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Am Fam Physician. 2003;68(1):154

Clinical Question: What is the best approach to evaluating fever of unknown origin that lasts at least three weeks in adults?

Setting: Various (meta-analysis)

Study Design: Systematic review

Synopsis: Fever of unknown origin in adults is defined as a temperature higher than 38.3°C (100.9°F) lasting at least three weeks. Investigators conducted a systematic review of the English language literature through the year 2000 by searching MEDLINE and the Cochrane Library, as well as the references of selected articles, after which they summarized the results and arrived at a set of recommendations.

Infection was identified as a cause of fever in only 28 percent of cases. Other identified causes included inflammatory diseases (21 percent), malignancies (17 percent), temporal arteritis (16 percent), and deep venous thrombosis (3 percent) in the elderly. Nineteen percent of patients will never be given a diagnosis; fortunately, 51 to 100 percent in this group will recover spontaneously.

For the initial work-up, patients should record their temperature daily. All medications should be discontinued for 72 hours, when possible, to rule out drug-induced fever. According to one study, computed tomography of the abdomen, which has a 19 percent diagnostic yield, should be one of the first tests performed. Using the Duke criteria (Hoen B, et al. The Duke criteria for diagnosing infective endocarditis are specific: analysis of 100 patients with acute fever or fever of unknown origin. Clin Infect Dis August 1996; 23:298–302.) to diagnose endocarditis will allow physicians to rule in (specificity: 99 percent) and rule out (sensitivity: 82 percent) this disease. Nuclear imaging using technetium is specific (93 to 94 percent) but not particularly sensitive (40 to 75 percent). Liver biopsy has a high diagnostic yield (14 to 17 percent) but is associated with harm. Empiric bone cultures rarely yield anything of value and should not be used.

Bottom Line: After ruling out endocarditis, using computed tomography of the abdomen, performing a nuclear scan using technetium, and perhaps doing a liver biopsy, physicians may arrive at a diagnosis for patients with fever of unknown origin. However, there will be no diagnosis for approximately one in five patients, although most fevers in this group (50 to 100 percent) will resolve spontaneously. (Level of Evidence: 3a)

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