# 8.6.29 Buruli ulcer Mycobacterium ulcerans infecti

# 8.6.29 Buruli ulcer: Mycobacterium ulcerans infection 1167

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8.6.29  Buruli ulcer: Mycobacterium ulcerans infection
arguments illustrate the difficulty in providing sound evidence for 
policy decisions when a decade-​long wait to establish relapse rates 
is needed.
Areas where further research is needed
The epidemiology of leprosy still poses unanswered questions. Why 
are 64% of all patients with leprosy in India? Is this due to living 
conditions, genetic susceptibility, or particular environmental con-
ditions in India?
Early detection of cases is vital at both an individual and a popu-
lation level. It is now recognized that substantial nerve damage oc-
curs before diagnosis. A test for early infection might help detect 
individual cases before nerve damage is established and before the 
spread of infection. Leprosy-​specific peptides for skin tests have 
been generated and are being evaluated.
The medical management of reactions and nerve damage is cur-
rently limited to steroids. These are not effective for about 30% of 
patients. Trials to determine the effectiveness of established and 
out-​of-​patent immunosuppressants, such as azathioprine and 
ciclosporin, are taking place.
The WHO started the 1990s with the bold slogan of ‘Eliminating 
leprosy as a public health problem by 2000’. This initiative gal-
vanized leprosy control programmes worldwide, but the unique 
biology of M. leprae and its interaction with the human host ren-
dered this target unattainable. However, there is a strong perception 
that leprosy has been eliminated and this has hindered research and 
planning. The WHO policy for 2011–​2015 focuses on sustaining 
leprosy work. Leprosy is a bacterial disease with challenging im-
munological complications and will be a global and individual 
problem for many decades. It is unlikely to be eradicated until there 
is considerable improvement in general health, wealth, living con-
ditions, and education.
FURTHER READING
Britton WJ, Lockwood DN (2004). Leprosy. Lancet, 363, 1209–​19.
Fine PE (2007). Leprosy: what is being ‘eliminated’? Bull World Health 
Organ, 85, 2.
International Federation of Anti-​Leprosy Associations (ILEP) (n.d.). 
Working for a world without leprosy. http://​www.ilep.org.uk
Lockwood DNJ, Lambert S (2010). HIV and leprosy? Where are we at? 
Lepr Rev, 81, 167–​75.
Monot M, et al. (2005). On the origin of leprosy. Science, 308, 1040–​2.
Rodrigues L, Lockwood DNJ (2011). Leprosy now: epidemiology, pro-
gress, challenges, and research gaps. Lancet Infect Dis, 11, 464–​70.
Scollard DM (2008). The biology of nerve injury in leprosy. Lepr Rev, 
79, 242–​53.
Setia MS, et al. (2006). The role of BCG in prevention of leprosy: a 
meta-​analysis. Lancet Infect Dis, 6, 162–​70.
Ustianowski AP, et al. (2006). Interactions between HIV infection and 
leprosy: a paradox. Lancet Infect Dis, 6, 350–​60.
Van Brakel WH, et al. (2005). The INFIR Cohort Study: assessment of 
sensory and motor neuropathy in leprosy at baseline. Lepr Rev, 76, 
277–​95.
World Health Organization (2006). Global strategy for further reducing 
the leprosy burden and sustaining leprosy control activities 2006–​2010. 
World Health Organization, Geneva.
8.6.29  Buruli ulcer: Mycobacterium 
ulcerans infection
Bouke de Jong, Françoise Portaels, and  
Wayne M. Meyers
ESSENTIALS
Buruli ulcer is caused by Mycobacterium ulcerans, which secretes a 
cytotoxic and immunosuppressive toxin, mycolactone. The disease is 
characterized by necrosis of skin, subcutaneous tissue, and bone, and 
is re-​emerging as a potentially disabling affliction of inhabitants of 
tropical wetlands. Major foci are in West and Central Africa, with an 
increasing focus in Australia, Mexico, South America, and Southeast 
Asia. It is not contagious; environmental sources include water, vege-
tation, and insects, with humans probably becoming infected by 
traumatic introduction of the bacillus into the skin from the overlying 
M. ulcerans-​contaminated surface in most instances. Clinical presen-
tation may be as a cutaneous nodule, undermined ulcer, plaque, or 
widely disseminated oedematous lesion. Clinical diagnosis is often 
accurate by experienced clinicians, and smears for acid-​fast bacilli, 
culture, polymerase chain reaction assays, and histopathology are 
confirmatory. Treatment was formerly by wide surgical excision and 
skin grafting, yet antibiotics (rifampicin with streptomycin given for 8 
weeks) have now been found effective, including an all-oral regimen.
