Buruli ulcer () is an
infectious disease
An infection is the invasion of tissues by pathogens, their multiplication, and the reaction of host tissues to the infectious agent and the toxins they produce. An infectious disease, also known as a transmissible disease or communicable dise ...
characterized by the development of painless open wounds. The disease is limited to certain areas of the world, most cases occurring in Sub-Saharan Africa and Australia. The first sign of infection is a small painless
nodule or area of swelling, typically on the arms or legs. The nodule grows larger over days to weeks, eventually forming an open
ulcer
An ulcer is a discontinuity or break in a bodily membrane that impedes normal function of the affected organ. According to Robbins's pathology, "ulcer is the breach of the continuity of skin, epithelium or mucous membrane caused by sloughing o ...
. Deep ulcers can cause scarring of
muscle
Skeletal muscles (commonly referred to as muscles) are organs of the vertebrate muscular system and typically are attached by tendons to bones of a skeleton. The muscle cells of skeletal muscles are much longer than in the other types of muscl ...
s and
tendon
A tendon or sinew is a tough, high-tensile-strength band of dense fibrous connective tissue that connects muscle to bone. It is able to transmit the mechanical forces of muscle contraction to the skeletal system without sacrificing its ability ...
s, resulting in permanent disability.
Buruli ulcer is caused by skin infection with
bacteria
Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria were among ...
called ''
Mycobacterium ulcerans
''Mycobacterium ulcerans'' is a species of bacteria found in various aquatic environments. The bacteria can infect humans and some other animals, causing persistent open wounds called Buruli ulcer. ''M. ulcerans'' is closely related to '' Mycob ...
''. The mechanism by which ''M. ulcerans'' is transmitted from the environment to humans is not known, but may involve the bite of an aquatic insect or the infection of open wounds. Once in the skin, ''M. ulcerans'' grows and releases the toxin
mycolactone
Mycolactone is a polyketide-derived macrolide produced and secreted by a group of very closely related pathogenic Mycobacteria species that have been assigned a variety of names including, ''Mycobacterium_ulcerans, M. ulcerans'', ''M. liflandii'' ...
, which blocks the normal function of cells, resulting in
tissue death and
immune suppression
Immunosuppression is a reduction of the activation or efficacy of the immune system. Some portions of the immune system itself have immunosuppressive effects on other parts of the immune system, and immunosuppression may occur as an adverse react ...
at the site of the ulcer.
The
World Health Organization
The World Health Organization (WHO) is a specialized agency of the United Nations responsible for international public health. The WHO Constitution states its main objective as "the attainment by all peoples of the highest possible level of h ...
(WHO) recommends treating Buruli ulcer with a combination of the antibiotics
rifampicin
Rifampicin, also known as rifampin, is an ansamycin antibiotic used to treat several types of bacterial infections, including tuberculosis (TB), mycobacterium avium complex, ''Mycobacterium avium'' complex, leprosy, and Legionnaires’ disease. ...
and
clarithromycin
Clarithromycin, sold under the brand name Biaxin among others, is an antibiotic used to treat various bacterial infections. This includes strep throat, pneumonia, skin infections, ''H. pylori'' infection, and Lyme disease, among others. Clarith ...
. With antibiotic administration and proper wound care, small ulcers typically heal within six months. Deep ulcers and those on sensitive body sites may require surgery to remove dead tissue or repair scarred muscles or joints. Even with proper treatment, Buruli ulcer can take months to heal. Regular cleaning and dressing of wounds aids healing and prevents secondary infections.
In 2018, WHO received 2,713 reports of Buruli ulcer globally.
[ Although rare, it typically occurs in rural areas near slow-moving or stagnant water. The first written description of the disease is credited to ]Albert Ruskin Cook
Sir Albert Ruskin Cook, Order of St Michael and St George, CMG, Order of the British Empire, OBE (22 March 1870 – 23 April 1951) was a British medical missionary in Uganda, and the founder of Mulago Hospital and Mengo Hospital. Together with ...
in 1897 at Mengo Hospital
Mengo Hospital, also known as Namirembe Hospital, is a private, faith-based, community, teaching hospital in Kampala, the capital and largest city of Uganda.
Location
The hospital is located on Namirembe Hill in Lubaga Division in northwestern ...
in Uganda. Fifty years later, the causative bacterium was isolated and identified by a group at the Alfred Hospital in Melbourne
Melbourne ( ; Boonwurrung/Woiwurrung: ''Narrm'' or ''Naarm'') is the capital and most populous city of the Australian state of Victoria, and the second-most populous city in both Australia and Oceania. Its name generally refers to a met ...
. In 1998, WHO established the Global Buruli Ulcer Initiative to coordinate global efforts to eliminate Buruli ulcer. WHO considers it a neglected tropical disease
Neglected tropical diseases (NTDs) are a diverse group of tropical disease, tropical infections that are common in low-income populations in Developing country, developing regions of Africa, Asia, and the Americas. They are caused by a variety ...
