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Prevacid is used for preventing or treating certain types of ulcers.
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Buruli ulcer (Causes of)
Buruli ulcer (Diagnosis)
Buruli ulcer (Care and treatment)
Buruli ulcer (Demographic aspects)
Mycobacteria (Health aspects)
Mycobacterium (Health aspects)
Palomino, Juan Carlos
Van Marck, Eric
Name. Emerging Infectious Diseases Publisher. U.S. National Center for Infectious Diseases Audience. Academic; Professional Format. Magazine/Journal Subject. Health Copyright. COPYRIGHT 2008 U.S. National Center for Infectious Diseases ISSN: 1080-6040
Date. March, 2008 Source Volume. 14 Source Issue. 3
Geographic Scope. Peru Geographic Code. 3PERU Peru
Eight adult patients (ages 18-58, 5 women) with Buruli ulcer (BU) confirmed by at least 2 diagnostic methods were seen in a 10-year period. Attempts to culture Mycobacterium ulcerans failed. Five patients came from jungle areas, and 3 from the swampy northern coast of Peru. The patients had 1-5 lesions, most of which were on the lower extremities. One patient had 5 clustered gluteal lesions; another patient had 2 lesions on a finger. Three patients were lost to follow-up. All 5 remaining patients had moderate disease. Diverse treatments (antituberculous drugs, World Health Organization [WHO] recommended antimicrobial drug treatment for BU, and for 3 patients, excision surgery) were successful. Only 1 patient (patient 7) received the specific drug treatment recommended by WHO. BU is endemic in Peru, although apparently infrequent. Education of populations and training of health workers are first needed to evaluate and understand the full extent of BU in Peru.
Buruli ulcer (BU), a chronic ulcerative disease, has been observed in many tropical areas, but patients have usually come from Africa and Australia (1-6). Cases were also described in the Americas, mostly in French Guiana (3,6). A few cases from Surinam have also been recorded in French Guiana, and 8 cases have been reported in Mexico since 1953 (3,6).
In 1969, the first 2 cases from Peru were reported (7). A new case was reported in 1988, along with a redescription of the first 2 cases (8). From 1996 through 2005, 8 additional cases, which we describe here, were found in Peru (Figure 1).
Material and Methods
We conducted a descriptive, retrospective survey of patients seen by members of the Instituto de Medicina Tropical Alexander von Humboldt in Lima and Iquitos. We requested referrals of new patients from other areas. The total of 8 cases occurred from 1996 through 2005.
We used a collective data sheet proposed by the World Health Organization (WHO) (9) to assess the magnitude and severity of the disease and to collect data from patients. We also obtained information from medical records. Patients who had a history of chronic ulcer and who had at least 2 different positive laboratory tests were included in this study (10). All the patients gave consent verbally. The publication was approved by the Human Protections Administration Office for Human Research Protection of the Universidad Peruana Cayetano Heredia (SIDISI code 52467).
[FIGURE 1 OMITTED]
Smears and Tissue Collection
Smears obtained by scalpel or swab were prepared with material from the necrotic base and undermined edges of the lesions and were stained with Ziehl-Neelsen. Skin biopsy samples were excised and cut into [greater than or equal to] 2 portions. At least 1 portion was fixed in 10% formalin and processed for histologic examination at the pathology laboratory of the Hospital Nacional Cayetano Heredia in Lima. The other portions, minced further, were inoculated after decontamination onto Lowenstein-Jensen medium in Lima as described previously (10); the rest was placed in a semisolid transport medium (11) and sent to the Institute of Tropical Medicine, Antwerp, for culture and PCR testing (10).
We found 8 cases of BU from 1996 to 2006. Case characteristics are indicated in Table 1. Five patients came from the Peruvian rainforest, the likely place of infection. Two patients reported close contact with water in the Maranon (patient 1) and Huallaga (patient 2) River basins. Three patients (patients 3, 4, and 6) lived close to Iquitos, a city on the Amazon River. One patient (patient 5) had briefly visited a swampy area in the north coast of Peru (Tumbes), and 2 other patients (patients 7 and 8) lived in the same area. All of the areas described are warm and humid. The age range at diagnosis was 18-58 years, with a male to female ratio of 3:5. No case patients had a medical or family history of tuberculosis or leprosy. The time between onset of illness and being seen by a physician was 1-8 months. Four patients noticed a nodular lesion before ulceration occurred. All patients had ulcers with typical undermined edges. The site of involvement in our patients was on the extremities, but 1 patient had gluteal lesions. The median number of lesions per patient was 2. Three patients (patients 1, 2, and 5) were lost to follow-up at an early stage, soon after diagnosis, and their disease course was unknown.
