Wednesday, December 10, 2008
Buruli ulcers illustrate the importance of skin infections among
public health concerns in developing countries. The disease is due
to skin and soft tissue invasion by Mycobacterium
ulcerans. It is seldom lethal by itself, but highly
destructive, leading to extensive tissue loss that causes severe
functional, aesthetic, psychological and socioeconomical
disabilities. Although it has been recognized for more than one
century, Buruli ulcers only got sufficient interest from the
medical community and health authorities after a solemn commitment
of the World Health Organization in 19981. The following
ten years were marked by substantial progress in the basic
knowledge of M. ulcerans, as well as the development of
diagnostic and therapeutic tools for this time-neglected
The genome sequence of Mycobacterium ulcerans has now
been completely determined3. The micro-organism is
closely related to M. marinum, with a unique
distinguishing feature: it produces mycolactones, a family of
macrolide toxins. Mycolactones are responsible for microbial
invasion and tissue necrosis; they inhibit the immune and
inflammatory responses to the mycobacteria and seem crucial to the
painlessness that typically characterizes the infected soft
tissues4. The unequal virulence properties of various
strains of M. ulcerans (eg, less aggressivity of the
Australian strains compared with the African ones) probably lies on
their distinct patterns of mycolactone
Epidemiology and transmission
Buruli ulcer owes its name to a pocket of infection that took
place during the 1960s in the district of Nakasongola, formerly
known as Buruli county, in Uganda. Indeed, most cases come from
Western and Central sub-Saharan Africa. About 1000 to 2000 cases
are reported annually from each of the three main endemic areas:
Ivory Coast, Benin, and Ghana1. The global prevalence of
Buruli ulcer is approximately 20 in 100,000 in these countries but
can reach up to 16% in some villages6. In addition, the
disease has been observed in at least 30 tropical or subtropical
countries in Africa, Central and South-America, South-East
Asia7 and Australasia. As Buruli ulcer has only
recently gained real attention from the health authorities,
it is difficult to comment about a hypothetic increase in its
prevalence; the disease is probably under-reported and a new
endemic focus may still be disclosed in the future. The only
involved temperate area is the state of Victoria in Australia,
including the city of Bairnsdale where M. ulcerans was
first recovered from a patient in 1948.
About half of the patients are children between 5 and 15 years
of age, without gender predilection. The disease is focally
distributed in small clusters, but there is no case of human to
human transmission. Actually, living near stagnant or slow-flowing
water appears to represent the main risk factor1,2.
Indirect evidence for the presence of M. ulcerans in
aquatic environments was brought about by molecular analysis of
water, sediments, plants and small animals. In particular, the
micro-organism has the ability to invade the salivary glands of
carnivorous water bugs and the biofilm surrounding their feeding
pincers, which then infect mice that have been bitten by these
insects2. In Australia, the possibility of mosquito
bites being involved in the transmission of M. ulcerans to
humans has been suggested8,9. Finally, environmental
M. ulcerans was first cultivated and characterized from a
water bug of Gerrida sp. (a kind of insect that does not usually
bite humans) gathered in Benin10. As attractive as the
insect bite hypothesis may seem, prolonged contact of the skin with
contaminated muddy fields1 could be involved as well. In
summary, the route of M. ulcerans transmission from the
aquatic environment to the human, and its potential reservoirs,
remains to be elucidated1,11.
Buruli ulcer typically begins as a single painless mobile
subcutaneous nodule that is usually located on the lower or upper
limbs, but may arise on any part of the integument. Less typical
cases present as a diffuse non-inflammatory (cold) edema, plaques
or multiple papules. The lesion then breaks down to form an ulcer
that slowly enlarges, giving the characteristic appearence of a
wide loss of substance with deep undermined edges. There is usually
no fever and no pain; however, pain may occur, especially in
cases of bacterial superinfection. The necrosis of the soft tissues
progresses for months and years and sometimes reaches the
underlying bone or joint, or even more critical organs such as the
eyes or genitalia. Systemic infection, malnutrition and even
squamous cell carcinoma may complicate the course of the disease.
Spontaneous healing occurs after months or years, leaving fibrotic
scars that compromise the function of the affected organ or
The risk and severity of M. ulcerans depends on several
factors. A potential aggravating role for HIV co-infection has been
debated1,6; in Benin, the prevalence of HIV
seropositivity appears to be higher in patients with Buruli ulcer
than in a control group12.
In many developing countries, the positive diagnosis of Buruli
ulcer mostly relies on physical examination. Direct microscopic
examination of smears from ulcer swabs or skin biopsies
(Ziehl-Neelsen stain) is the most available laboratory test, but
lacks sensitivity. Swabs and biopsies may allow the growth of
M. ulcerans at 30-33°C in a Löwenstein-Jensen medium;
however, the procedure is costly and usually takes 6 to 8 weeks.
Histological examination of a tissue biopsy is credited with a 90%
sensitivity. Polymerase Chain Reaction (PCR), with amplification of
the characteristic IS2404 repetitive sequence of M.
ulcerans DNA, is even more sensitive and highly specific, and
gives fast results in less than 24 hours. However, PCR and
histology are usually unavailable or difficult to implement in the
field. The development of new diagnostic tools that can be used in
endemic areas is now a priority for researchers1,6.
Differential diagnosis depends on the stage and type of lesion.
