Buruli ulcer
Encyclopedia
The Buruli ulcer is an infectious disease
caused by Mycobacterium ulcerans
. The genus
also includes the causative agents of tuberculosis
and leprosy
(M. tuberculosis
and M. leprae
, respectively). The early stage of infection is characterised by a painless nodule, with non-pyogenic, necrotising lesion
s developing in the skin, and occasionally in adjacent bone, as the disease progresses. M. ulcerans secretes a lipid toxin, mycolactone
, which functions as an immune suppressant, necrotising agent and activator of cellular apoptosis
in mammalian tissues.
, 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 oedematous 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
. 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
, near Melbourne, Australia
. They were the first to identify Mycobacterium ulcerans
as the pathogen
causing it. The disease was so 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.
In March 2008, researchers announced the first isolation of M. ulcerans from the environment. This indicates that the disease is transmitted via aquatic areas rather than person to person. An international team of researchers led by Monash University
scientist Dr Tim Stinear has sequenced the entire genome of M. ulcerans.
The infection in most instances presents as a subcutaneous nodule
, which is characteristically painless. In southern Australia the presentation is more often as a papule
(or pimple), which is in the skin
(dermis) rather than subcutaneous. The infection is mostly on the limbs, most often on exposed areas but not on the hands or feet. In children all areas may be involved, including the face or abdomen. A more severe form of infection produces diffuse swelling of a limb, which, unlike the papule or nodule, can be painful and accompanied by fever
. Infection may frequently follow physical trauma
, often minor trauma such as a small scratch.
Th1-mediated immune responses
are protective against M. ulcerans infection, whereas Th2-mediated responses are not.
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.
(removal) of the lesion, which may be only a minor operation and very successful if undertaken early. Advanced disease may require prolonged treatment with extensive skin grafting. Surgical practice can be dangerous and scarcely available in affected third world countries.
Antibiotics currently play little part in the treatment of Buruli ulcer. The WHO currently recommend rifampicin
and streptomycin
for eight weeks in the hope of reducing the need for surgery. The combination of rifampicin and clarithromycin
has been used for many years in Australia. Rifampicin must never be used alone because the bacterium quickly becomes resistant.
There are a number of experimental treatments currently being investigated:
In a small series of eight patients, local heat at 40°C led to complete healing without surgery (except the initial removal of dead tissue).
, 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. In East Africa, thousands of cases occur annually and in these areas the disease has displaced leprosy to become the second most important mycobacterial disease of man (after tuberculosis).
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 the 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.
Infectious disease
Infectious diseases, also known as communicable diseases, contagious diseases or transmissible diseases comprise clinically evident illness resulting from the infection, presence and growth of pathogenic biological agents in an individual host organism...
caused by Mycobacterium ulcerans
Mycobacterium ulcerans
Mycobacterium ulcerans is a slow-growing mycobacterium that classically infects the skin and subcutaneous tissues, giving rise to indolent nonulcerated and ulcerated lesions. After tuberculosis and leprosy, Buruli ulcer is the third most common mycobacteriosis of humans. M...
. The genus
Mycobacterium
Mycobacterium is a genus of Actinobacteria, given its own family, the Mycobacteriaceae. The genus includes pathogens known to cause serious diseases in mammals, including tuberculosis and leprosy...
also includes the causative agents of tuberculosis
Tuberculosis
Tuberculosis, MTB, or TB is a common, and in many cases lethal, infectious disease caused by various strains of mycobacteria, usually Mycobacterium tuberculosis. Tuberculosis usually attacks the lungs but can also affect other parts of the body...
and leprosy
Leprosy
Leprosy or Hansen's disease is a chronic disease caused by the bacteria Mycobacterium leprae and Mycobacterium lepromatosis. Named after physician Gerhard Armauer Hansen, leprosy is primarily a granulomatous disease of the peripheral nerves and mucosa of the upper respiratory tract; skin lesions...
(M. tuberculosis
Mycobacterium tuberculosis
Mycobacterium tuberculosis is a pathogenic bacterial species in the genus Mycobacterium and the causative agent of most cases of tuberculosis . First discovered in 1882 by Robert Koch, M...
and M. leprae
Mycobacterium leprae
Mycobacterium leprae, also known as Hansen’s coccus spirilly, mostly found in warm tropical countries, is a bacterium that causes leprosy . It is an intracellular, pleomorphic, acid-fast bacterium. M. leprae is an aerobic bacillus surrounded by the characteristic waxy coating unique to mycobacteria...