Patient 3 had lesions on both knees; he liked gardening and often knelt on soil and organic mulch that contained wood shavings. He first received rifampin and ethambutol for 5 weeks. Drug therapy was stopped because of hepatotoxicity. Trimethoprim-sulfamethoxazole and ciprofloxacin were then administered for 15 days. After completing oral therapy, he treated his lesions with a rifampin spray. Eight months after the start of drug therapy, the lesions were almost closed. A small ulcer remained on the right knee. The patient showed complete remission of lesions without any surgical intervention on his last control visits, 3 and 5 years after diagnosis.
Patient 4 had a medical history suggestive of leishmaniasis, and a smear from an ulcerated lesion was reported as positive for Leishmania. She was treated with intramuscular and intralesional sodium stibogluconate, including multiple inoculation sites. One month after receiving a course of 29 intramuscular injections, she showed more lesions in the left gluteal region and was treated with herbal medicine. BU was diagnosed from purulent material removed with a syringe and needle from a closed lesion. After drainage and biopsy her lesions showed improvement, and therefore no other treatment was instituted. She continued herbal treatment until total cure. The lesions have remained inactive for 5 years.
Patient 6 was treated by excision surgery and later received antituberculosis treatment (regimen 1) for 6 months. Patient 7 was pregnant when first seen. After tissue specimens were taken and BU was diagnosed, she was treated conservatively with topical disinfectants until delivery. She then received the WHO-recommended rifampin and streptomycin treatment (12) for 31 days and had excision surgery of the largest lesions. Later, all lesions were excised. Patient 8 had lesions on the right middle finger (Figure 2, panel A) that ulcerated after treatment for 1 month with ciprofloxacin, clindamycin, and dexametasone (Figure 2, panel B). Diagnosis was made on the basis of material obtained at the first extensive debridement (Figure 2, panel C). He received 5 weeks of regimen 1 treatment for tuberculosis, to which streptomycin was added for the last 3 weeks before surgical debridement and autologous skin graft. Antituberculous regimen 1 was continued for 2 more weeks. Figure 2, panel D shows the lesion 1 month after surgery. The patient then received 4 months of treatment with minocycline, ciprofloxacin, and trimethoprim-sulfamethoxazole and undertook rehabilitation including exercises. He recovered very good use of his right hand.
[FIGURE 2 OMITTED]
Patients 6, 7, and 8 were cured with antimicrobial agents and surgery. They had no recurrence after 2 years of follow-up.
As indicated in Table 2, all patients' cases were confirmed by at least 2 positive laboratory tests. Seven patients showed acid-fast bacilli (AFB) on the initial smear, and 1 was negative (patient 5). The biopsy specimens from all the patients had AFB in histopathologic sections and typical histologic lesions, i.e. necrosis of fat and an abundance of extracellular clumps of AFB. Most biopsy specimens showed little or no inflammatory infiltrate. A granulomatous infiltrate was seen in the biopsy specimen from patient 5. Cultures remained negative, and IS2404 PCR was positive for all 7 patients tested.
From 1969 until 2007, only 11 cases of BU have been reported in Peru, but no countrywide survey has been conducted to evaluate its true prevalence in Peru. BU is probably both infrequent and underreported in Peru and may often be misdiagnosed as leishmaniasis, which is more prevalent and better known. Three separate surveys suggest the rarity of BU. In the first, Saldana-Patino reviewed 1,620 ulcers biopsied from 1969 to 1981 and found no other BU patients apart from the 3 he reported (8). Second, a preliminary epidemiologic survey was conducted in the general area of the Huallaga Basin close to Tarapoto; several leishmaniasis and vascular lesions were found in 4 communities of [approximately equal to] 4,000 inhabitants, but no BU cases were seen (N. Donaires, MD thesis). Finally, physicians performing populationwide cysticercosis research in Tumbes (on the north coast) included a questionnaire and physical examination of all skin ulcers at the time, using as a guide a booklet in Spanish that was provided to familiarize them with BU (13). No skin ulcers were seen in the population surveyed.
