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.
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 of highly specific and sensitive immunologic testing has reduced the number of undetected cases of adult Still's disease, systemic lupus erythematosus, and polyarteritis nodosa.
Table 18-1 Classic FUO in Adults
| Save Table
Table 18-1 Classic FUO in Adults
|Authors (Year of Publication)||Years of Study||No. of Cases||Infections (%)||Neoplasms (%)||Noninfectious Inflammatory Diseases (%)||Miscellaneous Causes (%)||Undiagnosed Causes (%)|
|Petersdorf and Beeson (1961)||1952–1957||100||36||19||19a||19a||7|
|Larson and Featherstone (1982)||1970–1980||105||30||31||16a||11a||12|
|Knockaert and Vanneste (1992)||1980–1989||199||22.5||7||23a||21.5a||25.5|
|de Kleijn et al. (1997, Part I)||1992–1994||167||26||12.5||24||8||30|
|Bleeker-Rovers et al. (2007)||2003–2005||73||16||7||22b||4||51|
Infections such as extrapulmonary tuberculosis and—in endemic areas—typhoid fever and malaria remain a leading diagnosable cause of FUO. Prolonged mononucleosis syndromes caused by Epstein-Barr virus, cytomegalovirus (CMV), or HIV are conditions whose consideration as a cause of FUO are sometimes confounded by delayed antibody responses. Intraabdominal abscesses (sometimes poorly localized) and renal, retroperitoneal, and paraspinal abscesses continue to be difficult to diagnose. Renal malacoplakia, with submucosal plaques or nodules involving the urinary tract, may cause fatal FUO if untreated; it is associated with intracellular bacterial infection, is seen in patients with defects of intracellular bacterial killing, and is treated with fluoroquinolones or trimethoprim-sulfamethoxazole. Occasionally, other organs may be involved. Osteomyelitis, especially where prosthetic devices have been implanted, must be considered. Although true culture-negative infective endocarditis is rare, one may be misled by cryptic endocarditis caused by indolent, slow-growing microorganisms of the HACEK group (Haemophilus aphrophilus, Aggregatibacter (formerly Actinobacillus) actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, and Kingella kingae), Bartonella spp. (previously Rochalimaea), Legionella spp., Coxiella burnetii, Chlamydophila psittaci, and fungi. Prostatitis, dental abscesses, sinusitis, and cholangitis continue to be sources of occult fever.
Fungal diseases, most notably histoplasmosis involving the reticuloendothelial system, may cause FUO, particularly outside of the endemic regions where these diseases may be more readily recognized. FUO following travel to neotropical regions and the desert southwest of the United States, even for very limited periods, should prompt evaluation for paracoccidioidomycosis and coccidioidomycosis, respectively. The rising popularity of adventure travel among citizens of Western countries has increased the incidence in these nations of presentation for FUO due to otherwise uncommon endemic vector-borne infections, notably Chikungunya fever and scrub typhus. FUO with headache should prompt examination of spinal fluid for Cryptococcus neoformans, Mycobacterium tuberculosis, and travel-acquired trypanosomes. Malaria (which may result from transfusion, failure to take a prescribed prophylactic agent, or infection with a drug-resistant Plasmodium strain) continues to be a cause of FUO, particularly of the asynchronous variety. A related protozoan ...