Buruli ulcer
Buruli ulcer is an infectious disease characterized by the development of painless open wounds, most commonly on the limbs. The first sign of infection is often a small painless nodule or area of swelling. Over days to weeks, this nodule can grow larger under the skin. Eventually surface skin sloughs off the expanding wound, causing an open ulcer. Deep ulcers can cause scarring of muscles and tendons, resulting in permanent disability. Buruli ulcer most commonly affects the arms or legs, but can occur anywhere on the body.
Buruli ulcer is caused by skin infection with Mycobacterium ulcerans. The bacteria live in aquatic environments, particularly in slow-moving or stagnant water, from which they are introduced to humans. The mechanism by which M. ulcerans is transmitted from the environment to humans is not known; however, M. ulcerans cannot be transmitted from one human to another. 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.
The World Health Organization recommends treating Buruli ulcer with a combination of the antibiotics rifampicin and streptomycin, administered daily for eight weeks. Due to the inconvenience of taking streptomycin, which must be injected daily by a healthcare provider, several oral antibiotic combinations are used across the world. For severe ulcers, treatment may include surgery to remove dead tissue or repair scarred muscles or joints. Healthy skin may be grafted onto larger ulcers to promote healing. Even treated ulcers can take weeks or months to heal; regular wound cleaning and dressing is done to aid healing and prevent infection.
About 2,000 cases are reported a year. Buruli ulcers occur most commonly in rural sub-Saharan Africa and Australia with fewer cases in South America and the Western Pacific. Children are most commonly infected in Africa, while adults are most commonly affected in Australia. Cases have been reported in 33 countries. The disease also occurs in animals other than humans, though no link between animal and human infection has been established. Albert Ruskin Cook was the first to describe buruli ulcers in 1897. It is classified as a neglected tropical disease.
Signs and symptoms
The first sign of Buruli ulcer is the appearance of a painless swollen area on the arm or leg. This most commonly takes the form of a small bump, similar in appearance to an insect bite. Sometimes the first sign is 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 may expand, forming an irregularly shaped patch of swollen skin. After about four weeks, the affected skin sloughs off, leaving a large painless ulcer. In some people, the ulcer remains small and may linger unhealed for years. In others, the ulcer continues to grow wider and sometimes deeper, with skin at the margin dying and sloughing off. The underlying muscle, tendon, and bone may be exposed. Ulcers can extend into muscles and tendons, causing parts of these tissues to be replaced by inelastic scar tissue, immobilizing the body part and resulting in permanent disability. Large exposed ulcers are often infected by other bacteria, causing the wound to smell foul.Buruli ulcers can appear anywhere on the body, but are far more common on the limbs than elsewhere. Ulcers are most common on the lower limbs and upper limbs, but can also be found on the trunk, head/neck, or genitals. The World Health Organization classifies Buruli ulcer cases into three categories depending on the severity of their symptoms. A single small ulcer is category I. Larger ulcers are category II. Ulcers that are larger, disseminated across the body, or include particularly sensitive sites are called category III.
Cause
Buruli ulcer is caused by infection of the skin with the bacterium Mycobacterium ulcerans. M. ulcerans infections typically occur near slow-moving or stagnant bodies of water, where M. ulcerans can be 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. Disease is primarily caused by a toxin produced by the bacteria, mycolactone. As the bacteria grow, they release mycolactone, which diffuses into host cells and blocks the action of Sec61, the core translocation protein that serves as the gateway to the endoplasmic reticulum. When Sec61 is blocked, proteins that would normally enter the endoplasmic reticulum are instead translated into the cytosol, causing a pathological stress response that results in cell death by apoptosis. This results in large-scale tissue death at the site of infection, causing the large open ulcer characteristic of disease. At the same time, Sec61 inhibition prevents cells from signalling to activate the immune system, resulting in ulcers that lack infiltrating immune cells.Transmission
It is not known how M. ulcerans is introduced to humans. Human-to-human transmission is extremely rare, and Buruli ulcer is not considered contagious. In areas endemic for Buruli ulcer, cases tend to be found near stagnant bodies of water, leading to the long-standing hypothesis that M. ulcerans is somehow transmitted to humans from aquatic environments. Supporting this model, M. ulcerans is widespread in aquatic environments, where it can survive as free-living or associated 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 long 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 certain laboratory settings. Whether these insects are regularly involved in transmission remains unclear. Consistent with this, wearing long pants and long-sleeved shirts is associated with a lower risk of Buruli ulcer, possibly by preventing insect bites or protecting wounds. Pre-existing wounds have also been implicated in disease transmission, and poor wound care is associated with a higher risk of acquiring Buruli ulcer.Genetic susceptibility