The scarcity of BU cases in Peru and Mexico may be due to a lower virulence of the mycobacteria and a better immune response of patients when they become infected by M. ulcerans. It is clearly not related to infrequent contact with contaminated water. As in Africa, populations living in the Amazon River Basin have frequent contacts with water for domestic activities. Similarly, the low incidence of BU in Peru does not seem to be related to the absence of M. ulcerans in the environment, since the IS2404 PCR positivity of the environmental specimens from Peru (collected in Tarapoto, in the Huallaga River Basin) and Benin have given comparable results (14% positivity in Peru vs. 10%-20% positivity in Benin) (F. Portaels et al. unpub, data).
The distribution of BU in Peru and elsewhere is strongly associated with wetlands, especially those with slow-flowing or stagnant water (e.g. ponds, backwaters, and swamps) (4,5). All of our patients had contacts with swampy areas in the Amazon River Basin (5 patients) or on the northern coast (3 patients). The 3 previously reported patients (8) had been in contact with water bodies related to tributaries of the Amazon River. In Peru, therefore, BU is present in the Peruvian jungle (14) and other swampy regions of the north coast.
In our study, the age of patients when they were first seen with BU ranged from 18 to 58 years. M. ulcerans is seen mainly in children and young adults in other BU-endemic regions but may affect any age group (4,5,15). All patients except patient 8 had lesions on the lower limb (Table 1). A similar pattern has been reported in other countries (4,5,15).
Patients sought medical assistance [approximately equal to] 1 month after the first lesion appeared. The longest interval to final diagnosis was 8 months, which led to a very large lesion in patient 4, who was originally being treated for leishmaniasis.
In Africa, the stigma associated with BU appears to be important, and its mysterious nature is often attributed to witchcraft and curses (16-18). Such concerns were not voiced by any of our patients, as they all had actively sought medical help.
Beside patients lost to follow-up, the clinical outcome of all patients from Peru was favorable. One patient (patient 4) was cured with herbal medicine only. Several authors report that while some topical treatments may heal BU lesions (4,19), other lesions may heal spontaneously (20). Patient 4 may have healed spontaneously or because of herbal medicine. Surgical treatment alone, which was until recently the mainstay of clinical management of BU in BU-endemic areas (4) is not practiced in Peru. Surgery is always associated with antimycobacterial drug therapy. Several centers in Africa have started to treat patients with streptomycin and rifampin according to WHO guidelines (12), and a recent study indicates that after 8 weeks of drug therapy ulcers may heal without surgery (21). The patients with reported infections in Peru up to 1988 had a favorable response to antituberculous therapy, although their lesions were large (7). In our study, patient 3 was also successfully treated with drug therapy without surgery. The success of antimycobacterial therapy in some areas may be correlated with a lower virulence of the M. ulcerans strains and in particular with lower production of mycolactones. African strains, which produce the greatest number and quantity of mycolactones, are associated with more severe disease forms (22), which may explain the difficulty treating some patients with only antimycobacterial drugs.
All patients in our study were PCR positive, but we were unable to cultivate M. ulcerans from the clinical specimens in Lima or Antwerp. This is surprising since the procedures used to cultivate M. ulcerans in primary culture were identical to those used for thousands of specimens from patients from other parts of the world (which yielded 45% of positive primary cultures) (11). Peruvian M. ulcerans strains may have different growth requirements or may be more sensitive to the antimicrobial agents in semisolid transport medium (PANTA: polymixin B, amphothericin B, nalidixic acid, trimethoprim, and azlocillin) than those from other geographic locations.
In conclusion, our study confirms that, although infrequently diagnosed, BU is an endemic disease in tropical swampy areas of Peru. Proper diagnosis and treatment require inclusion of simple clinical and laboratory guidelines in tuberculosis, leprosy, and leishmaniasis control programs, which reach health workers at all levels. Known BU-endemic areas should receive special emphasis. Education of populations and training of health workers are first needed to evaluate and understand the full extent of this disease in Peru.
