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Dermatology > MYCOBACTERIAL INFECTIONS
Buruli Ulcer
Article Last Updated: Feb 28, 2006
AUTHOR AND EDITOR INFORMATION
Section 1 of 10  
Author: Brian P Green, DO, MS, PA-C, Staff Physician, Department of Dermatology, University of North Carolina
Brian P Green is a member of the following medical societies: American Medical Association
Coauthor(s):
Sean T Gunning, MD, Assistant Professor, Department of Dermatology, Department of Dermatology, Uniformed Services University of the Health Sciences; Consulting Staff, National Capital Consortium;
Mary K Mather, MD, Assistant Professor, Department of Internal Medicine, Dermatology Service, Walter Reed Army Medical Center, Uniformed Services University
Editors: Franklin Flowers, MD, Chief, Division of Dermatology, Professor, Department of Medicine and Otolaryngology, University of Florida College of Medicine; Richard P Vinson, MD, Assistant Clinical Professor, Department of Dermatology, Texas Tech University School of Medicine; Consulting Staff, Mountain View Dermatology, PA; Paul Krusinski, MD, Director of Dermatology, Professor, Department of Internal Medicine, Fletcher Allen Health Care, University of Vermont; Catherine Quirk, MD, Clinical Assistant Professor, Department of Dermatology, Brown University; William D James, MD, Paul R Gross Professor of Dermatology, University of Pennsylvania School of Medicine; Vice-Chair, Program Director, Department of Dermatology, University of Pennsylvania Health System
Author and Editor Disclosure
Synonyms and related keywords:
Mycobacterium ulcerans, M ulcerans
Background
Buruli ulcer is a chronic, indolent, necrotizing disease of the skin due to Mycobacterium ulcerans. It manifests initially as firm, nontender, subcutaneous nodules 1-2 cm in diameter at the sites of penetrating skin trauma (preulcerative stage). Within the next 1-2 months, these areas become fluctuant, followed by the formation of a painless, undermined ulceration (ulcerative stage.) Ulcerations can be extensive, involving as much as 15% of the patient's skin surface (see Media File 1). The infection may destroy nerves, appendages, and blood vessels, and it occasionally invades bone. Most lesions eventually heal spontaneously, but they frequently result in chronic lymphedema and disfiguring scarring. It was first described by Sir Albert Cook in patients from Buruli County in Uganda.
Pathophysiology
M ulcerans is a slow-growing mycobacterium affecting the skin and the mucous membranes. Inoculation into the skin occurs via trauma. The growing M ulcerans mycobacterium produces a soluble polyketide toxin called mycolactone. This toxin has been shown to have both immunosuppressive properties and cytotoxic properties, which explains the lack of host symptoms, such as fever, malaise, or adenopathy, and the extent of tissue undermining and destruction that is seen in Buruli ulcers.
Mycolactone has been shown to induce apoptosis without inducing inflammation. Thus, M ulcerans does not cause the inflammation associated with other mycobacterial infections, such as Mycobacterium leprae and Mycobacterium tuberculosis.
Frequency
United States
Three cases have been diagnosed in the United States, all of which originated from outside the United States.
International
Worldwide, M ulcerans infection is the third most common mycobacterial disease of humans who are immunocompetent. Endemic areas include much of central and western Africa, such as Zaire, Congo, Cameroon, Nigeria, Benin, Ghana, Liberia, and the Ivory Coast. Cases of Buruli ulcer have been reported in contiguous countries completely across Africa from Uganda to Guinea. Other involved geographic areas include Australia, Southeast Asia, and sporadic cases in Central America and South America. Subtropics and/or swampy terrain are major endemic foci for M ulcerans.
Mortality/Morbidity
Despite often extensive host involvement, little morbidity occurs with M ulcerans infection. Tissue necrosis may extend to muscle or bone, and metastatic bone lesions can develop. Healing with fibrosis may lead to significant deformity, with lymphedema, scarring, and contractures. Subclinical infections are common, as demonstrated by a positive burulin skin test.
Race
No specific racial predilection is known.
Sex
No differences in the rates of infection among males and females exist.
Age
Cases most commonly occur in children younger than age 15 years, but the condition may affect person from any age group. One study found that swimming in rivers on a regular basis was the only significant risk factor for developing a Buruli ulcer. Because this behavior is more common among children, they develop the infection more often than adults.
History
- Lesions usually begin as singular, painless, occasionally pruritic, subcutaneous nodules, which appear approximately 7-14 days after trauma to the overlying skin.
- Suppuration and ulceration occur within 1-2 months.
Physical
- Cutaneous ulceration may be extensive.
- Characteristic lesions have a scalloped border and a sloughing, necrotic base.
- Undermining necrosis along the panniculus may extend several centimeters.
- A few studies have shown relatively high frequencies of bone involvement (~15% of patients).
Causes
M ulcerans is the causative agent.
- While the mode of transmission remains unclear, a role has been suggested for fish, aquatic snails, and aquatic plants.
- Schistosomiasis has not been found to increase susceptibility to M ulcerans infection.
- The BCG vaccine has not been shown to protect against the onset of disease, although it has been shown to shorten its duration.
