Buruli Ulcer

Synonyms: Bairnsdale ulcer, Daintree ulcer, Mossman ulcer, Searl ulcer, Kakerifu ulcer, Toro ulcer

Buruli ulcer is a chronic, indolent, necrotising disease of the skin and soft tissue caused by Mycobacterium ulcerans. Lesions heal with scarring, which can result in contractures and deformities. Buruli ulcer was first described in patients from Buruli County in Uganda.^[1]

The largest number of endemic cases occurs in central and western Africa. Other affected areas include Australia, South-East Asia, and sporadic cases in Central America and South America. M. ulcerans has been isolated from biofilms and small aquatic animals in slow-moving or stagnant water. The exact mode of transmission is unknown.^[1]

Epidemiology

• Any age group can be affected, but peak incidence is 5-15 years.
• Buruli ulcer has been identified in many tropical and temperate regions of the world.
• After tuberculosis and leprosy, it is the third most common mycobacterial disease in immunocompetent people.^[2]
• Although the first cases of Buruli ulcer were reported by Sir Albert Cook in Uganda as early as 1897, it was not until 1961 that the number of cases significantly increased.
• There has been a further dramatic increase in the number of reported cases in several West African countries in the past two decades, with prevalence rates as high as 151 per 100,000 population reported.
• Foci have also been reported in South-East Asia, the Pacific Islands, Central America and Australia (where it is known as the Bairnsdale ulcer).
• Almost all reported cases have been in the inhabitants of endemic regions, although seven cases have been linked to international travel, including a case in the UK in 2003.^[3]
• As travel to endemic regions increases there will be a greater need to recognise and identify M. ulcerans infection in the UK.

Risk factors

• For many years the mode of transmission has been unknown, however use of polymerase chain reaction (PCR) has revealed that water bugs and small fish carry M. ulcerans in their salivary glands.^[4]
• Many victims are agricultural workers or children who live near slow-flowing or stagnant water.
• Direct skin inoculation is believed to be the route of transmission by a bite.

Presentation^[5]

Symptoms

• The incubation period varies from 2 months to several years.
• The initial injury often goes unnoticed; typically a single painless lesion appears on the leg or arm, which gradually ulcerates.
• Patients do not usually experience any systemic symptoms and consequently often present with advanced ulcerated disease.
• The infection may extend deep, exposing fascia, muscle and bone.^[1]

Signs

Three clinical stages of Buruli ulcer have been described:

• Pre-ulcerative; lesions can present as a nodule, papule, plaque or oedema.
• Ulcerative; as the lesion enlarges the skin and underlying tissue sloughs off to form an ulcer with an undermined edge.
• Healed (scarred) disease; a granulomatous healing response follows which ultimately results in fibrosis and scarring.

Differential diagnosis

These include:

• Filariasis
• Leprosy
• Yaws
• Deep fungal infection such as blastomycosis or coccidioidomycosis
• Mycetoma
• Ulcerative squamous cell carcinoma^[6]

Investigations

Improved definition of the diagnostic features in the early stages of Buruli ulcer would enable early treatment and prevent deforming sequelae.

• Swab samples from ulcers or skin biopsy specimens can be used to confirm the presence of acid fast bacilli,^[6] but unfortunately culture has a low sensitivity for M. ulcerans (40-43%).^[7]
• Histology is the most sensitive of readily available diagnostic methods:
  • Histology has a sensitivity of 82%.^[7]
  • The typical histopathological features are subcutaneous and dermal collagen necrosis, with minimal inflammation.
  • The necrosis has been attributed to mycolactone, a polyketide produced by M. ulcerans, which causes localised immune suppression in the tissues.^[8]
• Polymerase chain reaction can also be used to identify the bacterial DNA, but cost limits routine clinical use in endemic areas. It has a sensitivity over 90% and is available within 24 hours.^[7]
• X-rays and ultrasound may be required for deep lesions.

Management

• Although several anti-mycobacterial drugs have shown good in vitro activity against M. ulcerans, response to drug therapy is generally poor.^[5]
• Increased tissue involvement has been reported with more aggressive therapy, egwide excision of the lesion and skin grafting.^[9]
• There have been major advances in management of the disease with the introduction of rational antibiotic therapy.
• The WHO Advisory Group on Buruli ulcer has issued guidelines suggesting that:^[10]
  • Rifampicin and streptomycin be given to ambulant patients of any age with Buruli ulcers, and early lesions, for 8 weeks under careful observation.
  • Rifampicin 10 mg/kg orally and streptomycin 15 mg/kg intramuscularly, daily.
  • Limited surgery should be reserved for essential debridement and grafting used only to accelerate healing of large ulcers, or to excise lesions that continue to enlarge despite antibiotic therapy.
  • Evidence from a prospective, but uncontrolled study of patients treated in this way suggests that most ulcers heal following, but not necessarily during, therapy for 8 weeks. There is a low recurrence rate of less than 3% in the year after finishing treatment.^[11]
• However in 2007, the Australian Victorian Department of Human Services recommended:^[12]
  • Combination of rifampicin and clarithromycin, or ciprofloxacin or moxifloxacin for 3 months.
  • In severe disease, oral rifampicin with intravenous amikacin should be used.
  • Oral medications should be used for 12 weeks and intravenous amikacin should be used for 4 weeks.
• Treatments with hyperthermia and hyperbaric oxygen have shown some success.^[1]

Surgical

Approximately 33% of early nodules heal spontaneously, and simple excision under local anaesthetic is curative in 84% of cases where the lesion is small enough, ie less than 5 cm in diameter.^[13]

Complications

• Buruli ulcer has been associated with osteomyelitis during the ulcerative stage.
• Scarring, contractures, and lymphoedema may cause severe deformity and psychosocial difficulties.
• Untreated advanced disease can cause death by sepsis.

Prognosis

• Early aggressive surgical treatment appears to provide the best chance of cure.
• The best prognosis is when treatment is initiated in lesions less than 5 cm diameter.^[1]
• Ulcers have been reported to heal spontaneously, but can result in a depressed scar with contractures and consequent severe deformities.
• Circumferential involvement of extremities can require amputation.

Prevention

• Bacillus Calmette-Guérin vaccine has an incomplete protective effect against Buruli ulcer.^[5]
• In 1998 the WHO Global Buruli Ulcer Initiative was established to draw attention to, and mobilise international efforts to treat the disease effectively.