We thank the many physicians and laboratory workers who made it possible to collect the information provided in this article, including Julio Saldana for conversations on the first 3 patients described in Peru, whom he saw personally; Frine Samalvides for her observations and clinical workup of patient 1; Martin Casapia, Coralith Garcia, Juan Carlos Hinojosa, Cesar Miranda, Jessica Ricaldi, Eddy Segura, and Kristien Verdonck for the observations and clinical workup of patients from Iquitos, seen and followed in Iquitos and Lima; Fernando Caro, Juan Carlos Chero, Hector Hugo Garcia, Guillermo Gonzalvez, and Luz Maria Moyano for observations and clinical workup of the patients from Tumbes, seen and followed in Tumbes and Lima; Jaime Cok, Juan Carlos Ferrufino, Lucy Puell, and Cesar Salinas for support in the processing of patient samples in pathology laboratories in Lima; graduate students Jose Chauca, Oscar Nolasco, and Gabriel Rojas and technologists Martin Cabello, Isabel Mejia, Rocio Rupa for their dedicated microbiology and molecular biology work on the patient samples in the respective laboratories. We also thank Gladys Anyo, Karin Jansssens, and Gaelle Antoine for outstanding assistance in preparing the manuscript.
This study received financial support from the Directorate-General for Development Cooperation of the Belgian Government through a Framework Agreement with the Institute of Tropical Medicine of Antwerp and from the Damien Foundation, Brussels, Belgium.
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Address for correspondence: Francoise Portaels, Mycobacteriology Unit, Department of Microbiology, Institute of Tropical Medicine, Nationalestraat 155, B-2000 Antwerp, Belgium; email: email@example.com
[mi'-ko-bak-ter-eam], from the Greek--myces (fungus) and bakterion (little rod)
The Only genus of bacteria in the family Mycobacteriaceae. In 1882, German scientist Robert Koch reported the discovery of a bacillus from the lung tubercles that caused tuberculosis. Earlier, Norwegian researcher G.H.A. Hansen had identified a similar microbe which caused leprosy. In 1896, the genus name Mycobacterium, from the Middle Latin noun meaning fungus rodlet, was proposed to include these new pathogens, M. tuberculosis and M. leprae. The name does not mean that mycobacteria are fungi; rather, the tubercle bacilli grow on the surface of liquid media as moldlike pellicles when cultured. The nomotile, acid-fast, aerobic organisms in this genus Cause numerous human and animal diseases.
Source: Sources: Savin JA, Wilkinson DS. Mycobacterial infections including tuberculosis, In: Rook A, Wilkinson DS, Ebling FJG. Champion RH, Burton JL, editors. Textbook of dermatology. Vol.1, 4th ed. Boston: Blackwell Scientific Publications; 1986. p. 791822. Goodfellow M, Magee JG. Taxonomy of mycobacteria. In: Mycobacteria: basic aspects. Gangadharam PRJ, Jenkins PA editors, Boca Raton (FL): Chapman & Hall; 1998. p.1. Wayne LG. The "atypical" mycobacteria: recognition and disease association. CRC Crit Rev Microbiol. 1985:12:185-222.
Humberto Guerra, * Juan Carlos Palomino, ([dagger]) Eduardo Falconi, * ([double dagger]) Francisco Bravo, * Ninoska Donaires, * Eric Van Marck, ([section]) and Francoise Portaels ([dagger])
* Universidad Peruana Cayetano Heredia, Lima, Peru; ([dagger]) Institute of Tropical Medicine, Antwerp, Belgium; ([double dagger]) Instituto Nacional de Salud del Perth, Lima, Peru; and ([section]) University of Antwerp, Antwerp, Belgium
Dr Guerra is a full professor of medicine at the Peruvian University Cayetano Heredia and a member of the Institute of Tropical Medicine Alexander von Humboldt, at the same University.
Copyright 2008 Gale, Cengage Learning. All rights reserved.
