and disease process to develop a differential diagnosis.

• The serum ferritin level (often elevated with malignancy) and naproxen test (reduces fever with malignancy) may be helpful in determining an underlying malignant process.

• Initiation of empiric antibiotics should be done only in specific FUO situations to prevent skewing culture results, thus maximizing isolation of the causative organism.

Patients who have a persistent fever despite workup are generally classified as having a "fever of unknown origin" (FUO). In 1961, Petersdorf and Beeson described 100 patients with persistent fever, otherwise known as fever of unknown origin. They introduced the standard, classic definition of FUO: fever higher than 38.3° C (101° F) on several occasions, persisting without diagnosis for at least 3 weeks, with 1 week of investigational study in the hospital setting. With advancing technology, this definition has been revised to allow for more than two outpatient visits, or 3 days if investigation is in the hospital setting. Most patients with FUO have chronic or subacute symptoms and can be safely evaluated in the outpatient setting, with a median time to diagnosis of 40 days.

The differential diagnosis of FUO is quite broad and extensive. Determining an etiologic diagnosis of an FUO depends on generating a differential diagnosis compatible with the patient's history and physical examination. The principal disease categories for FUO include infection (30% overall), neoplasms (18%), collagen vascular diseases (12%), and miscellaneous (14%) (Box 16-5). Because of this broad differential, a newer classification system divides FUO into four groups: classic, nosocomial, neutropenic, and HIV associated, which helps narrow the differential diagnosis. Furthermore, classic FUO can be broken down into three subgroups: infants and children, elderly, and travelers. Despite an extensive workup, the etiologic diagnosis usually remains elusive in 7% to 30% of patients (Box 16-4).

The diagnostic workup of FUO should begin with a thorough history and physical examination, including documentation of the fever. The patient may provide a diary noting the date and time of fever. Routine noninvasive investigations are recommended in all patients before diagnosing FUO (Box 16-6). Acute febrile illness is never called an FUO. The patient's medication profile is reviewed because numerous drugs can be the cause. If unrevealing, a workup is initiated based on the differential diagnosis for the patient's age, travel history, geographic location, and disease process. Dukes criteria for infective endocarditis have 99% specificity in patients with FUO. When the initial investigations are not helpful in identifying a cause, imaging should be considered, such as computed tomography (CT) scans of the chest, abdomen, and pelvis; CT may reveal an abscess or suggest an underlying malignancy. An elevated serum ferritin level can suggest a neoplasm or myeloproliferative disorder and, if normal, greatly decreases the chance that the patient has an underlying malignancy. Lower-extremity Doppler ultrasound should be considered in the sedentary or obese patient to rule out deep venous thrombosis. A temporal artery biopsy should be considered in the elderly patient to rule out temporal arteritis. Liver biopsy has a high diagnostic yield with minimal toxicity, whereas bone marrow cultures usually have a low yield and should be considered only in special situations.

Empiric therapy with antibiotics is rarely appropriate for the patient with FUO. A diagnosis is essential to guide

Box 16-4 Differential Diagnosis for Fever of Unknown Origin (FUO)

Box 16-5 Causes of Fever of Unknown Origin

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