Clinical Pearls & Morning Reports

Posted by Carla Rothaus

Published February 2, 2022


What are some of the classic causes of fever of unknown origin?

Although any proposed definition of fever of unknown origin (FUO) is subjective, the core features are the absence of an identified cause of fever, despite reasonable investigations in either the inpatient or outpatient setting, and the persistence of fever for a sufficient time to rule out self-limiting fevers. Read the NEJM Review Article here.

Clinical Pearls

Q: What evidence suggests that fever is potentially beneficial to the host?

A: Phylogenetic conservation of fever for millions of years in the animal kingdom suggests that it is potentially beneficial to the host. Most pathogenic bacteria are mesophiles (i.e., organisms for which a temperature of approximately 35°C is ideal for their growth), and febrile-range temperatures inhibit their proliferation. Fever also generates hepatic iron-sequestering compounds that bind the free iron necessary for microbial replication, augments the antimicrobial activity of antibiotic agents, induces heat-sensitive shock proteins that activate host defenses, and enhances T-cell responses.

Q: How often does FUO remain undiagnosed in the current era?

A: Up to 51% of cases of FUO, even in the current era, remain undiagnosed. The likelihood of undiagnosed cases may be greater in higher-income regions, an association that is probably due to overrepresentation of patients with “difficult to diagnose” conditions.

Morning Report Questions

Q: What are some of the classic causes of FUO?

A: Historically, FUO has been divided into classic, nosocomial, immunodeficiency-related, and travel-associated cases. Despite its limitations, such a classification provides a useful framework with which to approach the patient with prolonged fever. The major causes of classic FUO are infections, cancers, autoinflammatory or autoimmune conditions, and miscellaneous causes. Tuberculosis has been among the most common infectious causes of FUO. The endemic mycoses (histoplasmosis, blastomycosis, coccidioidomycosis, and paracoccidioidomycosis) may be associated with FUO in both immunocompetent and immunocompromised hosts, with the exception of talaromycosis, which primarily affects immunocompromised persons. Approximately one half of human pathogens are vectorborne or zoonotic, and these infections are often manifested as FUO. Cancers constitute approximately 2 to 25% of cases of FUO. Neoplasms most frequently associated with FUO include renal-cell carcinoma, lymphomas, hepatocellular and ovarian cancer, atrial myxoma, and Castleman’s disease. Autoinflammatory and autoimmune diseases account for 5 to 32% of FUO cases. An estimated 3 to 7% of febrile episodes in hospitalized patients are attributable to drugs. However, drug-associated fever is frequently overlooked because of the lack of localizing signs. One third of drug-associated fevers are due to antibiotics, most commonly beta-lactams.

Q: Describe benefits and drawbacks of the use of 18F-fluorodeoxyglucose positron-emission tomography and CT (FDG PET-CT) in patients with FUO.

A: Meta-analyses have shown wide ranges in the performance of FDG PET-CT for FUO, with sensitivities ranging from 86 to 98% and specificities ranging from 52 to 85%. The diagnostic yield of FDG PET-CT appears to be more than 50%, and the yield is at least 30% greater than that of conventional CT. The performance appears to be better in patients with infections or neoplasms than in those who have autoimmune conditions. FDG PET-CT also appears to be superior to other nuclear imaging methods, such as PET without CT and gallium or leukocyte scintigraphy. In addition, negative FDG PET-CT results appear to be associated with a high likelihood of spontaneous remission of fever. Potential drawbacks of FDG PET-CT imaging include cost and limited availability in some centers.

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