Introduction
Buruli ulcer is an indolent necrotizing infection of the skin, sub-
cutaneous tissue, and bone caused by Mycobacterium ulcerans.
In 1962 Clancey and Dodge described many patients from 
Buruli County, Uganda, with cutaneous ulcers reminiscent of 
those Cook described in 1897 from the same area, and named the 
disease Buruli ulcer. Since the World Health Organization (WHO) 
Buruli ulcer initiative there has been increased attention to efforts 
for the treatment and control of Buruli ulcer.
Aetiology
MacCallum and colleagues first isolated the causative agent in 
1948 from patients in Australia. M. ulcerans, a slow-​growing acid-​
fast bacillus, grows optimally at 32° C and produces mycolactone, 
a cytotoxic and immunosuppressive polyketide assembled by 
plasmid-​encoded synthases of the aetiological agent. This toxin 
is the primary virulence factor of M. ulcerans. Data from whole 
genome sequencing define three major lineages of M.  ulcer-
ans that infect humans. Lineage 1 contains the South American 
strains, lineage 2 the Asian strains and lineage 3 the African and 
Australian subgroups. ​Single nucleotide polymorphism analysis 
through whole genome sequencing provides insights into the 
population structure and evolution of M. ulcerans across Africa. 
Portaels et al. were the first to culture M. ulcerans from the envir-
onment, in 2008.


section 8  Infectious diseases
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Epidemiology and transmission
Buruli ulcer is the third most common human mycobacterial in-
fection worldwide, after tuberculosis (Chapter 8.6.26) and leprosy 
(Chapter 8.6.28). It occurs in humid, rural tropical, subtropical re-
gions and temperate regions, and most endemic foci of Buruli ulcer 
are near rural freshwater wetlands, especially ponds and swamps. 
Presently, major endemic areas are Benin, Cameroon, Democratic 
Republic of Congo, Gabon, Ghana, Ivory Coast, and adjacent coun-
tries. Increasing case clusters have also been reported in Australia 
(Far North Queensland and Victoria, where it is known as Daintree 
or Bairnsdale ulcer) and sporadic cases in Mexico, South America, 
Malaysia, Japan, China, and Papua New Guinea.
Documented environmental sources of M. ulcerans DNA include 
irrigation systems, water bugs living among aquatic plant roots in 
swamps, terrestrial vegetation, and mosquitoes. In Australia, koalas, 
possums, potoroos, rats, some domestic animals (dogs, horses, and 
one cat) and imported alpacas acquire the infection naturally.
The mode of transmission is not fully understood, although dis-
ease is known to be linked to contaminated water. Outbreaks of dis-
ease often follow environmental changes that promote flooding or 
alter water courses, such as deforestation or construction of dams 
and irrigation systems. Increased farming activities near wet-
lands and global climatic changes may contribute to the rapid re-​
emergence of Buruli ulcer. In West Africa the peak age of onset is 5 to 
15 years, although the disease can affect any age group. In Australia 
the median age at presentation is 55–​65 years.
Transmission is probably via skin trauma, although insects may 
play a role. The trauma may be slight (e.g. hypodermic injection) 
or severe (e.g. land mine wound or snake bite). Biting insects (e.g. 