, respectively). The early stage of infection is characterised by a painless nodule, with non-pyogenic, necrotising lesion
Lesion
A lesion is any abnormality in the tissue of an organism , usually caused by disease or trauma. Lesion is derived from the Latin word laesio which means injury.- Types :...
s developing in the skin, and occasionally in adjacent bone, as the disease progresses. M. ulcerans secretes a lipid toxin, mycolactone
Mycolactone
Mycolactone is a polyketide-derived macrolide produced and secreted by a group of very closely related pathogenic mycobacteria that have been assigned a variety of species names including, M. ulcerans, M. liflandii , M. pseudoshottsii, and some strains of M. marinum...
, which functions as an immune suppressant, necrotising agent and activator of cellular apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
in mammalian tissues.
Identification of the disease and its pathogen
James Augustus GrantJames Augustus Grant
James Augustus Grant, CB, CSI, FRS, FRGS was a Scottish explorer of eastern equatorial Africa.Grant was born at Nairn in the Scottish Highlands, where his father was the parish minister, and educated at the grammar school and Marischal College, Aberdeen. In 1846 he joined the Indian army...
, 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 oedematous form of the disease, and is the first known description of the infection. Buruli ulcer disease was identified in 1897 by Sir Albert Cook
Albert Ruskin Cook
Sir Albert Ruskin Cook, CMG, OBE, MD was a British born medical missionary in Uganda, and founder of Mulago Hospital and Mengo Hospital. Together with his wife, Katharine Cook , he established a maternity training school in Uganda....
, a British physician, at Mengo Hospital
Mengo Hospital
Mengo Hospital, also known as Namirembe Hospital, is a hospital in Kampala, the capital city of Uganda.-Location:The hospital is located on Namirembe Hill, in Lubaga Division, in the northwestern Kampala, Uganda's capital and largest metropolitan area. The travel distance, by road, from the city's...
in Kampala
Kampala
Kampala is the largest city and capital of Uganda. The city is divided into five boroughs that oversee local planning: Kampala Central Division, Kawempe Division, Makindye Division, Nakawa Division and Lubaga Division. The city is coterminous with Kampala District.-History: of Buganda, had chosen...
, Uganda
Uganda
Uganda , officially the Republic of Uganda, is a landlocked country in East Africa. Uganda is also known as the "Pearl of Africa". It is bordered on the east by Kenya, on the north by South Sudan, on the west by the Democratic Republic of the Congo, on the southwest by Rwanda, and on the south by...
. A detailed description of the disease was written in 1948 by Professor Peter MacCallum
Peter MacCallum
Sir Peter MacCallum MC was a Scottish-born Australian oncologist and the co-founder and eponym of the Peter MacCallum Cancer Centre in Melbourne....
and his colleagues, who were treating patients from the Bairnsdale district
Bairnsdale, Victoria
Bairnsdale is a small city in Gippsland, Victoria, Australia. With a population at the 2006 census of 11,282, it is a major regional centre of eastern Victoria along with Traralgon and Sale....
, near Melbourne, Australia
Australia
Australia , officially the Commonwealth of Australia, is a country in the Southern Hemisphere comprising the mainland of the Australian continent, the island of Tasmania, and numerous smaller islands in the Indian and Pacific Oceans. It is the world's sixth-largest country by total area...
. They were the first to identify Mycobacterium ulcerans
Mycobacterium ulcerans
Mycobacterium ulcerans is a slow-growing mycobacterium that classically infects the skin and subcutaneous tissues, giving rise to indolent nonulcerated and ulcerated lesions. After tuberculosis and leprosy, Buruli ulcer is the third most common mycobacteriosis of humans. M...
as the pathogen
Pathogen
A pathogen gignomai "I give birth to") or infectious agent — colloquially, a germ — is a microbe or microorganism such as a virus, bacterium, prion, or fungus that causes disease in its animal or plant host...
causing it. The disease was so named after Buruli County in Uganda
Uganda
Uganda , officially the Republic of Uganda, is a landlocked country in East Africa. Uganda is also known as the "Pearl of Africa". It is bordered on the east by Kenya, on the north by South Sudan, on the west by the Democratic Republic of the Congo, on the southwest by Rwanda, and on the south by...