First online: 08 February 2008A Landscape-based Model for Predicting Mycobacterium ulcerans Infection (Buruli Ulcer Disease) Presence in Benin, West Africa
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* Final gross prices may vary according to local VAT.Abstract
Mycobacterium ulcerans infection (Buruli ulcer [BU] disease) is an emerging tropical disease that causes severe morbidity in many communities, especially those in close proximity to aquatic environments. Research and control efforts are severely hampered by the paucity of data regarding the ecology of this disease; for example, the vectors and modes of transmission remain unknown. It is hypothesized that BU presence is associated with altered landscapes that perturb aquatic ecosystems; however, this has yet to be quantified over large spatial scales. We quantified relationships between land use/land cover (LULC) characteristics surrounding individual villages and BU presence in Benin, West Africa. We also examined the effects of other village-level characteristics which we hypothesized to affect BU presence, such as village distance to the nearest river. We found that as the percent urban land use in a 50-km buffer surrounding a village increased, the probability of BU presence decreased. Conversely, as the percent agricultural land use in a 20-km buffer surrounding a village increased, the probability of BU presence increased. Landscape-based models had predictive ability when predicting BU presence using validation data sets from Benin and Ghana, West Africa. Our analyses suggest that relatively small amounts of urbanization are associated with a decrease in the probability of BU presence, and we hypothesize that this is due to the increased availability of pumped water in urban environments. Our models provide an initial approach to predicting the probability of BU presence over large spatial scales in Benin and Ghana, using readily available land use data.Keywords
Mycobacteriumulcerans Buruli ulcer infectious disease West Africa land use/cover landscape-based modelReferences
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Arabic Bulgarian Chinese Croatian Czech Danish Dutch English Estonian Finnish French German Greek Hebrew Hindi Hungarian Icelandic Indonesian Italian Japanese Korean Latvian Lithuanian Malagasy Norwegian Persian Polish Portuguese Romanian Russian Serbian Slovak Slovenian Spanish Swedish Thai Turkish Vietnamesedefinitions - Mycobacterium_ulcerans
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Mycobacterium ulcerans Infection (n.)
1. (MeSH ) A lesion in the skin and subcutaneous tissues due to infections by MYCOBACTERIUM ULCERANS. It was first reported in Uganda, Africa.
Mycobacterium ulcerans (n.)
1. (MeSH ) A slow-growing mycobacterium that infects the skin and subcutaneous tissues, giving rise to indolent BURULI ULCER.synonyms - Mycobacterium_ulcerans Mycobacterium ulcerans
Mycobacterium ulcerans (M. ulcerans ) is a slow-growing mycobacterium that classically infects the skin and subcutaneous tissues. giving rise to indolent nonulcerated (nodules, plaques) and ulcerated lesions. After tuberculosis and leprosy. Buruli ulcer is the third most common mycobacteriosis of humans. M. ulcerans grows optimally on routine mycobacteriologic media at 33°C and elaborates a necrotizing immunosuppressive cytotoxin (mycolactone). Large ulcers almost certainly caused by M. ulcerans were first observed by Cook in Uganda in 1897; however, the etiologic agent was not isolated and characterized until 1948 in Australia by MacCallum and associates. [ 1 ]
Lesions of M. ulcerans disease have several synonyms (e.g. Bairnsdale or Searle's ulcer). The name Buruli is probably most appropriate for historic reasons, as it is a county of Uganda where important foci of the disease were studied. [ 2 ]Contents Epidemiology and transmission
The source(s) of M. ulcerans in nature is becoming clearer from epidemiologic data and from molecular biologic findings. Because all major endemic foci are in wetlands of tropical or subtropical countries, environmental factors must play an essential role in the survival of the etiologic agent. Koalas and possums are naturally infected animals in Australia. The disease is rarely transmitted from patient to patient. Trauma is probably the most frequent means by which M. ulcerans is introduced into the skin from surface contamination. Individuals of all ages are affected, but the highest frequencies of infection are in children under 15 years of age (Debacker et al. accepted for publication).
The largest known concentrations of patients are 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, [ 3 ] 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 incidences of M. ulcerans infections, especially in West Africa, where the disease is rapidly emerging.Geographical distribution
Buruli ulcer has been reported from at least 32 countries around the world, mostly in tropical areas:
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:
In many areas, M. ulcerans infection has only occurred after significant environmental disturbance. In the original paper describing the disease, published in 1948, the first patients presented in 1939 in the Bairnsdale District of Victoria, Australia. [ 1 ] In December 1935, there had been terrible floods in the district, when all road and rail links had been cut and there had been considerable destruction of property. In Uganda, Barker examined cases of M. ulcerans infection (Buruli ulcer disease) occurring in the Busoga District on the east side of the Victoria Nile. north of Lake Victoria. [ 4 ] Although cases were known in the other parts of the country, cases were unknown in the district before 1965. Barker postulated that the outbreak was related to the unprecedented flooding of the lakes of Uganda between 1962 to 1964 as a result of heavy rainfall.
