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epidemiology and disease burden of Buruli ulcer:
a review
Katharina Röltgen 1,2
Gerd Pluschke 1,2
1
Molecular immunology, Swiss
Tropical and Public Health institute,
2
University of Basel, Basel, Switzerland
Introduction
Correspondence: Gerd Pluschke
Molecular immunology, Swiss
Tropical and Public Health institute,
Socinstrasse 57, 4002 Basel, Switzerland
Tel +41 61 284 8235
Fax +41 61 284 8101
email gerd.pluschke@unibas.ch
Chronic skin ulcers consistent with Mycobacterium ulcerans disease (Figure 1) were
first described in The Mengo Hospital Notes (Kampala, Uganda) in 1897 by the
British physician Albert Cook.1 However, it was only in 1948 when MacCallum and
Tolhurst were able to isolate the etiologic organism of these “unusual skin ulcers” in
patients from the Bairnsdale District in Australia, a mycobacterium later referred to
as M. ulcerans.2 In the Democratic Republic of the Congo (then the Belgian Congo),
chronic ulcers caused by mycobacteria were reported in 170 patients in the 1940s and
1950s.3 Infections occurred largely in a geographically restricted area situated between
two rivers, exemplifying two of the main characteristics of the disease – the highly
focal occurrence and the association with water bodies. Large numbers of cases were
reported from the Buruli County near the river Nile in Uganda in the early 1960s,4
giving rise to the official designation Buruli ulcer (BU) for the disease. In the following decades, cases of BU caused by the two main human pathogenic M. ulcerans
lineages have been reported from 34 countries mainly with tropical and subtropical
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http://dx.doi.org/10.2147/RRTM.S62026
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Abstract: Buruli ulcer (BU) is a neglected tropical skin disease caused by Mycobacterium
ulcerans. Infection foci occur mainly in remote, rural areas of Central and West Africa, but also
in Australia and Papua New Guinea. In addition, infections caused by M. ulcerans strains of a
different lineage are sporadically reported from scattered foci in Asia and the Americas. While
in the past decade more than 42,000 BU cases have been reported worldwide, an assessment of
the actual global disease burden is complicated by the remoteness of affected populations and a
lack of data on the incidence of BU in a number of countries, from which cases have been historically reported. Moreover, as BU patients present with diverse clinical manifestations ranging
from relatively unspecific nodules, plaques, or edema to necrotic, ulcerative lesions, differential
diagnosis is manifold and thus clinical misclassification may occur. Since to date reservoirs
and transmission pathways of M. ulcerans remain equivocal, early diagnosis and treatment of
patients are key determinants to control the disease. Particularly in view of the apparent decline
in BU incidence in regions of West Africa, awareness and knowledge of BU in endemic regions
must be retained to ensure a continuous monitoring and control. An integrated approach for the
control of tropical skin diseases should be considered to cope with this difficult task. This review
article aims at providing an overview of the current global burden of BU and summarizes the
state of knowledge on the various epidemiological aspects of this enigmatic disease.
Keywords: neglected tropical disease, chronic skin ulcers, Mycobacterium ulcerans, geographically confined infection foci
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Figure 1 Presentation of BU lesions.
Notes: (A) Small ulcerative and edematous BU lesion. (B) Large ulcer affecting the whole arm of a child.
Abbreviation: BU, Buruli ulcer.
climates (Angola, Australia, Benin, Brazil, Burkina Faso,
Cameroon, Central African Republic, People’s Republic
of China, Congo, Côte d’Ivoire, Democratic Republic of the
Congo, Equatorial Guinea, French Guiana, Gabon, Ghana,
Guinea, Indonesia, Japan, Kenya, Republic of Kiribati,
Liberia, Malawi, Malaysia, Mexico, Nigeria, Papua New
Guinea [PNG], Peru, Senegal, Sierra Leone, South Sudan,
Sri Lanka, Suriname, Togo, and Uganda). While only single,
sporadic BU cases have been reported from regions, where
the ancestral lineage of M. ulcerans is prevalent, strains of
the classical lineage account for infection foci in Africa and
Australia with often very high incidences. Since the 1980s,
such highly endemic areas were identified in several West
African countries, including Benin,5 Côte d’Ivoire,6,7 Ghana,8
and Cameroon9 as well as in Australia.10,11 Surveys for BU
in the endemic African countries revealed vast underreporting.7–9 Patients tend to report late or not at all to the formal
health system for many reasons, including limited access
to health facilities, stigmatization, and traditional beliefs,
prompting them to seek treatment with traditional healers.
In 1998, the World Health Organization (WHO) established the Global Buruli Ulcer Initiative in order to raise
awareness and to coordinate global BU control and multidisciplinary research efforts.12 Today, cases of BU are actively
reported from 13 countries in Africa (Benin, Cameroon,
Côte d’Ivoire, Democratic Republic of the Congo, Gabon,
Ghana, Guinea, Nigeria, and Togo), the Americas (French
Guiana), Asia (Japan), and the Western Pacific (Australia
and PNG).13 While more than 42,000 BU cases have been
reported worldwide by 20 countries in the last 10 years
(Table 1), case numbers seem to be declining in countries
actively reporting BU with a total of 2,251 cases reported by
the WHO in 2014 (Figures 2 and 3).13 However, the actual
worldwide disease burden is still not clear, since it can be
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assumed that BU continues to exist in many of the previously
reporting countries and that there may be underreporting by
some of the countries reporting to the WHO. Reasons for
under- or non-reporting of BU are manifold and include
lack of awareness or resources (health systems overburdened by other more prevalent diseases), limited access to
the remote populations affected, and political instability in
certain countries.