.
Signs and symptoms
The first sign of Buruli ulcer is a painless swollen bump on the arm or leg, often similar in appearance to an insect bite.[ Sometimes the swollen area instead appears as 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 expands to form an irregularly shaped patch of raised skin. After about four weeks, the affected skin sloughs off leaving a painless ulcer.] Buruli ulcers typically have "undermined edges", the ulcer being a few centimeters wider underneath the skin than the wound itself.
In some people, the ulcer may heal on its own or remain small but linger unhealed for years. In others, it continues to grow wider and sometimes deeper, with skin at the margin dying
Dying is the final stage of life which will eventually lead to death. Diagnosing dying is a complex process of clinical decision-making, and most practice checklists facilitating this diagnosis are based on cancer diagnoses.
Signs of dying ...
and sloughing off. Large ulcers may extend deep into underlying tissue, causing bone infection and exposing muscle, tendon, and bone to the air. When ulcers extend into muscles and tendons, parts of these tissues can be replaced by scar tissue, immobilizing the body part and resulting in permanent disability. Exposed ulcers can be infected by other bacteria, causing the wound to become red
Red is the color at the long wavelength end of the visible spectrum of light, next to orange and opposite violet. It has a dominant wavelength of approximately 625–740 nanometres. It is a primary color in the RGB color model and a secondar ...
, painful, and foul smelling. Symptoms are typically limited to those caused by the wound; the disease rarely affects other parts of the body.
Buruli ulcers can appear anywhere on the body, but are typically on the limbs. Ulcers are most common on the lower limbs (roughly 62% of ulcers globally) and upper limbs (24%), but can also be found on the trunk (9%), head or neck (3%), or genitals (less than 1%).
The World Health Organization
The World Health Organization (WHO) is a specialized agency of the United Nations responsible for international public health. The WHO Constitution states its main objective as "the attainment by all peoples of the highest possible level of h ...
classifies Buruli ulcer into three categories depending on the severity of its symptoms. Category I describes a single small ulcer that is less than . Category II describes a larger ulcer, up to , as well as plaques and broader swollen areas that have not yet opened into ulcers. Category III is for an ulcer larger than 15 centimeters, multiple ulcers, or ulcers that have spread to include particularly sensitive sites such as the eyes, bones, joints, or genitals.
Cause
Buruli ulcer is caused by infection of the skin with the bacterium
Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria were among ...
''Mycobacterium ulcerans
''Mycobacterium ulcerans'' is a species of bacteria found in various aquatic environments. The bacteria can infect humans and some other animals, causing persistent open wounds called Buruli ulcer. ''M. ulcerans'' is closely related to '' Mycob ...
''.[ ''M. ulcerans'' is a ]mycobacterium
''Mycobacterium'' is a genus of over 190 species in the phylum Actinomycetota, assigned its own family, Mycobacteriaceae. This genus includes pathogens known to cause serious diseases in mammals, including tuberculosis ('' M. tuberculosis'') and ...
, closely related to ''Mycobacterium marinum
''Mycobacterium marinum'' is a slow growing mycobacterium (SGM) belonging to the genus ''Mycobacterium'' and the phylum Actinobacteria. The strain marinum was first identified by Aronson in 1926 and it is observed as a pathogenic mycobacterium. F ...
'' which infects aquatic animals and, rarely, humans. It is more distantly related to other slow-growing mycobacteria that infect humans, such as ''Mycobacterium tuberculosis
''Mycobacterium tuberculosis'' (M. tb) is a species of pathogenic bacteria in the family Mycobacteriaceae and the causative agent of tuberculosis. First discovered in 1882 by Robert Koch, ''M. tuberculosis'' has an unusual, waxy coating on its c ...
'', which causes tuberculosis
Tuberculosis (TB) is an infectious disease usually caused by '' Mycobacterium tuberculosis'' (MTB) bacteria. Tuberculosis generally affects the lungs, but it can also affect other parts of the body. Most infections show no symptoms, in ...
, and ''Mycobacterium leprae
''Mycobacterium leprae'' (also known as the leprosy bacillus or Hansen's bacillus), is one
of the two species of bacteria that cause Hansen’s disease (leprosy), a chronic but curable infectious disease that damages the peripheral nerves and ...
'', which causes leprosy
Leprosy, also known as Hansen's disease (HD), is a long-term infection by the bacteria ''Mycobacterium leprae'' or ''Mycobacterium lepromatosis''. Infection can lead to damage of the nerves, respiratory tract, skin, and eyes. This nerve damag ...
. Buruli ulcer typically occurs near slow-moving or stagnant bodies of water, where ''M. ulcerans'' is 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. Ulceration is primarily caused by the bacterial toxin mycolactone
Mycolactone is a polyketide-derived macrolide produced and secreted by a group of very closely related pathogenic Mycobacteria species that have been assigned a variety of names including, ''Mycobacterium_ulcerans, M. ulcerans'', ''M. liflandii'' ...
