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Synopsis: The recent description of a patient with Buruli ulcer originating from China presents an opportunity to review the somewhat atypical and frankly unusual manifestations of this disease. Its epidemiology, pathology, and even the growth characteristics of the causative organism make this an easily missed infectious disease, with a clear potential for harm to travelers in certain environments. Yet, as this case will illustrate, we can expect to see more of Buruli ulcer where we least expect to find it.
Source: Faber WR, et al. First reported case of Mycobacterium ulcerans infection in a patient from China. Trans R Soc Trop Med Hyg 2000;94:277-279.
A 40-year-old Chinese woman, who had been living in Europe for nine years, traveled during July and August to Shan Dong province, People’s Republic of China. She walked barelegged in grassy areas near fruit trees, and noted numerous apparent "mosquito bites." Three months later, a pale swelling, with a slightly depressed center, appeared on her left leg. Four months later it was excised while she again visited China, but it ulcerated instead of healing. When she returned to The Netherlands, a Ziehl-Neelson stain showed acid-fast bacteria that had been obtained from a painless 3 × 3.5-cm lesion with undermined borders and a necrotic bed.
Histopathological examination of tissue did not reveal granulomata; instead, there was extensive eosinophilic necrosis and some mononuclear cell infiltrate containing both scattered and clumped extracellular acid-fast bacteria. PCR analysis ultimately demonstrated sequences specific for Mycobacterium ulcerans. The causative organism was isolated after 40 days culture but only at 30°C. The organism was later found to be resistant to rifampicin in vitro and required additional curative surgery in addition to antituberculous therapy with ciprofloxacin and rifabutin. As the acid-fast organisms were gradually eliminated, tissue biopsies taken from the healing area changed and only then demonstrated a granulomatous reaction at this later stage of her disease.
Recent World Health Organization (WHO) initiatives aimed at stopping the spread of Buruli ulcer disease, particularly in West Africa, underscore the potential importance of this disease, potentially for travelers to countries such as Ghana, Benin, the Ivory Coast, and Togo.1-5 MacCallum et al established the association between M. ulcerans and the Australians noted lesions of Bairnsdale ulcer in 1948. Sir Albert Cook had first described this disease in Uganda as early as 1897.2 The name, Buruli ulcer, now derives from the 1961 outbreak in Uganda, but the disease has been identified not only in Australia but also in Papua New Guinea, Sri Lanka, Mexico, Peru, and French Guyana. Disease distribution is not even throughout what are considered endemic areas. Rather, it tends to be both focal and intense, at times affecting more than 20% of the population, particularly those residing or working in low lying river and swamp regions, and possibly involving aquatic water insects as vectors living in slow-flowing stagnant water.4
Pediatric cases outnumber adults in most series and approximately 70% of cases occur in children younger than 15 years of age. The disease begins as a subcutaneous nodule that appears spontaneously, as opposed to arising from a previous site of traumatic injury. It is not known whether the source of infection is actually either traumatic or due to aerosol transmission of organisms—possibly even inoculated by insect vectors. However, there is no known person-to-person spread of this disease nor association with HIV infections.
In the experimental guinea pig model, areas of fibroblastic cell growth and necrosis within cutaneous lesions are found. The role of mycolactone toxin production in the destruction of subcutaneous tissue is critical.2 Mycolactone is a nonimmunogenic polyketide-derived macrolide. Once an ulcerative lesion is established, antibiotics alone, without aggressive surgical intervention, will not be curative.
M. ulcerans is rather slow growing mycobacteria and may require upward of 6-9 months for primary isolation on solid media. It is analogous to M. marinum, being thermosensitive, growing best at 31-33ºC, but not at 37ºC, and like M. marinum, causing cutaneous disease. Semret et al reported a better experience isolating M. ulcerans with selective liquid media containing antibiotics, supplemented with 10% lysed sheep blood cells and polyoxyethylene stearate.1 Because of its slow rate of growth on solid media, overgrowth by contaminants is frequently a problem during isolation. Unfortunately, NaOH is used in standard decontamination procedures and it inhibits the growth of M. ulcerans. Although a polymerase chain reaction (PCR) test is available in reference laboratories, clinical diagnosis determines therapy in endemic regions of the world.
To understand the evolution of clinical Buruli ulcer disease, it is critical to realize that the pathogenesis of this infection is quite unlike that of any other mycobacterial disease. Early lesions contain many bacteria and show extensive coagulative necrosis in the lower dermis and subcutaneous fat. Clumps of organisms are visualized, but unlike lepromatous leprosy they are rarely intracellular and there is little inflammatory response or granuloma formation. Disease progression involves both nerves and blood vessels. When epidermal undermining occurs, ulceration follows. During healing, granuloma formation and granulation tissue with epidermal ingrowth become evident. The initial necrosis within skin lesions is found beyond the site of bacterial proliferation, suggesting the macrolide toxin mediated effects are occurring without inducing any inflammatory responses. Sterile filtered supernatants of M. ulcerans are capable of producing these cytotoxic and ulcerative effects. Skin test positivity (burulin test) does not occur until patients are well into the healing phase of the disease.
Antibiotics administered without surgical intervention may simply not be efficacious and could lead to disfiguring lesions. These may require extensive surgical excision and skin grafting, possibly even amputation. Although the antileprosy agent, clofazimine, has in vitro activity against M. ulcerans, without surgery, it has not been beneficial. Usually resistant to isoniazid, other agents such as dapsone, streptomycin, rifampicin, and, more recently, clarithromycin have all been shown to have activity against M. ulcerans; however, adjunctive surgery appears to be critical for cure. Antibiotic sensitivity patterns alone do not predict clinical responses.
Lesions may progress and accelerate with aggressive antimicrobial therapy alone. The role of localized heat application to skin lesions and the topical application of phenytoin to skin ulcers have unclear benefits, if any, for current therapy.3
1. Semret M, et al. Mycobacterium ulcerans infection (Buruli ulcer): First reported case in a traveler. Am J Trop Med Hyg 1999;61:689-693.
2. Thangaraj HS, et al. Mycobacterium ulcerans disease: Buruli ulcer. Trans R Soc Trop Med Hyg 1999;93: 337-340.
3. van der Werf TS, et al. Mycobacterium ulcerans infection. Lancet 1999;354:1013-1018.
4. Portaels F, et al. Insects in the transmission of Mycobacterium ulcerans infection. Lancet 1999;353: 986.
5. Tappero J. Mycobacterium ulcerans infection—Buruli ulcer disease: An emerging problem in west Africa. Program and Abstracts of the 38th annual meeting of the Infectious Diseases Society of America. New Orleans La., Sept. 7-10, 2000;S77:12.