The current downward trend in case numbers in several
BU endemic African countries may in part be due to the
establishment of effective national BU control programs.
In this regard, it has been hypothesized that humans with
active BU lesions that are not treated appropriately may
play a role in transmission by shedding the bacteria into
the environment.14–16 Transmission may thus be reduced by
active case search followed by adequate treatment with the
WHO-recommended antibiotic combination therapy of daily
rifampicin and streptomycin for 8 weeks.17,18 The mechanism
by which M. ulcerans is transmitted from the environment
to humans thereby remains inconclusive.
Methods
We conducted an extensive review of the literature from all
years by searching PubMed for the term “Buruli ulcer” or
“Mycobacterium ulcerans”. All titles (N=∼980) and available abstracts (N=∼750) were screened for their epidemiological relevance. A total of 310 publications were selected
for full-text review and the reference lists of included
papers were perused for additional articles/webpages of
interest. Due to the multitude of identified publications
for certain endemic regions and epidemiological aspects,
a selection of representative references had to be made
that was mainly based on the scale/comprehensiveness of
the studies.
Research and Reports in Tropical Medicine 2015:6
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epidemiology of Buruli ulcer
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Table 1 Number of reported BU cases worldwide between 2004 and 2014
Côte d’ivoire
Ghana
Benin
Cameroon
DRC
Togo
Congo
Guinea
Australia
Gabon
Nigeria
Uganda
PNG
South Sudan
Japan
French Guiana
Liberia
Sierra Leone
CAR
equatorial Guinea
Total
2004
2005
2006
2007
2008
2009
2010
2011
2012
2013
2014
Total
1,153
1,157
925
914
487
800
235
146
34
43
Nd
7
31
4
1
17
Nd
Nd
Nd
Nd
5,954
1,564
1,005
1,045
265
51
317
53
208
47
91
Nd
72
Nd
24
1
2
Nd
Nd
Nd
3
4,748
1,872
1,096
1,195
271
74
40
370
279
72
54
9
5
Nd
38
1
2
Nd
Nd
Nd
Nd
5,378
2,191
668
1,203
230
340
141
99
Nd
61
32
Nd
31
26
8
3
2
Nd
Nd
Nd
Nd
5,035
2,242
986
897
312
260
95
126
80
40
53
Nd
24
24
3
2
8
Nd
1
3
Nd
5,156
2,679
853
674
323
172
52
147
61
35
41
24
3
8
5
5
2
Nd
Nd
Nd
Nd
5,084
2,533
1,048
572
287
136
67
107
24
42
65
7
Nd
5
4
9
7
Nd
Nd
Nd
Nd
4,913
1,659
971
492
256
209
52
56
59
143
59
4
Nd
8
Nd
10
3
Nd
28
Nd
0
4,009
1,386
632
365
160
284
51
38
82
105
45
40
Nd
Nd
Nd
4
2
21
Nd
Nd
Nd
3,215
1,039
550
378
133
214
37
6
96
74
59
23
Nd
Nd
Nd
10
3
8
Nd
Nd
Nd
2,630
827
443
330
126
192
67
Nd
54
89
47
65
Nd
3
Nd
7
1
Nd
Nd
Nd
Nd
2,251
19,145
9,409
8,076
3,277
2,419
1,719
1,237
1,089
742
589
172
142
105
86
53
49
29
29
3
3
48,373
Abbreviations: DRC, Democratic Republic of the Congo; Nd, no data; CAR, Central African Republic; PNG, Papua New Guinea; BU, Buruli ulcer.
Genomic diversity, ecology, and
virulence of M. ulcerans
The occurrence of BU is often perceived as mysterious,
mainly due to incomplete knowledge regarding reservoirs
and transmission pathways of M. ulcerans. Detailed genomic
investigations on the origin and evolution of this enigmatic
pathogen have at least provided some clarifications. Genetic
analyses indicate that M. ulcerans has diverged from the
ubiquitous waterborne organism Mycobacterium marinum19
perhaps around a million years ago.20 While M. marinum
usually infects fish and frogs and only occasionally causes
granulomatous skin lesions in humans,21 emergence of the
Legend
Never reported
Previously reported
1–10
>10–100
>100–500
>500–1,000
Figure 2 worldwide distribution of BU.
Notes: Global map showing countries that have reported cases of BU in 2014. The map was created using ArcGiS. Data from world Health Organization.13
Abbreviation: BU, Buruli ulcer.
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8,000
BU cases reported
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6,000
2,000
0
2004
2005
2006
2007
2008
2009
2010
2011
2012
2013
2014
Year
Figure 3 Number of BU cases reported worldwide.
Notes: Graph showing the downward trend of BU case numbers reported between 2004 and 2014. Data from world Health Organization.13
Abbreviation: BU, Buruli ulcer.
new, more pathogenic species M. ulcerans from M. marinum
was coined primarily by the adoption of a virulence plasmid
(pMUM). pMUM was shown to carry genes encoding the
enzymatic machinery required for the synthesis of a unique
macrocyclic polyketide toxin referred to as mycolactone22
that proved to be a key player in the pathogenesis of BU.
