Buruli ulcer
(Mycobacterium ulcerans infection)
Key facts
- Buruli ulcer is a chronic debilitating skin and soft tissue infection that can lead to permanent disfigurement and disability.
- It is caused by the Mycobacterium ulcerans bacterium.
- At least 33 countries with tropical, subtropical and temperate climates have reported Buruli ulcer.
- Between 5000–6000 cases are reported annually from 15 of the 33 countries.
- Most cases occur in rural communities in sub-Saharan Africa.
- Nearly half of people affected in Africa are children under 15.
- 80% of cases detected early can be cured with a combination of antibiotics.
Buruli ulcer is a neglected tropical disease. It is caused by infection with Mycobacterium ulcerans, an organism which belongs to the family of bacteria that causes tuberculosis and leprosy.
Infection leads to destruction of skin and soft tissue with large ulcers usually on the legs or arms. Patients who are not treated early suffer long-term functional disability like restricted joint movement and noticeable cosmetic problems. Early diagnosis and treatment are vital in preventing such disabilities.
Scope of the problem
Buruli ulcer has been reported in 33 countries in Africa, the Americas, and the Western Pacific. The majority of cases occur in tropical and subtropical regions, although, cases have been reported in Australia, China, and Japan.
Most cases are from West Africa notably Benin, Côte d’Ivoire and Ghana. Côte d’Ivoire is the most affected country reporting over 2500 cases per year. Globally, between 5000–6000 cases are reported every year from 15 of the 33 countries but considerable under-reporting exists within countries.
Clinical and epidemiological characteristics of cases
The clinical and epidemiological aspects of cases vary (according to geographic area) from different countries and settings. Differences largely depend on the demographical characteristics of the population, level of endemicity and awareness about the disease, extent of active detection efforts, and accessibility to treatment.
In Africa, the majority of patients are children compared to Australia and Japan where most patients are adults (Table I). The sex distribution in Africa and Australia is the same but it appears that more females are affected in Japan (Table II). In general, most lesions occur on exposed parts of the body, particularly the limbs (Table III). The lesions are more frequent on the lower limbs in Africa and Australia compared to Japan.
Table I. Age distribution in years
| <15 years | Mean | Median | Range | |
| Africa | 48% | 24 | 15 | 0.5–90 |
| Australia | 10% | 50 | 62 | 1–96 |
| Japan | 19% | 41 | 48 | 2–81 |
Table II. Sex distribution
| Males | Females | |
| Africa | 52% | 48% |
| Australia | 55% | 45% |
| Japan | 34% | 66% |
Table III. Location of lesions
| Upper limb | Lower limb | Other parts of the body | |
| Africa | 25% | 63% | 11% |
| Australia | 31% | 64% | 5% |
| Japan | 50% | 38% | 13% |
Causative organism
M. ulcerans needs a temperature between 29–33 °C (M. tuberculosis grows at 37 °C) and a low (2.5%) oxygen concentration to grow. The organism produces a destructive toxin – mycolactone – which causes tissue damage and inhibits the immune response.
Transmission
The disease is usually found in communities near rivers, swamps and wetlands. Human-linked environmental changes such as deforestation, construction of dams and irrigation systems, sand mining, surface mining of minerals, and agriculture have been linked to the occurrence or exacerbation of the disease.
The exact mode of transmission of M. ulcerans is still unknown. However, it appears that different modes of transmission occur in different geographic areas and epidemiological settings. There may be some role for living agents as reservoirs and as vectors of M. ulcerans, in particular aquatic insects, adult mosquitoes or other biting arthropods.
In south-eastern Australia for example, there is growing evidence that mosquitoes may be involved in the transmission cycle. Recently, Australian scientists discovered high levels of M. ulcerans DNA in the faeces of common ringtail and common brushtail possums collected in endemic areas. However, studies done in Africa on small mammals in endemic areas did not find any M. ulcerans.
Buruli ulcer in wild and domestic animals
In Victoria, Australia, Buruli ulcer also occurs in native wildlife and domestic animals. Laboratory-confirmed cases have been diagnosed in koalas, common ringtail possums, a common brushtail possum, a mountain brushtail possum, a long-footed potoroo, horses, dogs, alpacas and a cat.
