Unlocking of the secrets of Mycobacterium ulcerans disease transmission
Authors: Daniel Patrick O'Brien
Journal: The Lancet Planetary Health (2017)

Mycobacterium ulcerans is a bacterial infection causing necrotising lesions of skin and subcutaneous tissue. Widely known as Buruli ulcer, it is classified as a neglected tropical disease by WHO. If diagnosed and treated early, outcomes are good,1Friedman ND Athan E Walton AL O'Brien DP Increasing experience with primary oral medical therapy for Mycobacterium ulcerans disease in an Australian cohort.Antimicrob Agents Chemother. 2016; 60: 2692-2695Crossref PubMed Scopus (25) Google Scholar but if left untreated it can progress to a severe disease resulting in high levels of morbidity and permanent disability.2Vincent QB Ardant MF Adeye A et al.Clinical epidemiology of laboratory-confirmed Buruli ulcer in Benin: a cohort study.Lancet Glob Health. 2014; 2: e422-e430Summary Full Text Full Text PDF PubMed Scopus (74) Google Scholar Occurring in 33 countries worldwide, the largest burden of disease is found in children living in rural and resource-limited areas of central and western Africa where limited access to health care and community beliefs and stigma—in Ghana, witchcraft and curses are among the explanations for this disease—lead to delays in diagnosis and treatment, with devastating outcomes.3Stienstra Y van der Graaf WT Asamoa K van der Werf TS Beliefs and attitudes toward Buruli Ucer in Ghana.Am J Trop Med Hyg. 2002; 67: 207-213Crossref PubMed Scopus (118) Google Scholar As a result, since its first description in Australia in 1948,4MacCallum P Tolhurst JC Buckle G et al.A new mycobacterial infection in man.J pathol bacteriol. 1948; 60: 93-122Crossref PubMed Scopus (250) Google Scholar affected communities, clinicians, and researchers have been searching for ways to prevent this disease. This search has been thwarted by the fact that the exact environmental reservoir and method of transmission have not been established. Prevailing opinion is that human beings are infected from the environment: in endemic regions, the disease is highly focal and usually associated with wetlands or coastal regions,5Williamson HR Benbow ME Nguyen KD et al.Distribution of Mycobacterium ulcerans in Buruli ulcer endemic and non-endemic aquatic sites in Ghana.PLoS Negl Trop Dis. 2008; 2: e205Crossref PubMed Scopus (103) Google Scholar and PCR testing of environmental samples, such as water, aquatic plants, soil, and detritus from swamps, can find evidence of the organism.6Fyfe JA Lavender CJ Handasyde KA et al.A major role for mammals in the ecology of Mycobacterium ulcerans.PLoS Negl Trop Dis. 2010; 4: e791Crossref PubMed Scopus (127) Google Scholar, 7Vandelannoote K Durnez L Amissah D et al.Application of real-time PCR in Ghana, a Buruli ulcer-endemic country, confirms the presence of Mycobacterium ulcerans in the environment.FEMS Microbiol Lett. 2010; 304: 191-194Crossref PubMed Scopus (39) Google Scholar, 8Johnson PD Azuolas J Lavender CJ et al.Mycobacterium ulcerans in mosquitoes captured during outbreak of Buruli ulcer, southeastern Australia.Emerg Infect Dis. 2007; 13: 1653-1660Crossref PubMed Scopus (161) Google Scholar Insects such as mosquitoes7Vandelannoote K Durnez L Amissah D et al.Application of real-time PCR in Ghana, a Buruli ulcer-endemic country, confirms the presence of Mycobacterium ulcerans in the environment.FEMS Microbiol Lett. 2010; 304: 191-194Crossref PubMed Scopus (39) Google Scholar and water-residing biting arthropods9Marsollier L Robert R Aubry J et al.Aquatic insects as a vector for Mycobacterium ulcerans.Appl Environ Microbiol. 2002; 68: 4623-4628Crossref PubMed Scopus (252) Google Scholar have been associated with M ulcerans epidemiologically and via PCR testing and therefore proposed as vectors for transmission. In Victoria, Australia, evidence suggests that native possums might be involved in transmission.6Fyfe JA Lavender CJ Handasyde KA et al.A major role for mammals in the ecology of Mycobacterium ulcerans.PLoS Negl Trop Dis. 2010; 4: e791Crossref PubMed Scopus (127) Google Scholar The Article in The Lancet Planetary Health by Maylis Douine and colleagues10Douine M Gozlan R Nacher M et al.Mycobacterium ulcerans infection (Buruli ulcer) in French Guiana, South America, 1969–2013: an epidemiological study.Lancet Planet Health. 2017; 1: e65-e73Summary Full Text Full Text PDF Scopus (16) Google Scholar provides an important epidemiological and clinical description of M ulcerans infection diagnosed and managed in French Guiana from 1969 to 2013. The great strength of the study is the long time period over which cases have been prospectively followed—to my knowledge, the longest known longitudinal recording of cases worldwide. It covers a period of substantial population expansion and increasing wealth. The long time period of this study represents a unique opportunity to study disease epidemiology over time and could provide insights into the environmental reservoirs and disease transmission in both this region and globally. Some of the study observations are worth highlighting. First, as described in many African regions, the number of cases reported yearly has decreased, from 6·07 infections per 100 000 person-years (95% CI 4·46–7·67) in 1969–83 to 3·49 infections per 100 000 person-years (2·83–4·16) in 1999–2013. Reasons are unknown, but perhaps relate to changing environmental conditions in the era of climate change, the change in population dynamics and land use, or possibly some success with prevention methods such as mosquito