Mycolactone has cytotoxic and immunosuppressive activities
leading to the formation of chronic ulcerative skin lesions23
and the killing of infiltrating immune cells before they reach
the active center of the lesions. In the course of the evolution of
M. ulcerans, acquisition and expansion of insertion sequence
(IS) elements (IS2404 and IS2606) have caused inactivation
of genes and extensive loss of DNA.24 This became evident
from a comparison of the whole-genome sequences of
M. marinum strain M, comprising a 6.6 Mb circular chromosome with 5,424 coding sequences and 65 inactivated
genes25 and the African M. ulcerans strain Agy99, consisting
of two circular replicons with a size of 5.8 Mb, 4,241 coding
sequences and a total of 771 pseudogenes.24 These genomic
signatures (acquisition of foreign DNA, proliferation of IS
elements, extensive gene loss through pseudogene formation,
and genome downsizing) are indicative of an adaptation of
M. ulcerans to a protected niche environment, where genes
once needed for survival under diverse conditions are no
longer required.24,26,27 However, it is not clear, to which environmental niche M. ulcerans is adapting to and by which
mechanism the pathogen is transmitted. An adaptation within
the aquatic ecosystem appears very likely, considering the
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origin of M. ulcerans as well as the association of BU infection foci with stagnant water bodies or river basins. Deletion
or inactivation of genes required for pigment biosynthesis and
anaerobiosis indicate that M. ulcerans is adapting to a dark and
oxygen-poor ecological niche. Rather than free-living, it may
persist in the environment as a commensal, associated with
other protective organisms such as amoebae.28–30 However,
detection of M. ulcerans-specific DNA sequences in many
biotic components of aquatic ecosystems, such as plants,
snails, fish, or insects, has been also interpreted as indication
for the ubiquitous presence of this pathogen in these habitats.
Furthermore, mycolactone-producing mycobacteria have been
isolated from different fish and frog species presenting with
mycobacterial infections. While these isolates have initially
been given distinct species names, such as M. marinum,31
Mycobacterium pseudoshottsii,32 and Mycobacterium liflandii,33 genetic analyses suggest that all mycolactone-producing
mycobacteria are derived from a common ancestor and should
be considered a single (M. ulcerans) species.27,34
A detailed analysis of M. ulcerans human isolates of
diverse geographical origin based on comparative genomic
hybridization analysis revealed extensive large sequence
polymorphisms, enabling a differentiation of M. ulcerans
clinical isolates into two principal lineages. These lineages
were designated “ancestral” in reference to M. ulcerans
strains from Asia (People’s Republic of China and Japan) and
the Americas (Mexico, French Guiana, and Suriname) being
closely related to M. marinum, and “classical”, with most BU
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cases worldwide – namely those from Africa, Australia, and
PNG – being caused by isolates belonging to this lineage.
A comparative whole-genome sequencing analysis including strains isolated from infected fish and frogs have suggested the presence of at least three different lineages within
the species M. ulcerans:27 lineage 1, including frog and fish
isolates of worldwide origin, but also a human isolate from
French Guiana; lineage 2 represented by a human isolate from
Japan; and lineage 3 comprising human isolates from Africa
and Australia. In view of the broad host range of M. ulcerans
including humans, other mammals35–39 and ectotherms, the
different lineages appear to have adapted to distinct niche
environments and may be considered as ecovars.
Different patterns of BU case distribution with highly
endemic foci in Africa and Australia associated with the
classical lineage as compared with only scattered, sporadic
cases in Asia and the Americas associated with the ancestral lineage support the idea of the development of distinct
M. ulcerans ecovars. The ancestral M. ulcerans lineage may
thus be adapted to an ecological niche, from which strains
only occasionally infect humans. In contrast, strains of the
classical lineage may be present in an environmental reservoir
that is associated with a higher risk for humans to contract an
M. ulcerans infection. The pathology caused by American
and Asian ancestral lineage strains40,41 may be as severe as
the one observed in Africans and Australians infected by
classical lineage strains.
Geographical distribution and
disease burden of BU
Ancestral lineage
Americas (French Guiana, Suriname, Peru,
Brazil, and Mexico)
There is only sparse information on the prevalence and
geographical distribution of BU in the Americas. Published
reports on the occurrence of M. ulcerans infections are limited41–44,47,48 and only very few cases of BU have been reported
to the WHO. While fewer than ten cases per country have
been confirmed in Suriname, Mexico, Peru, and Brazil in
the past 50 years,42 .250 cases have been notified between
1969 and 2014 in French Guiana, which borders Brazil to the
east and south, and Suriname to the west. Most inhabitants
of French Guiana reside along a 50 km wide coastal strip
dominated by swampy areas, with the rest of the country
consisting of dense tropical rainforest. Considering the small
population, the number of infections is relatively high with an
average annual incidence of .2/100,000.43 Construction of
the Petit-Saut Dam in 1994 upstream the BU endemic area has
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epidemiology of Buruli ulcer
been associated with a significant decline in case numbers,
possibly by a better regulation of water flows. Recently, M.
ulcerans DNA (IS2404 and the ketoreductase B domain gene)
has been detected in specimens from three of 23 different
freshwater bodies sampled in French Guiana, indicative for
the presence of this species in the environment.43 The recent
observation of genetic heterogeneity among 23 isolates
from patients living along the coastline of French Guiana
as revealed by Multilocus Variable Number Tandem Repeat
Analysis44 is uncommon for M. ulcerans, which usually shows
very limited genetic diversity within particular endemic
areas.14,45,46 While two of the genotypes detected in French
Guiana showed high similarity, one had distinctly different
characteristics and shared more sequence similarity with the
M. ulcerans ecovar liflandii. No geographical clustering of the
genotypes was observed.44 While French Guiana is the only
country in the Americas actively reporting BU cases to the
WHO,13 sporadic infections have been reported from other
American countries dating back several years.
