How to deal with the major diagnostic challenges in fever of unknown origin: an expert opinion.

In this review we summarize the current knowledge on fever of unknown origin (FUO). Fever of unknown origin remains a diagnostic challenge even despite increasing diagnostic possibilities since its first definition. Uniform definition of FUO is pivotal to correctly select patients that benefit from the extensive workup that may be needed. The number of conditions associated with FUO is still increasing. Epidemiologic differences and differences in diagnostic possibilities are a challenge when comparing outcomes from cohorts with different epidemiologic backgrounds. The diagnostic protocol that was proposed as early as 2007, with a central role for ¹⁸F-FDG-PET/CT, still remains the golden standard for the workup of FUO. Early use of new diagnostic modalities, including the use of metagenomic next generation sequencing and artificial intelligence, may shorten the diagnostic delay. In patients remaining undiagnosed, second opinion in an expert center can be considered, especially when therapeutic trials are considered. An increasing subset of patients presents with absent inflammatory parameters. Correct evaluation within a febrile episode is important in patients with intermittent disease, but these patients may also suffer from habitual or functional hyperthermia. We advise to let go of these terms and introduce the criteria for temperature elevation with missing inflammatory parameters (TEMP) syndrome.