Buruli ulcer disease is a health problem in tropical areas of many emerging countries. Caused by Mycobacterium ulcerans, an organism from the family of bacteria that causes tuberculosis and leprosy, it destroys skin and underlying tissue and produces severe, disabling deformities.

Since 1980, Buruli ulcer disease has been regarded as a significant cause of human suffering. However, it is not a new disease: It was most likely first encountered in 1897, when Sir Albert Cook described large ulcers in people in Uganda.1 Peter MacCallum identified an organism similar to M ulcerans in an ulcer of a 15-year-old child in Bainsdale, Australia, in 1940.1 Large ulcers were then observed in people living along the Nile River in the Buruli county of Uganda in 1961.1 The disease has carried the name of this region ever since.1

Buruli ulcer disease is characterized by extensive cutaneous ulcers that occur as the disease progresses from the early, more treatable, nodular form to the ulcerative form. This later form can result in the loss of skin and soft tissue covering an entire extremity or a significant percentage of the torso. Healing is often slow and associated with significant functional incapacity due to contractures and amputation. Treatment is complicated by the resistance of the organism to most medical regimens due to the organism's ability to suppress the host's immune system. Early diagnosis, while the disease is in the nodular stage, allows curative surgical resection to minimize late complications.

Buruli ulcer disease is among the most neglected diseases in terms of primary health care strategies and funding. However, that is changing as the World Health Organization (WHO) launches a number of major global initiatives. Recent progress includes the unraveling of the genetic structure of the pathogen, examination of the mechanisms of virulence, and the emergence of a possible role of chemotherapy in disease treatment and prevention of recurrence. Strategies aimed at reducing the economic burden placed on the health care budgets of poorer nations have also been initiated.2

Epidemiology of Disease in Ghana

In Ghana, more than 2000 cases of Buruli ulcer disease were reported from 1994 through 2003; outbreaks have occurred in at least 90 of the country's 138 administrative districts.3 In a study of 750 consecutive patients with Buruli ulcer disease from a highly endemic area in Amansie West, Ghana, more lesions were found on the right side of the body, and a comparison of lesions on the arms and legs showed bilaterally symmetrical distribution.4 Upper and lower extremities were affected equally by Buruli ulcers, if correction was made for differences in body surface area.4 A disseminated, nonulcerative form of M ulcerans infection is also now increasingly frequent in some highly endemic areas, especially in West Africa.5Figure 1 identifies countries where Buruli ulcer disease has been reported.

Figure 1. COUNTRIES WHERE BURULI ULCER DISEASE IS PRESENT

In 2005, the age distribution at diagnosis of Buruli ulcer disease in Ghana was 53.1% for patients younger than 15 years, 33.9% for those aged 15 to 49 years, and 12.9% for those older than 50 years. Presentation by sex was 52.7% male and 47.3% female. High prevalence among people living near water suggests transmission of the disease by the bite of an infected aquatic insect; however, this remains to be proven. See The public health response in Ghana and Table 1 for more information.

Table 1. SECTORWIDE INDICATOR TARGETS FOR GHANA, 2006-2011

Clinical Presentation and Diagnosis

The WHO has defined Buruli ulcer disease as an infectious disease of the skin and subcutaneous tissue characterized by painless nodules, papules, plaques, or edema (Figure 2), evolving into painless ulcer with undermined edges and edema (Figure 3). Progression of the disease is associated with extensive sloughing and massive ulceration that can span joints (Figure 4), which may result in contractures (Figure 5), and involve significant areas of the torso (Figure 6) or face (Figure 7). Amputation may be required when a limb is involved (Figure 8).