From warm and humid areas of Peru, eight laboratoryconfirmed BU cases have been recorded between 1996 and
2006. Five of these patients came from the Peruvian rainforest, while the other three patients lived near or visited Tumbes,
a swampy area at the north coast of Peru. One of the patients
presented with lesions on both knees and reported to often
kneel on soil and organic mulch that contained wood shavings while carrying out gardening activities.47 In addition to a
single case of BU reported from Brazil in 2007,48 a returning
traveler from the UK in the same year was reported to most
probably have contracted his M. ulcerans infection during a
visit of the Pantanal Region of Southern Brazil.49 Cases of
two laboratory-confirmed BU patients from Central Mexico
with unusually disseminated infections have been reported
in 2005.41
The larger number of reported BU cases from French
Guiana as compared with the other South American countries
might have various reasons, including increased awareness
of the disease among the relatively small population and an
efficient reporting system, the prevalence of more pathogenic
variants of M. ulcerans, and/or a closer contact of the population to environments contaminated with the pathogen.
Asia (Japan and People’s Republic of China)
The causative agent of BU in Japan and People’s Republic
of China is often referred to as “M. ulcerans subspecies
shinshuense”.50 While the severity of the disease seems to be
comparable to that caused by other M. ulcerans sublineages,
pain was reported to be more common in Japanese than in
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African patients. Until 2014, a total of 53 BU cases have
been reported from Japan with the first report dating back
to 1980.50 After that no further cases had been reported until
2003.51 Between 2003 and 2011, there has been a steady
increase in the number of reported cases, summing up to
a total of 32 well-documented cases: 20 females and 12
males with an average age of 42 years. Most of these cases
(25/32; 86%) were diagnosed during autumn and winter,52
which may speak for contraction of the slowly progressing
infection in summer. All but one of the patients originated
from different regions of the mountainous Honshu Island, a
typical temperate region of Japan. None of the 19 patients
that had been reported until 2010 could be linked to an
aquatic environment.40 In contrast, a rare instance of familial
occurrence of BU, in which three family members developed
the disease, has been linked to a stagnant agricultural water
channel. Detection of IS2404 from a crayfish within the water
channel suggested that the pathogenic organism may reside
in aquatic environmental reservoirs in Japan.53
The increased number of reported cases in Japan may
rather be caused by increased awareness of the disease than
by an actual rise in incidence. A case of BU in a patient with
travel history in the People’s Republic of China infected with
M. ulcerans ecovar shinshuense published in 2000 indicates
the probable risk for M. ulcerans infection in other Asian
countries.54
Classical lineage
Western Pacific (Australia, PNG, and Republic of
Kiribati)
In Australia, two geographically and climatically very distinct
BU endemic foci exist. An endemic area in the temperate
southeastern state of Victoria, where the disease is known
as “Bairnsdale ulcer”, has been extensively studied. A less
well-known BU endemic area exists in tropical Far North
Queensland, where the disease is often called “Daintree
ulcer”.
In Victoria, BU outbreaks are typically observed
along the highly populated coast and have been reported
from Gippsland, Phillip Island, 10 and towns located on
the Mornington55 and Bellarine56,57 peninsulas. More than
430 cases have been reported for Victoria between 1939
and 2008,58 with the majority of cases notified after 1980.
Disease foci are gradually moving along the coastal settlements, with the most severe BU outbreak in Point Lonsdale,
where nearly 70 cases were recorded during 2004 and 2006.58
In a well-characterized cohort of 180 BU patients from
the Bellarine Peninsula recorded between 1998 and 2011,
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the median patient age was 61 years and 49% of patients
were male.57
In the BU endemic setting of Victoria, a new facet of
the disease was revealed by the identification of possums as
terrestrial animal reservoirs of M. ulcerans.59,60 Testing of
environmental samples by polymerase chain reaction (PCR)
revealed outstandingly high concentrations of M. ulcerans
DNA in the feces of these animals. Subsequently, it was
found that in areas endemic for human BU, a large proportion of possums had skin lesions caused by M. ulcerans.
