Buruli ulcer - Management of Mycobacterium ulcerans disease
Introduction
Key points
- About 70% of those infected with Buruli ulcer are children under 15 years old.
- In Ghana the average cost to treat Buruli ulcer is over US$ 780 per person.
- The accepted current treatment for Buruli ulcer is usually surgery.
In 1998, the World Health Organization (WHO) established the Global Buruli Ulcer Initiative (GBUI) in response to the growing spread and impact of Buruli ulcer, Mycobacterium ulcerans disease. The disease exists or has been suspected in at least 31 countries (Fig. 1). The primary objectives of the GBUI are: to raise awareness of the disease, to mobilize support for affected countries, to promote and to coordinate research activities and to coordinate the work of nongovernmental organizations (NGOs) and other partners. A summary of the achievements of the GBUI is presented in Annex 12.
In 1897, Sir Albert Cook in Uganda described skin ulcers consistent with Buruli ulcer but he did not publish these cases in the medical literature. In 1948, MacCallum et al. published the first confirmed cases of the disease. These patients were in Australia. The disease was called Bairnsdale ulcer after the main town in the original endemic region. In southeastern Australia, the disease is still often referred to as Bairnsdale ulcer but, in parts of Africa, it is called “Buruli ulcer”, the name coming from a county in Uganda where large numbers of cases were reported in the 1950s.
It is called “Buruli ulcer”, the name coming from a county in Uganda where cases were reported in the 1950s.
Epidemioliogy and transmission
After tuberculosis and leprosy, Buruli ulcer is the most common mycobacterial infection of humans. It is caused by Mycobacterium ulcerans. The disease often occurs in people who live or work close to rivers and stagnant bodies of water. Changes in the environment, such as the construction of irrigation systems and dams, seem to have played a role in the resurgence of the disease.
The mode of transmission is not known, but recent evidence suggests that aquatic insects (Naucoris and Dyplonychus species) may be involved. Trauma to contaminated skin sites appears to be the means by which the organism enters the body. There is little proven evidence of transmission from person to person. No racial or social group is exempt. Infection with the human immunodeficiency virus (HIV) is not a known risk factor.
The disease is more severe in impoverished inhabitants of remote rural areas. About 70% of those affected are children under the age of 15 years. Mortality due to the disease is low, but morbidity is high. Complications include contracture deformities, amputation of limbs, and involvement of the eye, breast and genitalia. In some localities 20–25% of those with healed lesions are left with disabilities that have a longterm social and economic impact. The current economic and social burden imposed by Buruli ulcer is enormous. In Ghana, the average cost of treatment per patient is estimated to be US$ 780.
The prevalence of the disease is not accurately known. In Côte d’Ivoire, over 15 000 cases were recorded between 1978 and 1999. Prevalence rates have been estimated at 16% in some communities in Côte d’Ivoire and at 22% in a community in Ghana. In Benin, nearly 4 000 cases were reported between 1989 and 1999. In Ghana, a survey conducted in 1999 identified over 6 000 cases and showed for the first time that all 10 regions of the country are affected. Cases have also been reported in Burkina Faso, Togo, Guinea and other West African countries.
A few cases have been reported in non-endemic areas in North America and Europe as a sequel to international travel. Lack of familiarity with Buruli ulcer has frequently resulted in significant delays in the diagnosis and treatment of these cases.
The causative organism
Mycobacterium ulcerans is a slow growing environmental mycobacterium. It is an acid-fast micro-organism that grows on common mycobacteriological media, e.g. Löwenstein- Jensen (L-J) medium.
It grows best at low temperatures (30–32 °C), at lower than atmospheric oxygen tension (pO2 < 2.5 kPa) and within a pH range of 5.4–7.4. A positive culture requires incubation for 6 to 8 weeks (or longer) under appropriate conditions.
Toxin
A toxin that causes tissue necrosis has been known for some time. Recently, one such compound—a polyketidederived macrolide called mycolactone—has been identified and its chemical structure established.
The toxin has both cytotoxic and local immunosuppressive properties. Injection of the purified toxin into experimental animals causes changes in subcutaneous fat similar to those seen in Buruli ulcers.
This is the first macrolide known to be produced by a human pathogen and the only macrolide identified in the genus Mycobacterium.
