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

Abstract

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 January 1, 1997 to March 31, 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 to 44.0%) of FUO patients had an infectious disease etiology. Infections were more likely from Southeastern Asia (pooled proportion = 0.49; 95.0% CI 0.43-0.55) than from Europe (pooled proportion = 0.31; 95.0% CI 0.22-0.41). 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 (e.g., CMV and EBV) 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.

Geographic Influence Upon Noninfectious Diseases Accounting for Fever of Unknown Origin: A Systematic Review and Meta-Analysis

“…Of 732 screened articles, 48 publications were included for full-text review ( Supplementary Figure 1 ) [ 13 ]. The use of Google’s web-based electronic translating tool was successful in the screening and review process of published reports for this study.…”

“…The protocol for this study was registered at the International Prospective Register of Systematic Reviews (PROSPERO) [ 13 ]. The study followed the guidelines of preferred reporting items for systematic reviews and meta-analyses ( Supplementary Table 1 .…”

“…A systematic literature search of studies published from January 1, 1997 to March 31, 2021 was conducted across Medline (PubMed), Embase, Scopus, and Web of Science [ 13 ]. These databases were searched for terms constructed by a university librarian that included the query strings of (FUO), (fever of unknown origin [Mesh]), (PUO), (pyrexia of unknown origin [Mesh]), (clinical trial), (clinical trial [Publication Type]), and (Prospective Studies [Mesh]) [ 13 ]. The starting period was chosen based on the suggested significant modification to the adult FUO criteria by de Kleijn et al [ 3 , 4 ] in 1997.…”

“…In a more recent systematic review of the literature with a meta-analysis examining rigorous prospective studies, we reported geographic variation among infectious FUO diagnoses [ 13 ]. The 10 most frequent diagnoses were tuberculosis, brucellosis, endocarditis, abscesses, viral infections, pneumonia, urinary tract infections, enteric fever, human immunodeficiency virus (HIV), and malaria.…”

“…This systematic review aimed to evaluate relevant prospective FUO clinical trials [ 13 ], summarize their noninfectious diseases findings, and assess the certainty of their evidence to provide a comprehensive understanding of the associations between geographical location and diagnostic yield. The primary objective of this second study companion to our recent report [ 13 ] was to establish a global benchmark description of regional noninfectious disease diagnoses that may further assist all physicians in their FUO approach and serve as a comparison basis for future studies.…”