These observations may speak for a zoonotic risk of BU in
Victoria.16 M. ulcerans DNA has also been detected in a small
proportion of captured mosquitoes from Victoria.56 Furthermore, correlations have been found between the occurrence
of BU and of other mosquito vector-borne diseases in this
region, giving rise to speculations that mosquitoes might be
vectors of M. ulcerans in southeastern Australia.61
The Daintree River catchment and adjacent swampy
coastal lowlands in tropical Far North Queensland constitute
another BU endemic focus in Australia. Settlement in this
region is sparse and is composed of smaller communities
and farms. While there are numerous anecdotal reports about
patients having suffered from BU, a consistent recording was
only available from 1964 onward. Between 1964 and 2008,
92 cases were recorded with a median age of 42 years. Most
of the patients (53 males and 39 females) presented during
the dry season and a number of patients reported spider or
insect bites preceding development of their lesion.11
Historic reports indicate the presence of hundreds of
BU cases in PNG, mainly in association with the Sepik and
Kumusi River valleys.62 There is one published report on a
case series of 13 BU patients detected between 1964 and
1965 in the Western (two cases) and Northern (eleven cases)
districts of PNG.63 Another report described 46 cases of BU
seen from 1979 to 1983 in PNG, mainly from villages on
the Sepik River.64 Two cases of extensive limb ulcers with
clinical features of M. ulcerans infection have been reported
in the Republic of Kiribati.65
Southeast Asia (indonesia, Malaysia, and Sri Lanka)
While a few cases have been historically reported to the
WHO from Indonesia and Sri Lanka, no published reports
are available. M. ulcerans infections have also been reported
from Malaysia.66
Africa
The major burden of BU falls on populations living in West
and Central Africa, where the disease typically occurs in
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rural, isolated foci associated with swampy lowlands and river
valleys. Historically, outbreaks of BU have been associated
with various ecological and environmental disturbances,
including alterations of water systems such as irrigation or
damming of streams or rivers connected with the creation
of wetlands and impoundments67 or severe flooding of lakes
and rivers exposing people to swampy terrain.68,69 Moreover,
some infection foci were associated with agricultural activities leading to flooding or the creation of irrigation systems as
well as land development accompanied by resettlement near
water bodies.70 The first BU patients detected in West Africa
came from Nigeria, where cases emerged in proximity to a
small stream that was dammed to create an artificial lake.67
Step-by-step highly endemic BU foci – all located in and connected to river basins – were identified in several other West
African countries including Benin,5 Côte d’Ivoire,6,7 Ghana,8
and Cameroon9 with more than 40,000 BU cases reported
only from these four countries in the last decade.
Much of the basic knowledge about the distribution of BU
cases among exposed populations in Africa can be extracted
from an intensive study of 220 BU cases that occurred within
a community of 2,500 Rwandan refugees between 1964 and
1969.71 The refugees settled in Kinyara, an area near the river
Nile in Central Uganda, which turned out to be a focus for M.
ulcerans infection, providing the opportunity of investigating
epidemiological features of the disease in this population.
Although BU was shown to affect individuals at every age,
the highest incidence in the Rwandan refugee community was
in children aged between 5 and 15 years. Despite the small
extent of the settlement, a higher BU incidence was observed
in sectors located close to the Nile and a small tributary,
although actual contact with the river water appeared not
necessary for infection. Seasonal fluctuation in BU incidence
was observed with an estimated maximum spread between the
two rainy seasons. The majority of patients presented with a
single lesion, while the anatomical site of lesions varied with
both sex and age. These valuable data were complemented
by other studies conducted in different BU endemic areas in
the last decades, including a recently published large study
carried out between 2005 and 2011 at the BU Treatment
Centre (Centre de Dépistage et de Traitement de l’Ulcère
de Buruli [CDTUB]) in Benin.72 Prospective clinical data
collected from 1,227 laboratory-confirmed BU patients from
Benin revealed features similar to those found in many other
African BU endemic areas. Typically, patients were children
with a median age at diagnosis of 12 years and most lesions
occurred on the limbs. The overall sex distribution was
balanced. In all, 96% of the patients presented with a single
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epidemiology of Buruli ulcer
lesion and 36% with an advanced lesion of more than 15
cm in diameter. Moreover, findings of this study support the
view that the BU burden in Africa is underestimated, since
in the past years, more patients from the neighboring country
Nigeria were treated at the CDTUB in Benin than actually
reported by Nigeria to the WHO.72
Risk factors and transmission
Since in recent years various environmental and animal
reservoirs as well as different vectors were proposed to be
involved in the transmission of M. ulcerans, consideration
should be given to the possibility that multiple modes of
infection may exist. In order to better understand how
M. ulcerans is transmitted, a multitude of BU case series was
analyzed. A number of case-control studies allowed for the
direct identification of potential risk factors for contracting
the disease (Table 2).6,73–87 A review article evaluating identified risk factors was published in 2010.88
Age and sex
While it has long been recognized that the majority of patients
in the African BU endemic settings are children with a peak
of BU incidence between 10 and 14 years of age,6,89 a bimodal
age-related risk of developing BU is observed, when the
population age distribution is taken into account. In one of
the few case-control studies that did not match participants
by age, an increased risk of BU in children aged below
15 years and adults aged above 49 years was found.87
A recent survey for BU in Cameroon has revealed that the
risk is highest in children aged between 4 and 14 years and
in the elderly aged above 50 years. Furthermore, a marked
underrepresentation of children below 4 years of age became
apparent.90 In line with this observation, sero-epidemiological
studies in Ghana and Cameroon have indicated that children below 5 years of age are considerably less exposed to
M. ulcerans than older children.91 Infection by M. ulcerans
might thus occur outside the relatively small movement
range of very young children. Exposure and the associated
risk of developing BU disease appears to increase at an age
when the children are having more intense environmental
contacts, including direct exposure to water bodies peripheral
to their homes. While young adults are less often affected by
BU and may have developed a certain degree of immunity
to M. ulcerans, the higher risk of BU in the elderly56,89 may
be related to the age-dependent decrease in immunological
competence. Sero-epidemiological studies also indicate that
only a small proportion of exposed individuals develop clinical M. ulcerans disease.
