Buruli ulcer

Buruli ulcer
Synonyms	Bairnsdale ulcers, Searls ulcer, Daintree ulcer<ref name="Andrews"/><ref name="Lavender CJ, Senanayake SN, Fyfe JA, et al. 62–3"/>
Pronounce	N/A
Field	Infectious disease
Symptoms	Area of swelling that becomes an ulcer<ref name=WHO2013/>
Complications
Onset
Duration
Types	N/A
Causes	Mycobacterium ulcerans<ref name=WHO2013/>
Risks
Diagnosis
Differential diagnosis
Prevention
Treatment	Rifampicin and streptomycin<ref name=WHO2013/>
Medication
Prognosis
Frequency	~ 2,000 cases reported (2015)<ref name=WHO2013/>
Deaths

Buruli ulcer is an infectious disease caused by Mycobacterium ulcerans.<ref name=WHO2013>

Buruli ulcer (Mycobacterium ulcerans infection) Fact sheet N°199(link). {{{website}}}.

June 2013.

</ref> The early stage of the infection is characterised by a painless nodule or area of swelling.<ref name=WHO2013/> This nodule can turn into an ulcer.<ref name=WHO2013/> The ulcer may be larger inside than at the surface of the skin,<ref name=Nak2013>Nakanaga, K,

 Buruli ulcer and mycolactone-producing mycobacteria., 
 Japanese Journal of Infectious Diseases, 
 2013,
 Vol. 66(Issue: 2),
 pp. 83–8,
 DOI: 10.7883/yoken.66.83,
 PMID: 23514902,</ref> and can be surrounded by swelling.<ref name=Nak2013/> As the disease worsens, bone can be infected.<ref name=WHO2013/> Buruli ulcers most commonly affect the arms or legs;<ref name=WHO2013/> fever is uncommon.<ref name=WHO2013/>

M. ulcerans releases a toxin known as mycolactone, which decreases immune system function and results in tissue death.<ref name=WHO2013/> Bacteria from the same group also cause tuberculosis and leprosy (M. tuberculosis and M. leprae, respectively).<ref name=WHO2013/> How the disease is spread is not known.<ref name=WHO2013/> Sources of water may be involved in the spread.<ref name=Nak2013/> As of 2018, there is no effective vaccine.<ref name=WHO2018/><ref name=Ein2011/> The Bacillus Calmette–Guérin (BCG) vaccine has demonstrated limited protection.<ref name=WHO2013/>

If people are treated early, antibiotics for eight weeks are effective in 80% of cases.<ref name=WHO2013/><ref name=Guidance2012>

Treatment of Mycobacterium ulcerans disease (Buruli ulcer): guidance for health workers.(link). World Health Organization.

2012.

Accessed 17 April 2018.

</ref> The treatment often includes the medications rifampicin and streptomycin.<ref name=WHO2013/> Clarithromycin or moxifloxacin are sometimes used instead of streptomycin.<ref name=WHO2013/> Other treatments may include cutting out the ulcer.<ref name=WHO2013/><ref name=Siz2006>,

 Mycobacterium ulcerans infection: control, diagnosis, and treatment, 
 Lancet Infect Dis, 
 2006,
 Vol. 6(Issue: 5),
 pp. 288–296,
 DOI: 10.1016/S1473-3099(06)70464-9,
 PMID: 16631549,
 
 
 Full text,</ref> After the infection heals, the area typically has a scar.<ref name=Ein2011>, 
 Buruli ulcer, 
 Hum Vaccin, 
 
 Vol. 7(Issue: 11),
 pp. 1198–203,
 DOI: 10.4161/hv.7.11.17751,
 PMID: 22048117,
 
 
 Full text,</ref>

About 2,000 cases are reported a year.<ref name=WHO2018>

Buruli ulcer (Mycobacterium ulcerans infection) Fact sheet N°199(link). {{{website}}}.

April 2018.

</ref> Buruli ulcers occur most commonly in rural sub-Saharan Africa and Australia with fewer cases in South America and the Western Pacific.<ref name=WHO2018/> Children are most commonly infected in Africa, while adults are most commonly affected in Australia.<ref name=WHO2018/> Cases have been reported in 33 countries.<ref name=WHO2018/> The disease also occurs in animals other than humans, though no link between animal and human infection has been established.<ref>

Buruli Ulcer: Transmission(link). Centers for Disease Control and Prevention.

26 January 2015.

Accessed 17 April 2018.

</ref> Albert Ruskin Cook was the first to describe buruli ulcers in 1897.<ref name=Nak2013/> It is classified as a neglected tropical disease.<ref name=NTD2017>

Neglected Tropical Diseases(link). cdc.gov.

June 6, 2011.