mosquitoes, water bugs) may serve as vectors. In Australia, risk 
for Buruli ulcer in humans is associated with the frequency of de-
tection of M. ulcerans in the local possum faeces, as well as mos-
quitoes, suggesting a possible role in transmission. Possums tend 
to be symptomatic with M. ulcerans ulcerations and are the likely 
reservoir in South Eastern Australia, with transmission possibly 
caused by mosquitoes that developed in water sources contamin-
ated with possum faeces, or rested on M. ulcerans-​contaminated 
vegetation. Possums may be useful sentinels to predict spread of 
Buruli ulcer in humans in South Eastern Australia, though no such 
link has been established in Far North Queensland. Extensive sur-
veillance of rodents in Africa has failed to identify a similar res-
ervoir to date. Mosquitoes do not seem to play a major role in 
ecology of M. ulcerans in Africa. Aerosols arising from ponds and 
swamp surfaces may disseminate M. ulcerans. Rare instances of 
person-​to-​person transmission of Buruli ulcer are anecdotal, and 
to our knowledge, none of these events has been established as 
M. ulcerans infection.
Pathogenesis
Predisposing host factors are poorly understood. Putatively, severity 
and course of infection are related to pathogen virulence, mode of 
infection, inoculum size, host genetic factors, and immunological 
response of the host. A T-​helper 1 cell (Th1) response tends to lo-
calize and heal infections while a T-​helper 2 cell (Th2) type response 
is associated with dissemination. Once introduced, the small amount 
of mycolactone produced by inoculated M. ulcerans causes tissue 
necrosis and apoptosis, suppressing local immune responses, and 
ensuring survival of the bacillus in necrotic tissue. Mycolactone tar-
gets subcutaneous fat cells, permitting necrosis to spread just super-
ficial to fascial planes. M. ulcerans may invade lymphatic and blood 
vessels, causing metastatic spread of the mycobacterium despite its 
preference for cooler temperatures (32°C).
Clinical features
Except for those with massive lesions, patients are usually surprisingly 
well without systemic symptoms or abnormal laboratory findings. 
Meyers et al. have published a model for the natural history and inter-
relationships of the forms of Buruli ulcer disease. Buruli ulcer may 
be localized or disseminated, and can be classified in three categories 
based on the extent of the ulceration, per WHO guidelines.
Localized disease
Typically, the initial cutaneous lesion is a single, firm, painless, 
non​tender, movable, subcutaneous nodule up to 3 cm in diameter. 
Limbs are preferred sites, often around joints. The natural history 
of the disease is markedly variable, but nodules usually ulcerate 
within l to 3 months of inoculation. A whitish necrotic slough de-
velops in the ulcer base with induration and hyperpigmentation 
of surrounding skin. Ulcer borders are undermined, sometimes 
extending widely (major ulcerative disease) (Fig. 8.6.29.1). Some 
small (1–​2 cm in diameter) ulcerated lesions with shallow under-
mining self-​heal (minor ulcerative disease). Without treatment, 
major ulcerative lesions tend to become inactive, after months or 
years, and heal by scarring. Scars are depressed and stellate, often 
causing disfiguring and crippling cicatricial contractures.
Fig. 8.6.29.1  Pristine Buruli ulcer on the left deltoid area in a 12-​year-​
old Congolese boy who had received a hypodermic injection at this site 
3 months previously. Note central necrotic slough in the base of the ulcer 
and undermined edges.


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Disseminated disease
Disseminated disease may develop from nodules, arise from local-
ized major ulcerative lesions, or disseminate directly and rapidly 
from the site of inoculation, causing indurated plaques covering 
even an entire limb or vast areas of the trunk. Without treatment, 
such lesions will eventually slough, leaving a large ulcer with con-
tinuing extension of disease at the borders. Eyes, breasts, and geni-
talia may be damaged or destroyed.
While metastatic spread may arise from localized disease, patients 
with the high bacterial loads and disseminated disease are most 
prone to metastatic lesions. Spread may be to distant skin sites or 
bone, especially bones of the limbs. In Africa, M. ulcerans osteomye-
litis develops in approximately 10% of patients and often leads to 
amputations or other disabilities.
Differential clinical diagnosis
Clinical diagnosis is sometimes perplexing. Differential diagnoses 
include bacterial, mycotic, and parasitic infections, inflammatory 
lesions, and tumours. Ulcers resembling Buruli ulcer include trop-
ical phagedenic ulcer (malodorous and not undermined), venous 
stasis ulcer (not undermined), and venomous snake bite or spider 
bite (history helpful).