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No of cases
confirmationa
No of controls
(background)
Assessed risk factors
Risk factors identified
Protective factors identified
Reference
Confirmed
Australia (1998–2005)
49
609 (community)
Lifestyle and insect exposure
Mosquito bites on lower legs and
lower arms
Use of insect repellent, wearing
protective clothing, washing of
wounds
73
Benin (2006–2008)
104
DRC, Ghana, and Togo
(2010–2013)
Ghana (2010–2011)
401
312 (community, matched
by age, sex, and village)
826 (community, mostly
family and neighbors)
113 (community, matched
for age, sex, and village)
water sources, family
relationships
BCG vaccination
BU history in the family, contact
with natural water sources
None
Ghana (2000)
116
116 (community, matched
by age and village)
Demography, socio-economy,
health and hygiene as well as
environment
environment and behavior
Presence of wetland, insect bites
in water, use of adhesive when
injured, and washing in the river
wading in a river
Ghana (1999)
51
51 (community, matched
by age, sex, and BCG)
Water-related activities
Swimming in rivers on a habitual
basis
Partially confirmed
Benin (2002–2003)
Benin (2002–2003)
426
324
613 (community)
1,173 (neighborhood,
matched by age and sex)
Hiv infection
Environmental- and healthrelated behaviors
Hiv infection
Frequent contact with stagnant
water
Benin (2002–2003)
Benin (2002–2003)
179
279
Hemoglobin variants S or C
BCG vaccination
None
None
Cameroon (2007–2009)
77
242 (community)
988 (neighborhood,
matched by age and sex)
153 (community, matched
by age, sex, and village)
Activities and habits
Bathing in the river, reporting
scratch lesions after insect bites
Cameroon (2006)
163
163 (community, matched
by age and village),
118 (family)
Demography, environment,
and behavior
Côte d’ivoire (2001)
116
116 (community, matched
by age, sex, and village)
Uganda (1969–1972)
45
Hundreds (cohort,
population-based)
Socio-demographic
characteristics, BCG vaccine
status, water-related
activities
environment
Low level of education, swamp
wading, wearing short, lowerbody clothing while farming, living
near cocoa plantation or woods,
using adhesive bandages when
hurt
No history of BCG vaccination,
having river/lake/dam near
housing, place for fishing
113
Swamps as a domestic water
source
74
None
75
Use of alcohol for injuries,
covering limbs during farming
76
wearing a shirt while farming,
sharing indoor living space
with livestock, bathing with
toilet soap
77
78
Regular use of soap for washing,
treating injuries with soap/
antibiotic powder, frequent
contact with flowing water
None
None
Systematic use of a bed net,
cleansing wounds with soap,
growing cassava
washing clothes, using bed
nets, treating wounds with
rubbing alcohol or leaves
79
80
81
82
83
84
85
86
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Research and Reports in Tropical Medicine 2015:6
Country (period of
study conduction)
Röltgen and Pluschke
66
Table 2 Risk factors for BU identified in comparative case-control studies
water exposure, farming
practices, exposure to BU
patients with ulcers, use of
protective clothing
100 (community,
unmatched)
50
Côte d’ivoire (1991)
Note: aLaboratory confirmation of clinically diagnosed patients by at least one diagnostic test.
Abbreviations: DRC, Democratic Republic of the Congo; HIV, Human immunodeficiency virus; BCG, Bacillus Calmette–Guérin; BU, Buruli ulcer.
wearing protective clothing
6
epidemiology of Buruli ulcer
Age (children ,15 years and
adults .49 years), use of
unprotected water from swamps,
BCG vaccination in patients
.5 years
Participation in farming activities
near the river
Age, sex, place of residence,
BCG vaccination, type of water
for domestic use, occupation
1,444 (hospital,
unmatched)
Not confirmed
Benin (1997–2003)
2,399
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Research and Reports in Tropical Medicine 2015:6
The higher proportion of older people affected is very
pronounced in southeastern Australia, where in a BU outbreak in Point Lonsdale, the risk of contracting BU was
calculated to be about seven times higher for individuals
$55 years of age than in those below 55 years of age.56
The high average age of BU patients from Victoria57 may at
least be partly related to the high average age of the general
population in the affected communities at the seaside, where
many retired people have their homes.
A nearly equal sex distribution among patients was
reported in most of the studies in African and Australian
settings.6,8,9,57,72,89 However, differences in the occurrence
of BU have been observed between groups, if stratified for
age. In the refugee population in Kinyara, the incidence of
BU among adults was considerably higher in women than
in men.71 Several studies have reconfirmed this observation reporting that male patients were more prevalent in
the younger age groups than females, but less prevalent in
adults.8,72,92,93
Risk factors connected with behavior
Various behavioral factors that may lead to an increased or
decreased probability of acquiring BU have been analyzed
in populations living in African and Australian BU endemic
settings (Table 2). In accordance with the prevailing assumption that M. ulcerans infection foci are associated with wetlands, most of the case-control studies conducted identified
contact with or proximity to water bodies as a risk factor for
contracting BU.6,74,76–78,80,83–87 Common factors associated with
a lower risk for BU reported in several comparative studies
were wound care and hygiene73,76,77,80,83,84 as well as wearing
protective clothing.6,73,76,77,84
In southeastern Australia, exposure to mosquitoes was
identified as an additional risk,73 implicating mosquitoes in
the transmission of M. ulcerans in this region. Two studies
conducted in Cameroon suggest an association between bed
net use and protection against M. ulcerans infection.83,84
Only in a minority of the published case-control studies,
clinical diagnosis of all suspected BU cases enrolled was
confirmed by laboratory diagnosis. In view of the limited
reliability of clinical diagnosis, laboratory confirmation
should be a strict quality standard in future studies.