net use. Some have even speculated that increasing antibiotic use against M ulcerans could be responsible if human beings represent the disease reservoir, although the situation in Victoria, Australia, where antibiotic treatment is widely used and cases of disease are rapidly increasing,11Victoria State GovernmentSurveillance of notifiable conditions in Victoria.https://www2.health.vic.gov.au/public-health/infectious-diseases/infectious-diseases-surveillance/search-infectious-diseases-data/victorian-summaryGoogle Scholar argues against this explanation. An alternative explanation could be improvements in the accuracy of diagnosis. For example, in the study of Douine and colleagues, an increased proportion of cases were classified as suspected in the early period (1969–98) before PCR confirmation testing for M Ulcerans became available in the year 2000.12Ross BC Marino L Oppedisano F Edwards R Robins-Browne RM Johnson PD Development of a PCR assay for rapid diagnosis of Mycobacterium ulcerans infection.J Clin Microbiol. 1997; 35: 1696-1700PubMed Google Scholar Thus, the reduced incidence worldwide13WHOBuruli ulcer. Situation and trends.http://www.who.int/gho/neglected_diseases/buruli_ulcer/en/Google Scholar could reflect the increased accuracy of diagnosis since PCR confirmation was introduced. Second, despite an increasing proportion of children in the general population, a decrease was found in the incidence and proportion of cases diagnosed in children over the study period. Once again, the reasons are unclear, but the authors have postulated that this decrease could reflect improved living conditions and hygiene, presumably related to improved population wealth or possibly a change in clothing or children's activities. Alternatively, as the periods in which most cases in children were reported coincided with a much higher proportion of non PCR-confirmed cases, overdiagnosis of disease could be responsible. Third, sex differences were noted with respect to location of lesions, with men more often affected on the chest and upper limbs than women and women more likely to be affected on the lower limbs than men. Sex differences in disease presentation have also been noted in Africa2Vincent QB Ardant MF Adeye A et al.Clinical epidemiology of laboratory-confirmed Buruli ulcer in Benin: a cohort study.Lancet Glob Health. 2014; 2: e422-e430Summary Full Text Full Text PDF PubMed Scopus (74) Google Scholar and Australia.14Boyd SC Athan E Friedman ND et al.Epidemiology, clinical features and diagnosis of Mycobacterium ulcerans in an Australian population.Med J Aust. 2012; 196: 341-344Crossref PubMed Scopus (55) Google Scholar These differences provide some clues about disease transmission—for example, they might argue against insect vectors, whose biting patterns are unlikely to be sex specific (unless the disease patterns represent differences in use of protective clothing, bed nets, or sleeping patterns), but perhaps point to trauma as a method of infection, as body areas prone to trauma might differ by gender. Finally, various observations were similar to those from other world regions, suggesting a common link between world regions in environmental reservoirs and disease transmission. These observations include the fact that cases were limited to coastal regions, the number of cases varied from year to year and region to region, and the number of cases was sex balanced.2Vincent QB Ardant MF Adeye A et al.Clinical epidemiology of laboratory-confirmed Buruli ulcer in Benin: a cohort study.Lancet Glob Health. 2014; 2: e422-e430Summary Full Text Full Text PDF PubMed Scopus (74) Google Scholar, 14Boyd SC Athan E Friedman ND et al.Epidemiology, clinical features and diagnosis of Mycobacterium ulcerans in an Australian population.Med J Aust. 2012; 196: 341-344Crossref PubMed Scopus (55) Google Scholar No information was provided on seasonality of disease presentation—observations that have been noted elsewhere.14Boyd SC Athan E Friedman ND et al.Epidemiology, clinical features and diagnosis of Mycobacterium ulcerans in an Australian population.Med J Aust. 2012; 196: 341-344Crossref PubMed Scopus (55) Google Scholar, 15Landier J Constantin de Magny G Garchitorena A Texier G Seasonal patterns of Buruli ulcer incidence, central Africa, 2002–2012.Emerg Infect Dis. 2015; 21: 1414-1417Crossref PubMed Scopus (18) Google Scholar This study raises many interesting questions about M ulcerans disease epidemiology, which require intensive research into factors such as climate, local flora and fauna, and population characteristics, building on the clues from this and other studies. Answers to these and other questions are urgently required16O'Brien DP Comte E Serafini M et al.The urgent need for clinical, diagnostic, and operational research for management of Buruli ulcer in Africa.Lancet Infect Dis. 2014; 14: 435-440Summary Full Text Full Text PDF PubMed Scopus (27) Google Scholar as the world desperately requires concrete public health interventions based on solid evidence to truly hope that we can consign the devastating health consequences of this infection to history. I declare no competing interests. Mycobacterium ulcerans infection (Buruli ulcer) in French Guiana, South America, 1969–2013: an epidemiological studyThe decrease of M ulcerans infection incidence and the proportion of children with infections over a 45 year period in this ultra-peripheral French territory might have been mostly driven by improving living conditions, prophylactic recommendations, and access to health care. Full-Text PDF Open Access