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Buruli ulcer

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Buruli ulcer
Other namesBairnsdale ulcers, Searls ulcer, Daintree ulcer[1][2]
Buruli ulcer left ankle EID.jpg
Buruli ulcer on the ankle of a person from Ghana.
SpecialtyInfectious disease
SymptomsArea of swelling that becomes an ulcer[3]
CausesMycobacterium ulcerans[3]
TreatmentRifampicin and streptomycin[3]
Frequency~ 2,000 cases reported (2015)[3]

Buruli ulcer is an infectious disease caused by Mycobacterium ulcerans.[3] The early stage of the infection is characterised by a painless nodule or area of swelling.[3] This nodule can turn into an ulcer.[3] The ulcer may be larger inside than at the surface of the skin,[4] and can be surrounded by swelling.[4] As the disease worsens, bone can be infected.[3] Buruli ulcers most commonly affect the arms or legs;[3] fever is uncommon.[3]

M. ulcerans releases a toxin known as mycolactone, which decreases immune system function and results in tissue death.[3] Bacteria from the same group also cause tuberculosis and leprosy (M. tuberculosis and M. leprae, respectively).[3] How the disease is spread is not known.[3] Sources of water may be involved in the spread.[4] As of 2018, there is no effective vaccine.[5][6] The Bacillus Calmette–Guérin (BCG) vaccine has demonstrated limited protection.[3]

If people are treated early, antibiotics for eight weeks are effective in 80% of cases.[3][7] The treatment often includes the medications rifampicin and streptomycin.[3] Clarithromycin or moxifloxacin are sometimes used instead of streptomycin.[3] Other treatments may include cutting out the ulcer.[3][8] After the infection heals, the area typically has a scar.[6]

About 2,000 cases are reported a year.[5] Buruli ulcers occur most commonly in rural sub-Saharan Africa and Australia with fewer cases in South America and the Western Pacific.[5] Children are most commonly infected in Africa, while adults are most commonly affected in Australia.[5] Cases have been reported in 33 countries.[5] The disease also occurs in animals other than humans, though no link between animal and human infection has been established.[9] Albert Ruskin Cook was the first to describe buruli ulcers in 1897.[4] It is classified as a neglected tropical disease.[10]

Signs and symptoms

Development of Buruli ulcer on the hand of a person from Peru. A) Swollen patch on the middle finger B) about 4 weeks later, ulcers form on the middle finger C) 5.5 weeks after first seen, a large ulcer covers the finger D) cured lesion 5 months after first seen, 1 month after autologous skin graft.

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.[11][12] 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.[11][12] Over the course of a few weeks, the original swollen area may expand, forming an irregularly shaped patch of swollen skin.[11][13] After about four weeks, the affected skin sloughs off, leaving a large painless ulcer.[12] In some people, the ulcer remains small and may linger unhealed for years.[13] 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.[13] 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.[13] Large exposed ulcers are often infected by other bacteria, causing the wound to smell foul.[13]

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 (62%) and upper limbs (24%), but can also be found on the trunk (9%), head/neck (3%), or genitals (less than 1%).[14] The World Health Organization classifies Buruli ulcer cases into three categories depending on the severity of their symptoms. A single small (less than five centimeters) ulcer is category I. Larger ulcers (up to 15 centimeters) are category II. Ulcers that are larger, disseminated across the body, or include particularly sensitive sites (e.g. the eyes, bones, joints, or genitals) are called category III.[13]

Cause

Buruli ulcer is caused by infection of the skin with the bacterium Mycobacterium ulcerans.[12] 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.[15] 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.[16] 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.[17] 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.[17] This results in large-scale tissue death at the site of infection, causing the large open ulcer characteristic of disease.[17] At the same time, Sec61 inhibition prevents cells from signalling to activate the immune system, resulting in ulcers that lack infiltrating immune cells.[17]

Transmission

A riverine site in Ghana endemic for Buruli ulcer

It is not known how M. ulcerans is introduced to humans.[12] Human-to-human transmission is extremely rare, and Buruli ulcer is not considered contagious.[15] In areas endemic for Buruli ulcer, cases tend to be near stagnant bodies of water, leading to the long-standing hypothesis that M. ulcerans is somehow transmitted to humans from aquatic environments.[18] Supporting this, M. ulcerans is widespread in aquatic environments, where it can survive as free-living or associated with other aquatic organisms.[14] 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.[18] 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.[14] Whether these insects are regularly involved in transmission remains unclear.[15][18] Pre-existing wounds have also been implicated in disease transmission, and poor wound care is associated with a higher risk of acquiring Buruli ulcer.[19] 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.[15][19]

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.[20][21] 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.[20]