. As the bacteria grow, they release mycolactone into the surrounding tissue. Mycolactone diffuses into host
A host is a person responsible for guests at an event or for providing hospitality during it.
Host may also refer to:
Places
* Host, Pennsylvania, a village in Berks County
People
*Jim Host (born 1937), American businessman
* Michel Host ...
cells and blocks the action of Sec61
Sec61, termed SecYEG in prokaryotes, is a membrane protein complex found in all domains of life. As the core component of the translocon, it transports proteins to the endoplasmic reticulum in eukaryotes and out of the cell in prokaryotes. It is ...
, the molecular channel that serves as a gateway to the endoplasmic reticulum
The endoplasmic reticulum (ER) is, in essence, the transportation system of the eukaryotic cell, and has many other important functions such as protein folding. It is a type of organelle made up of two subunits – rough endoplasmic reticulum ( ...
. When Sec61 is blocked, proteins that would normally enter the endoplasmic reticulum are mistargeted to the cytosol
The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells (intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondri ...
, causing a pathological stress response that leads to cell death
Cell death is the event of a biological cell ceasing to carry out its functions. This may be the result of the natural process of old cells dying and being replaced by new ones, as in programmed cell death, or may result from factors such as dis ...
by apoptosis
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
. This results in tissue death at the site of infection, causing the open ulcer characteristic of the disease. At the same time, Sec61 inhibition prevents cells from signaling
In signal processing, a signal is a function that conveys information about a phenomenon. Any quantity that can vary over space or time can be used as a signal to share messages between observers. The ''IEEE Transactions on Signal Processing'' ...
to activate the immune system
The immune system is a network of biological processes that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as cancer cells and objects such as wood splinte ...
, leaving ulcers largely free of immune cells. Immune cells that do reach the ulcer are killed by mycolactone, and tissue examinations of the ulcer show a core of growing bacteria surrounded by debris from dead and dying neutrophil
Neutrophils (also known as neutrocytes or heterophils) are the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. They form an essential part of the innate immune system, with their functions varying in ...
s (the most common immune cell).
Transmission
It is not known how ''M. ulcerans'' is introduced to humans.[ Buruli ulcer does not spread from one person to another. In areas ]endemic
Endemism is the state of a species being found in a single defined geographic location, such as an island, state, nation, country or other defined zone; organisms that are indigenous to a place are not endemic to it if they are also found elsew ...
for Buruli ulcer, disease occurs near stagnant bodies of water, leading to the long-standing hypothesis that ''M. ulcerans'' is somehow transmitted to humans from aquatic environments. ''M. ulcerans'' is widespread in these environments, where it can survive as free-living or in association 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
Crayfish are freshwater crustaceans belonging to the clade Astacidea, which also contains lobsters. In some locations, they are also known as crawfish, craydids, crawdaddies, crawdads, freshwater lobsters, mountain lobsters, rock lobsters, mu ...
, aquatic insects, and other animals that live in or near water. A role for biting insects in transmission has been investigated, with particular focus on mosquitoes, giant water bugs, and Naucoridae
Naucoridae is a small family of insects commonly known as the creeping water bugs and saucer bugs. They are similar in appearance and behavior to Belostomatidae (giant water bugs), but considerably smaller, at long. Naucoridae are found around the ...
. ''M. ulcerans'' is occasionally found in these insects, and they can sometimes transmit the bacteria in laboratory settings. Whether these insects are regularly involved in transmission remains unclear. Pre-existing wounds have been implicated in disease transmission, and people who immediately wash and bandage open wounds are less likely to acquire Buruli ulcer. Wearing pants and long-sleeved shirts is associated with a lower risk of Buruli ulcer, possibly by preventing insect bites or protecting wounds.
Genetic susceptibility
While Buruli ulcer is not contagious, susceptibility sometimes runs in families, suggesting genetics could play a role in who develops the disease. Severe Buruli ulcer in a Benin
Benin ( , ; french: Bénin , ff, Benen), officially the Republic of Benin (french: République du Bénin), and formerly Dahomey, is a country in West Africa. It is bordered by Togo to the west, Nigeria to the east, Burkina Faso to the north ...
ese family was attributed to a loss of 37 kilobase
A base pair (bp) is a fundamental unit of double-stranded nucleic acids consisting of two nucleobases bound to each other by hydrogen bonds. They form the building blocks of the DNA double helix and contribute to the folded structure of both DNA ...
s of chromosome 8 in a region that included a long non-coding RNA
Long non-coding RNAs (long ncRNAs, lncRNA) are a type of RNA, generally defined as transcripts more than 200 nucleotides that are not translated into protein. This arbitrary limit distinguishes long ncRNAs from small non-coding RNAs, such as mic ...
and was near the genes for beta-defensins, which are antimicrobial peptide
Antimicrobial peptides (AMPs), also called host defence peptides (HDPs) are part of the innate immune response found among all classes of life. Fundamental differences exist between prokaryotic and eukaryotic cells that may represent targets for a ...
s involved in immunity and wound healing. Broader studies have focused on genes involved in susceptibility to other mycobacterial infections, finding susceptibility to Buruli ulcer may be linked to variants in six immunity-related genes: ''SLC11A1
Natural resistance-associated macrophage protein 1 is a protein that in humans is encoded by the ''SLC11A1'' gene.