In Nigeria, cases have occurred among Caucasians living on the campus of University of Ibadan only after 1965, [ 5 ] when a small stream flowing through the campus was dammed to make artificial lake. The first case reported in Côte d'Ivoire was a French boy of seven years who lived with his parents beside lake Lake Kossou, [ 6 ] an artificial lake in the center of the country. In Liberia, cases have been reported in the north of the country [ 7 ] following the introduction of swamp rice to replace upland rice. This introduction has been associated with construction of dams on the Mayor river and extended wetlands. In Papua New Guinea. the infection occurs mainly in relation to the Sepik and Kumusi rivers; in the later areas, the disease is known as the "Kumusi ulcer". [ 8 ] The disease occurred after flooding and devastation, which followed the eruption of Mount Lamington in 1951. Reid described how older people living in the villages blamed the volcano for the disease. [ 8 ] The recent outbreak of the disease on Philip Island, Victoria, [ 9 ] was initially associated with the building of a roadway, inadvertently forming marshlands at the headwaters of an estuary, which was divided by the construction. Again in Australia, the recent increase in the number of cases between 1991 and 1994 in Victoria was associated with the use of recycled wastewater to irrigate a golf course.
A recent visit to Papua New Guinea has not identified any case along the Fly River, that country's largest river, despite significant environmental disturbance due to mining operations in the headwaters. It is clear that other factors must be responsible apart from simple disturbance, one of these must be formation of new water areas where the water is stagnant or only slow moving. A delay between one or three years occurs between the environmental changes and the first patients appearing. Severe flooding has occurred again in the last few days in the Bairnsdale District of Australia, exceeding the severity of the floods of 1935. It will be interesting to see if this disaster is again followed by increased numbers of patients with M. ulcerans infection.Seasonal variation
A series of epidemiological studies show the existence of seasonal variation in the appearance of Buruli ulcer cases. It seems that the number of cases augments during dry periods or after inundations. [ 10 ] [ 11 ] These conditions are probably favorable for the development of M. ulcerans. because of the concentration of possible vectors in areas that are frequently visited by humans.Reservoir(s) and mode(s) of transmission
The disease often occurs in close proximity to water bodies, but no specific activities that bring people into contact with water have been identified (i.e. fetching of water, fishing, washing, bathing, etc). The mode of transmission of Buruli ulcer is not entirely known. Recent evidence suggests that insects may be involved in the transmission of the infection. [ 12 ] These insects are aquatic bugs belonging to the genus Naucoris (family Naucoridae) and Diplonychus (family Belostomatidae). Trauma is probably the most frequent means by which M. ulcerans is introduced into the skin from surface contamination. [ 13 ] The initial trauma can be as slight as a hypodermic needle puncture or as severe as gunshot or exploding land mine wounds. [ 14 ] Other studies have suggested aerosol spread but these are not proven. [ 15 ] In Australia, animals such as koalas and possums are naturally infected. [ 16 ] [ 17 ] 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. [ 18 ] 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.
After considering the various suspected agents, Portaels et al. proposed the hypothesis that human beings as well as domestic and wild animals could be contaminated or infected by biting insects such as water bugs. [ 19 ] Aquatic bugs are cosmopolite insects found throughout temperate and tropical regions especially rich in freshwater. They represent about 10% of all species of Hemiptera associated with water and belong to two series of the suborder Heteroptera. the Nepomorpha. which include four superfamilies whose members spend most of their time under water, and the Naucoridae. which include a single family, the Naucoridae, whose members are commonly termed creeping water bugs.
Whether found in temperate countries like France or tropical ones like Ivory Coast, aquatic bugs exhibit the same way of life, preying, according to their size, on mollusks, snails, young fish, and the adults and larvae of other insects that they capture with their raptorial front legs and bite with their rostrum. These insects can inflict painful bites on humans as well. In the Ivory Coast, where Buruli ulcer is endemic, the water bugs are present in swamps and rivers, where human activities such as farming, fishing, and bathing take place. Present findings [ 20 ] describing the experimental transmission of M. ulcerans from water bugs to mice are in good agreement with the possibility of this mode of transmission to humans by bites.
Also in strong support of this hypothesis was the localization of M. ulcerans within the salivary glands of Naucoridae. [ 20 ] Local physiological conditions of this niche appear to fit the survival and the replication needs of M. ulcerans but not those of other mycobacteria. Surprisingly, infiltration of the salivary glands of Naucoridae by M. ulcerans does not seem to be accompanied by any tissue damage similar to the ulcerative skin lesions developed by bitten individuals and mediated by the cytotoxic activity of the mycolactone [ 21 ] and other toxins produced by M. ulcerans. [ 22 ] The inactivation of the latter toxins could be the result of salivary enzymatic activities, which remain to be determined.