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.[22] Diagnosis is then confirmed by polymerase chain reaction (PCR) to detect M. ulcerans DNA or microscopy to detect mycobacteria.[23] The gold standard test is real-time PCR to detect a DNA sequence termed IS2404 that is unique to M. ulcerans.[24] This method detects 54–84% of cases, and is highly specific to M. ulcerans.[25] 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.[22] 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.[23] In practice microscopy detects just 30–40% of cases, making it a relatively insensitive diagnostic test.[25]

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.[25] 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.[26]

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 rifampicin plus twice daily oral clarithromycin, recommended by the World Health Organization.[27][28] Several other antibiotics are sometimes used to partner with rifampicin, namely ciprofloxacin, moxifloxacin, ethambutol, amikacin, azithromycin, and levofloxacin.[27] 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.[29] Approximately 1 in 5 people with Buruli ulcer experience a temporary worsening of symptoms 3 to 12 weeks after they begin taking antibiotics.[30] 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.[30] 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.[30]

Treatment may also include surgery to remove necrotic ulcer tissue as well as scar tissue that can deform the muscles and joints.[30] As ulcers can take months to heal, regular wound care plays a major role in treatment.[27] The healing of severe ulcers can sometimes require skin grafts and/or daily wound dressings.[30]

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.[27] 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.[30] While there is no specific vaccine for Buruli ulcer, vaccination with the BCG vaccine offers temporary protection from disease.[30][31]

Epidemiology

Cases of Buruli ulcer reported to the World Health Organization in 2018. Shades of orange indicate case number: lightest (1–150 cases), medium-light (151–300 cases), medium-dark (301–450 cases), darkest (451+ cases). Not shown are Australia (358 cases), Papua New Guinea (12 cases) and Japan (3 cases).

Buruli ulcer is relatively rare, with between 2000 and 5000 cases reported to the World Health Organization each year.[12] 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.[32][33] Cases are also regularly reported from southeastern Australia, and more rarely from Papua New Guinea and Japan.[34] Most countries do not report data on Buruli ulcer to the World Health Organization, and the extent of Buruli ulcer's spread is unknown.[35] 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.[36] 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.[37]

Within affected countries, Buruli ulcer cases tend to occur in rural areas near slow-moving or stagnant water.[15] 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.[15] Within endemic communities, few characteristics predict who will acquire Buruli ulcer. Males and females are equally likely to be infected.[15] 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.[38]

History

While M. ulcerans may have infected humans throughout history, the first written description of Buruli ulcer is credited to a British missionary doctor, Albert R. Cook.[39][40] In 1897, at Mengo Hospital in Uganda, Cook noted several patients with slow-healing ulcers, consistent with Buruli ulcer.[41][42] The cause of these slow-healing ulcers was identified 50 years later in 1948, when Peter MacCallum, Jean Tolhurst, Glen Buckle, and H. A. Sissons at Melbourne University described a series of cases from Bairnsdale, Victoria, isolated the causative mycobacterium, and showed it could cause ulcers in laboratory rats.[15][43] Over the following decades, more cases were described in Africa, including a particularly high prevalence in Uganda's Buruli County, leading to the disease becoming more widely known as "Buruli ulcer".[41] In 1998, the World Health Organization started the Global Buruli Ulcer Initiative with the aim of coordinating global efforts to control Buruli ulcer.[41] 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.[44][45]

Other names

Buruli ulcer is known by several other names in different parts of the world. In southeastern Australia, it was originally called "Searls' ulcer" after the physician J. R. Searls who saw the first Australian cases at the Bairnsdale Clinic and sent material to Peter MacCallum's group at Melbourne University for further examination.[46] The disease later became more generally known as "Bairnsdale ulcer" after the district where those cases were described.[41] In northeastern Australia, north of Cairns, the disease is called "Daintree ulcer" or "Mossman ulcer" after the nearby Daintree River and the town of Mossman.[47][48] In Papua New Guinea, the disease is called "Kumusi ulcer" after the Kumusi River along which villages with cases of the disease were originally described.[49]

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.[15][43] 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.[50] 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.[50] 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.[51] Strains of M. ulcerans used in laboratores are less standardized than their murine hosts, with different laboratories using different strains based on convenience and accessibility.[52] Three M. ulcerans strains are particularly common: "Cu001", isolated from a person in Adzopé, Côte d'Ivoire in 1996; "Mu1615", from a person in Malaysia in the 1960s; and "S1013" from someone in Cameroon in 2010.[52] Most Buruli ulcer research is focused on testing new antibiotics against the bacteria, testing vaccine candidates, and better understanding how M. ulcerans infection causes disease.[53]

References

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  45. World Health Organization (2004) pp. 1–2
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Works cited

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