Buruli ulcer: here today but where tomorrow?
Authors: Paul D R Johnson
Journal: The Lancet Global Health (2019)

Buruli ulcer is a destructive, geographically restricted infection caused by Mycobacterium ulcerans. Although generally not fatal, people with Buruli ulcer might be left with cosmetic or functional deformity that can last a lifetime if effective treatment is unavailable or delayed. In The Lancet Global Health, Hope Simpson and colleagues1Simpson H Deribe K Tabah EN et al.Mapping the global distribution of Buruli ulcer: a systematic review with evidence consensus.Lancet Glob Health. 2019; 7: e912-e922Summary Full Text Full Text PDF PubMed Scopus (30) Google Scholar show us the power of modern desktop epidemiology with a whole-world quantitative snapshot—graded for evidence reliability—that maps where and how likely we are to encounter Buruli ulcer in our global communities. By use of all available data sources, including peer-reviewed and grey literature (ie, reports, presentations, and abstracts), they have produced a credible picture at the national and subnational level that makes a valuable contribution to our current understanding of the distribution and burden of Buruli ulcer. However, at a more granular level, the truly local nature of Buruli ulcer is harder to appreciate with this approach. In Australia, we have mapped outbreaks to single small towns2Johnson 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 or even part of a town,3Veitch MG Johnson PD Flood PE Leslie DE Street AC Hayman JA A large localized outbreak of Mycobacterium ulcerans infection on a temperate southern Australian island.Epidemiol Infect. 1997; 119: 313-318Crossref PubMed Scopus (80) Google Scholar with peak disease incidence as high as 77 cases per 10 000 population. Meanwhile, the disease remains rare in nearby regions just a few kilometres away that appear to share the same geography. We have also mapped the slow staccato westward movement along the coast of one Australian state (Victoria) and, most recently, have observed not only the appearance but also the decline of Buruli ulcer activity by local region.4Loftus MJ Tay EL Globan M et al.Epidemiology of Buruli ulcer infections, Victoria, Australia, 2011–2016.Emerg Infect Dis. 2018; 24: 1988-1997Crossref PubMed Scopus (19) Google Scholar In contrast to Victoria, but still in Australia, there is a small endemic region in Queensland that has remained fixed over time but where disease incidence varies markedly by year: in the Douglas shire in the far north of Queensland, there are generally just two to five cases annually but in exceptional years the incidence can increase 20-fold before settling back to baseline.5Steffen CM Freeborn H Mycobacterium ulcerans in the Daintree 2009–2015 and the mini-epidemic of 2011.ANZ J Surg. 2018; 88: e289-e293Crossref PubMed Scopus (11) Google Scholar Similar but less extreme observations about local variation in incidence within known endemic regions have been made in west and central Africa.6Johnson RC Sopoh GE Boko M et al.Distribution of Mycobacterium ulcerans (Buruli ulcer) in the district of Lalo in Benin.Trop Med Int Health. 2005; 10 (in French).: 863-871Crossref PubMed Scopus (22) Google Scholar The appearance and decline of Buruli ulcer are even captured in its name—Buruli was once a county of Uganda (now renamed) where the disease was intensely studied in the 1960s and 1970s, but where it now appears to have become rare. How can we explain the ephemeral nature of Buruli ulcer? Although we are far from understanding the full story, we have considerable new evidence with which to speculate and then to generate testable hypotheses. The genome of M ulcerans is pitted with insertion sequences and pseudogenes and is in the process of undergoing reductive evolution.7Stinear TP Seemann T Pidot S et al.Reductive evolution and niche adaptation inferred from the genome of Mycobacterium ulcerans, the causative agent of Buruli ulcer.Genome Res. 2007; 17: 192-200Crossref PubMed Scopus (285) Google Scholar This process can only happen if damaged or deleted genes are no longer required for a new successful lifestyle somewhere away from free living competitors. The process has been triggered by the acquisition of a plasmid8Stinear TP Mve-Obiang A Small PL et al.Giant plasmid-encoded polyketide synthases produce the macrolide toxin of Mycobacterium ulcerans.Proc Natl Acad Sci USA. 2004; 101: 1345-1349Crossref PubMed Scopus (286) Google Scholar