</ref>

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.<ref name=Yotsu2015/><ref name=WHO2019/> 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.<ref name=Yotsu2015/><ref name=WHO2019/> Over the course of a few weeks, the original swollen area may expand, forming an irregularly shaped patch of swollen skin.<ref name=Yotsu2015>,

 Revisiting Buruli Ulcer, 
 The Journal of Dermatology, 
 
 Vol. 42(Issue: 11),
 pp. 1033-41,
 DOI: 10.1111/1346-8138.13049,</ref><ref name=Guarner2018>Guarner J, 
 Buruli Ulcer: Review of a Neglected Skin Mycobacterial Disease, 
 Journal of Clinical Microbiology, 
 
 Vol. 56(Issue: 4),
 pp. e01507-17,
 DOI: 10.1128/JCM.01507-17,
 
 PMC: 5869816,</ref> After about four weeks, the affected skin sloughs off, leaving a large painless ulcer.<ref name=WHO2019>

Buruli ulcer (Mycobacterium ulcerans infection)(link). {{{website}}}. World Health Organization. 21 May 2019.

</ref> 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.<ref name=Guarner2018/> Oftentimes, these large exposed ulcers are infected by other bacteria, causing the wound to smell foul.<ref name=Guarner2018/>

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%).<ref name=Zingue2018>,

 Buruli Ulcer, a Prototype for Ecosystem-Related Infection, Caused by Mycobacterium ulcerans, 
 Clinical Microbiology Reviews, 
 
 Vol. 31(Issue: 1),
 pp. e0004-17,
 DOI: 10.1128/CMR.00045-17,
 
 PMC: 5740976,</ref> 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.<ref name=Guarner2018/> 

• 
  A typical Buruli ulcer on the left hand of a 17-year-old boy in Nigeria
• 
  Ear of an 18-month-old with confirmed Buruli ulcer
• 
  Buruli ulcer in a long-term traveler to Senegal

Cause

Buruli ulcer is caused by infection of the skin with the bacterium Mycobacterium ulcerans.<ref name=WHO2019/> 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.<ref name=Guarner2018/> 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.<ref name=Yotsu2018>,

 Buruli Ulcer: a Review of the Current Knowledge, 
 Current Tropical Medicine Reports, 
 
 Vol. 5(Issue: 4),
 pp. 247-256,
 DOI: 10.1007/s40475-018-0166-2,
 
 PMC: 6223704,</ref> 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.<ref name=Yotsu2018/> 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.<ref name=Yotsu2018/> This cell death results in large-scale tissue death at the site of infection, causing the large open ulcer characteristic of disease.<ref name=Yotsu2018/> At the same time, Sec61 inhibition prevents cells from signalling to activate the immune system, resulting in ulcers that lack infiltrating immune cells.<ref name=Yotsu2018/>

Transmission

It is not known how M. ulcerans is introduced to humans.<ref name=WHO2019/> Human-to-human transmission is extremely rare, and Buruli ulcer is not considered contagious.<ref name=Guarner2018/> 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.<ref name=Yotsu2018/> Supporting this model, M. ulcerans is widespread in aquatic environments, where it can survive as free-living or associated with other aquatic organisms.<ref name=Zingue2018/> 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.<ref name=Yotsu2018/> 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.<ref name=Zingue2018/> However, whether these insects are regularly involved in transmission remains unclear.<ref name=Guarner2018/><ref name=Yotsu2018/> Pre-existing wounds have also been implicated in disease transmission, and poor wound care is associated with a higher risk of acquiring Buruli ulcer.<ref name=Jacobsen2010>,

 Risk factors for Mycobacterium ulcerans infection, 
 International Journal of Infectious Diseases, 
 
 Vol. 14(Issue: 8),
 pp. e677-e681,
 DOI: 10.1016/j.ijid.2009.11.013,</ref> 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.<ref name=Guarner2018/><ref name=Jacobsen2010/>

Other mammals are also susceptible to ulcers caused by M. ulcerans, and could serve as environmental reservoirs of M. ulcerans.<ref name=Guarner2018/>

In Australia, animals such as koalas and possums are naturally infected.<ref>,

 Skin ulcers caused by Mycobacterium ulcerans in koalas near Bairnsdale, Australia, 
 Pathology, 
 1984,
 Vol. 16(Issue: 3),
 pp. 256–260,
 DOI: 10.3109/00313028409068533,
 PMID: 6514393,</ref><ref>, 
 Mycobacterium ulcerans infection on Phillip Island, Victoria, 
 Med. J. Aust., 
 
 Vol. 160(Issue: 3),
 
 DOI: 10.5694/j.1326-5377.1994.tb126569.x,
 PMID: 8295586,</ref> 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.<ref>, 
 Buruli ulcer in Benin., 
 Lancet, 
 1990,
 Vol. 336(Issue: 8723),
 pp. 1109–1111,
 DOI: 10.1016/0140-6736(90)92581-2,
 PMID: 1977990,</ref> 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.<ref name=Portaels08>,

 First Cultivation and Characterization of Mycobacterium ulcerans from the Environment, 
 PLoS Negl Trop Dis, 
 2008,
 Vol. 2(Issue: 3),
 pp. e178,
 DOI: 10.1371/journal.pntd.0000178,
 PMID: 18365032,
 PMC: 2268003, 

