Buruli Ulcer (Mycobacterium ulcerans Infection)
Wayne M. Meyers, Françoise Portaels, and Douglas S. Walsh
Mycobacterium ulcerans causes indolent, necrotizing cutaneous lesions known as Buruli ulcers.1M ulcerans infections present a spectrum of clinical disease: nodules, plaques, severe edemas and massive ulcers in the skin, and osteomyelitis. In contrast to tuberculosis and leprosy, Buruli ulcer is closely related to environmental factors.2
EPIDEMIOLOGY
Endemic foci of Buruli ulcer are most common near rural permanent wetlands in warm geographic regions, especially in areas prone to seasonal flooding. Buruli ulcers have been reported from at least 27 countries, principally in the tropics.2 The greatest number of reported patients live in West Africa (Benin, Burkina Faso, Côte d’Ivoire, Ghana, Guinea, Liberia, and Nigeria), with an estimated total annual incidence exceeding 7000 patients.2,14,15 In South America, known countries in which Buruli ulcer is endemic include French Guyana, Suriname, and Peru.3,4 While Mexico is the only North American country in which it is endemic, travelers to endemic areas occasionally present to European, American, and Canadian medical centers.5-8
Individuals of all ages are affected, but children 15 years of age or younger constitute about 75% of all cases.22 Approximately 80% of the lesions are located on the limbs, with highest frequencies involving the lower extremities. 
Buruli ulcer infection is rarely, if ever, contagious. The distribution of patients, even in highly endemic foci, is random, suggesting that each patient is exposed to environmental sources such as swamps where villagers work their gardens, obtain water for domestic use, and where children play. The following additional risk factors have been determined in African populations: use of unprotected water for domestic purposes, swimming and wading in rivers, low level of schooling, and HIV infection.34,35
MYCOBACTERIOLOGY AND PATHOPHYSIOLOGY
M ulcerans is strongly acid-fast, with an optimal growth temperature of 30°C to 32°C on routine mycobacteriologic media. The organism is a slow grower, often requiring several months’ incubation to achieve isolation in primary culture. 
Modes of transmission to humans have not been delineated completely; however, the most plausible route is by trauma at sites of skin recently contaminated by M ulcerans.41,46 Many patients give a history of specific antecedent penetrating trauma at the site of the initial lesion, which may include wounds from a gunshot or land mine, thrown stones, human bite, and hypodermic injection (eFig. 272.1 
).46,47 The organism may be spread by aerosol from the surface of ponds or be carried by fomites or insects to skin surfaces. Insects may introduce M ulcerans into the skin, but this means of transmission has not been confirmed in humans.48
M ulcerans elaborates a necrotizing and immunosuppressive toxin,48a-c mycolactone 
.49,50
Based on the current understanding of the natural history of M ulcerans infection, pathogenesis may proceed as follows: After inoculation, there is a latent phase during which the mycobacterium proliferates slowly, possibly intracellularly at first, and begins to elaborate small amounts of the toxin causing necrosis, especially of fatty tissue (eFig. 272.2 
). In highly resistant patients, this lesion may self-heal, perhaps without ulceration, or it may form a small, sharply defined ulcer. In others, the skin is undermined by the necrosis and eventually breaks down into larger ulcers with widely undermined skin. In the least-resistant individuals, a nodule never develops and the necrosis spreads rapidly and widely to cover large body surface areas, but ulceration, if it takes place at all, is a late event. Eventually, the necrotic stage ceases in most patients from reduced immunosuppression and reduction of viable M ulcerans. At this time, a granulomatous stage begins to develop, followed by healing and scarring. Some of the variability in clinical presentation and progression of the disease may be related to heterogeneity in the M ulcerans genome, as well as in the plasmid that encodes the production of mycolactone.53-56
CLINICAL FEATURES AND PATHOLOGY
In eFigure 272.5 
a proposed classification of most of the clinical forms of M ulcerans is provided. World Health Organization (WHO) designations of the various forms of lesions of M ulcerans infection include: (1) papules that are painless, elevated, measure up to 1 cm in diameter, and ulcerate early (seen only in Australia); (2) nodules that are primarily subcutaneous and firm, measure approximately 2 cm in diameter, and are painless, though often pruritic [the initial stage in most African patients (eFig. 272.6 
)], (3) plaques that are firm, elevated, painless, well-defined lesions more than 2 cm in the largest dimension with skin over the lesion that is reddened or discolored, these lesions may ulcerate late, producing stellate ulcers without extensive undermining (eFig. 272.7 
); (4) edematous lesions that do not begin in the nodular stage but spread rapidly from the initial nidus of infection and often cover wide areas like entire limbs or major portions of the face or trunk (eFigs. 272.8 and 272.9 
); and (5) ulcerative lesions that are more or less symmetric, have undermined edges surrounded by a zone of induration, and often have desquamation of the surrounding epidermis. These are classified as minor (eFig. 272.10 
) and major (eFig. 272.1 
) lesions. In the base of the ulcerated area, a whitish necrotic slough and, sometimes, eschar develop.57
Microscopically, the active ulcer shows extensive coagulation necrosis of the subcutaneous tissue down to and often including the fascia (eFig. 272.3 
).18,58 Marked edema is present, and fat cells are enlarged and dead, leaving only their cellular ghost outlines (eFig. 272.4 
).
