buruli ulcer buruli ulcer buruli ulcer (/bəˈruːli/) is an infectious disease characterized by the development of painless open wounds. the disease is limited to certain areas of the world, 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. buruli ulcerother namesbairnsdale ulcer, daintree ulcer, mossman ulcer, kumasi ulcer, searls ulcerburuli ulcer lesions. top-left, an early ulcer. top-right, a larger ulcer across the lower arm and wrist. bottom, a large ulcer on the thigh.specialtyinfectious diseasesymptomsarea of swelling that becomes an ulcercausesmycobacterium ulceranstreatmentrifampicin and clarithromycinfrequency2,713 cases reported to who in 2018 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. the world health organization (who) recommends treating buruli ulcer 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 ulcer can take months to heal. regular cleaning and dressing of wounds aids healing and prevents secondary infections. in 2018, who received 2,713 reports of buruli ulcer globally. although rare, it typically occurs in rural areas near slow-moving or stagnant water. the first written description of the disease is credited to albert ruskin cook in 1897 at mengo hospital in uganda. fifty years later, the causative bacterium was isolated and identified by a group at the alfred hospital in melbourne. in 1998, who established the global buruli ulcer initiative to coordinate global efforts to eliminate buruli ulcer. who considers it a neglected tropical disease. signs and symptoms early signs of buruli ulcer in cameroon. top, painless swollen bumps. bottom-left, a "plaque". bottom-right, widespread swelling of the lower arm. the first sign of buruli ulcer is a painless swollen bump on the arm or leg, often similar in appearance to an insect bite. sometimes the swollen area instead appears as a patch of firm, raised skin about three centimeters across called a "plaque"; or a more widespread swelling under the skin. over the course of a few weeks, the original swollen area expands to form an irregularly shaped patch of raised skin. after about four weeks, the affected skin sloughs off leaving a painless ulcer. 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 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 5 centimetres (2.0 inches). category ii describes a larger ulcer, up to 15 centimetres (5.9 in), 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. m. ulcerans is a mycobacterium, closely related to mycobacterium marinum which infects aquatic animals and, rarely, humans. it is more distantly related to other slow-growing mycobacteria that infect humans, such as mycobacterium tuberculosis, which causes tuberculosis, and mycobacterium leprae, which causes leprosy. buruli ulcer typically occurs near slow-moving or stagnant bodies of water, where m. ulcerans is found in aquatic insects, mollusks, fish, and the water itself. how m. ulcerans is transmitted to humans remains unclear, but somehow bacteria enter the skin and begin to grow. ulceration is primarily caused by the bacterial toxin mycolactone. as the bacteria grow, they release mycolactone into the surrounding tissue. mycolactone diffuses into host cells and blocks the action of sec61, the molecular channel that serves as a gateway to the endoplasmic reticulum. when sec61 is blocked, proteins that would normally enter the endoplasmic reticulum are mistargeted to the cytosol, causing a pathological stress response that leads to cell death by apoptosis. this results in tissue death at the site of infection, causing the open ulcer characteristic of the disease. at the same time, sec61 inhibition prevents cells from signaling to activate the immune system, leaving ulcers largely free of immune cells. immune cells that do reach the ulcer are killed by mycolactone, and tissue examinations of the ulcer show a core of growing bacteria surrounded by debris from dead and dying neutrophils (the most common immune cell). transmission a riverine site in ghana endemic for buruli ulcer it is not known how m. ulcerans is introduced to humans. 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 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 healed buruli ulcer lesions in a ghanaian woman 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 ulcer are occasionally used