Function
This gene is a member of the solute carrier family 11 (proton-coupled divalent metal ion transporters) family and encode ...
'', ''PRKN
Parkin is a 465-amino acid residue (chemistry), residue E3 ubiquitin ligase, a protein that in humans and mice is encoded by the ''PARK2'' gene. Parkin plays a critical role in ubiquitination – the process whereby molecules are covalently labell ...
'', ''NOD2
Nucleotide-binding oligomerization domain-containing protein 2 (NOD2), also known as caspase recruitment domain-containing protein 15 (CARD15) or inflammatory bowel disease protein 1 (IBD1), is a protein that in humans is encoded by the ''NOD2'' g ...
'', '' ATG16L1'', '' iNOS'', and '' IFNG'', as well as in two long non-coding RNAs. A genome-wide association study
In genomics, a genome-wide association study (GWA study, or GWAS), also known as whole genome association study (WGA study, or WGAS), is an observational study of a genome-wide set of Single-nucleotide polymorphism, genetic variants in different i ...
linked resistance to Buruli ulcer to a variant of ''ATG16L1'' associated with susceptibility to Crohn's disease
Crohn's disease is a type of inflammatory bowel disease (IBD) that may affect any segment of the gastrointestinal tract. Symptoms often include abdominal pain, diarrhea (which may be bloody if inflammation is severe), fever, abdominal distension ...
.
Diagnosis
As Buruli ulcer most commonly occurs in low-resource settings, treatment is often initiated by a clinician based on signs and symptoms alone. Where available, diagnosis may then be confirmed by polymerase chain reaction
The polymerase chain reaction (PCR) is a method widely used to rapidly make millions to billions of copies (complete or partial) of a specific DNA sample, allowing scientists to take a very small sample of DNA and amplify it (or a part of it) t ...
(PCR) to detect ''M. ulcerans'' DNA or microscopy to detect mycobacteria. The gold standard
A gold standard is a monetary system in which the standard economic unit of account is based on a fixed quantity of gold. The gold standard was the basis for the international monetary system from the 1870s to the early 1920s, and from the la ...
test is real-time PCR
A real-time polymerase chain reaction (real-time PCR, or qPCR) is a laboratory technique of molecular biology based on the polymerase chain reaction (PCR). It monitors the amplification of a targeted DNA molecule during the PCR (i.e., in real ...
to detect a DNA sequence termed IS''2404'' that is unique to ''M. ulcerans''. This method detects ''M. ulcerans'' in 54–84% of infected people, and is highly specific to ''M. ulcerans''. In wealthier healthcare settings, diagnosis is routinely based on PCR results. In low-resource settings, PCR is often unavailable, or can only be performed later at a centralized diagnostic laboratory. For microscopy, fluid is typically taken from the ulcer's edge by fine-needle aspiration
Fine-needle aspiration (FNA) is a diagnostic procedure used to investigate lumps or masses. In this technique, a thin (23–25 gauge (0.52 to 0.64 mm outer diameter)), hollow needle is inserted into the mass for sampling of cells that, aft ...
or by swabbing the edge of the ulcer. The fluid is then stained with the Ziehl–Neelsen stain
Ziehl–Neelsen staining is a type of acid-fast stain, first introduced by Paul Ehrlich. Ziehl–Neelsen staining is a bacteriological stain used to identify acid-fast organisms, mainly Mycobacteria. It is named for two German doctors who modi ...
which makes mycobacteria visible. In practice microscopy detects ''M. ulcerans'' in just 30–40% of infected people, making it a relatively insensitive diagnostic test. 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. Another method of diagnosis is to take a tissue sample
In medicine, sampling is gathering of matter from the body to aid in the process of a medical diagnosis and/or evaluation of an indication for treatment, further medical tests or other procedures. In this sense, the sample is the gathered matter ...
from the ulcer and examine it under histological
Histology,
also known as microscopic anatomy or microanatomy, is the branch of biology which studies the microscopic anatomy of biological tissues. Histology is the microscopic counterpart to gross anatomy, which looks at larger structures vis ...
stains. This requires more invasive sampling and review by a trained pathologist, and is rarely used in places where Buruli ulcer is endemic.
Other ulcerative diseases can appear similar to Buruli ulcer at its various stages. The nodule that appears early in the disease can resemble a bug bite, sebaceous cyst
A sebaceous cyst is a term commonly used to refer to either:
* Epidermoid cysts (also termed epidermal cysts, infundibular cyst)
* Pilar cysts (also termed trichelemmal cysts, isthmus-catagen cysts)
Both of the above types of cysts contain kera ...
