Buruli ulcer, caused by Mycobacterium ulcerans is a chronic debilitating disease that affects mainly affects the skin and sometime bone. The organism belongs to the family of bacteria that causes tuberculosis and leprosy and provide an opportunity for collaboration with these 2 disease programmes. However, M. ulcerans is an environmental bacterium and the mode of transmission to humans remains unknown. Currently, early diagnosis and treatment are crucial to minimizing morbidity, costs and prevent long-term disability.
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 annual number of suspected Buruli ulcer cases reported globally was around 5000 cases up until 2010 when it started to decrease until 2016, reaching its minimum by 1961 cases reported. Since then, then number of cases has started to rise again every year up to 2713 cases in 2018. The reasons for the decline and for the recent increase in not clear (1).
In Africa, the majority of cases are reported from West and Central Africa, including Benin, Cameroon, Côte d’Ivoire, Democratic Republic of the Congo, Nigeria and Ghana. Liberia has recently started to report large number of suspected cases, while Côte d’Ivoire which used to report the highest number of cases in the world (2242 cases in 2008) reported only 261 cases in 2018. Outside Africa, the Australia remains a major endemic country where cases have been reported since 1930s.
Clinical and epidemiological characteristics of cases
The clinical and epidemiological aspects of cases vary considerably within and across different countries and settings. In Africa, for example, about 48% of those affected are observed to be children under 15 years, whereas in Australia, 10% are children under 15 years and in Japan, 18% are children under 15 years. No significant difference exists between the rates of affected males and affected females. In Africa slightly more males are affected before the age of 20 and more females after the age of 20.
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 as other causes of ulceration such as diabetes, arterial and venous insufficiency lesion especially in people over 40 years should be carefully made.
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. Since 2013, severe cases are being reported in Australia and it is unclear the reasons for this observation. In all countries, at least 70% of all cases are diagnosed in the ulceration stage.
Causative organism
Mycobacterium ulcerans grows at temperatures 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.
Transmission
The exact mode of transmission of M. ulcerans is still unknown.
Signs and symptoms
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.
Diagnosis
Clinical
In most cases, experienced health professionals in endemic areas can make a reliable clinical diagnosis but training is essential.
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 ducreyi.
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. A simple method developed by researchers at Harvard University in USA using fluorescent thin-layer chromatography to selectively detect mycolactone (2) can provide rapid results in the field and it has been evaluated in Benin, the Democratic Republic of the Congo and Ghana (3).
Treatment
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
The preliminary results of a randomized controlled trial concluded in 2017 shows no difference in cure rates between the two treatments implying that a combination of rifampicin and clarithromycin can now be used to treat patients. Full results expected to be published this year. Moreover, this combination is also safe for pregnant women.
On the basis of this study, 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 by randomized trial.
Morbidity management, disability prevention and rehabilitation
Interventions such as wound and lymphoedema 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 which can be integrated into other rehabilitation activities. 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. The integrated approach to the control of skin-related NTDs provides an opportunity to integrate Buruli ulcer detection and its management with these diseases.
Prevention
There are currently no primary preventive measures that can be applied. The mode of transmission is not known. Bacillus Calmette–Guérin (BCG) vaccination appears to provide a limited protection.
Control
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.
Research priorities
There are three key research priorities for Buruli ulcer:
1. Mode of transmission
The recent increase in the number of cases in Australia has highlighted the urgency to understand the mode of transmission so that preventive measures can be taken. Despite extensive research over the past decade, the mode of transmission remains unclear.
2. Development of rapid diagnostic tests
In March 2018, WHO and Foundation for Innovative New Diagnostics (FIND) organized a meeting to assess progress in the development of rapid diagnostic test for Buruli ulcer. The meeting agreed on further work to target mycolactone as a diagnostic test, including improvements to the fluorescent thin-layer chromatography technique, currently being piloted in selected countries. Other methods such as LAMP are also being evaluated (4).
3. 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 final results will be published in 2019. Further research is needed to determine whether the duration of treatment can be reduced so Category 1 and 2 cases. New TB medicines are also being evaluated for Buruli ulcer treatment and can possibly feed into research to reduce the duration of treatment (5).
WHO and global 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.
These efforts have also helped to raise the visibility of Buruli ulcer, and mobilized resources to fight it. The implementation of the skin-NTD approach is expected to help maximize case detection for a number of diseases and bring efficiency in utilization of resources.
(1) Loftus M et al. Epidemiology of Buruli Ulcer Infections, Victoria, Australia, 2011–2016
Emerging Infectious Diseases: 2018, Vol. 24, No. 11: 1988-1997
(2) Converse P et al. Accelerated Detection of Mycolactone Production and Response to Antibiotic Treatment in a Mouse Model of Mycobacterium ulcerans Disease
PLOS Neglected Tropical Diseases: 2014, Vol. 8, Issue 1:1-6
(3) Wadagni A et al. Simple, Rapid Mycobacterium ulcerans Disease Diagnosis from Clinical Samples by Fluorescence of Mycolactone on Thin Layer Chromatography
PLOS Neglected Tropical Diseases: 2015: 1-8
(4) Frimpong M et al. Rapid detection of Mycobacterium ulcerans with isothermal recombinase polymerase amplification assay
PLOS Neglected Tropical Diseases: 2019: 1-14
(5) Scherr N et al. Targeting the Mycobacterium ulcerans cytochrome bc1:aa3 for the treatment of Buruli ulcer
Nature communications: 2018, 9:5370: 1-9