(now called Nakasongola District
Nakasongola District
Nakasongola District is a district in Central Uganda. The district is named after its 'chief town' of Nakasongola.-Location:Nakasongola District is bordered by Apac District to the northwest, Amolatar District to the northeast, Kayunga District to the east, Luweero District to the south, Nakaseke...
), because of the many cases that occurred there in the 1960s. The incidence of the disease has recently been rising in tropical Africa.
In March 2008, researchers announced the first isolation of M. ulcerans from the environment. This indicates that the disease is transmitted via aquatic areas rather than person to person. An international team of researchers led by Monash University
Monash University
Monash University is a public university based in Melbourne, Victoria. It was founded in 1958 and is the second oldest university in the state. Monash is a member of Australia's Group of Eight and the ASAIHL....
scientist Dr Tim Stinear has sequenced the entire genome of M. ulcerans.
Symptoms
Nodule (medicine)
For use of the term nodule in dermatology, see Nodule In medicine, a nodule refers to a relatively hard, roughly spherical abnormal structure....
, which is characteristically painless. In southern Australia the presentation is more often as a papule
Papule
A papule is a circumscribed, solid elevation of skin with no visible fluid, varying in size from a pinhead to 1 cm.With regard to the quote "...varying in size from a pinhead to 1cm," depending on which text is referenced, some authors state the cutoff between a papule and a plaque as 0.5cm,...
(or pimple), which is in the skin
Skin
-Dermis:The dermis is the layer of skin beneath the epidermis that consists of connective tissue and cushions the body from stress and strain. The dermis is tightly connected to the epidermis by a basement membrane. It also harbors many Mechanoreceptors that provide the sense of touch and heat...
(dermis) rather than subcutaneous. The infection is mostly on the limbs, most often on exposed areas but not on the hands or feet. In children all areas may be involved, including the face or abdomen. A more severe form of infection produces diffuse swelling of a limb, which, unlike the papule or nodule, can be painful and accompanied by fever
Fever
Fever is a common medical sign characterized by an elevation of temperature above the normal range of due to an increase in the body temperature regulatory set-point. This increase in set-point triggers increased muscle tone and shivering.As a person's temperature increases, there is, in...
. Infection may frequently follow physical trauma
Physical trauma
Trauma refers to "a body wound or shock produced by sudden physical injury, as from violence or accident." It can also be described as "a physical wound or injury, such as a fracture or blow." Major trauma can result in secondary complications such as circulatory shock, respiratory failure and death...
, often minor trauma such as a small scratch.
Pathology
The disease is primarily an infection of subcutaneous fat, resulting in a focus of necrotic (dead) fat containing myriads of the mycobacteria in characteristic spherules formed within the dead fat cells. Skin ulceration is a secondary event. The mycobacterium produces a toxin, named mycolactone, which causes this fat necrosis and inhibits an immune response. Healing may occur spontaneously but more often the disease is slowly progressive with further ulceration, granulation, scarring, and contractures. Secondary infection may occur with other nodules developing and infection may occur into bone. Although seldom fatal, the disease results in considerable morbidity and hideous deformity.Th1-mediated immune responses
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
are protective against M. ulcerans infection, whereas Th2-mediated responses are not.
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 PCRPolymerase chain reaction
The polymerase chain reaction is a scientific technique in molecular biology to amplify a single or a few copies of a piece of DNA across several orders of magnitude, generating thousands to millions of copies of a particular DNA sequence....
using the IS2404 target is helpful, but this is not specific for M. ulcerans. The Ziehl-Neelsen stain
Ziehl-Neelsen stain
The Ziehl–Neelsen stain, also known as the acid-fast stain, was first described by two German doctors; Franz Ziehl , a bacteriologist and Friedrich Neelsen , a pathologist. It is a special bacteriological stain used to identify acid-fast organisms, mainly Mycobacteria...
is only 40–80% sensitive, and culture is 20–60% sensitive. Simultaneous use of multiple methods may be necessary to make the diagnosis.
Treatment
Treatment is by surgical excisionSurgery
Surgery is an ancient medical specialty that uses operative manual and instrumental techniques on a patient to investigate and/or treat a pathological condition such as disease or injury, or to help improve bodily function or appearance.An act of performing surgery may be called a surgical...
(removal) of the lesion, which may be only a minor operation and very successful if undertaken early. Advanced disease may require prolonged treatment with extensive skin grafting. Surgical practice can be dangerous and scarcely available in affected third world countries.