Actinomycosis
Herpes Zoster
Leprosy
Yaws
Other Problems to be Considered
Deep fungal infection
Abscess
Elephantiasis
Scrofuloderma
Mycosis
Cutaneous leishmaniasis
Tropical phagedenic ulcer
Venous ulcer
Lab Studies
- A smear from the necrotic base of the lesion may be stained with Ziehl-Neelsen, revealing clumps of acid-fast bacilli.
- M ulcerans can be cultured from ulcer exudate or fresh tissue. The inoculum must be incubated between 30-35°C (most sources recommend 32-33°C) on Lowenstein-Jensen medium for 6-8 weeks before colonies can be visualized.
- Polymerase chain reaction (PCR) testing of a punch biopsy specimen is another option. One study found PCR targeting the IS2404 insertion sequence useful in cases when histopathology findings are not diagnostic and Ziehl-Neelsen staining and culture results are negative. Additionally, the following has been demonstrated with semiquantitative reverse-transcription PCR analysis:
- High interferon gamma but low interleukin 10 mRNA levels in nodular lesions
- High interleukin 10 but low interferon gamma mRNA levels in ulcerative lesions
Histologic Findings
Pathologic specimens reveal extensive coagulation necrosis in the dermis and the subcutaneous fat, with destruction of cutaneous nerves, blood vessels, and cutaneous appendages. The necrosis may extend well beyond the edges of the ulceration. Extracellular clumps of acid-fast bacilli, usually seen at the base of the ulcer and in the surrounding necrotic tissue, are abundant. In active lesions, little or no acute or chronic inflammatory infiltrate is present, although a leukocytoclastic vasculitis or thrombosis of small- and medium-sized vessels may be seen. In healing lesions, a granulomatous reaction commences, eventuating in extensive dermal fibrosis and epidermal atrophy.
Medical Care
- Rifampin may promote healing of preulcerative and small lesions, but it is ineffective in the treatment of large ulcers.
- Some advocate postexcision treatment with rifampin alone or in combination with co-trimoxazole or clofazimine.
- Hyperthermia with a 40°C water bath, such as a circulating water jacket, has shown some success.
- The use of hyperbaric oxygen has also been reported as effective in a small number of patients.
- One study (n = 12) found a significant decrease in the size of ulcers with the use of sodium nitrite (6% wt/wt) and citric acid monohydrate (9% wt/wt) creams topically. The decrease was most significant in the first 3 weeks.
Surgical Care
Excision is the treatment of choice for most lesions.
- Subcutaneous nodules or small ulcerations may be excised en bloc with primary closure.
- Large lesions are often excised with skin graft closure.
The goal of therapy is to reduce morbidity and prevent complications.
Drug Category: Antibiotics
Pharmacotherapy is of very limited benefit in the treatment of Buruli ulcer. Rifampin has been used with marginal benefit for the treatment of very early lesions and for medical supplementation after excision.
| Drug Name | Rifampin (Rifadin, Rimactane) |
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| Description | Inhibits DNA-dependent bacterial but not mammalian RNA polymerase. Cross-resistance may occur. Treat for 6-9 mo or until 6 mo have elapsed from conversion to negative sputum culture results. |
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| Adult Dose | 600 mg PO qd |
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| Pediatric Dose | 10-20 mg/kg/d PO; not to exceed 600 mg/d |
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| Contraindications | Documented hypersensitivity |
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| Interactions | Induces microsomal enzymes, which may decrease effects of acetaminophen, oral anticoagulants, barbiturates, benzodiazepines, beta-blockers, chloramphenicol, oral contraceptives, corticosteroids, mexiletine, cyclosporine, digitoxin, disopyramide, estrogens, hydantoins, methadone, clofibrate, quinidine, dapsone, tazobactam, sulfonylureas, theophyllines, tocainide, and digoxin; blood pressure may increase with coadministration of enalapril; coadministration with isoniazid may result in higher rate of hepatotoxicity than with either agent alone (discontinue 1 or both agents if alterations in LFTs occur); halothane and rifampin together have been reported to increase hepatotoxicity of both drugs |
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| Pregnancy | C - Safety for use during pregnancy has not been established.
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| Precautions | Flulike medication reactions, hematopoietic reactions (eg, leukopenia, thrombocytopenia, acute hemolytic anemia), flushing, pruritus, gastrointestinal disturbances, and hepatic and renal reactions may occur; obtain CBC counts and baseline clinical chemistries prior to and throughout therapy; interruption of therapy and high-dose intermittent therapy are associated with thrombocytopenia that is reversible if therapy is discontinued as soon as purpura occurs; if treatment is continued or resumed after appearance of purpura, cerebral hemorrhage or death may occur |
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Complications
- Scarring, fibrosis, and lymphedema may result after healing of Buruli ulcers.
Prognosis
- Most patients have complete healing, with or without significant scarring or impairment.
| Media file 1:
Buruli ulcer can extend to 15% of a person's skin surface and may destroy nerves and blood vessels. Little morbidity occurs with the disease, unless ulcers extend to muscle or bone. Metastatic bone lesions may develop. |
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Media type: Photo
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Buruli Ulcer excerpt Article Last Updated: Feb 28, 2006
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