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Buruli ulcer (<!--changed from /'bʊrəli/ in the 7th ed.-->) is an infectious disease characterized by the development of painless open wounds. The disease is limited to certain areas of the world, with most cases occurring in Sub-Saharan Africa and Australia. The first sign of infection is a small painless nodule or area of swelling, typically on the arms or legs. The nodule grows larger over days to weeks, eventually forming an open ulcer. Deep ulcers can cause scarring of muscles and tendons, resulting in permanent disability.
<!-- Cause -->Buruli ulcer is caused by skin infection with bacteria called Mycobacterium ulcerans. The mechanism by which M. ulcerans is transmitted from the environment to humans is not known but may involve the bite of an aquatic insect or the infection of open wounds. Once in the skin, M. ulcerans grows and releases the toxin mycolactone, which blocks the normal function of cells, resulting in tissue death and immune suppression at the site of the ulcer.
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The World Health Organization (WHO) recommends treating Buruli ulcers with a combination of the antibiotics rifampicin and clarithromycin. With antibiotic administration and proper wound care, small ulcers typically heal within six months. Deep ulcers and those on sensitive body sites may require surgery to remove dead tissue or repair scarred muscles or joints. Even with proper treatment, Buruli ulcers can take months to heal. Regular cleaning and dressing of wounds aid healing and prevent secondary infections.
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In 2026, WHO received 1,862 reports of Buruli ulcer globally. Buruli ulcers typically have "undermined edges", the ulcer being a few centimeters wider underneath the skin than the wound itself.
In some people, the ulcer may heal on its own or remain small but linger unhealed for years. In others, it continues to grow wider and sometimes deeper, with the skin at the margin dying and sloughing off. Large ulcers may extend deep into underlying tissue, causing bone infection and exposing muscle, tendon, and bone to the air. When ulcers extend into muscles and tendons, parts of these tissues can be replaced by scar tissue, immobilizing the body part and resulting in permanent disability. Exposed ulcers can be infected by other bacteria, causing the wound to become red, painful, and foul smelling. Symptoms are typically limited to those caused by the wound; the disease rarely affects other parts of the body.
Buruli ulcers can appear anywhere on the body but are typically on the limbs. Ulcers are most common on the lower limbs (roughly 62% of ulcers globally) and upper limbs (24%), but can also be found on the trunk (9%), head or neck (3%), or genitals (less than 1%).
The World Health Organization classifies Buruli ulcer into three categories depending on the severity of its symptoms. Category I describes a single small ulcer that is less than . Category II describes a larger ulcer, up to , as well as plaques and broader swollen areas that have not yet opened into ulcers. Category III is for an ulcer larger than 15 centimeters, multiple ulcers, or ulcers that have spread to include particularly sensitive sites such as the eyes, bones, joints, or genitals.
Cause
Buruli ulcer is caused by infection of the skin with the bacterium Mycobacterium ulcerans. Buruli ulcer does not spread from one person to another. In areas endemic for Buruli ulcer, disease occurs near stagnant bodies of water, leading to the long-standing hypothesis that M. ulcerans is somehow transmitted to humans from aquatic environments. M. ulcerans is widespread in these environments, where it can survive as free-living or in association with other aquatic organisms. Live M. ulcerans has been isolated from aquatic insects, mosses, and animal feces, and its DNA has been found in water, soil, mats of bacteria and algae, fish, crayfish, aquatic insects, and other animals that live in or near water. A role for biting insects in transmission has been investigated, with particular focus on mosquitoes, giant water bugs, and Naucoridae. M. ulcerans is occasionally found in these insects, and they can sometimes transmit the bacteria in laboratory settings. Whether these insects are regularly involved in transmission remains unclear. Pre-existing wounds have been implicated in disease transmission, and people who immediately wash and bandage open wounds are less likely to acquire Buruli ulcer. Wearing pants and long-sleeved shirts is associated with a lower risk of Buruli ulcer, possibly by preventing insect bites or protecting wounds.
