Fever of unknown origin (FUO) FADOI-SIMIT Italian registry: can demographics, comorbidities, and clinical variables predict the etiology of classic FUO?—a prospective Italian study

Fever of Unknown Origin (FUO) remains a diagnostic challenge, defined by prolonged fever lasting for more than three weeks without a clear cause despite a minimum of three days of hospital investigations or three outpatient visits at least. This study aims to explore the etiologies and potential predictive factors for classic FUO in Italy, updating prior data from earlier studies. Conducted from October 2019 to June 2023, this prospective, multi-center registry enrolled 188 patients from 25 Italian hospitals, assessing demographics, comorbidities, and clinical characteristics in relation to FUO causes. Results indicated that 72.1% of cases reached a final diagnosis, with etiologies primarily in non-infectious inflammatory (31.8%), infectious (25.7%), and neoplastic (8.4%) categories, while 27.9% remained undiagnosed. Younger patients (under 55 years) were more likely to lack a definitive diagnosis, suggesting that advanced investigations might benefit early this patient population. Comorbid conditions like chronic obstructive pulmonary disease and cardiovascular symptoms were associated with infectious causes, whereas musculoskeletal and dermatologic signs suggested a non-infectious inflammatory origin. The overall mortality rate was 2.8% at a 6-month follow-up. This study highlights the need for improved diagnostic tools to address the substantial number of undiagnosed FUO cases. Trial registration: NCT05254522 ClinicalTrials.gov identifier.