Buruli ulcer

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

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

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

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

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 signs of Buruli ulcer can vary, but usually involve 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. However, 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. The ulcer continues to grow wider and sometimes deeper, with skin at the margin dying and sloughing off, and underlying muscle, tendon, and bone sometimes exposed. Oftentimes, these large exposed ulcers are 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 (62%) and upper limbs (24%), but can also be found on the trunk (9%), head/neck (3%), or genitals (less than 1%). 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.

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  A typical Buruli ulcer on the left hand of a 17-year-old boy in Nigeria

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  Ear of an 18-month-old with confirmed Buruli ulcer

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  Buruli ulcer in a long-term traveler to Senegal

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 cell death 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. However, whether these insects are regularly involved in transmission remains unclear. Pre-existing wounds have also been implicated in disease transmission, and poor wound care is associated with a higher risk of acquiring Buruli ulcer. 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.

Other mammals are also susceptible to ulcers caused by M. ulcerans, and could serve as environmental reservoirs of M. ulcerans.

In Australia, animals such as koalas and possums are naturally infected. Epidemiological evidence has not clearly supported person-to-person transmission. However, Muelder & Nourou found that 10 out of 28 patients had relatives who had also had the disease, and cautioned against the dismissal of person-to-person transmission. Given the number of patients who shed large numbers of bacilli from their wounds and live in very close contact with relatives, more cases should have been observed. The cases reported by Muelder & Nourou could perhaps have been exposed to a common source of infection, and there might also be genetic component to sensitivity to the disease.

Mycobacterium ulcerans was first cultivated and characterized from the environment in 2008.

Diagnosis

The diagnosis of Buruli ulcer is usually based on the characteristic appearance of the ulcer in an endemic area. If there is any doubt about the diagnosis, then PCR using the IS2404 target is helpful, but this is not specific for M. ulcerans. The Ziehl-Neelsen stain is only 40–80% sensitive, and culture is 20–60% sensitive. Simultaneous use of multiple methods may be necessary to make the diagnosis.

Prevention

There is no specific vaccine for Myocobacterium ulcerans. The Bacillus Calmette-Guérin vaccine may offer temporary protection.

Treatment

Healed Buruli ulcer lesions in a Ghanaian woman

If treated early, antibiotics for eight weeks are effective in 80% of people. This often includes the medications rifampicin and streptomycin. Clarithromycin or moxifloxacin are sometimes used instead of streptomycin.

Treatment may also include cutting out the ulcer. This may be a minor operation and very successful if undertaken early. Advanced disease may require prolonged treatment with extensive skin grafting. Surgical practice can be dangerous in the developing countries where the disease is common.

Epidemiology

Map with number of reported cases of Buruli ulcer in 2009.

The infection occurs in well-defined areas throughout the world, mostly tropical areas — in several areas in Australia, in Uganda, in several countries in West Africa, in Central and South America, in southeast Asia and New Guinea. It is steadily rising as a serious disease, especially in West Africa and underdeveloped countries, where it is the third leading cause of mycobacterial infection in healthy people, after tuberculosis and leprosy.

The disease is more likely to occur where there have been environmental changes such as the development of water storages, sand mining, and irrigation.

Buruli ulcer is currently endemic in Benin, Côte d'Ivoire, Ghana, Guinea, Liberia, Nigeria, Sierra Leone and Togo. In Ghana, 1999 data indicated that the prevalence rate of the disease in the Ga West District was 87.7 per 100,000, higher than the estimated national prevalence rate at 20.7 per 100,000 generally, and 150.8 per 100,000 in the most disease-endemic districts.

Geographical distribution

Buruli ulcer has been reported from at least 32 countries around the world, mostly in tropical areas:

• West Africa: Benin, Burkina Faso, Côte d'Ivoire, Ghana, Liberia, Nigeria, Togo, Guinea, Sierra Leone.
• Other African Countries: Angola, Cameroon, Congo, Democratic Republic of Congo, Equatorial Guinea, Gabon, Sudan, Uganda.
• Western Pacific: Australia, Papua New Guinea, Kiribati.
• Americas: French Guiana, Mexico, Peru, Suriname.
• Asia: China, Malaysia, Japan.

In several of these countries, the disease is not considered to be a public health problem, hence the current distribution and the number of cases are not known. Possible reasons include:

• the distribution of the disease is often localized in certain parts of endemic countries;
• Buruli ulcer is not a notifiable disease
• In most places where the disease occurs, patients receive care from private sources such as voluntary mission hospitals and traditional healers. Hence the existence of the disease may not come to the attention of the ministries of health.

It most commonly occurs in Africa: Congo and Cameroon in Central Africa, Côte d'Ivoire, Ghana and Benin in West Africa. Some Southeast Asian countries (Papua New Guinea) and Australia have major foci, and there have been a few patients reported from South America (French Guyana and Surinam) and Mexico. Focal outbreaks have followed flooding, human migrations, and man-made topographic modifications such as dams and resorts. Deforestation and increased basic agricultural activities may significantly contribute to the recent marked increases in the incidence of M. ulcerans infections, especially in West Africa, where the disease is rapidly emerging.

Race, age and sex

Buruli ulcer commonly affects poor people in remote rural areas with limited access to health care. The disease can affect all age groups, although children under the age of 15 years (range 2–14 years) are predominantly affected. There are no sex differences in the distribution of cases among children. Among adults, some studies have reported higher rates among women than males (Debacker et al. accepted for publication). No racial or socio-economic group is exempt from the disease. Most ulcers occur on the extremities; lesions on the lower extremities are almost twice as common as those on the upper extremities. Ulcers on the head and trunk accounted for less than 8% of cases in one large series.

History

James Augustus Grant, in his book A Walk across Africa (1864), describes how his leg became grossly swollen and stiff with later a copious discharge. This was almost certainly the severe edematous form of the disease, and is the first known description of the infection. Buruli ulcer disease was identified in 1897 by Sir Albert Cook, a British physician, at Mengo Hospital in Kampala, Uganda. The disease was named after Buruli County in Uganda (now called Nakasongola District), because of the many cases that occurred there in the 1960s. The incidence of the disease has recently been rising in tropical Africa and in certain parts of Australia.

A detailed description of the disease was written in 1948 by Professor Peter MacCallum and his colleagues, who were treating patients from the Bairnsdale district, in the Gippsland region in eastern Victoria, Australia. MacCallum and his team were the first to identify Mycobacterium ulcerans as the pathogen causing the condition. In Australia it is also known as Bairnsdale or Daintree ulcer.

In March 2008, researchers announced the first isolation of M. ulcerans from the environment. This suggested that the disease might be transmitted via contact with the environment rather than person to person. The entire genome of M. ulcerans has been sequenced.

Certain types of clay have historically been used in an attempt to treat the condition.

Other names

Other names include Bairnsdale ulcer, Searls ulcer, Daintree ulcer, Kumusi ulcer, and mycoburuli ulcers. Searls was one of the first physicians to describe it.

External links

Classification	ICD-10: A31.1 (ILDS A31.120) ICD-9-CM: 031.1 MeSH: D054312 DiseasesDB: 8568

• World Health Organization buruli ulcer page
• "Mycobacterium ulcerans". NCBI Taxonomy Browser. 1809.
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