Pathology
Optimal biopsy specimens contain the necrotic base of ulcers and 
undermined edge of lesions including subcutaneous tissue and fa-
scia. Histopathological sections reveal a contiguous coagulation 
necrosis (non​caseating) of the deep dermis, panniculus, and fa-
scia. Vasculitis and mineralization are common. Clumps of extra-
cellular acid-​fast bacilli are most plentiful in the base of the ulcer; 
however, intracellular M. ulcerans may be seen in inflammatory cells 
at the edge of necrotic foci. Necrosis extends well beyond the loca-
tion of bacilli. Local and regional lymph nodes are often invaded 
and sometimes necrotic. In bone, the marrow is necrotic and con-
tains acid-​fast bacilli, and trabeculae are eroded. These features are 
distinct from those of osteomyelitis of all other known aetiologies. 
Development of delayed-​type hypersensitivity granulomas heralds 
healing by fibrosis.
Laboratory diagnosis
Fine needle aspirates are often employed for laboratory studies 
on closed lesions. Smears stained by the Ziehl-​Neelsen method 
from the ulcer base reveal acid-​fast bacilli in clumps in around 
30–​60% of polymerase chain reaction confirmed Buruli ulcer le-
sions. M. ulcerans is a slow-​growing organism that can be cultured 
in vitro at 29–​33°C, albeit with low rate of cultivability (20–​60%). 
Polymerase chain reaction provides specific identification of 
M. ulcerans, with IS2404 as the most sensitive target given the pres-
ence of over 200 copies per genome. Histopathological changes are 
characteristic.
Treatment
The former recommended treatment for most patients was wide 
surgical excision followed by skin grafting. Heating the lesion 
at 40°C can be a useful adjunct. Today, antimicrobial therapy (ri-
fampicin 10 mg/​kg by mouth plus streptomycin 15 mg/​kg by intra-
muscular injection, or rifampicin plus clarithromycin) without 
surgery is recommended and heals most nodular and minor ul-
cerative disease, and some advanced lesions. Controlled trials have 
established efficacy. Physiotherapy is essential to prevent contrac-
ture deformities.
Prevention and control
Bacille Calmette-​Guérin (BCG) vaccination provides short-​lived 
protection. Practical control measures for inhabitants of endemic 
areas are usually ineffective; however, use of a protected water 
supply is important. Tourists should avoid wetlands in endemic 
countries.
Socioeconomic impact
Patients are often stigmatized by disability or cosmetic damage, 
and may require welfare services for life, but such services are often 
locally limited or unavailable. They also often require protracted 
hospital stays, taxing overburdened services.
Given certain similarities between Buruli ulcer and leprosy, 
combined control and prevention strategies could be put in place 
in countries endemic for both diseases.
FURTHER READING
Alffenaar JW, et  al. (2010). Pharmacokinetics of rifampin and 
clarithromycin in patients treated for Mycobacterium ulcerans in-
fection. Antimicrob Agents Chemother, 54, 3878–​83.
Buultjens AH, et  al. (2018). Comparative genomics shows that 
Mycobacterium ulcerans migration and expansion preceded 
the rise of Buruli Ulcer in Southeastern Australia. Appl Environ 
Microbiol, 84, e02612–17.
Carson C, et  al. (2014). Potential wildlife sentinels for monitoring 
the endemic spread of human Buruli ulcer in South-​East Australia. 
PLoS Negl Trop Dis, 8, e2668. 
Converse PJ, et al. (2011). Treating Mycobacterium ulcerans disease 
(Buruli ulcer): from surgery to antibiotics, is the pill mightier than 
the knife? Future Microbiol, 6, 1185–​98.
Doig KD, et al. (2012). On the origin of Mycobacterium ulcerans, the 
causative agent of Buruli ulcer. BMC Genomics, 13, 258.
Fyfe JA, et al. (2010). A major role for mammals in the ecology of 
Mycobacterium ulcerans. PLoS Negl Trop Dis, 4, e791.
Kiszewski AE, et al. (2006). The local immune response in ulcerative 
lesions of Buruli disease. Clin Exp Immunol, 143, 445–​51.
Lavender CJ, et  al. (2011). Risk of Buruli ulcer and detection of 
Mycobacterium ulcerans in mosquitoes in southeastern Australia. 
PLoS Negl Trop Dis, 5, e1305.
8.6.29  Buruli ulcer: Mycobacterium ulcerans infection