Genetic susceptibility
While Buruli ulcer is not contagious, susceptibility sometimes runs in families, suggesting genetics could play a role in who develops the disease. Severe Buruli ulcer in a Beninese family was attributed to a loss of 37 kilobases of chromosome 8 in a region that included a long non-coding RNA and was near the genes for beta-defensins, which are antimicrobial peptides involved in immunity and wound healing. Broader studies have focused on genes involved in susceptibility to other mycobacterial infections, finding susceptibility to Buruli ulcer may be linked to variants in six immunity-related genes: SLC11A1, PRKN, NOD2, ATG16L1, iNOS, and IFNG, as well as in two long non-coding RNAs. A genome-wide association study linked resistance to Buruli ulcer to a variant of ATG16L1 associated with susceptibility to Crohn's disease.
Diagnosis
thumb|upright=1.1|alt=See caption.|[[Photomicrographs of a punch biopsy from a Buruli ulcer plaque lesion. In the left image, the tissue sample has been stained with hematoxylin and eosin, a common stain for histopathology examination. In the right image, it has been stained with Ziehl–Neelsen stain, which helps to visualize mycobacteria. The inset shows red-staining (acid-fast) bacilli, suggestive of mycobacteria.]]
As Buruli ulcer most commonly occurs in low-resource settings, treatment is often initiated by a clinician based on signs and symptoms alone. Where available, diagnosis may then be confirmed by polymerase chain reaction (PCR) to detect M. ulcerans DNA or microscopy to detect mycobacteria. The gold standard test is real-time PCR to detect a DNA sequence termed IS2404 that is unique to M. ulcerans. This method detects M. ulcerans in 54–84% of infected people, and is highly specific to M. ulcerans. In wealthier healthcare settings, diagnosis is routinely based on PCR results. In low-resource settings, PCR is often unavailable, or can only be performed later at a centralized diagnostic laboratory. For microscopy, fluid is typically taken from the ulcer's edge by fine-needle aspiration or by swabbing the edge of the ulcer. The fluid is then stained with the Ziehl–Neelsen stain which makes mycobacteria visible. In practice microscopy detects M. ulcerans in just 30–40% of infected people, making it a relatively insensitive diagnostic test. For many bacterial infections, the gold standard for diagnosis is isolating and growing the infective organism in laboratory media. M. ulcerans can be grown in laboratory media, but its extremely slow growth rate prevents this from being used diagnostically; even under optimal growth conditions, the bacteria must grow for 9 to 12 weeks before they can be easily detected and identified. Another method of diagnosis is to take a tissue sample from the ulcer and examine it under histological stains. This requires more invasive sampling and review by a trained pathologist and is rarely used in places where Buruli ulcer is endemic.
Other ulcerative diseases can appear similar to Buruli ulcer at its various stages. The nodule that appears early in the disease can resemble a bug bite, sebaceous cyst, lipoma, onchocerciasis, other mycobacterial skin infections, or an enlarged lymph node. Skin ulcers can resemble those caused by leishmaniasis, yaws, squamous cell carcinoma, Haemophilus ducreyi infection, and tissue death due to poor circulation. More diffuse lesions can resemble cellulitis and fungal infections of the skin.
Treatment
thumb|Healed Buruli ulcer lesions in a [[Ghanaian woman |left|alt=A woman's leg with a large discolored patch.]]
Buruli ulcer is treated through a combination of antibiotics to kill the bacteria, and wound care or surgery to support the healing of the ulcer. The most widely used antibiotic regimen is once daily oral rifampicin plus twice-daily oral clarithromycin, recommended by the World Health Organization. Several other antibiotics are sometimes used in combination with rifampicin, namely ciprofloxacin, moxifloxacin, ethambutol, amikacin, azithromycin, and levofloxacin. A 2018 Cochrane review suggested that the many antibiotic combinations being used are effective treatments, but there is insufficient evidence to determine if any combination is the most effective. Approximately 1 in 5 people with Buruli ulcer experience a temporary worsening of symptoms 3 to 12 weeks after they begin taking antibiotics. This syndrome, called a paradoxical reaction, is more common in those with larger ulcers and ulcers on the trunk, and occurs more frequently in adults than in children. The paradoxical reaction in Buruli ulcer is thought to be due to the immune system responding to the wound as bacteria die and the immune-suppressing mycolactone dissipates.