Figure 2. BURULI ULCER DISEASE

Figure 3. BURULI ULCER OF THE FOOT

Figure 4. JOINT INVOLVEMENT

Figure 5. CONTRACTURE

Figure 6. BURULI ULCER OF THE TORSO

Figure 7. BURULI ULCER OF THE FACE

Figure 8. BURULI ULCER INVOLVING AN ENTIRE LIMB

Clinical diagnosis of Buruli ulcer disease has been difficult until recently. Fortunately, diagnostic tests are now available. An IS2404-based nested polymerase chain reaction (PCR) test has been shown to accurately diagnose Buruli ulcer disease in regions of Ghana where the disease is endemic. The 2 nested PCR tests on 21 culture-positive samples were able to detect M ulcerans DNA in all 21 culture-confirmed patients.6

In addition, a dry reagent-based PCR formulation for the detection of M ulcerans in diagnostic specimens has been developed at the Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany. Following technical and clinical validation, the assay has been successfully installed and field tested at the Kumasi Centre for Collaborative Research in Tropical Medicine, Kumasi, Ghana. Preliminary results showed a diagnostic sensitivity of >95%.7 The Zeil-Nielsen test, however, remains the standard for diagnosis in the field.

THE PUBLIC HEALTH RESPONSE IN GHANA

Treatment Options

Unfortunately, there is no effective medical treatment for Buruli ulcer disease. Simple plastic surgical techniques remain the standard treatment for early cases.8 In one study of progressive Buruli ulcers, 118 patients were treated surgically.9 The surgical procedures included excision of necrotic lesions and grafts for clean wounds. Seventy-three patients (62%) underwent excision followed by thin skin grafts and 35 patients (30%) with clean wounds were treated with grafts only. The number of excisions varied from 1 to 7 per patient, with the number of skin grafts varying from 1 to 4. All patients healed within a range of 14 to 265 days, with an average of 120 days. Complications were noted in 26 patients (22%): 8 new foci, 7 infectious complications, 6 recurrences, and 5 contractures and joint ankyloses. This study concluded that the surgical treatment of Buruli ulcers by excision and grafts is effective but does not prevent new foci or recurrences from developing.9 Recurrence rates as high as 17% have been reported.10

Nonexcisional, traditional treatment consists of debridement, wound care, and exorcism. The cost of this form of traditional treatment is high, not only in currency, but also in payment in kind (eg, livestock and land).11 Topical treatment of Buruli ulcers with topical nitrogen oxides has been reported.12

The need to discover pharmaceutical molecules that are effective for the treatment of M ulcerans is strongly advocated.8 Despite uncertainties of in vivo efficacy of antibiotics in this disease, chemotherapy with rifampicin and an aminoglycoside or a fluoroquinolone and an aminoglycoside has been suggested as a means of reducing the need for surgery.13 In more extensive cases, wide excision and graft are often recommended; however, limited excision followed by small islet grafts may be successful, especially if medical treatment can halt or reverse the progression of the disease.13 One report indicates that treatment with rifampin and streptomycin for 4 weeks or more inhibited growth of M ulcerans in human tissue.14 The investigators stated that the results provide the basis for proceeding to a trial of antibiotic therapy as an alternative to surgery for early M ulcerans disease.14 This treatment regimen has been effective in Ghana. Nevertheless, it would be optimal to use interventions with fewer adverse effects.

Immunology

Buruli ulcer disease generates an immunologic response, as evidenced by the presence of immunoglobulin M antibody to M ulcerans, which have been shown to allow discrimination between cases of active Buruli ulcer disease and matched family controls in areas where the disease is endemic.15 However, the immunodeficiency of M ulcerans is associated with the production of an extracellular cutaneous infection (Buruli ulcer), characterized by cytokine-driven immunosuppression. This is in stark contrast to all other pathogenic Mycobacteria species that cause intracellular, granulomatous infections. The unique mycobacterial pathology of M ulcerans infection is attributed to a plasmid-encoded immunomodulatory macrolide toxin, mycolactone.16 It appears that mycolactone expression during the intracellular life of M ulcerans may contribute to immune evasion by inhibiting phagocytosis, provoking apoptosis of antigen-presenting cells, and altering the establishment of an appropriate inflammatory reaction.17