Mycobacterium ulcerans was first cultivated and characterized from the environment in 2008. [ 23 ]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. [ 24 ]Clinical manifestations
Lesions are usually single and begin as firm, painless, non-tender, movable, subcutaneous nodules 1 to 2 cm in diameter or as small papules. Many patients complain of itching in the lesion. In 1 or 2 months, the nodule may become fluctuant and ulcerates, with an undermined edge that often extends 15 cm or more. The skin adjacent to the lesion, and often that of the entire corresponding limb, may be indurated by edema. Ordinarily, no regional lymphadenopathy or systemic manifestations are noted. There is, however, speculation that massive disseminated lesions may cause systemic toxic effects. Ulcers may remain small and heal without treatment, or may spread rapidly, undermining the skin over large areas, even an entire leg, thigh, or arm. Important structures such as the eye, breast, or genitalia are sometimes severely damaged. Most lesions heal spontaneously but without appropriate therapy frequently leave extensive scarring, with deformity. Osteomyelitis may lead to amputation.Pathogenesis and pathology Symptoms
After inoculation into the skin, M. ulcerans proliferates extracellular and elaborates a toxin, mycolactone. that enters the cells and causes necrosis of the dermis, panniculus, and deep fascia. Early lesions are closed, but as the necrosis spreads, the overlying dermis and epidermis eventually ulcerate, with undermined edges and a necrotic slough in the base of the ulcer. Histopathologic sections reveal a contiguous coagulation necrosis of the deep dermis and panniculus, with destruction of nerves, appendages, and blood vessels. Interstitial edema is noted. Clumps of extracellular acid-fast bacilli are plentiful and are frequently limited to the base of the ulcer and adjacent necrotic subcutaneous tissue. Bone is sometimes involved, and specific osteomyelitis is well known. Histologically there may be local and regional lymphadenitis with invasion by M. ulcerans. In active lesions, inflammatory cells are conspicuously few, presumably as a result of the immunosuppressive activity of the toxin. With healing, there is a granulomatous response, and the ulcerated area is eventually replaced by a depressed scar. HIV infection does not seem to predispose to Buruli ulcer but may facilitate dissemination of M. ulcerans. [ 25 ]Mycolactone
The major virulence determinant in M. ulcerans is a polyketide-derived macrolide: mycolactone. Mycolactone was originally isolated from M. ulcerans 1615, a Malaysian isolate, as a mixture of cis/trans isomers designated mycolactone A and mycolactone B. Identical molecules were also found to be present in two M. ulcerans isolates from the Democratic Republic of Congo. [ 26 ] More recent evidence shows that M. ulcerans 1615 produces a family of mycolactone congeners which differ primarily in the number of hydroxyl groups and double bonds. [ 27 ]
Mycolactone appears to play a key role in the pathogenesis of Buruli ulcer. In vivo studies using a guinea pig model of infection suggest that mycolactone is responsible for both the extensive tissue damage and immunosuppression which accompanies Buruli ulcer. [ 26 ] The activity of mycolactone on cultured fibroblasts and macrophage cell lines produces a distinct cytopathic phenotype. The earliest effect is cell rounding, which occurs within 10 h after addition of mycolactone to cultured cells. At 36 h, treated cells are arrested in G1 of the cell cycle, and by 72 h, cells begin to die via apoptosis. [ 21 ]
Bacterial macrolides are produced as secondary metabolites by soil bacteria, particularly bacteria such as Streptomyces and Saccharopolyspora species in the order Actinomycetales. [ 28 ] Interestingly, a number of related macrolides or congeners are often produced by a single bacterial isolate. [ 29 ]Diagnosis Classical approach for identification of mycobacteria
According to the traditional methods, mycobacteria are preliminarily identified by growth rate and pigmentation. [ 30 ] This preliminary grouping may provide presumptive identification of the organism and directs the selection of key biochemical tests to characterize an unknown mycobacterium. [ 31 ] [ 32 ]Clinical diagnosis
Because M. ulcerans infection is associated with nonspecific clinical manifestations and indolent course, it is important to consider every nodule or ulcer in an endemic area as a suspected M. ulcerans infection until proven otherwise. A nodule is firm and painless. In the absence of superinfection(s) an ulcer is painless or minimally painful, has the characteristic undermined edge and a whitish-yellow necrotic base. Previous residence in an endemic area should raise the suspicion of M. ulcerans infection.Laboratory diagnosis