Signs and symptoms
Buruli ulcer often starts as a painless, swelling (nodule). It can initially also present as a large painless area of induration (plaque) or a diffuse painless swelling of the legs, arms or face (oedema). Local immunosuppressive properties of the mycolactone toxin enable the disease to progress with no pain and fever. Without treatment or sometimes even during antibiotics treatment, the nodule, plaque or oedema will ulcerate within four weeks with the classical, undermined borders. Occasionally, bone is affected causing gross deformities.
Clinical forms and categories
There are two ways of recording and classifying the disease. The first way is the clinical form of disease: non-ulcerative (nodule, plaque and oedema) versus ulcerative (Table IV). The second way is based on the size of the lesion (Table V). Category I lesions are < 5 cm in diameter; Category II lesions are between 5–15 cm and Category III lesions are above 15 cm.
Table IV. Clinical forms
| Non-ulcerative | Ulcerative | |
| Africa | 26% | 74% |
| Australia | 13% | 87% |
| Japan | 6% | 94% |
Table V. Categories of lesions
| Category I | Category II | Category III | |
| Africa | 32% | 35% | 33% |
| Australia | 90% | 5% | 5% |
| Japan | 81% | 19% | 0% |
The second classification was introduced following the implementation of antibiotic treatment in 2004 to provide a better appreciation of early detection efforts and how lesions would respond to antibiotic treatment.
Diagnosis
There is no diagnostic test that can be used in the field. Research is in progress to develop one.
Four standard laboratory methods can be used to confirm Buruli ulcer1. IS2404 polymerase chain reaction (PCR) is the main method for confirmation because it has the highest sensitivity and results can be available within 48 hours.
WHO recommends that at least 50% of cases reported should be confirmed by PCR. Due to logistical and operational difficulties, results of laboratory confirmation by PCR are not immediately available. However, in experienced hands, clinical diagnosis may be sufficient to make decisions about treatment. A WHO network comprising 16 laboratories2 in 13 endemic and non-endemic institutions support national control programmes to implement this recommendation.
Depending on the patient’s age, location of lesions, pain, and geographic area, other conditions should be excluded from the diagnosis. These include tropical phagedenic ulcers, chronic lower leg ulcers due to arterial and venous insufficiency (often in the older and elderly populations), diabetic ulcer; cutaneous leishmaniasis, extensive yaws. Early nodular lesions are occasionally confused with boils, lipomas, ganglions, lymph node tuberculosis, onchocerciasis nodules or other subcutaneous infections such as fungal infection. In Australia, papular lesions may initially be confused with an insect bite. Cellulitis may look like oedema caused by M. ulcerans infection but in the case of cellulitis, the lesions are painful and the patient is ill and febrile.
Treatment
Current treatments3 for Buruli ulcer are:
1. Antibiotics kill M. ulcerans bacilli, stop further production of mycolactone, arrest the progression of the disease, and promote healing. The following combinations of antibiotics for eight weeks may be used to treat the disease:
- Rifampicin (10 mg/kg once daily) and streptomycin (15mg/kg once daily) (standard treatment and effectiveness proven by a randomised controlled trial); or
- Rifampicin (10 mg/kg once daily) and clarithromycin (7.5 mg/kg twice daily) has been used but effectiveness not proven by a randomized trial. Since streptomycin is contraindicated in pregnancy, the combination of rifampicin and clarithromycin is also considered the safer option for this group of patients.
- Rifampicin (10 mg/kg once daily) and moxifloxacin (400 mg once daily) in adults has also been used, though effectiveness not proven by randomized trial.
2. Complementary treatment such as wound care, surgery (mainly debridement and skin grafting) and interventions to minimize or prevent disabilities are necessary depending on the stage of the disease.
If cases are detected early (Category I), more than 80% of people will heal without the need for hospitalization, surgery and without any disability.