While Buruli ulcer is not contagious, susceptibility sometimes runs in families, suggesting genetics could play a role in who develops 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. Additionally, genome-wide association studies have linked susceptibility to Buruli ulcer to variations in six genes: SLC11A1, PRKN, NOD2, ATG16L1, iNOS, and IFNG, as well as in two long non-coding RNAs.Diagnosis
As most cases of Buruli ulcer arise in low-resource settings, treatment for Buruli ulcer is often initiated by a clinician based on the signs and symptoms alone. Diagnosis is then confirmed by microscopy to detect mycobacteria or polymerase chain reaction to detect M. ulcerans DNA. For microscopy, ulcer material is typically taken by fine-needle aspiration or swabbing the edge of the ulcer, then stained with the Ziehl-Neelsen stain which makes mycobacteria easy to see. In practice this method detects just 30–40% of cases, making it a relatively insensitive diagnostic test. The gold standard test is real-time PCR to detect a sequence termed IS2404 that is unique to M. ulcerans. This method detects 54–84% of cases, and is highly specific to M. ulcerans. Equipment required to run real-time PCR is prohibitively expensive, and often available only at centralized diagnostic laboratories so PCR may be used to confirm a diagnosis well after treatment has begun, rather than to guide initial treatment decisions.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. An additional method of diagnosis is microscopic examination of ulcer tissue by a trained pathologist. However, this requires more invasive sampling of ulcer tissue, as well as specifically trained personnel, and so is rarely used in places where Buruli ulcer is endemic.
Treatment
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. Since 2004, the World Health Organization has recommended eight weeks of daily treatment with oral rifampicin and intramuscular streptomycin. However, due to the nephrotoxicity of streptomycin, and the inconvenience of daily injections, several other antibiotics to partner with rifampicin have been investigated. The most widely used alternative is rifampicin plus twice daily oral clarithromycin, which is now also recommended by the World Health Organization. Several other antibiotics are sometimes used to partner 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 more effective than the others. 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 is more common in adults than 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.Treatment may also include surgery to remove necrotic ulcer tissue as well as scar tissue that can deform the muscles and joints. As ulcers can take months to heal, regular wound care plays a major role in treatment. The healing of severe ulcers can sometimes require skin grafts and/or daily wound dressings.
Prevention
Buruli ulcer can be prevented by avoiding contact with aquatic environments in endemic areas; however, for those living in endemic areas, this may not be possible. The risk of acquiring Buruli ulcer can be reduced by wearing long sleeves and pants, using insect repellent, and cleaning and covering any wounds as soon as they're noticed. While there is no specific vaccine for Buruli ulcer, vaccination with the BCG vaccine offers temporary protection from disease.Epidemiology
Buruli ulcer is relatively rare, with between 2000 and 5000 cases reported to the World Health Organization each year. The overwhelming majority of cases are reported from countries in southern West Africa, namely Benin, Côte d'Ivoire, Cameroon, Gabon, Ghana, Guinea, Liberia, Nigeria, and Togo. Cases are also regularly reported from southeastern Australia, and more rarely from Papua New Guinea and Japan. Most countries do not report data on Buruli ulcer to the World Health Organization, and the extent of Buruli ulcer's spread is unknown. A 2019 systematic review of existing Buruli ulcer prevalence studies found a clear consensus that Buruli ulcer is present in 12 countries: Australia, Japan, Benin, Côte d'Ivoire, Cameroon, Democratic Republic of Congo, Gabon, Ghana, Liberia, Nigeria, Togo, and South Sudan, as well as "strong" or "very strong" evidence that Buruli ulcer is present in eight additional countries: Republic of Congo, Sierra Leone, Central African Republic, Papua New Guinea, Guinea, Uganda, Peru, and French Guiana. Even in countries that do report Buruli ulcer, health systems likely do not record each case due to insufficient reach and resources, and so the reported case numbers are likely underestimates of the true disease prevalence.Within affected countries, Buruli ulcer cases tend to occur in rural areas near slow-moving or stagnant water. In particular, cases tend to appear near water that has experienced human intervention, such as the building of dams or irrigation systems, flooding, or deforestation. Within endemic communities, few characteristics predict who will acquire Buruli ulcer. Males and females are equally likely to be infected. Ulcers can appear in people of all ages, although infections are most common among children between 5 and 15 years in West Africa, and adults over 40 in Australia and Japan.