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Clinicians commonly refer to any febrile illness without an initially obvious etiology as fever of unknown origin (FUO). Most febrile illnesses either resolve before a diagnosis can be made or develop distinguishing characteristics that lead to a diagnosis. The term FUO should be reserved for prolonged febrile illnesses without an established etiology despite intensive evaluation and diagnostic testing. This chapter focuses on classic FUO in the adult patient.

FUO was originally defined by Petersdorf and Beeson in 1961 as an illness of >3 weeks’ duration with fever of ≥38.3°C (≥101°F) on two occasions and an uncertain diagnosis despite 1 week of inpatient evaluation. Nowadays, most patients with FUO are hospitalized only if their clinical condition requires it, and not for diagnostic purposes alone; thus the in-hospital evaluation requirement has been eliminated from the definition. The definition of FUO has been further modified by the exclusion of immunocompromised patients, whose workup requires an entirely different diagnostic and therapeutic approach. For optimal comparison of patients with FUO in different geographic areas, it has been proposed that the quantitative criterion (diagnosis uncertain after 1 week of evaluation) be changed to a qualitative criterion that requires the performance of a specific list of investigations. Accordingly, FUO is now defined as follows:

  1. Fever ≥38.3°C (≥101°F) on at least two occasions

  2. Illness duration of ≥3 weeks

  3. No known immunocompromised state

  4. Diagnosis that remains uncertain after a thorough history-taking, physical examination, and the following obligatory investigations: determination of erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) level; platelet count; leukocyte count and differential; measurement of levels of hemoglobin, electrolytes, creatinine, total protein, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, creatine kinase, ferritin, antinuclear antibodies, and rheumatoid factor; protein electrophoresis; urinalysis; blood cultures (n = 3); urine culture; chest x-ray; abdominal ultrasonography; and tuberculin skin test (TST) or interferon γ release assay (IGRA).


The range of FUO etiologies has evolved over time as a result of changes in the spectrum of diseases causing FUO, the widespread use of antibiotics, and especially the availability of new diagnostic techniques. The proportion of cases caused by intraabdominal abscesses and tumors, for example, has decreased because of earlier detection by CT and ultrasound. In addition, infective endocarditis is a less frequent cause because blood culture and echocardiographic techniques have improved. Conversely, some diagnoses, such as acute HIV infection, were unknown four decades ago.

image Table 17-1 summarizes the findings of large studies on FUO conducted over the past 25 years. In general, infection accounts for about one-fifth of cases of FUO in Western countries; next in frequency are noninfectious inflammatory diseases (NIIDs, which include “collagen or rheumatic diseases,” vasculitis syndromes, granulomatous disorders, and autoinflammatory syndromes) and neoplasms. In geographic areas outside the West, infections are a much more common cause of FUO (43% vs 17%), while the proportions of cases due to ...

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