Individual and clinical variables associated with the risk of Buruli ulcer acquisition: A systematic review and meta-analysis

Background: Buruli ulcer (BU) is a necrotizing skin disease, caused by Mycobacterium ulcerans, with poorly understood acquisition risk factors. This review aims at evaluating the importance of individual–sex, age, family ties with history of BU, gene variants–and clinical–Bacillus Calmette-Guérin (BCG) immunization, Human Immunodeficiency Virus (HIV) infection–variables in this process. Methods: A systematic review was performed considering the following databases: ClinicalTrials.gov, Cochrane Controlled Register of Trials (CENTRAL), Current Contents Connect, Embase, MEDLINE, SciELO, Scopus and Web of Science. Eligible studies were critically appraised with The Joanna Briggs Institute checklists and heterogeneity was assessed with Cochran Q-test and I2 statistic. Published demographic data was descriptively analysed and clinical data pooled within random-effects modelling for meta-analysis. Results: A total of 29 studies were included in the systematic review. Two randomized controlled trials (RCTs) and 21 case-control studies were selected for meta-analysis. Studies show that BU mainly affects age extremes, more preponderately males among children. Data pooled from RCTs do not reveal BCG to be protective against BU (odds ratio (OR) = 0.63; 95% CI = 0.38–1.05; I2 = 56%), a finding case-control studies appear to corroborate. HIV infection (OR = 6.80; 95% CI = 2.33–19.85; I2 = 0%) and SLC11A1 rs17235409 A allele (OR = 1.86; 95% CI = 1.25–2.77; I2 = 0%) are associated with increased prevalence of the disease. No definite conclusions can be drawn regarding the influence of previous family history of BU. Discussion: While available evidence warrants further robustness, these results have direct implications on current interventions and future research programs, and foster the development of more cost-effective preventive and screening measures. Registration: The study was registered at PROSPERO with number CRD42019123611. Author summary: Buruli ulcer (BU) is a devastating neglected tropical disease, whose worldwide notification to the WHO is currently on the rise. However, evidence has been so far conflicting as to the individual and clinical risk factors underlying the acquisition of the disease. Thus, considering the increasing body of literature made available in the last decade, it becomes essential to revisit this subject. To this aim, a temporal-unrestricted systematic review of published literature was undertaken in eight different online databases and meta-analysis conducted with clinical data. The randomized controlled trials and cohort studies reviewed supported the idea that male children or older adults are more susceptible to BU, BCG vaccination is insufficient to prevent BU in the mid-long term, and the prevalence of the disease is higher among HIV-infected individuals or carriers of genetic polymorphisms in SLC11A1. This knowledge, together with recommendations to tackle some drawbacks found within the reviewed studies, not only underlines the importance of searching for better vaccination alternatives, but also provides guidance for current and future screening and prevention programs.