Fever of Unknown Origin MKSAP

Introduction

The classic definition of fever of unknown origin (FUO) has changed over time (including removing the requirement for in-hospital evaluation), and three categories have been added: health care–associated, neutropenic, and HIV-associated (Table 37). Diagnostic advances have revealed a spectrum of diseases causing FUO, with origins more rapidly identifiable for many cases.

Causes

The differential diagnosis of FUO includes more than 200 diseases, although most adult cases are attributed to one of several dozen causes. Common causes of FUO include infections, neoplasm or malignancy, rheumatologic or inflammatory disorders, and miscellaneous causes (see Table 37).

Evaluation

Many FUO occurrences are atypical presentations of common diseases. A careful history and physical examination should be performed and repeated intermittently during the period of evaluation. The history should include procedures, surgeries, presence of foreign bodies or implants, immunosuppression, travel, animal and other exposures (including hobbies), dietary habits, and medications (including over-the-counter medications). The degree and pattern of fever is not specific and not diagnostic in most instances.

Initial testing for the evaluation of classic FUO includes complete blood count with differential, electrolyte levels, kidney and liver function tests (hepatitis serology if results are abnormal), lactate dehydrogenase level, urinalysis or microscopy and urine culture, erythrocyte sedimentation rate, C-reactive protein, antinuclear antibodies, rheumatoid factor, HIV testing, cytomegalovirus polymerase chain reaction testing, blood cultures (three sets, each set obtained at least several hours apart), tuberculosis testing, and chest radiography (or chest CT). Q-fever serology should be considered if risk factors exist, and mycobacterial blood cultures should be obtained in HIV-positive patients with CD4 cell counts of 50/µL or less.

If initial tests do not suggest a cause, abdominal or pelvic CT may be considered to evaluate for intra-abdominal abscess or lymphoproliferative disorders. Liver, lymph node, and temporal artery biopsies have a diagnostic yield of about 35%, particularly when performed when infection is unlikely. Posterior cervical, supraclavicular, infraclavicular, epitrochlear, hilar, mediastinal, and mesenteric lymph node biopsies are more likely to provide a diagnosis than that of other lymph nodes. Bone marrow biopsy can be helpful when leukopenia or thrombocytopenia is present.

A definitive diagnosis is lacking in up to half of patients after extensive evaluation. FUO lasting more than 1 year is unlikely to be caused by infection or malignancy. Undiagnosed FUO is generally associated with a benign long-term course, particularly when fever is not associated with weight loss or other signs of underlying serious disease.