1. 
   

   What are the major categories of fever of unknown origin (FUO)?

   
   
2. 
   

   What basic tests should be done in evaluating patients with FUO?

   
   
3. 
   

   When is more specific laboratory testing or diagnostic imaging indicated?

   
   
4. 
   

   Which patients should receive empiric therapy?

   
   
5. 
   

   What is the prognosis of FUO?

The classic definition of fever of unknown origin (FUO) by Petersdorf and Beeson in 1961 was a fever greater than 38.3°C (101°F) on several occasions, persisting without diagnosis for at least 3 weeks, in spite of 1 week’s investigation in hospital. In the 50 years since, medical practice has changed substantially, and much of the diagnostic evaluation for FUO can be accomplished on an outpatient basis. One proposed revision of the classic definition of FUO defines it as a febrile illness that has not been diagnosed after at least three outpatient visits or 3 days of hospitalization (Table 191-1). In practice, while an exact definition is difficult, FUO can be thought of as a persistent febrile illness that has eluded diagnosis despite a thorough history, physical examination, and routine diagnostic testing. Additionally, several specific categories of FUO have been proposed, including nosocomial FUO, HIV-related FUO, and FUO in the returning traveler. Over 200 different causes of FUO have been reported, but all etiologies fall into four broad groups: infectious, neoplastic, rheumatologic, and miscellaneous. The incidence of each etiology will vary with different patient populations and geographic locations.

Physiology of Fever

Fever is a complex common response to disparate diseases. The febrile response includes not only elevation of core body temperature but also activation of numerous physiological, endocrine, and immunologic systems. Although the neural regulation of body temperature involves several parts of the brain, the preoptic and anterior regions of the hypothalamus have the greatest role. Pyrogens—either endogenous or exogenous—can stimulate pyrogenic cytokines such as interleukin (IL)-1, IL-6, tumor necrosis factor alpha (TNF-α), interferon gamma (IFN-γ) or act directly on hypothalamic neurons and decrease their firing rate, leading to physiological responses that decrease heat loss and increase heat production. Exogenous pyrogens include microbes and toxins, whereas endogenous pyrogens include antigen-antibody complexes, complement, tissue necrosis, and sensitized lymphocytes.

Patterns of Fever

Throughout medical history, clinicians have tried to link patterns of fever with specific diseases. In saddleback or biphasic fever, fever is present for several days, remits for a day, and then relapses for several days. This pattern has been associated with dengue, yellow fever, influenza, leptospirosis, ehrlichiosis, and tickborne relapsing fever. In Pel-Ebstein fevers, patients have days or even weeks of fever, followed by remission of equal duration, then another recurrence. Pel-Ebstein fevers are generally considered to suggest Hodgkin disease. However, with the exception of the tertian fever (recurring every 48 hours) of vivax malaria and the quartan fever (recurring every 72 hours) of Plasmodium malariae, fever patterns are not specific and are unreliable for diagnosis.

Major Infectious Causes

Since the 1950s the percentage of FUOs attributable to infections has decreased, but infection still makes up a large proportion of FUO cases. Tuberculosis—mostly reactivation of latent disease—is the most important infectious cause of FUO (Table 191-2). While PPD testing and chest x-ray are helpful for diagnosis, they may be falsely negative due to either anergy or extrapulmonary disease. Similarly, patients with advanced HIV disease and coinfection with tuberculosis may lack typical signs of TB infection.

Subacute bacterial endocarditis (SBE) was once a common cause of FUO, but it is now relatively uncommon. The diagnosis can typically be made by blood culture and echocardiography, but prior antibiotics may render blood cultures sterile. The classic physical findings associated with SBE—Roth spots, Janeway lesions, and splinter hemorrhages—are late findings seen in a small proportion of cases. True culture-negative endocarditis is less common in the United States than in Europe or the developing world. Organisms that cause culture-negative endocarditis include Coxiella brunetti (Q fever), Bartonella species, Tropheryma whipplei, Brucella, and the so-called Haemophilus parainfluenzae, Aggregatibacter aphrophilus, Aggregatibacter actinomyce-temcomitans, Cardiobacterium hominis, Eikenella corrodens, and Kingella kingae (HACEK) organisms. Special microbiological techniques to facilitate the growth of fastidious organisms, as well as polymerase chain reaction (PCR), may help identify specific pathogens. When culture-negative endocarditis is suspected, the microbiology lab should be asked to hold blood cultures for up to 21 days.