Peripheral blood mononuclear cells (PBMCs) from subjects with past or current M ulcerans disease show significantly reduced proliferation and production of interferon-[gamma] (IFN-[gamma]) in response to stimulation with live M ulcerans or M bovis than PBMCs from healthy, tuberculin test-positive subjects (P< .001). Results in these assays were also comparable to those of tuberculin test-negative subjects (P > .2). Serum from 9 of 11 patients with M ulcerans disease mounted an immune response to M ulcerans as evidenced by antibody production; however, they demonstrated profound systemic T-cell anergy to mycobacterial antigens. These findings may explain some of the distinct clinical and pathologic features of M ulcerans-induced disease.18

It has been hypothesized that interleukin-4 (IL-4) or IL-50-induced down-regulation of Th1 responses plays a key role in the progression of early Buruli ulcer disease, and it has been found that healing is accompanied by an augmented Th1 response.19 The mechanism of the reversal of Th1 response back to more normal levels as the disease resolves is unknown; however, it appears to be directly related to the level of IFN-[gamma], a key Th1 cytokine. Cell culture studies have suggested that this may be the case.

In one such study, IFN-[gamma] production was significantly lower (P < .05) in PBMC cultures from patients with ulcers (late stage) after stimulation with M ulcerans than in those from patients with nodules (early stage).20 In another study, PBMCs from patients with Buruli ulcer disease produced significant levels of the Th2 cytokine IL-10 in response to M ulcerans (but not to M bovis BCG). Production of IL-10 was highest in patients with the late, ulcerative form of Buruli ulcer disease. In addition, semiquantitative reverse transcription-PCR analysis demonstrated a similar difference in the local, intralesional cytokine profile for the 2 forms of the disease: high IFN-[gamma] but low IL-10 mRNA levels in nodular lesions and high IL-10 but low IFN-[gamma] mRNA levels in ulcerative lesions.20 Intralesional IL-4 and IL-13 mRNA levels were low and only detected in patients with the ulcerative form.20 These results indicate, although they do not formally prove, that it is the production of IL-10, rather than production of IL-4 or IL-13 by Th2-type T cells, that may be involved in the low M ulcerans-specific IFN-[gamma] response in patients with Buruli ulcer disease.

Another study showed that following stimulation with M ulcerans or M bovis BCG, PBMCs from patients with Buruli ulcer disease mounted the expected Th2-type response, whereas unaffected persons responded mainly with the Th1 cytokines IFN-[gamma] and IL-12.21 These findings suggest that a Th1-type immune response to M ulcerans may prevent the development of Buruli ulcer disease in people exposed to M ulcerans, but a Th2 response does not.21

In the final analysis, the immunologic nature of this disease may hold the key to its solution. Novel molecular approaches, as advocated by the authors of one of the reports above,8 need thorough evaluation, particularly if evidence exists that suggests such a material could have an impact on the immunodeficiency caused by mycolactone. Such a material should be evaluated to see whether it could change the clinical dynamics of Buruli ulcer disease in the hopes of decreasing the need for wide surgical resection, severe lifelong disabilities in young people, and amputations. Until then, early detection and surgery remain the solutions of today.

Summary

Buruli ulcer disease is a significant health problem in tropical areas of many emerging countries including Ghana, where the medical, social, and economic challenges caused by the disease are being met head on. Extensive cutaneous ulcers are extremely troublesome to patients, their families, and the medical community. Treatment of the early, nodular form of the disease is medically effective and socially optimal, but it is undermined by the slow, painless progression of the disease that is often ignored by the patients and their families until ulceration occurs. When ulceration is present, healing is slow and is associated with significant functional incapacity due to contractures and amputation. A medical cure for this later form of Buruli ulcer disease is lacking, although a combination of antituberculosis and aminoglycoside drugs has improved outcomes in Ghana. Treatment is complicated by the resistance of the organism to most other medical regimens due to the ability of the organism to suppress the host's immune system. Besides excellent wound care, novel, effective treatment regimens are needed to enhance healing of Buruli ulcers, minimize the time course of the disease, and reduce the occurrence of serious complications.

Buruli ulcer disease presents a challenge and an opportunity to tackle a unique immunodeficiency condition. If successful, the lessons learned from overcoming this challenge may be applied to other immunodeficiency states.

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