Geographic Variation of Infectious Disease Diagnoses Among Patients With Fever of Unknown Origin: A Systematic Review and Meta-analysis

Background: Fever of unknown origin (FUO) investigations yield a substantial number of patients with infectious diseases. This systematic review and meta-analysis aimed to quantify more common FUO infectious diseases etiologies and to underscore geographic variation. Methods: Four databases (PubMed, Embase, Scopus, and Web of Science) were searched for prospective studies reporting FUO rates among adult patients from 1 January 1997 to 31 March 2021. The pooled proportion for infectious diseases etiology was estimated using the random-effects meta-analysis model. Results: Nineteen prospective studies were included with 2667 total cases. No studies were available for Africa or the Americas. Overall, 37.0% (95.0% confidence interval [CI], 30.0%-44.0%) of FUO patients had an infectious disease etiology. Infections were more likely from Southeastern Asia (pooled proportion, 0.49 [95% CI,. 43-.55]) than from Europe (pooled proportion, 0.31 [95% CI,. 22-.41]). Among specifically reported infectious diseases (n = 832), Mycobacterium tuberculosis complex predominated across all geographic regions (n = 285 [34.3%]), followed by brucellosis (n = 81 [9.7%]), endocarditis (n = 62 [7.5%]), abscesses (n = 61 [7.3%]), herpesvirus (eg, cytomegalovirus and Epstein-Barr virus) infections (n = 60 [7.2%]), pneumonia (n = 54 [6.5%]), urinary tract infections (n = 54 [6.5%]), and enteric fever (n = 40 [4.8%]). Conclusions: FUO patients from Southeastern Asia were more likely to have an infectious diseases etiology when compared to other regions. The predominant factor for this finding appears to be differences in disease prevalence among various geographical locations or other factors such as access to timely care and diagnosis. Noting epidemiological disease factors in FUO investigations could improve diagnostic yields and clinical outcomes.