Bone involvement occurs due to both contiguous or metastatic osteomyelitis in about 10% of all patients.59 Reactive osteitis occasionally develops beneath destroyed overlying skin and soft tissue. Bone subjacent to the Buruli ulcer lesion may become devitalized and necrotic, with the development of sequestra (eFigs. 272.11 and 272.12 
).59 Metastatic osteomyelitis most likely results from lymphohematogenous spread of M ulcerans from a cutaneous lesion (eFig. 272.13 
). The overlying skin ordinarily is intact, but swelling and inflammation develop over the site of bone involvement. Bone scans, if available, are helpful in diagnosis.60 If the condition goes untreated, a draining fistula may develop. Both contiguous and metastatic osteomyelitis often result in deformity and amputation (eFigs. 272.14 and 272.15 
).
DIAGNOSIS
An accurate clinical diagnosis often can be made by an experienced observer.57,61 In the ulcerative forms, a Ziehl-Neelsen stain of exudate from the undermined edge obtained with a cotton swab will reveal clusters of extracellular acid-fast bacilli (eFig. 272.21 
). The same material, obtained by swab after decontamination, may be used for culture on Löwenstein-Jensen or other suitable mycobacterial media. The incubation temperature must be 30°C to 32°C. If culture cannot be performed locally, transport media may be inoculated with material from the cotton swab and maintained at 4°C while in transport to a specialized laboratory. The transport medium is composed of Middlebrook 7H9 broth supplemented with polymyxin B, amphotericin B, nalidixic acid, trimethoprim, azlocillin, and 0.5% agar.62 Molecular biologic analysis techniques consisting of PCR for the identification of M ulcerans are available, convenient, and growing in popularity.43,53,63 Tissue for histopathologic analysis should be obtained from the edge of the ulcer or presumed center of edematous or plaque lesions and must include all levels of the integument, including the fascia. Fixation in 10% buffered formalin is adequate.
Other diagnosis that can be mistaken for Buruli ulcers include papules from insect bites, verruca vulgaris, pityriasis, granuloma annulare; nodules from lipomas, sebaceous cysts, onchocerciasis, furuncle; plaques from leprosy, mycosis, necrobiosis, psoriasis, Mkar disease (granuloma multiforme); edema from bacterial cellulitis, necrotizing fasciitis, actinomycosis, elephantiasis, pyomyositis; and ulcers from tropical phagedenic ulcer, noma, stasis ulcer, leishmaniasis, or injection abscesses (eFig. 272.22 
)
TREATMENT
Treatment options for Buruli ulcer are antibiotics and surgical intervention. Current WHO guidelines are available, both for the surgical and antibiotic management of Buruli ulcer.59,64 Physiotherapeutic evaluation and management is imperative for all Buruli ulcer patients.65 Minor Buruli ulcers are believed to self-heal. 
Historically, surgical intervention has been the standard treatment for all forms of Buruli ulcer disease (eFigs. 272.18 and 272.19 
).57,59 In recent times, to minimize the possibility of M ulcerans spread, many surgeons give clarithromycin and rifampin for 1 to 2 days before surgery and continue antibiotic therapy for several weeks after surgery. However, this antibiotic adjunct to surgery is of variable efficacy.66
Very small ulcers can also be excised and closed primarily. Large ulcers are excised widely. Split-skin autografts are applied (eFigs 272.18 and 272.19 
).
Bone lesions should be referred to specialists to minimize disabilities.59,65 Antibiotic treatment as recommend by the WHO includes at least an 8-week course of daily oral rifampin (10 mg/kg) and streptomycin (15 mg/kg) given daily as an intramuscular injection. eFigures 272.16 and 272.17 
show a patient treated successfully with rifampin. 
Healing leads to fibrosis and scarring and can limit movement, causing lifestyle alterations.71 The scar may form keloids and often causes major contraction deformities, especially in lesions that cross joints (eFig. 272.20 
). Squamous cell carcinoma may develop in healed lesions, especially those that are non-pigmented. Skin grafting and physiotherapy prevent most of these complications. 
Without treatment, Buruli ulcer often leads to deforming depressed scars, contracture deformities, or amputations. The stigma of deformities and the socioeconomic burden disease often are marked.72 With early appropriate treatment, the prognosis usually is excellent. 
Preventive measures include frequent use of soap for washing, treating injuries with soap or antibiotic powder, use of bed nets and insect repellent.35,48,74 Vaccination with bacille Calmette-Guérin has a protective effect against M ulcerans infections for 6 to 12 months.75 HIV infection does appear to increase the risk for Buruli ulcer.34
REFERENCES
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