Antibiotics currently play little part in the treatment of Buruli ulcer. The WHO currently recommend rifampicin
Rifampicin
Rifampicin or rifampin is a bactericidal antibiotic drug of the rifamycin group. It is a semisynthetic compound derived from Amycolatopsis rifamycinica ...
and streptomycin
Streptomycin
Streptomycin is an antibiotic drug, the first of a class of drugs called aminoglycosides to be discovered, and was the first antibiotic remedy for tuberculosis. It is derived from the actinobacterium Streptomyces griseus. Streptomycin is a bactericidal antibiotic. Streptomycin cannot be given...
for eight weeks in the hope of reducing the need for surgery. The combination of rifampicin and clarithromycin
Clarithromycin
Clarithromycin is a macrolide antibiotic used to treat pharyngitis, tonsillitis, acute maxillary sinusitis, acute bacterial exacerbation of chronic bronchitis, pneumonia , skin and skin structure infections...
has been used for many years in Australia. Rifampicin must never be used alone because the bacterium quickly becomes resistant.
There are a number of experimental treatments currently being investigated:
- SitafloxacinSitafloxacinSitafloxacin is a fluoroquinolone antibiotic that shows promise in the treatment of Buruli ulcer. The molecule was identified by Daiichi Sankyo Co., which brought ofloxacin and levofloxacin to the market. Sitafloxacin is currently marketed in Japan by Daiichi Sankyo under the tradename...
and rifampicinRifampicinRifampicin or rifampin is a bactericidal antibiotic drug of the rifamycin group. It is a semisynthetic compound derived from Amycolatopsis rifamycinica ...
is a synergistic combination that has only been trialled in mice. - Rifalazil is a rifamycinRifamycinThe rifamycins are a group of antibiotics that are synthesized either naturally by the bacterium Amycolatopsis mediterranei or artificially. They are a subclass of the larger family Ansamycin...
antibiotic that appears to be more potent than rifampicinRifampicinRifampicin or rifampin is a bactericidal antibiotic drug of the rifamycin group. It is a semisynthetic compound derived from Amycolatopsis rifamycinica ...
that has only been trialled in mice. - Epiroprim and dapsoneDapsoneDapsone is a medication most commonly used in combination with rifampicin and clofazimine as multidrug therapy for the treatment of Mycobacterium leprae infections . It is also second-line treatment for prophylaxis against Pneumocystis pneumonia caused by Pneumocystis jiroveci Dapsone...
are synergistic when used in combination (in vitro studies only at present) - Diarylquinoline shows high potency in vitro
- Application of French clayMontmorilloniteMontmorillonite is a very soft phyllosilicate group of minerals that typically form in microscopic crystals, forming a clay. It is named after Montmorillon in France. Montmorillonite, a member of the smectite family, is a 2:1 clay, meaning that it has 2 tetrahedral sheets sandwiching a central...
.
In a small series of eight patients, local heat at 40°C led to complete healing without surgery (except the initial removal of dead tissue).
Global spread
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 AfricaWest Africa
West Africa or Western Africa is the westernmost region of the African continent. Geopolitically, the UN definition of Western Africa includes the following 16 countries and an area of approximately 5 million square km:-Flags of West Africa:...
, in Central
Central America
Central America is the central geographic region of the Americas. It is the southernmost, isthmian portion of the North American continent, which connects with South America on the southeast. When considered part of the unified continental model, it is considered a subcontinent...
and South America
South America
South America is a continent situated in the Western Hemisphere, mostly in the Southern Hemisphere, with a relatively small portion in the Northern Hemisphere. The continent is also considered a subcontinent of the Americas. It is bordered on the west by the Pacific Ocean and on the north and east...
, in southeast Asia
Southeast Asia
Southeast Asia, South-East Asia, South East Asia or Southeastern Asia is a subregion of Asia, consisting of the countries that are geographically south of China, east of India, west of New Guinea and north of Australia. The region lies on the intersection of geological plates, with heavy seismic...
and New Guinea
New Guinea
New Guinea is the world's second largest island, after Greenland, covering a land area of 786,000 km2. Located in the southwest Pacific Ocean, it lies geographically to the east of the Malay Archipelago, with which it is sometimes included as part of a greater Indo-Australian Archipelago...
. 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. In East Africa, thousands of cases occur annually and in these areas the disease has displaced leprosy to become the second most important mycobacterial disease of man (after tuberculosis).
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 the 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.
External links
- World Health Organization buruli ulcer page
- Buruli Action Page (Warning: Graphic Images)