</ref>

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.<ref>,

 Comparative study of the sensitivity of different diagnostic methods for the laboratory diagnosis of Buruli ulcer disease, 
 Clin Infect Dis, 
 2009,
 Vol. 48(Issue: 8),
 pp. 1055–64,
 DOI: 10.1086/597398,
 PMID: 19275499,</ref>

Prevention

There is no specific vaccine for Myocobacterium ulcerans.<ref name=Ein2011/> The Bacillus Calmette-Guérin vaccine may offer temporary protection.<ref name=WHO2013/>

Treatment

Healed Buruli ulcer lesions in a Ghanaian woman

If treated early, antibiotics for eight weeks are effective in 80% of people.<ref name=WHO2013/> This often includes the medications rifampicin and streptomycin.<ref name=WHO2013/> Clarithromycin or moxifloxacin are sometimes used instead of streptomycin.<ref name=WHO2013/>

Treatment may also include cutting out the ulcer.<ref name=Siz2006/> 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.<ref name="statistics1">WHO, (2000) Buruli ulcer: Mycobacterium ulcerans infection. Geneva</ref> 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.<ref name="statistics2">,

 Buruli ulcer in Ghana: results of a national case search, 
 Emerging Infect. Dis., 
 
 Vol. 8(Issue: 2),
 pp. 167–70,
 DOI: 10.3201/eid0802.010119,
 PMID: 11897068,
 PMC: 2732443,</ref>

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,<ref name=Group1971>Uganda Buruli Group,

 Epidemiology of Mycobacterium ulcerans infection (Buruli ulcer) at Kinyara, Uganda, 
 Trans R Soc Trop Med Hyg, 
 1971,
 Vol. 65(Issue: 6),
 pp. 763–775,
 DOI: 10.1016/0035-9203(71)90090-3,
 PMID: 5157438,</ref> 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.<ref name=Marston1995>,

 Emergence of Buruli Ulcer disease in the Daloa region of Côte d'Ivoire, 
 Am J Trop Med Hyg, 
 1995,
 Vol. 52(Issue: 3),
 pp. 219–224,
 DOI: 10.4269/ajtmh.1995.52.219,
 PMID: 7694962,</ref>

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 ^{(November 2009)} . 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.<ref>

Buruli ulcer disease -Mycobacterium ulcerans infection(link). {{{website}}}.

</ref> 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.<ref name=Portaels08/> This suggested that the disease might be transmitted via contact with the environment rather than person to person.<ref name=Portaels08/> The entire genome of M. ulcerans has been sequenced.<ref name="pmid27688344">,

 Complete Genome Sequence of Mycobacterium ulcerans subsp. shinshuense, 
 Genome Announc, 
 2016,
 Vol. 4(Issue: 5),
 
 DOI: 10.1128/genomeA.01050-16,
 PMID: 27688344,
 PMC: 5043562,</ref>

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

New answer to MRSA, other 'superbug' infections: clay minerals? | NSF - National Science Foundation(link). www.nsf.gov.

</ref>

Other names

Other names include Bairnsdale ulcer, Searls ulcer, Daintree ulcer,<ref name="Andrews">,

 Andrews' Diseases of the Skin: clinical Dermatology, 
  
 Saunders Elsevier, 
 2006, 
  
  
 ISBN 978-0-7216-2921-6,</ref><ref name="Bolognia">, 
  
 Dermatology: 2-Volume Set, 
  
 St. Louis:Mosby, 
 2007, 
  
  
 ISBN 978-1-4160-2999-1,</ref><ref name="Lavender CJ, Senanayake SN, Fyfe JA, et al. 62–3">, 
 First case of Mycobacterium ulcerans disease (Bairnsdale or Buruli ulcer) acquired in New South Wales, 
 Med. J. Aust., 
 
 Vol. 186(Issue: 2),
 pp. 62–3,
 DOI: 10.5694/j.1326-5377.2007.tb00801.x,
 PMID: 17223764,
 
 
 Full text,</ref><ref name="Bolognia"/> Kumusi ulcer,<ref>, 
  
 Microbial zoonoses and sapronoses. online version, 
  
 Dordrecht:Springer, 
  
  
  
 ISBN 9789048196579,</ref> and mycoburuli ulcers.<ref>{{{last}}}, 
 Yann A. Meunier, 
  
 Tropical diseases : a practical guide for medical practitioners and students. online version, 
  
 Oxford:Oxford University Press, 
  
  
  
 ISBN 9780199997909,</ref> Searls was one of the first physicians to describe it.<ref>, 
  
 Medical Journal of Australia. online version, 
  
 Australasian Medical Publishing Company, 
 1966, 
  
 Volume: 2,</ref>

External links

• World Health Organization buruli ulcer page

'Mycobacterium ulcerans'(link). {{{website}}}.

• ,

 Ecology and Transmission of Buruli Ulcer Disease: A Systematic Review, 
 PLoS Neglected Tropical Diseases, 
 2010,
 Vol. 4(Issue: 12),
 pp. e911,
 DOI: 10.1371/journal.pntd.0000911,
 PMID: 21179505,
 PMC: 3001905,