, lipoma, onchocerciasis
Onchocerciasis, also known as river blindness, is a disease caused by infection with the parasitic worm ''Onchocerca volvulus''. Symptoms include severe itching, bumps under the skin, and blindness. It is the second-most common cause of blindne ...
, other mycobacterial skin infections, or an enlarged lymph node. Skin ulcers can resemble those caused by leishmaniasis, yaws
Yaws is a tropical infection of the skin, bones, and joints caused by the spirochete bacterium ''Treponema pallidum pertenue''. The disease begins with a round, hard swelling of the skin, in diameter. The center may break open and form an ulce ...
, squamous cell carcinoma, ''Haemophilus ducreyi
''Haemophilus ducreyi'' is a fastidious gram-negative coccobacillus bacteria.
It causes the sexually transmitted disease chancroid, a major cause of genital ulceration in developing countries characterized by painful sores on the genitalia. Ch ...
'' infection, and tissue death due to poor circulation. More diffuse lesions can resemble cellulitis
Cellulitis is usually a bacterial infection involving the inner layers of the skin. It specifically affects the dermis and subcutaneous fat. Signs and symptoms include an area of redness which increases in size over a few days. The borders of t ...
and fungal infections of the skin.
Treatment
Buruli ulcer is treated through a combination of antibiotic
An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting bacterial infections, and antibiotic medications are widely used in the treatment and prevention of ...
s to kill the bacteria, and wound care or surgery to support the healing of the ulcer. The most widely used antibiotic regimen is once daily oral rifampicin
Rifampicin, also known as rifampin, is an ansamycin antibiotic used to treat several types of bacterial infections, including tuberculosis (TB), mycobacterium avium complex, ''Mycobacterium avium'' complex, leprosy, and Legionnaires’ disease. ...
plus twice daily oral clarithromycin
Clarithromycin, sold under the brand name Biaxin among others, is an antibiotic used to treat various bacterial infections. This includes strep throat, pneumonia, skin infections, ''H. pylori'' infection, and Lyme disease, among others. Clarith ...
, recommended by the World Health Organization. Several other antibiotics are sometimes used in combination with rifampicin, namely ciprofloxacin
Ciprofloxacin is a fluoroquinolone antibiotic used to treat a number of bacterial infections. This includes bone and joint infections, intra abdominal infections, certain types of infectious diarrhea, respiratory tract infections, skin inf ...
, moxifloxacin
Moxifloxacin is an antibiotic, used to treat bacterial infections, including pneumonia, conjunctivitis, endocarditis, tuberculosis, and sinusitis. It can be given by mouth, by injection into a vein, and as an eye drop.
Common side effects in ...
, ethambutol
Ethambutol (EMB, E) is a medication primarily used to treat tuberculosis. It is usually given in combination with other tuberculosis medications, such as isoniazid, rifampicin and pyrazinamide. It may also be used to treat ''Mycobacterium avi ...
, amikacin
Amikacin is an antibiotic medication used for a number of bacterial infections. This includes joint infections, intra-abdominal infections, meningitis, pneumonia, sepsis, and urinary tract infections. It is also used for the treatment of mu ...
, azithromycin
Azithromycin, sold under the brand names Zithromax (in oral form) and Azasite (as an eye drop), is an antibiotic medication used for the treatment of a number of bacterial infections. This includes middle ear infections, strep throat, pneumon ...
, and levofloxacin
Levofloxacin, sold under the brand name Levaquin among others, is an antibiotic medication. It is used to treat a number of bacterial infections including acute bacterial sinusitis, pneumonia, H. pylori (in combination with other medications), ...
. A 2018 Cochrane review
Cochrane (previously known as the Cochrane Collaboration) is a British international charitable organisation formed to organise medical research findings to facilitate evidence-based choices about health interventions involving health professi ...
suggested that the many antibiotic combinations being used are effective treatments, but there is insufficient evidence to determine if any combination is the most effective. 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 A paradoxical reaction (or paradoxical effect) is an effect of a chemical substance, such as a medical drug, that is opposite to what would usually be expected. An example of a paradoxical reaction is pain caused by a pain relief medication.
Parad ...
, is more common in those with larger ulcers and ulcers on the trunk, and occurs more frequently in adults than in 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.
