Buruli ulcer

**Buruli ulcer** is an infectious disease caused by bacteria. These bacteria are related to the ones that cause leprosy and those that cause tuberculosis. The disease can be found in tropical regions, but is not limited to the tropics. It is common in Africa, Southeast Asia and Australia. Currently, it is unknown in what way the disease spreads. It often occurs in rural areas close to swamps, rivers, or lakes. For this reason, vector organisms such as mosquitoes appear likely. However, M. ulcerans is an environmental bacterium and produces unique toxin – mycolactone. The way it transfers to humans remains unknown. Currently, early diagnosis and treatment are crucial to minimizing death, costs and prevent long-term disability.

There are different forms of therapy: the most common one is a combination of two or three different drugs and removing the affected tissue. Simple tissue removal works best when no ulcers have formed yet. The bacterium cannot live in temperatures above 40 °C. For this reason, some forms of therapy have included heating the affected skin parts above 40°C. This will kill the bacteria. First attempts suggest that after killing the bacteria, the ulcer will heal in several cases. Even 18 months after the treatment, the disease no longer shows. This means that the method can be tested on more people.

## Scope of the problem

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, 14 regularly report data to WHO.
The yearly number of suspected Buruli ulcer cases reported globally was around 5000 cases until 2010. Then, it started to decrease until 2016, reaching its minimum with 1961 cases reported. Since then, the number of cases has started to rise again every year, up to 2713 cases in 2018. In 2020 1258 cases were reported compared with 2271 cases in 2019. The decrease in 2020 might be connected to Covid-19 decreasing how often new cases are found.

## Transmission

Mycobacterium ulcerans grows at temperatures between 29–33 °C (Mycobacterium tuberculosis grows at 37 °C) and needs a low (2.5%) oxygen concentration. 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.

## Signs and symptoms

Buruli ulcer often starts as a painless swelling in a particular place (nodule), a large painless area of induration (plaque) or a painless swelling over a large area of the legs, arms or face (oedema). The disease may progress with no pain and fever. Without treatment or sometimes during antibiotics treatment, the nodule, plaque or oedema will ulcerate within 4 weeks. Bone is occasionally affected, causing deformities.
The disease has been classified into three categories of severity: 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 and joint involvement (33%).
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. Health workers should be careful in the diagnosis of Buruli ulcer in patients with lower leg lesions to avoid confusion with other causes of ulceration such as diabetes, arterial and venous insufficiency lesion.

## Diagnosis

In most cases, experienced health professionals in the areas Buruli ulcers are common can make a reliable clinical diagnosis but training is essential.

Differential diagnoses of Buruli ulcer include tropical phagedenic ulcers, chronic lower leg ulcers due to arterial and venous insufficiency (often in elderly populations), diabetic ulcers, cutaneous leishmaniasis, extensive ulcerative yaws and ulcers caused by Haemophilus ducreyi.
Early nodular lesions may be confused with boils, lipomas, ganglions, lymph node tuberculosis, onchocerciasis nodules or deep fungal subcutaneous infections.

In Australia, papular lesions may at first be confused with an insect bite.
HIV infection complicates the management of the patient, making clinical progression more aggressive and resulting in poor treatment outcomes. WHO has published a technical guide to help clinicians in the management of co-infection.

Four standard laboratory methods can be used to confirm Buruli ulcer: IS2404 polymerase chain reaction (PCR), direct microscopy, histopathology and culture.
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.

In 2019, WHO established the Buruli ulcer Laboratory Network for Africa 2 to help strengthen PCR confirmation in 9 endemic countries in Africa. 13 laboratories participate in this network - supported by the American Leprosy Missions, Anesvad, Raoul Follereau Foundation and the Foundation for Innovative Diagnostic and coordinated by the Pasteur Center of Cameroon.
In 2021, WHO completed on online consultation for  a draft document on Target Product Profiles3 to develop rapid test for the diagnosis of Buruli ulcer.

~~The final document to be published in 2022 will guide manufacturers in the development of appropriate diagnostic tests. With the availability of simple oral treatment for Buruli ulcer, a rapid test to allow early confirmation of diagnosis can facilitate the timely management of the disease. The turnaround time of a PCR test is too long.~~

## Treatment

Treatment consists of a combination of antibiotics and complementary treatments. Treatment guidance for health workers can be found in the WHO publication Treatment of mycobacterium ulcerans disease (Buruli ulcer).

A recent study suggests the combination of rifampicin (10 mg/kg once daily) and clarithromycin (7.5 mg/kg twice daily) is now the recommended treatment.

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.

Efforts to shorten the duration of treatment are in progress involving two studies:
- Telacebec is a new anti-tuberculous drug developed by a Korean company Qurient.4 The drug has demonstrated extreme potent activity against Mycobacterium ulcerans in animal studies5, reducing treatment duration from 8 to 2 weeks. In January 2021, the US Food and Drug Administration granted orphan drug designation (ODD) to Telacebec, a Buruli ulcer treatment. A clinical trial is being planned to evaluate the drug in patients.

- A clinical trial comparing the standard treatment of the combination of rifampicin and clarithromycin for 8 weeks and standard treatment plus amoxicillin/clavulanate for 4 weeks.

Interventions such as wound and lymphoedema management and surgery (mainly debridement and skin grafting) are used to speed up healing, thereby shortening the duration of hospitalization. Physiotherapy is needed in severe cases to prevent disability. Those left with disability require long-term rehabilitation. These same interventions are applicable to other neglected tropical diseases, such as leprosy and lymphatic filariasis.

## Prevention and control

There are currently no primary preventive measures for Buruli ulcer. The mode of transmission is not known. Bacillus Calmette–Guérin (BCG) vaccination appears to provide limited protection.

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

These are the core indicators to measure the progress in the control of Buruli ulcer;
- Proportion of cases in category III (late stage) at diagnosis
- Proportion of laboratory-confirmed1 cases
- Proportion of confirmed cases who have completed a full course of antibiotic treatment

## WHO response

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.

WHO supports worked towards three research priorities:
- understand the mode of transmission.
- develop rapid diagnostic tests.
- establish best-case antibiotic treatments.
To ensure efficiency, sustainability and scale, WHO recommends that Buruli ulcer control should be integrated within skin NTDs approach adapted to the diseases present in a particular country. WHO has developed a Skin App to assist health workers in the field in the diagnosis of skin NTDs including Buruli ulcer.