OVERVIEW

Fever of unknown origin (FUO) describes prolonged fevers >101°F lasting for 3 or more weeks that remain undiagnosed after a focused FUO outpatient/inpatient workup. The causes of FUO include infectious and noninfectious disorders. A variety of infectious, malignant, rheumatic/inflammatory disorders may be associated with prolonged fevers, but relatively few persist undiagnosed for sufficient duration to be classified as FUOs.

CAUSES OF FUO

The distribution of disorders causing FUOs is dependent on age, demographics, family history, zoonotic exposures, and previous/current conditions, e.g., malignancies, rheumatic/inflammatory disorders, cirrhosis. Each category of FUO may also be approached by subgroups, e.g., elderly, immunosuppressed, transplants, febrile neutropenia, zoonoses, HIV, nosocomial, returning travelers. The differential diagnosis in each subgroup reflects the relative distribution of disorders within the subgroup, and the geographic distribution of endemic diseases. The relative distribution of causes of FUO has changed over time but, with few exceptions, the disorders responsible for FUOs have remained relatively constant over time (Table 1.1).

DIAGNOSTIC APPROACH TO FUOs

In patients presenting with prolonged fevers, the clinician should first determine if the patient indeed has an FUO. Because there are many causes of FUO, there is no “cookbook or algorithmic approach” for diagnosing FUOs. In medicine, the history provides important initial diagnostic clues and a general sense of the likely FUO category, e.g., weight loss with early anorexia suggests malignancy, arthralgias/myalgias suggest a rheumatic/inflammatory disorder, and fever with chills suggests an infectious etiology.

After an FUO category is suggested by historical clues, the physical examination should focus on history relevant findings in the differential diagnosis. The physical examination should not be comprehensive but more importantly should be carefully focused on demonstrating the presence or absence of key findings in the differential diagnosis, e.g., a complete neurologic exam is unhelpful in an FUO patient with probable adult Still’s disease.