Various infectious diseases may be considered: soft tissue
tuberculosis; deep mycosis; and benign or malignant
Although M. ulcerans has been shown to be susceptible
in vitro to a variety of antibiotics14, the
treatment has long been exclusively based on a wide surgical
excision, which is still mandatory in most ulcerated
lesions1,6. Prolonged stays in hospital,
physiotherapy, long-lasting wound dressings and other nursing care
are frequently required after surgery.
Promising preliminary results were obtained with a 4- to 12-week
regimen of oral rifampicin (10 mg/kg/day) combined with
intramuscular streptomycin (15 mg/kg/day) in 16 out of 21 patients
with early lesions (diameter <10 cm)15. These
results, together with in vitro studies, prompted the
World Health Organization to publish guidelines for a systematic
first-line medical treatment for 8 weeks for these antibiotics. An
open-label trial of this treatment in Benin (n = 224) showed an
elevated cure rate of 47% with antibiotics alone, especially for
early lesions (< 5 cm diameter), and also suggested a protective
effect against recurrence after surgical excision in more advanced
stages16. This regimen remains to be accurately
evaluated in comparison to other antimicrobial agents. There are
also some concerns regarding the risk of selecting resistant
strains of M. tuberculosis with rifampicin therapy, the
choice of a parenteral route of administration in the setting of
HIV endemics and the long-term tolerance of
streptomycin6. Finally, the potential role of heparin in
improving antibiotic penetration at the lesional site should also
Neither environmental nor individual preventive measures can yet
be defined, because the mode of transmission of M.
ulcerans to human and its potential intermediary hosts
are still largely unknown. However, public information and
education remain critical, especially for an early diagnosis
of the disease, which may allow a medical cure with
limited, if any, residual disabilities. A good understanding of the
knowledge, beliefs and attitudes of exposed populations towards
Buruli ulcer is mandatory for targeting information
It appears that BCG vaccination may offer a moderate protection
against M. ulcerans infection1,6,17. However, a
more efficient vaccine would provide an essential advance in the
control of the disease.
Public health measures against Buruli ulcer are still waiting
for a precise understanding of the way in which humans get infected
by this organism from the environment. Nevertheless, dramatic
progress has been made since 1998 in the comprehension and
management of this disease, bringing hope for hundreds of thousands
of children around the world. In particular, sequencing the entire
genome of the micro-organism could now allow the development of
specific treatments or vaccines17 targeted against
mycolactones or other components of M. ulcerans.
- Anonymous. Buruli ulcer: progress report, 2004-2008. Wkly
Epidemiol Rec 2008;83(17):145-54.
- Wansbrough-Jones M, Phillips R. Buruli ulcer: emerging from
- Stinear 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(2):192-200.
- En J, Goto M, Nakanaga K, Higashi M, et al.
Mycolactone is responsible for the painlessness of Mycobacterium
ulcerans infection (buruli ulcer) in a murine study. Infect
- van der Werf TS, Stinear T, Stienstra Y, et al.
Mycolactones and Mycobacterium ulcerans disease. Lancet.
- Sizaire V, Nackers F, Comte E, Portaels F. Mycobacterium
ulcerans infection: control, diagnosis, and treatment. Lancet
Infect Dis. 2006;6(5):288-96.
- Nakanaga K, Ishii N, Suzuki K, et al.
"Mycobacterium ulcerans subsp. shinshuense" isolated from a skin
ulcer lesion: identification based on 16S rRNA gene sequencing.
- Johnson PD, Azuolas J, Lavender CJ, et
al. Mycobacterium ulcerans in mosquitoes captured during
outbreak of Buruli ulcer, southeastern Australia. Emerg Infect
- Quek TY, Athan E, Henry MJ, et al. Risk factors for
Mycobacterium ulcerans infection, southeastern Australia. Emerg
Infect Dis. 2007;13(11):1661-6.
- Portaels F, Meyers WM, Ablordey A, et al. First
cultivation and characterization of Mycobacterium ulcerans from the
environment. PLoS Negl Trop Dis.
- Stinear T, Johnson PD. First isolation of Mycobaterium ulcerans
from an aquatic environment: The end of a 60-year search? PLoS
Negl Trop Dis. 2008;2(3):e216.
- Johnson RC, Nackers F, Glynn JR, et al. Association of
HIV infection and Mycobacterium ulcerans disease in Benin.
- Kanga JM, Kacou ED, Kouamé K, et al. La lutte contre
l'ulcère de Buruli. Expérience de la Côte d'Ivoire. Bull Soc
Pathol Exot. 2006;99(1):34-8.
- Ji B, Chauffour A, Robert J, Jarlier V. Bactericidal and
sterilizing activities of several orally administered combined
regimens against Mycobacterium ulcerans in mice. Antimicrob
- Etuaful S, Carbonnelle B, Grosset J, et al. Efficacy
of the combination rifampin-streptomycin in preventing growth of
Mycobacterium ulcerans in early lesions of Buruli ulcer in humans.
Antimicrob Agents Chemother.
- Chauty A, Ardant MF, Adeye A, et al. Promising
clinical efficacy of streptomycin-rifampin combination for
treatment of Buruli ulcer (Mycobacterium ulcerans disease).
Antimicrob Agents Chemother.
- Tanghe A, Dangy JP, Pluschke G, Huygen K. Improved protective
efficacy of a species-specific DNA vaccine encoding
mycolyl-transferase Ag85A from Mycobacterium ulcerans by homologous
protein boosting. PLoS Negl Trop Dis.