Buruli ulcer

Information gathered from scientific literature shows that Buruli ulcer has been reported in 33 countries in Africa, the Americas, Asia and the Western Pacific. Most cases occur in tropical and subtropical regions except in Australia, China and Japan. Out of the 33 countries 15 regularly report data to WHO.

The majority of cases are reported from West and Central Africa, including Benin, Cameroon, Côte d’Ivoire, Democratic Republic of the Congo and Ghana. In recent years Australia has been reporting a higher number of cases.

In 2015, 13 of the 15 countries that regularly report data to WHO reported nearly 2037 new cases. Except for a few countries, the number of cases has generally declined since 2010. The exact cause of decline is unknown.

The clinical and epidemiological aspects of cases vary considerably within and across different countries and settings.

In Africa, about 48% of those affected are children under 15 years, whereas in Australia, 10% are children under 15 years and in Japan, 19% are children under 15 years. No significant difference exists between the rates of affected males and affected females.

Lesions frequently occur in the limbs: 35% on the upper limbs, 55% on the lower limbs, and 10% on the other parts of the body.

In terms of severity, the disease has been classified into three categories: Category I single small lesion (32%), Category II non-ulcerative and ulcerative plaque and oedematous forms (35%) and Category III disseminated and mixed forms such as osteitis, osteomyelitis, joint involvement (33%). In Australia and Japan, most lesions (>90%) are diagnosed in Category I.

In all countries, at least 70% of all cases are diagnosed in the ulceration stage.

Mycobacterium ulcerans needs a temperature between 29–33 °C (Mycobacterium tuberculosis grows at 37°C) and a low 2.5% oxygen concentration to grow. The organism produces a unique toxin – mycolactone – which causes tissue damage and inhibits the immune response.

The exact mode of transmission of M. ulcerans is still unknown.

Buruli ulcer often starts as a painless swelling (nodule). It can also initially 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 during antibiotics treatment, the nodule, plaque or oedema will ulcerate within 4 weeks with the classical, undermined borders. Occasionally, bone is affected causing gross deformities.

Clinical

In most cases, experienced health professionals in endemic areas can make a reliable clinical diagnosis.

Depending on the patient’s age, the patient’s geographical area, the location of lesions, and the extent of pain experienced, other conditions should be excluded from the diagnosis. These other conditions include tropical phagedenic ulcers, chronic lower leg ulcers due to arterial and venous insufficiency (often in the older and elderly populations), diabetic ulcers, cutaneous leishmaniasis, extensive ulcerative yaws and ulcers caused by Haemophilus ducreyi¹.

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.

HIV infection is not a risk factor, but in co-endemic countries HIV infection complicates the management of the patient. The weakened immune system makes the clinical progression of Buruli ulcer more aggressive, and as a result the treatment outcomes are poor.

Due to international travel, cases can appear in non-endemic areas. It is therefore important that health workers are knowledgeable about Buruli ulcer and its clinical presentations.

Laboratory

Four standard laboratory methods can be used to confirm Buruli ulcer; IS2404 polymerase chain reaction (PCR), direct microscopy, histopathology and culture. PCR is the most commonly used method. WHO has recently published a manual on these 4 methods to guide laboratory scientists and health workers.

Treatment consists of a combination of antibiotics and complementary treatments (under morbidity management and disability prevention/rehabilitation). Treatment guidance for health workers can be found in the WHO publication "Treatment of mycobacterium ulcerans disease (Buruli ulcer)."

Antibiotics

Different combination of antibiotics given for 8 weeks are used to treat the Buruli ulcer irrespective of the stage. One of the following combinations may be used depending on the patient:

• a combination of rifampicin (10 mg/kg once daily) and streptomycin (15 mg/kg once daily); or
• a combination of rifampicin (10 mg/kg once daily) and clarithromycin (7.5 mg/kg twice daily) has been used. A randomized controlled trial concluded recruitment in 2016 and results expected in 2017.

For pregnant women, the combination of rifampicin and clarithromycin is considered the safer option because of contraindication to streptomycin.

In Australia, a combination of rifampicin (10 mg/kg once daily) and moxifloxacin (400 mg once daily) is routinely used with good results but its effectiveness has not been proven by randomized trial.

Morbidity management, disability prevention and rehabilitation

Interventions such as wound management and surgery (mainly debridement and skin grafting) are used to speed up the healing thereby shortening the duration of hospitalization. In addition, physiotherapy is needed in severe cases to prevent disability. Those who are left with disability require long-term rehabilitation. These same interventions are applicable to other neglected tropical diseases, such as leprosy and lymphatic filariasis so it is important to integrate a long-term care approach into the health system to benefit all patients.

There are currently no primary preventive measures that can be applied. The mode of transmission is not known and there is no vaccine.

The objective of Buruli ulcer control is to minimize the suffering, disabilities and socioeconomic burden. Early detection and antibiotic treatment is the cornerstone of the WHO Buruli ulcer control strategy.

There are 2 ongoing research activities aimed to improve the management of the disease.

1. Development of oral antibiotic treatment

A randomized clinical trial coordinated by WHO started in Benin and Ghana in 2013 with the objective of developing an oral-based treatment for Buruli ulcer. The recruitment was completed at the end of 2016 and the one-year follow-up will end in December 2017.

2. Validation of fluorescent thin layer chromatography as point of care test

Preliminary results from the initial analysis of patients’ samples, using the fluorescent thin layer chromatography method to detect mycolactone, has shown great potential for a rapid diagnosis at district-level health facilities. In collaboration with the Foundation for Innovative New Diagnostics (FIND), Geneva, Switzerland, and Harvard University, a field evaluation of the method started in 2016 in Benin, Democratic Republic of the Congo, and Ghana. The study will be completed in 2017.

WHO provides technical guidance, develops policies, and coordinates control and research efforts. WHO brings together all major actors involved in Buruli ulcer on a regular basis to share information, coordinate disease control and research efforts, and monitor progress.

These efforts have also helped to raise the visibility of Buruli ulcer, and mobilized resources to fight it. Under WHO’s leadership and with support of nongovernmental organizations, research institutions and governments of affected countries, steady and impressive progress has been made.

Mitjà, O et al. Haemophilus ducreyi as a cause of skin ulcers in children from a yaws-endemic area of Papua New Guinea.
Lancet Global Health: 2014; Vol 2, Issue 4: e235 - e241.