Small or medium-sized ulcers (WHO categories I and II) typically heal within six months of antibiotic treatment, whereas larger ulcers can take over two years to fully heal. Given the long healing times, wound care is a major part of treating Buruli ulcer. The World Health Organization recommends standard wound care practices: covering the ulcer to keep it moist and protected from further damage; regularly changing wound dressings to keep the ulcer clean, removing excess fluid, and helping prevent infection. Treatment sometimes includes surgery to speed healing by removing necrotic ulcer tissue, grafting healthy skin over the wound, or removing scar tissue that can deform muscles and joints. Specialized wound dressings developed for non-infectious causes of ulcers are occasionally used for treating Buruli ulcer but can be prohibitively expensive in low-resource settings.
Prevention
Buruli ulcers can be prevented by avoiding contact with aquatic environments in endemic areas, although this may not be possible for people living in these areas. The risk of acquiring it can be reduced by wearing long sleeves and pants, using insect repellent, and cleaning and covering any wounds as soon as they are noticed. There is no specific vaccine for preventing Buruli ulcer.<!--These are photos of Cook's actual notes. Several cases bear resemblance to Buruli ulcer (case # annotated at left of each page) including cases #2, 3, 9, 28, and more --> The cause of these slow-healing ulcers was identified 50 years later in 1948, when Peter MacCallum, Jean Tolhurst, Glen Buckle, and at The Alfred Hospital's Baker Institute described a series of cases from Bairnsdale, Victoria, isolated the causative mycobacterium, and showed it could cause ulcers in laboratory rats. Over the following decades, more cases were described in Africa. A particularly high prevalence in Uganda's Buruli County led to the disease becoming more widely known as "Buruli ulcer".
In 1998, the World Health Organization started the Global Buruli Ulcer Initiative to coordinate global efforts to control the disease. This was followed in 2004 by World Health Organization Resolution WHA57.1 calling upon member countries to support the Global Buruli Ulcer Initiative and increase research on Buruli ulcer diagnostics and treatment. Interest in Buruli ulcer has been encouraged by its branding as a "neglected tropical disease", first in a 2005 PLOS Medicine article, and later by both the World Health Organization and PLOS Neglected Tropical Diseases.
From the time the disease was described, Buruli ulcer was treated with surgery to remove all affected tissue, followed by prolonged wound care. This treatment regimen was expensive, sometimes disfiguring, and often ineffective, with ulcers recurring in up to a third of cases. Treatment dramatically improved in 2004, when the World Health Organization recommended an eight-week course of daily oral rifampicin and injected streptomycin. The introduction of antibiotics reduced the rate of ulcer recurrence to fewer than 2% of cases. However, streptomycin can be toxic to the ears and kidneys, and administering daily injections is challenging in low-resource settings. In 2017, the World Health Organization updated its recommendation to replace streptomycin with the oral antibiotic clarithromycin.
Research
Buruli ulcer has been the subject of scientific research since the description of M. ulcerans in 1948, and the demonstration that the bacteria could cause ulcers in laboratory animals. While several animals are susceptible to M. ulcerans ulcers, mice (particularly BALB/c and C57BL/6 mice) are most commonly used to model Buruli ulcer in modern laboratories. Since M. ulcerans can only grow in relatively cool temperatures, mice are typically infected in furless parts of the body: the ear, tail, or footpad. After injection into the mouse, bacteria double every three to four days, and the first signs of skin disease appear after three to four weeks. This mouse model of Buruli ulcer has primarily been used to test antibiotics. The antibiotic combinations, dose frequencies, and treatment durations currently in use were first tested in laboratory-infected mice. Some vaccine platforms have been tested in M. ulcerans-infected mice, mostly based on the Mycobacterium bovis strain used in the BCG vaccine. The BCG vaccine and versions of the vaccine that also express M. ulcerans antigens prolong the survival of mice after M. ulcerans infection. As of 2019, no vaccine tested completely protects mice from infection.
M. ulcerans can be grown in laboratory media, although its slow growth makes it challenging to study. Bacteria plated on laboratory media can take up to three months to form visible colonies. Strains of M. ulcerans used in laboratories are less standardized than the mice they infect; different laboratories use different strains based on convenience and accessibility. Three M. ulcerans strains are particularly common, each isolated from an infected person: "Cu001" from Adzopé, Côte d'Ivoire in 1996; "Mu1615" from Malaysia in the 1960s; and "S1013" from Cameroon in 2010.