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The definition of FUO requires an immunologically normal host with oral or rectal temperature ⩾38.0°C (100.4°F) at least twice a week for more than 3 weeks, a noncontributory history and physical examination, and 1 week of outpatient investigation.6-9 Early diagnostic studies normally include a complete blood cell count; lactate dehydrogenase (LDH); uric acid; urinalysis and culture; chest roentgenogram; tuberculin skin test; erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP); and, in the older child, a titer of antinuclear antibodies. Management of patients with comorbidity factors such as acquired or congenital immunodeficiency, neutropenia, and occurrence of fever during prolonged hospital stays is not considered in the following discussion.

The greatest clinical concern in evaluating FUO is identifying patients whose fever has a serious or life-threatening etiology for whom a delay in diagnosis could jeopardize successful intervention. Cancer and severe bacterial infections are the causes most frequently discussed and most likely to influence diagnostic and management approaches. However, the vast majority of children with prolonged FUO resolve their illnesses without a diagnosis and do not exhibit long-lasting effects. Therefore, it appears appropriate for most children to delay extensive diagnostic evaluation until the child has remained febrile for at least 6 weeks.

Because of the ready availability of more sensitive serologic assays and more precise radiographic scanning procedures, the etiologies of FUO in children, as well as in adults, have changed over the past three decades (Table 228-1). The most striking change has been the virtual elimination of laparotomy as a final step in evaluation, a procedure routinely recommended in the 1970s, but now eliminated due to advances in radiologic imaging technology.

Table 228-1. Etiology of Fever of Unknown Origin in Children

Three newly defined infectious diseases now account for a moderate number of cases: Epstein-Barr virus infection, cat-scratch disease, and Lyme disease. All three can be confirmed with serologic assays showing both IgM and, later, IgG antibodies to the respective pathogens. Cat-scratch disease can also be confirmed with compatible liver lesions documented by abdominal sonograms or CT scans.

Two-thirds of children who now present with fever of unknown origin resolve their fever without determination of a cause, in contrast to only 10% to 20% in a series published 20 to 30 years ago.7-12 In addition, a higher percentage of children with malignancies is ...

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