Fever of unknown origin

Fever of unknown origin (FUO) is classically defined as a fever above 38.3C persisting for at least three weeks with no diagnosis despite three outpatient visits or three days as an inpatient; a related entity, inflammation of unknown origin (IUO), is unexplained, persistently raised inflammatory markers without fever. Causes span infection, autoimmune and inflammatory disease, and malignancy, and in a substantial fraction of patients no cause is ever found. Because FDG PET/CT can survey the entire body at once for areas of increased glucose metabolism, it has become the nuclear medicine test of choice for this problem once routine work-up (history, examination, standard blood tests and cultures, chest imaging) has failed to find a cause.

The joint 2024 SNMMI/Infectious Diseases Society of America/American College of Nuclear Medicine appropriate use criteria rate FDG PET/CT as appropriate for both adult and paediatric FUO, and reserve older techniques - gallium-67 scintigraphy and radiolabelled leukocyte scintigraphy - for situations in which FDG PET/CT is unavailable, with leukocyte scintigraphy specifically for cases where infection is strongly suspected. The 2024/2025 EANM/SNMMI FDG hybrid PET guideline for infection and inflammation gives protocol detail specific to this indication: the scan should ideally be performed before, or as early as possible after, starting antibiotics or oral glucocorticoids, since both can suppress the very uptake being sought, and myocardial suppression preparation should be considered if endocarditis or cardiac sarcoidosis is part of the differential.

Diagnostic yield, rather than sensitivity or specificity in isolation, is the relevant performance measure, because many patients with FUO never get a final causative diagnosis by any test; FDG PET/CT is valued for how often it identifies a focus that can be biopsied or otherwise pinned down, and for its high negative predictive value - a negative scan is associated with a good prognosis and can support a watch-and-wait approach rather than further invasive testing.