Small or medium-sized ulcers (WHO categories I and II) typically heal within six months of antibiotic treatment, whereas larger ulcers can take over two years to fully heal. Given the long healing times, wound care is a major part of treating Buruli ulcer. The World Health Organization recommends standard wound care practices: covering the ulcer to keep it moist and protected from further damage; regularly changing wound dressings to keep the ulcer clean, removing excess fluid, and helping prevent infection. Treatment sometimes includes surgery
Surgery ''cheirourgikē'' (composed of χείρ, "hand", and ἔργον, "work"), via la, chirurgiae, meaning "hand work". is a medical specialty that uses operative manual and instrumental techniques on a person to investigate or treat a pat ...
to speed healing by removing necrotic ulcer tissue, grafting
Grafting or graftage is a horticultural technique whereby tissues of plants are joined so as to continue their growth together. The upper part of the combined plant is called the scion () while the lower part is called the rootstock. The succ ...
healthy skin over the wound, or removing scar tissue that can deform muscles and joints. Specialized wound dressings developed for non-infectious causes of ulcer are occasionally used for treating Buruli ulcer, but can be prohibitively expensive in low-resource settings.
Prevention
Buruli ulcer can be prevented by avoiding contact with aquatic environments in endemic areas, although this may not be possible for people living in these areas. The risk of acquiring it can be reduced by wearing long sleeves and pants, using insect repellent, and cleaning and covering any wounds as soon as they are noticed. There is no specific vaccine for preventing Buruli ulcer.[ The ]BCG vaccine
Bacillus Calmette–Guérin (BCG) vaccine is a vaccine primarily used against tuberculosis (TB). It is named after its inventors Albert Calmette and Camille Guérin. In countries where tuberculosis or leprosy is common, one dose is recommended ...
typically given to children to protect against tuberculosis offers temporary partial protection from Buruli ulcer.
Epidemiology
Buruli ulcer is relatively rare, with 2,713 cases reported to the World Health Organization in 2018.[ Most countries do not report data on Buruli ulcer to the World Health Organization, and the extent of its spread is unknown. In many endemic countries, health systems likely do not record each case due to insufficient reach and resources, and so the reported numbers probably underestimate the true prevalence of the disease.
Buruli ulcer is concentrated in ]West Africa
West Africa or Western Africa is the westernmost region of Africa. The United Nations defines Western Africa as the 16 countries of Benin, Burkina Faso, Cape Verde, The Gambia, Ghana, Guinea, Guinea-Bissau, Ivory Coast, Liberia, Mali, Maurit ...
and coastal Australia, with occasional cases in Japan, Papua New Guinea and the Americas. In West Africa, the disease is predominantly reported from remote, rural communities in Benin, Côte d'Ivoire, Cameroon, and Ghana. Other countries in the region also have Buruli ulcer to some degree; a 2019 systematic review
A systematic review is a Literature review, scholarly synthesis of the evidence on a clearly presented topic using critical methods to identify, define and assess research on the topic. A systematic review extracts and interprets data from publ ...
of prevalence studies found a clear consensus that it is present in the Democratic Republic of the Congo, Gabon, Liberia, Nigeria, Togo, and South Sudan, as well as "strong" or "very strong" evidence of the disease in the Republic of the Congo, Sierra Leone, the Central African Republic, Guinea, and Uganda. Buruli ulcer is regularly reported from Australia, where it occurs in coastal clusters—two in Queensland (near Rockhampton
Rockhampton is a city in the Rockhampton Region of Central Queensland, Australia. The population of Rockhampton in June 2021 was 79,967, Estimated resident population, 30 June 2018. making it the fourth-largest city in the state outside of the ...
and north of Cairns
Cairns (, ) is a city in Queensland, Australia, on the tropical north east coast of Far North Queensland. The population in June 2019 was 153,952, having grown on average 1.02% annually over the preceding five years. The city is the 5th-most-p ...
) and two in Victoria (near Bairnsdale
Bairnsdale () ( Ganai: ''Wy-yung'') is a city in East Gippsland, Victoria, Australia in a region traditionally owned by the Tatungalung clan of the Gunaikurnai people.
The estimated population of Bairnsdale urban area was 15,411 at Ju ...
and Melbourne
Melbourne ( ; Boonwurrung/Woiwurrung: ''Narrm'' or ''Naarm'') is the capital and most populous city of the Australian state of Victoria, and the second-most populous city in both Australia and Oceania. Its name generally refers to a met ...
). It is more rarely reported from Japan, Papua New Guinea, and the Americas. Japan reports a few locally acquired cases per year scattered across the main island, Honshu
, historically called , is the largest and most populous island of Japan. It is located south of Hokkaidō across the Tsugaru Strait, north of Shikoku across the Inland Sea, and northeast of Kyūshū across the Kanmon Straits. The island separ ...
. Papua New Guinea sporadically reports cases to the World Health Organization, typically less than a dozen per year. In the Americas, most Buruli ulcer is reported from French Guiana, with few cases described in surrounding countries. A 2019 review found "strong" evidence for the presence of Buruli ulcer in French Guiana and Peru, and "moderate" evidence in Brazil, Mexico and Suriname.
Within affected countries, Buruli ulcer tends to occur in rural areas near slow-moving or stagnant water. In particular, the disease tends 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.