Host genetics
In a descriptive review of all BU cases that had occurred in the
endemic region of Far North Queensland, ten asynchronous
cases in genetically related family members suggested the
possibility of a genetic predisposition.11 However, this has
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not been studied further. In one of the case-control studies
conducted in Benin, a history of BU in the family was
associated with an increased risk of BU.74 Whether family
relationships of BU are due to genetic factors or simply due to
similar exposure to the pathogen remains to be investigated.
Only one human host genetic study has been published so far,
reporting that susceptibility to BU may be associated with a
polymorphism in a NRAMP gene, which had already been
associated with tuberculosis and leprosy.94
inoculation dose of M. ulcerans which may be higher in the
African setting.
The rapidly decreasing number of new infections after
the move of the refugee community from Kinyara to a new
locality in Uganda in late 1969, despite the continued presence of untreated patients with open, ulcerative wounds,
speaks against an important role of direct person-to-person
transmission and for the involvement of an environmental
reservoir.71
Bacillus Calmette–Guérin vaccination
Site of lesion – clues on vectors?
Even though Mycobacterium bovis Bacillus Calmette–Guérin
(BCG) is the most widely administered vaccine in human
history, its efficacy in preventing mycobacterial diseases
remains controversial.95–97 Results of early clinical trials in
Uganda indicated a protective effect of BCG vaccination
against M. ulcerans infection.98,99 However, no evidence of
a protective effect on the risk of developing BU was found
in a number of case-control studies.75,77,82,87 BCG vaccination
may at least confer some protection against severe forms of
BU.100,101
Since most of the BU patients present with a single lesion,
it is commonly assumed that the site of the lesion is also
the site of inoculation. Therefore, a number of studies
have analyzed the distribution of lesions on the body in
order to draw conclusions on the mechanism of infection.
In the majority of the patients, lesions occur on the lower
limbs, followed by the upper limbs, the trunk, and the neck/
head.8,72,90,93,110 In the refugee population in Kinyara, the site
of the lesion varied with both sex and age. Among children
below 5 years of age, the lesions were distributed over all
parts of the body, while with increasing age, lesions on the
head and trunk were less common and largely confined to
the limbs.71 These differences in the distribution of lesions
among children and adults were reconfirmed in other studies.89,90,93 While some studies have reported that among
females, arms were more71 and the trunk less90 frequently
affected as compared with males, other data indicate a
similar distribution of lesion sites in both sexes.93 Variations in the affected anatomical sites by age and sex may
be due to differences in domestic or agricultural activities
(eg, females fetching water and working in the fields with
their bare hands; males farming, carrying out work using
hoes and other tools) or different behaviors (males and
children more commonly exposing their upper trunk than
females).
While all studies agree that most lesions occur on body
sites, which are not commonly protected by clothing, no
definite mode of transmission can be established from these
observations, since the described distribution of BU lesions
may be related to insect bites, skin injuries, or both.
Hiv status
Information on the epidemiological and clinical consequences of BU–HIV coinfection is scarce and contradictory.
While results of the case-control studies conducted in Benin
suggested that HIV infection increases the risk of BU,79 no
significant association was found in a comparative analysis in
Ghana.77 Two recent case-control studies carried out in Benin
and Ghana reported a significant effect of HIV infection on
the severity of M. ulcerans infections and provided evidence
suggestive of a higher HIV incidence in patients with BU
compared with the general population.102,103 Furthermore,
observations in case studies indicate a more severe disease
in HIV patients.104–108
Transmission hypotheses
incubation period – clues on exposure?
Due to the extremely slow growth rate of M. ulcerans, the
incubation period of BU is very long. In the Kinyara refugee camp, the period between short stays of visitors and
the development of BU was estimated to be 4–10 weeks.
In a more recent study from Australia, the mean incubation
period of BU patients who reported a single visit to the
Victorian BU endemic area was 4.5 months. The shortest
period recorded was 32 days and the longest was 254 days.109
The discrepancy between the two studies may possibly be
related to differences in the mode of transmission and the
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Hypotheses on the mode(s) of M. ulcerans
transmission
In the BU focus in southeastern Australia, possums (small
arboreal marsupials native to Australia) seem to represent an
animal reservoir59,60 and mosquitoes are considered potential
vectors61,111 of M. ulcerans.
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In African BU endemic settings, no similar animal
reservoir has been identified so far. However, shedding of
M. ulcerans from ulcerative lesions of humans with active BU
disease may play a role in the dissemination of M. ulcerans
in the African BU endemic regions.14–16 Since recent studies
indicated that M. ulcerans may persist for many months in
underwater decaying organic matter,112 it may be considered
that infection occurs at contaminated water contact sites. Seroepidemiological studies in Ghana and Cameroon have shown
that children are much earlier exposed to malaria parasites
than to M. ulcerans, indicating that an involvement of insect
vectors commonly found close to the households is highly
unlikely.91 Results of other studies have been compiled in a
conceptual model, where M. ulcerans, present in the aquatic
environment such as in detritus, mud, or plant biofilms, is concentrated by water-filtering organisms70,113 and subsequently
passed on to predatory aquatic vertebrates and invertebrates
feeding on this prey. Infection from potential environmental
reservoirs may take place via puncture wounds or lacerations
after contact with concentrated M. ulcerans sources or via
invertebrate vectors, such as aquatic insects.16,114,115
Disease burden for individuals and
households affected
In Africa, BU typically affects rural, impoverished populations with limited access to medical care. In addition to
geographical and financial constraints, beliefs and stigma
regarding the origin of the disease, as well as the often
slow progression of M. ulcerans infections combined with
an indolent course result in delayed reporting of patients.