that encodes the production of mycolactone, a potent diffusible polyketide toxin that is the key virulence factor of M ulcerans. There is emerging evidence from Australia that small marsupials (possums and bandicoots) can excrete M ulcerans DNA in their faeces and that possums are themselves susceptible to infection. In temperate Australia, one current hypothesis is that Buruli ulcer in humans is secondary to Buruli ulcer in possums, with humans getting caught up as spillover hosts.9Fyfe 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 However, in Africa, no analogous small animal reservoir has been consistently identified, and it is possible that humans with chronic Buruli infections could themselves act as amplifiers and reservoirs of M ulcerans. If true, this is likely to be an indirect result of shedding to the environment because Buruli ulcer does not seem to be directly transmissible between humans.10O'Brien DP Wynne JW Buultjens AH et al.Exposure risk for infection and lack of human-to-human transmission of Mycobacterium ulcerans disease, Australia.Emerg Infect Dis. 2017; 23: 837-840Crossref PubMed Scopus (19) Google Scholar We also know from comparative genomics that outbreaks of Buruli ulcer in humans result from clones of M ulcerans that are brought into a receptive environment by unknown means, and which then expand, causing intense clonal outbreaks. On the Mornington peninsula near Melbourne, there are now two competing clones of M ulcerans that seem to have appeared at different times in the recent past from their ancestral home near Bairnsdale almost 300 km away.11Buultjens AH Vandelannoote K Meehan CJ et al.Comparative genomics shows that Mycobacterium ulcerans migration and expansion preceded the rise of Buruli ulcer in southeastern Australia.Appl Environ Microbiol. 2018; 84: e02612-e02617Crossref PubMed Scopus (22) Google Scholar Going back even further, the original Bairnsdale strains might have been delivered to us after European settlement from Papua New Guinea, perhaps via 19th century coastal shipping.11Buultjens AH Vandelannoote K Meehan CJ et al.Comparative genomics shows that Mycobacterium ulcerans migration and expansion preceded the rise of Buruli ulcer in southeastern Australia.Appl Environ Microbiol. 2018; 84: e02612-e02617Crossref PubMed Scopus (22) Google Scholar This insight is important because, although specific geographical regions seem favourable to Buruli ulcer, such as inland river valleys in tropical Africa, coastal or riverine environments in tropical Australia, and beachside towns and suburbs in temperate Victoria, the environmental conditions that support new human outbreaks might be much more widespread than they seem to be at present—perhaps all that is missing is M ulcerans itself. If we are to stop Buruli ulcer, we will need to be vigilant, to recognise that it is under-reported, to be alert to its presence, and to diagnose it accurately. In this way, we can bring the best of modern therapy to people affected, and in Africa at least practise treatment-as-prevention by reducing environmental shedding.12Vandelannoote K Phanzu DM Kibadi K et al.Mycobacterium ulcerans population genomics to inform on the spread of Buruli ulcer across central Africa.mSphere. 2019; 4: e00472-e00518Crossref PubMed Scopus (9) Google Scholar Ultimately, we need to understand how M ulcerans moves around in this world because its future geographical range might be broader than has been so clearly mapped for us.1Simpson H Deribe K Tabah EN et al.Mapping the global distribution of Buruli ulcer: a systematic review with evidence consensus.Lancet Glob Health. 2019; 7: e912-e922Summary Full Text Full Text PDF PubMed Scopus (30) Google Scholar It has been more than 70 years since M ulcerans was definitively shown to be the cause of Buruli ulcer. Simpson and colleagues have systematically described where Buruli has travelled and emerged since then—it will be fascinating to see how the global overview of Buruli ulcer changes during the next 70 years. I declare no competing interests. Mapping the global distribution of Buruli ulcer: a systematic review with evidence consensusThe global distribution of Buruli ulcer is uncertain and potentially wider than currently recognised. Our findings represent the strongest available evidence on Buruli ulcer distribution so far and have many potential applications, from directing surveillance activities to informing burden estimates. Full-Text PDF Open Access