Other animals
''M. ulcerans'' infection can cause Buruli ulcer-like lesions in some non-human animals. Natural non-human infections have only been described in coastal Victoria
Victoria most commonly refers to:
* Victoria (Australia), a state of the Commonwealth of Australia
* Victoria, British Columbia, provincial capital of British Columbia, Canada
* Victoria (mythology), Roman goddess of Victory
* Victoria, Seychelle ...
, near Melbourne. There, ''M. ulcerans''-positive lesions have been described in koala
The koala or, inaccurately, koala bear (''Phascolarctos cinereus''), is an arboreal herbivorous marsupial native to Australia. It is the only extant representative of the family Phascolarctidae and its closest living relatives are the womb ...
s, common ringtail possums, and common brushtail possums, with lesions typically on the face, limbs, and tail. Ulcers have also been reported on domesticated animals, namely dogs, horses, alpacas, and a cat. In laboratories several species of animals have been infected with ''M. ulcerans'' in an attempt to model the course of Buruli ulcer. Injection of ''M. ulcerans'' can cause ulcers in several rodents (mice, guinea pigs, greater cane rat
The greater cane rat (''Thryonomys swinderianus''), also known as the grasscutter (in Ghana, Nigeria and other regions of West Africa), is one of two species of cane rats, a small family of African hystricognath rodents. It lives by reed-beds a ...
s and common African rats), larger mammals (nine-banded armadillo
The nine-banded armadillo (''Dasypus novemcinctus''), also known as the nine-banded long-nosed armadillo or common long-nosed armadillo, is a mammal found in North, Central, and South America, making it the most widespread of the armadillos. It ...
s, common brushtail possums, pigs, and Cynomolgus monkeys
The crab-eating macaque (''Macaca fascicularis''), also known as the long-tailed macaque and referred to as the cynomolgus monkey in laboratories, is a cercopithecine primate native to Southeast Asia. A species of macaque, the crab-eating macaqu ...
), and anole lizards.
Society and culture
In endemic areas, particularly rural communities in Africa, people may be aware of Buruli ulcer's association with the environment, yet simultaneously associate it with witchcraft or other supernatural causes. This dual understanding of disease—combined with poor access to conventional medicine—drives many to seek traditional healers for primary care. Traditional healers often treat Buruli ulcer with two simultaneous approaches: herbs and sometimes burning or bleeding to treat the physical wound; and confession, ritual purification, and prohibitions on food, interpersonal contact, or sex to treat the spiritual component of the disease. Those with Buruli ulcer report feeling shame and experiencing social stigma
Social stigma is the disapproval of, or discrimination against, an individual or group based on perceived characteristics that serve to distinguish them from other members of a society. Social stigmas are commonly related to culture, gender, rac ...
that could affect their relationships, school attendance, and marriage prospects.
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 who saw the first Australian patients at the Bairnsdale Clinic and sent material to Peter MacCallum's group for further examination. The disease later became more generally known as "Bairnsdale ulcer" after the district where it was described. In northeastern Australia, north of Cairns, the disease is called "Daintree ulcer" or "Mossman ulcer" after the nearby Daintree River
The Daintree River is a river that rises in the Daintree Rainforest near Cape Tribulation in Far North Queensland, Australia. The river is located about northwest of Cairns in the UNESCO World Heritagelisted Wet Tropics of Queensland. The area ...
and the town of Mossman. In Papua New Guinea, the disease is called "Kumusi ulcer" after the Kumusi River
The Kumusi River (also known as the Kamusi River) is a river located in the Oro Province of Papua New Guinea. Known for its width and its strength, the Kumusi has had a significant impact on the history of the Oro Province. It was a significant fac ...
along which villages with Buruli ulcer were originally described.
History
The first written description of Buruli ulcer is credited to a British missionary doctor, Albert R. Cook. In 1897, at Mengo Hospital
Mengo Hospital, also known as Namirembe Hospital, is a private, faith-based, community, teaching hospital in Kampala, the capital and largest city of Uganda.
Location
The hospital is located on Namirembe Hill in Lubaga Division in northwestern ...
in Uganda, Cook noted several patients with slow-healing ulcers. The cause of these slow-healing ulcers was identified 50 years later in 1948, when Peter MacCallum
Sir Peter MacCallum (14 July 1885 – 4 March 1974) was a Scottish-born Australian oncologist and the co-founder and eponym of the Peter MacCallum Cancer Centre in Melbourne.
Background and early life
Peter MacCallum was born in Glasgow, ...
, Jean Tolhurst, Glen Buckle, and at The Alfred Hospital's Baker Institute described a series of cases from Bairnsdale, Victoria
Bairnsdale () ( Ganai: ''Wy-yung'') is a city in East Gippsland, Victoria, Australia in a region traditionally owned by the Tatungalung clan of the Gunaikurnai people.
The estimated population of Bairnsdale urban area was 15,411 at J ...
, isolated the causative mycobacterium, and showed it could cause ulcers in laboratory rats. Over the following decades, more cases were described in Africa. A particularly high prevalence in Uganda's Buruli County led to the disease becoming more widely known as "Buruli ulcer".