Recurrence of Buruli ulcer after antibiotic treatment is less than 2% compared to 16–30% for surgical treatment alone. In cases where surgery is needed, the extent of surgical removal is reduced after antibiotic treatment.
The average cost of drugs for the 2-month treatment of a patient is 45 Euros or US$ 60.
Paradoxical reaction
Paradoxical reactions have been recently recognized during or after antibiotic treatment when there is new inflammatory disease (presenting as a nodule, plaque or oedema) leading to extension of the existing ulcer, increased local induration or a new lesion on a different part of the body, usually, with pus formation and pain. Sometimes, these are also seen in parts of the body where there was no evidence of disease prior to antibiotic treatment; this may be a result of subclinical infection. These seem to be triggered by mycobacterial antigens and immunostimulators released from clinically unrecognized bacterial foci.
Buruli ulcer and HIV
Until now, coinfection of HIV and Buruli ulcer has not been adequately investigated. However, currently available data on frequency of coinfection suggests this is an area of increasing concern. A study conducted from 2002–2003 found that HIV prevalence among patients with Buruli ulcer was higher (2.6%, 11/426) than among controls (0.3%, 2/613). In Benin, 6 (3.6%) out of 156 patients treated at Pobé Buruli Ulcer Treatment Center in 2006 were positive for HIV, and in 2010, 2 (1.5%) out of 135 patients were HIV positive. In the Akonolinga hospital, Cameroon, systematic HIV screening of all newly-hospitalized patients was introduced in 2008. Out of 60 adults tested, 20 were HIV positive (33%). However, as only Buruli ulcer adult patients with major lesions were tested, there is a bias in this estimate. The prevalence of HIV in Cameroon in 2008 was 5%. Most reported co-infected patients are females.
HIV weakens the immune system, making Buruli ulcer progress more aggressive and possibly affects the response to antibiotic treatment. Co-infected patients are often adults (>15 years old) who present with multifocal lesions and osteomyelitis.
Although further studies are required to improve our understanding of this issue, the management of Buruli ulcer/HIV co-infection may follow the guidelines for managing TB/HIV co-infection.
- HIV counselling and testing should be offered for all patients presenting with BU.
- Buruli ulcer/HIV co-infected patients should be screened for tuberculosis.
- For TB, Buruli ulcer/HIV co-infected patients may receive early antiretroviral treatment to ensure a better response to treatment.
Prevention
There is no vaccine for primary prevention of Buruli ulcer. Bacille Calmette–Guérin (BCG) vaccination appears to offer some short-term protection from the disease.
Secondary prevention is based on early detection of cases.
Control
The objective of Buruli ulcer control is to minimize the suffering, disabilities and socioeconomic burden.
The strategy is based on early detection and antibiotic treatment. The following activities are essential for implementing this strategy:
- information, education and communication at the community level to enhance early reporting;
- training of health workers and village volunteers;
- laboratory confirmation of cases;
- standardized recording and reporting system and mapping;
- strengthening of health facilities;
- monitoring and evaluation of control activities.
WHO has developed technical and information materials to support the implementation of these activities.
Research priorities
Based on the need to improve control measures in the field, there are three main priorities for BU research:
- improvements in antibiotic treatment
- development of simple diagnostic tests
- deciphering the mode of transmission.
Basic and applied research is necessary to achieve these priorities.
WHO and global response
WHO provides technical guidance, develops policies and coordinates control and research efforts.
WHO convenes all major actors involved in Buruli ulcer on a regular basis which provides an opportunity to share information, coordinate disease control and research efforts, and monitor progress. These efforts have helped to raise the visibility of Buruli ulcer, and mobilized resources to fight it.
Under WHO’s leadership and with support of non-governmental organizations, research institutions and governments of affected countries, steady and impressive progress has been made, changing the face of Buruli ulcer from a devastating, debilitating and difficult disease to one that can be treated and cured.
1Guidance on sampling techniques for laboratory of Mycobacterium ulcerans infection (Buruli ulcer disease)
2Laboratory network
3Treatment of Mycobacterium ulcerans disease (Buruli ulcer) : guidance for health workers 2012 (in press)