Pathogenesis
Once introduced into the subcutaneous tissue the organism proliferates and elaborates a toxin that has affinity for fat cells. The resulting necrosis then provides a favourable milieu for further proliferation of the organism. During the necrotic phase, there is very little or no cellular immune response and the burulin skin test is negative. By an unknown mechanism, either the toxin may be neutralized or the organism may cease to proliferate or to produce toxin. Healing seems to begin when the host develops cellmediated immunity, at which time the burulin skin test may become positive.
The inflammatory cells then destroy the etiological agent (M. ulcerans) and the disease subsides with scarring. Bones may be affected by direct spread from the lesion or as a result of M. ulcerans bacteraemia. In contrast to other pathogenic mycobacteria, which are facultative intracellular parasites of macrophages, M. ulcerans occurs primarily as extracellular microcolonies.
Clinical spectrum of the disease
Clinically the disease manifests as papules, nodules, plaques, oedematous forms and ulcers. The disease may be active (ongoing infection) or inactive (previous infection with characteristic depressed stellate scars with or without other sequelae). A new case is a patient with no previous history of, or treatment for, Buruli ulcer. A recurrent case is a patient presenting within one year with a further lesion at the same or a different site. Recurrence rates vary from 16% for patients presenting early to 28% for patients presenting late. Recurrence at the same site may be due to inadequate excision. Recurrence at a different site may be due to haematogenous or lymphatic spread.
Diagnosis
Clinical
In a known endemic area, an experienced person can make the diagnosis of Buruli ulcer on clinical grounds. The following clinico-epidemiological features are important diagnostic clues:
- the patient lives in or has travelled to a known endemic area;
- most patients are children under 15 years of age;
- about 85% of lesions are on the limbs;
- lower limb lesions are twice as common as upper limb lesions.
Laboratory
Any two of the following findings are required to positively diagnose Buruli ulcers:
- acid-fast bacilli in a smear stained by the Ziehl-Neelsen (ZN) technique;
- positive culture of M. ulcerans (but this requires 6–8 weeks or longer);
- histopathological study of excisional biopsy specimen (result available rapidly);
- positive polymerase chain reaction (PCR) for DNA from M. ulcerans.
Treatment
Drug treatment
Several antimycobacterial agents have in vitro activity against the causative organism but no single agent has been proven to be regularly useful in the treatment of the disease. Agents used include rifampicin, rifabutin, clarithromycin, azithromycin, streptomycin and amikacin.
Combinations of agents have been used, with apparently varying success. Drug treatment alone, even with combinations of drugs, is usually ineffective when there is an established, progressing lesion. Research into drug treatment is a priority.
Surgical treatment
This is accepted as the current definitive treatment. Limiting factors include:
- inadequate surgical facilities;
- need for prolonged stay in hospital;
- high treatment costs;
- recurrence after surgical treatment (rates of 16% to 28%);
- the risk of transmission of infections such as HIV.
Other adjuncts to treatment include heat and hyperbaric oxygen, which have not been definitively proven and may be impractical in developing countries.
Control and prevention
Community control strategies are currently limited by a lack of knowledge regarding the source of infection and the mode of transmission. The current standard treatment is surgery. Expert opinion is that early surgical management leads to improved results and resolution that are both cost saving. Early treatment is best promoted by an effective village-based surveillance programme. Current attitudes and beliefs may stigmatize and create fear in the affected individuals thereby delaying early and effective treatment. Educational materials should dispel such misinformation and focus on early detection and surgery. Minor surgery (e.g., nodulectomies) may be performed at the local level.
What you should do
The current control strategy promoted by the Global Buruli Ulcer Initiative consists of:
- health education and staff training in the communities most affected;
- strengthening the health care capacity in endemic areas by upgrading surgical facilities, ensuring adequate treatment supplies and improving laboratories;
- surgical training to enable other health workers (e.g. nurses, medical assistants) to perform effective minor surgery;
- community-based surveillance to improve early detection and rapid referral for treatment in collaboration with disease control programmes such as those for leprosy and dracunculiasis;
- adoption of educational material adapted to the needs of each country;
- developing successful motivational strategies;
- rehabilitation of those already deformed by the disease.