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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 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).

Closely related to FUO is inflammation of unknown origin (IUO), which has the same definition as FUO, except for the body temperature criterion: IUO is defined as the presence of elevated inflammatory parameters (CRP or ESR) on multiple occasions for a period of at least 3 weeks in an immunocompetent patient with normal body temperature, for which a final explanation is lacking despite history-taking, physical examination, and the obligatory tests listed above. It has been shown that the causes and workup for IUO are the same as for FUO. Therefore, for convenience, the term FUO will refer to both FUO and IUO within the remainder of this chapter.


Table 20-1 summarizes the findings of large studies on FUO conducted over the past 20 years.

TABLE 20-1Etiology of FUO: Pooled Results of Large Studies Published in the Past 20 Years (1999–2019)

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