Aetiology of fever of unknown origin in people living with HIV: A systematic review and meta-analysis

Introduction: Fever of unknown origin (FUO) in people living with HIV presents a significant diagnostic challenge due to its broad range of potential aetiologies. Objective: The aims of this study were to evaluate the prevalence of different aetiologies causing FUO in people living with HIV through a systematic review and meta-analysis. Additionally, we assessed the prevalence of FUO and its associated mortality. Methods: We searched PubMed/Medline, Scopus, Web of Science, Embase and the Virtual Health Library, up to September 2024. We included observational studies that evaluated the aetiology, prevalence and mortality of FUO in people living with HIV. We performed meta-analyses using a random-effects model to estimate the pooled effects for each outcome. Risk of bias was performed using the Joanna Briggs Institute (JBI) Critical Appraisal Checklist for Studies Reporting Prevalence Data. Results: A total of 1678 studies were screened, of which 23 studies comprising 1592 people living with HIV were included. The pooled prevalence of FUO was 9.7% (95% confidence interval [CI]: 4.7%–16.3%; I² = 99%). FUO prevalence varied across continents, with higher rates in Asia (21.8%) and South America (17.1%) than in Europe (8.9%) and North America (8.5%). The pooled mortality rate was 15.2% (95% CI: 5.6%–28.2%; I² = 92%), with long-term follow-up studies reporting higher mortality (≥24 months: 63.0%). Bacterial infections were the leading cause of FUO (49.2% [95% CI: 40.8%–57.6%]; I² = 92%), followed by fungal infections (11.8%), non-haematologic cancers (2.1%) and rheumatologic diseases (1.5%). Tuberculosis was the most prevalent aetiology (27.6%), followed by nontuberculous mycobacteria (13.4%), leishmaniasis (10.1%) and pneumocystis pneumonia (6.6%). Other common causes included non-Hodgkin's lymphoma (6.3%), histoplasmosis (4.7%), cytomegalovirus (4.6%) and cryptococcosis (4.1%). Conclusion: Infections remain the predominant cause of FUO in people living with HIV, with significant heterogeneity among studies. The findings underscore the need for region-specific diagnostic approaches and early intervention to reduce mortality in this population.