Fever of unknown origin (FUO) is relatively common in patients with advanced human immunodeficiency virus (HIV) infection. However, most of the studies of HIV-associated FUO have been from Europe. Only 37 cases have been reported from two U.S. series. To characterize patients with HIV-associated FUO in this country, Armstrong and colleagues performed a retrospective analysis of cases of HIV-associated FUO seen from 1992 to 1997 at two U.S. hospitals.
HIV-associated FUO was defined as a temperature higher than 38.3°C (101°F) on multiple occasions; fever for more than four weeks in outpatients or for more than three weeks in hospitalized patients, including at least two days' incubation of microbiologic cultures; and a diagnosis that remained uncertain after three days despite appropriate investigation. An “appropriate investigation” included a complete blood count, liver enzymes, urinalysis and urine culture, blood culture, chest radiograph and the initial identification of localizing symptoms or specific findings on physical examination. The primary study that identified the cause of the FUO was noted. If more than one study was diagnostic, only the first study to yield the diagnosis was considered.
Seventy cases of HIV-associated FUO were identified among 65 patients (54 men and 11 women, mean age 36 ± 7 years) at Brigham and Women's Hospital, Boston, and the University of Michigan Medical Center, Ann Arbor. Homosexual contact was the primary risk factor for HIV infection (61 percent), followed by heterosexual contact (19 percent) and intravenous drug use (16 percent). The mean CD4+ count was 58 ± 78 cells per mm3; CD4+ counts ranged from zero to 457 cells per mm3. Prophylaxis against Pneumocystis carinii pneumonia had been instituted in 78 percent of subjects. Almost every patient (99 percent) had a previous diagnosis of acquired immunodeficiency syndrome.
In 58 of the 70 cases (82 percent), patients were admitted to the hospital for evaluation of the persistent fever. In 49 of the 58 cases, patients had undergone outpatient evaluation of FUO, but the results were nondiagnostic. The etiology of the fever was determined in 56 cases (80 percent). In 43 cases, a single diagnosis was made and in the remaining 13 cases, two or more causes of fever were uncovered. The etiology of fever remained unidentified in 14 cases; in 12 of these cases the fever spontaneously disappeared, and the other two patients died. Patients in whom the etiology of FUO was identified did not differ significantly from those in whom the cause remained undiagnosed. They were similar with respect to gender, HIV risk factors, CD4+ count, duration of fever and use of prophylactic drug regimens.
An infectious cause was found in 63 of the 72 cases (88 percent) in which an etiology was identified. The most common infection was disseminated Mycobacterium avium complex, which was found in 31 percent of the identifiable cases. The second most common infection (found in 13 percent) was P. carinii pneumonia, followed by cytomegalovirus infection (11 percent) and disseminated histoplasmosis (7 percent). M. tuberculosis accounted for only 5 percent of cases. With respect to neoplasms as a cause of the FUO, lymphoma was identified in 7 percent and Kaposi's sarcoma in 1 percent of patients.
Regarding noninvasive diagnostic methods, blood cultures had the greatest yield, uncovering the etiology of FUO in 22 percent of the cases. The second most helpful diagnostic study was examination of a respiratory specimen, which yielded a diagnosis in 10 percent of patients. In cases diagnosed invasively, respiratory specimens obtained by bronchoscopy had the best diagnostic yield (15 percent), followed by bone marrow examination (7 percent), lymph node biopsy (6 percent) and liver biopsy (6 percent).
The authors conclude that disseminated M. avium complex infection is the most common cause of FUO in patients with advanced HIV infection. An infectious source is much more likely to be the reason for FUO in a patient with HIV infection than in a patient without HIV infection. In addition, multiple etiologies for fever must also be considered in patients with HIV infection. Multiple causes were uncovered in 19 percent of the patients in this series and in 14 percent of the patients in another, previously published report.