Chapter 18

### Definition and Classification

Fever of unknown origin (FUO) was defined by Petersdorf and Beeson in 1961 as (1) temperatures of >38.3°C (>101°F) on several occasions; (2) a duration of fever of >3 weeks; and (3) failure to reach a diagnosis despite 1 week of inpatient investigation. While this classification has stood for more than 30 years, Durack and Street have proposed a revised system for classification of FUO that better accounts for nonendemic and emerging diseases, improved diagnostic technologies, and adverse reactions to new therapeutic interventions. This updated classification includes (1) classic FUO, (2) nosocomial FUO, (3) neutropenic FUO, and (4) FUO associated with HIV infection.

Classic FUO corresponds closely to the earlier definition of FUO, differing only with regard to the prior requirement for 1 week's study in the hospital. The newer definition is broader, stipulating three outpatient visits or 3 days in the hospital without elucidation of a cause or 1 week of “intelligent and invasive” ambulatory investigation. In nosocomial FUO, a temperature of ≥38.3°C (≥101°F) develops on several occasions in a hospitalized patient who is receiving acute care and in whom infection was not manifest or incubating on admission. Three days of investigation, including at least 2 days' incubation of cultures, is the minimum requirement for this diagnosis. Neutropenic FUO is defined as a temperature of ≥38.3°C (≥101°F) on several occasions in a patient whose neutrophil count is <500/μL or is expected to fall to that level in 1–2 days. The diagnosis of neutropenic FUO is invoked if a specific cause is not identified after 3 days of investigation, including at least 2 days' incubation of cultures. HIV-associated FUO is defined by a temperature of ≥38.3°C (≥101°F) on several occasions over a period of >4 weeks for outpatients or >3 days for hospitalized patients with HIV infection. This diagnosis is invoked if appropriate investigation over 3 days, including 2 days' incubation of cultures, reveals no source.

Adoption of these categories of FUO in the literature has allowed a more rational compilation of data regarding these disparate groups. In the remainder of this chapter, the discussion will focus on classic FUO in the adult patient unless otherwise specified.

### Causes of Classic FUO

Table 18-1 summarizes the findings of several large studies of FUO carried out since the advent of the antibiotic era, including a prospective study of 167 adult patients with FUO encompassing all eight university hospitals in the Netherlands and using a standardized protocol in which the first author reviewed every patient's case. Coincident with the widespread use of antibiotics, increasingly useful diagnostic technologies—both noninvasive and invasive—have been developed. Newer studies reflect not only changing patterns of disease but also the impact of diagnostic techniques that make it possible to eliminate many patients with specific illness from the FUO category. The ubiquitous use of potent broad-spectrum antibiotics may have decreased the number of infections causing FUO. The wide availability of ultrasonography, CT, MRI, radionuclide scanning, and positron emission tomography (PET) scanning has enhanced the detection of localized infections and of occult neoplasms and lymphomas in patients previously thought to have FUO. Likewise, the widespread availability ...

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