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

Abstract

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-Gué rin (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 I 2 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; I 2 = 56%), a finding case-control studies appear to corroborate. HIV infection (OR = 6.80; 95% CI = 2.33-19.85; I 2 = 0%) and SLC11A1 rs17235409 A allele (OR = 1.86; 95% CI = 1.25-2.77; I 2 = 0%) are associated with increased prevalence of the disease. No definite conclusions can be drawn regarding the influence of previous family history of BU.

Genetics in the Host‐Mycobacterium ulcerans interaction

“…266 How these bacteria interfere with the immune response against M. ulcerans or impact the outcome of BU is currently a mystery, but differences in the relative abundance of bacterial taxa have already been associated with the prognosis of wound healing. 267 Since the launching of the 2004 Global Buruli Ulcer Initiative, there is now a more consistent framework on the ecology of BU, 268 associated risk factors, 143,231 diagnostic methods 269 and treatment strategies. 270,271 However, despite a downward trend observed in the incidence of BU in the last two decades, the disease is currently gaining impetus in scattered worldwide foci.…”

“…Pooled evidence from case-control studies on BU, including HIV-infected patients, indicates that the disease is actually more frequent amongst immunocompromised patients. 231 Not only that, but the viral infection was similarly described to foster the development of the most severe forms of BU. 232,233 This suggests that the maintenance of a functional CMI is indeed critical to contain M. ulcerans.…”

“…183,184 Currently, Bacillus Calmette-Guérin (BCG) is the only vaccine available in the clinics that has been studied for BU prevention, 236 but a recent meta-analysis of clinical trials and case-control studies showed it lacked efficacy. 231 Over the years, several immunization alternatives against M. ulcerans infection were developed and tested in animal models, obtaining mixed results in the best case scenarios, and none proceeding to human clinical trials. 36,123,208,[237][238][239][240][241][242][243][244][245][246][247][248] A closer look to many of these attempts reveals that despite a more vigorous production of T h 1-associated cytokines following immunization, upon subsequent challenge with M. ulcerans, the infection eventually progresses after a lag period, probably as a consequence of mycolactone production.…”

“…The paramount example of compromised CMI has been HIV infection. Pooled evidence from case‐control studies on BU, including HIV‐infected patients, indicates that the disease is actually more frequent amongst immunocompromised patients 231 . Not only that, but the viral infection was similarly described to foster the development of the most severe forms of BU 232,233 .…”

“…Currently, Bacillus Calmette‐Guérin (BCG) is the only vaccine available in the clinics that has been studied for BU prevention, 236 but a recent meta‐analysis of clinical trials and case‐control studies showed it lacked efficacy 231 . Over the years, several immunization alternatives against M. ulcerans infection were developed and tested in animal models, obtaining mixed results in the best case scenarios, and none proceeding to human clinical trials 36,123,208,237‐248 .…”