According to the WHO classification, three stages of BU can
be distinguished: 1) category I lesions with a cross-sectional
diameter of less than 5 cm, 2) category II lesions with a size
of 5–15 cm, and 3) category III lesions with diameter more
than 15 cm as well as lesions at crucial sites (eye, breast, and
genitalia), multiple lesions, and osteomyelitis.18 Until today
only a minority of patients in Africa presents with category I
disease.72 In the past, the only treatment option has been wide
surgical excision of the affected tissue, followed by skin
grafting, demanding wound management, and rehabilitative
physiotherapy, if available.116 Major advances have been made
in the management of BU after 2004 with the introduction
of antibiotic therapy.117–119 However, while early stages of
the disease can usually be treated with an 8-week course of
streptomycin and rifampicin alone, a substantial proportion
of patients presents in many African settings with massive
necrotizing lesions, often necessitating adjunct surgery, skin
grafting, and prolonged hospitalization.
Research and Reports in Tropical Medicine 2015:6
epidemiology of Buruli ulcer
Debilitating sequelae resulting from the massive destruction of tissue and joints are socially stigmatizing and may
lead to a decreased quality of life. In hospitals of many BU
endemic countries, medical treatment is free of charge.
However, other expenditures such as costs for transportation,
feeding, or accommodation of patients and their caregivers
as well as indirect costs such as productivity loss often have
devastating implications on household economies. Even if
medical costs for hospital treatment and supplementary aid
for everyday needs were provided to BU patients and their
caretakers in a hospital in Central Cameroon, the median
cost burden of hospitalization was reported to be 25% of
household’s annual earnings due to high nonmedical costs
and productivity loss.120 In another study carried out in the
Ga West Municipality of Ghana, hospital-based treatment
of BU patients with ulcerative lesions resulted in a mean
loss of 265 productive workdays.121 For nonhospitalized BU
patients, transportation and other costs can be overwhelming.
A recent cost-of-illness study in the Ga South Municipality of
Ghana including 63 BU outpatients has shown that the mean
cost of BU treatment of US$570 constituted approximately
45% of the household annual income. It can be concluded
that impoverishment is likely among BU-affected African
households.122 Strategies to cope with the costs such as sale
of assets, borrowing of money, use of savings, reduction
of nonessentials and essentials, and the social isolation of
the patient have been described.120,121 In one study, it was
calculated that household costs were eight times higher for
households involved in the care of patients compared with
those for socially isolated patients.120 Therefore, new intervention strategies that are socially more compatible such as
a decentralized system of care are of urgent need.
Conclusion
Intensified research activities after the establishment of the
Global Buruli Ulcer Initiative by the WHO in 1998 have
yielded: 1) advances in the treatment and management of
the disease, 2) a better understanding of the pathogenesis of
BU and the origin and evolution of M. ulcerans, 3) various
hypotheses on potential reservoirs and modes of transmission, and 4) evidence for some more or less preventable risk
factors for contracting the disease. Research activities toward
the design of a BU vaccine have shown that in spite of the
extracellular localization of M. ulcerans, the development
of such a vaccine is a major challenge. Therefore, control
of BU still relies mainly on active case search and adequate
treatment of the patients coordinated by national BU control
programs established in several endemic countries.
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Röltgen and Pluschke
While in recent years a reduction of the worldwide
incidence of BU was noted, infection foci continue to exist,
particularly in remote, rural areas of West and Central Africa
and represent a considerable disease burden for the affected
populations. One of the main tasks for BU control will thus
be to maintain public awareness of this rare, but highly
debilitating disease and to sustain expertise to diagnose and
treat it among local health staff.
Globally, chronic skin conditions with diverse infectious and
noninfectious etiologies constitute a substantial public health
concern. In contrast to BU, some other neglected infectious diseases with cutaneous manifestations such as lymphatic filariasis,
onchocerciasis, yaws, and scabies can be simultaneously treated
through once-annual administration of an integrated package of
medicines.123 For BU, treatment regimens suitable for application at peripheral health centers should be further developed,
and the development of a point-of-care rapid diagnostic test to
avoid both over- and under-treatment is a key research priority.
BU and other tropical skin diseases share similarities in terms
of causing long-term disabilities, reinforcing poverty, and the
geographical distribution. There is great need for a robust integrated diagnostic and therapeutic approach for the management
of skin lesions at primary health care facilities of the resource
poor African BU endemic countries. BU control and research
activities should therefore be more efficiently integrated into
combined programs with other skin diseases.
Acknowledgments
The authors thank Kobina Ampah for creating the map of the
worldwide BU distribution with ArcGIS. Parental consent
was obtained for the use of the images in Figure 1.
Disclosure
The authors report no conflicts of interest in this work.
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