In 1998, the World Health Organization started the Global Buruli Ulcer Initiative with the aim of coordinating global efforts to control the disease. 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. Interest in Buruli ulcer has been encouraged by its branding as a "neglected tropical disease
Neglected tropical diseases (NTDs) are a diverse group of tropical disease, tropical infections that are common in low-income populations in Developing country, developing regions of Africa, Asia, and the Americas. They are caused by a variety ...
", first in a 2005 ''PLOS Medicine
''PLOS Medicine'' (formerly styled ''PLoS Medicine'') is a peer-reviewed weekly medical journal covering the full spectrum of the medical sciences. It began operation on October 19, 2004, as the second journal of the Public Library of Science (PLO ...
'' article, and later by both the World Health Organization and '' PLOS Neglected Tropical Diseases''.
From the time the disease was described, Buruli ulcer was treated with surgery to remove all affected tissue, followed by prolonged wound care. This treatment regimen was expensive, sometimes disfiguring, and often ineffective, ulcers recurring in up to a third of cases. Treatment dramatically improved in 2004, when the World Health Organization recommended an eight-week course of daily oral rifampicin and injected streptomycin
Streptomycin is an antibiotic medication used to treat a number of bacterial infections, including tuberculosis, ''Mycobacterium avium'' complex, endocarditis, brucellosis, ''Burkholderia'' infection, plague, tularemia, and rat bite fever. Fo ...
. The introduction of antibiotics reduced the rate of ulcer recurrence to fewer than 2% of cases. However, streptomycin can be toxic to the ears and kidneys, and administering daily injections is challenging in low-resource settings. In 2017, the World Health Organization updated its recommendation to replace streptomycin with the oral antibiotic clarithromycin.
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. While several animals are susceptible to ''M. ulcerans'' ulcers, mice (particularly BALB/c
BALB/c is an albino, laboratory-bred strain of the house mouse from which a number of common substrains are derived. Now over 200 generations from New York in 1920, BALB/c mice are distributed globally, and are among the most widely used inbred ...
and C57BL/6
C57BL/6, often referred to as "C57 black 6", "C57" or "black 6", is a common inbred strain of laboratory mouse.
It is the most widely used "genetic background" for genetically modified mice for use as models of human disease. They are the most wid ...
mice) are most commonly used to model Buruli ulcer in modern laboratories. 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. 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. This mouse model of Buruli ulcer has primarily been used to test antibiotics. The antibiotic combinations, dose frequencies, and treatment durations currently in use were first tested in laboratory-infected mice. Some vaccine platforms have been tested in ''M. ulcerans''-infected mice, mostly based on the ''Mycobacterium bovis
''Mycobacterium bovis'' is a slow-growing (16- to 20-hour generation time) aerobic bacterium and the causative agent of tuberculosis in cattle (known as bovine TB). It is related to ''Mycobacterium tuberculosis'', the bacterium which causes tube ...
'' strain used in the BCG vaccine
Bacillus Calmette–Guérin (BCG) vaccine is a vaccine primarily used against tuberculosis (TB). It is named after its inventors Albert Calmette and Camille Guérin. In countries where tuberculosis or leprosy is common, one dose is recommended ...
. The BCG vaccine and versions of the vaccine that also express ''M. ulcerans'' antigen
In immunology, an antigen (Ag) is a molecule or molecular structure or any foreign particulate matter or a pollen grain that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune response. ...
s prolong the survival of mice after ''M. ulcerans'' infection. As of 2019, no vaccine tested completely protects mice from infection.
''M. ulcerans'' can be grown in laboratory media, although its slow growth makes it challenging to study. Bacteria plated
Plating is a surface covering in which a metal is deposited on a conductive surface. Plating has been done for hundreds of years; it is also critical for modern technology. Plating is used to decorate objects, for corrosion inhibition, to improv ...
on laboratory media can take up to three months to form visible colonies
In modern parlance, a colony is a territory subject to a form of foreign rule. Though dominated by the foreign colonizers, colonies remain separate from the administration of the original country of the colonizers, the '' metropolitan state'' ...
. Strains of ''M. ulcerans'' used in laboratories are less standardized than the mice they infect; different laboratories use different strains based on convenience and accessibility. Three ''M. ulcerans'' strains are particularly common, each isolated from an infected person: "Cu001" from Adzopé
Adzopé is a town in south-eastern Ivory Coast. It is a sub-prefecture of and the seat of Adzopé Department. It is also a commune and the seat of La Mé Region in Lagunes District. In the 2021 census, the sub-prefecture of Adzopé had a populati ...
, Côte d'Ivoire in 1996; "Mu1615" from Malaysia in the 1960s; and "S1013" from Cameroon in 2010.
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{{DEFAULTSORT:Buruli Ulcer
Bacterial diseases
Mycobacterium-related cutaneous conditions
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Tropical diseases