Appropriately selected tissue specimen that include necrotic subcutaneous tissue and the undermined edge of ulcerated lesions are frequently diagnostic. Specimens from skin and subcutaneous tissue from nonulcerated lesions are likewise often diagnostic.Modern diagnostic techniques
Buruli ulcer is often diagnosed late, when treatment can be very difficult and frustrating. Confirmation by culture takes 6–8 weeks. Rapid diagnostic methods for M. ulcerans infection, as well as methods of rapid identification of the organism in clinical and environmental specimens would be a significant advance in the management of M. ulcerans infection. Screening to detect early infection could guide early intervention.Polymerase chain reaction (PCR) in diagnosis
There are several PCR methods available that could increase the speed of diagnosis of M. ulcerans infection. [ 33 ] PCR is relatively expensive compared to microscopy, and is notorious for producing false-positive results in laboratories that lack experience with PCR. In high-prevalence regions such as West Africa, PCR may not be any more rapid than an accurate clinical case definition combined with a smear that shows acid-fast bacilli. In countries such as Australia, where the incidence is low, the great majority of patients who have nodules, papules or skin ulcers do not have M. ulcerans disease. In this situation, PCR is a quicker way of making the diagnosis with a high degree of confidence. The main advantage of PCR is that M. ulcerans disease can be diagnosed within 24 hours. PCR usefulness for mycobacterial infections is generally limited, however, and at present it is recommended that PCR is used as a rapid ancillary test, not as a replacement for culture and histology.
The PCR method developed by Stinear et al. [ 34 ] targets a DNA insertion sequence in M. ulcerans. When genomic M. ulcerans DNA is digested with the restriction enzyme AluI, many 1109 base-pair fragments were obtained. These AluI fragments have been shown to be part of a larger 1293 base-pair repeated sequence that, by chance, happened to contain two AluI restriction sites. The sequence has been named IS2404 (Genbank accession number AF003002) [ 34 ] [ 35 ] It has been recently discovered that IS2404 copies are also present in a large circular plasmid. The total number of IS copies is thus 220. It has been identified in all isolates of M. ulcerans tested to date and has not been found in at least 45 other mycobacterial species, including M. marinum. M. leprae and M. tuberculosis. Recent publications have however demonstrated the presence of IS2404 in M. marinum -like bacteria (Trott et al. accepted for publication). [ 36 ]
PCR methods that have been developed are based on the 16S rRNA gene, [ 37 ] the hsp65 gene, [ 38 ] or the insertion sequence IS2404. [ 35 ] In 1999, Guimaraes-Peres et al. [ 39 ] evaluated two nested PCRs: the nested IS2404-based PCR and the nested 16S rRNA gene-based PCR. IS2404-based PCR was positive only with M. ulcerans isolates and the closely related M. shinshuense. The 16S rRNA gene-based PCR was positive not only for these two strains but also for M. marinum. The use of IS2404-based PCR as a detection method for M. ulcerans showed better sensitivity and specificity, required less time, and was less costly than the 16S rRNA gene-based PCR. [ 39 ]
To date, it has been established that PCR has a specificity of 100% and a sensitivity of 96% compared with culture.PCR for detecting M. ulcerans in environmental samples
M. ulcerans belongs to the group of occasional pathogens. Most species belonging to this group are found almost everywhere in nature, and may become pathogenic under special circumstances. Some of them have rarely (e.g. M. malmoense) or never (M. ulcerans ) been isolated from the environment. The epidemiological profiles of the diseases they cause, however, suggest that they are present in nature. [ 40 ] Recently, M. ulcerans has been detected by molecular biological techniques in water samples collected in Australia [ 35 ] [ 41 ] and in bugs collected from roots of aquatic plants in swamps in endemic regions of Benin and Ghana. [ 12 ] M. ulcerans was, however, not recovered by culture from these environmental samples.
PCR is not inhibited by the presence of culturable organisms. Unfortunately, PCR is exquisitely sensitive to inhibition by many compounds such as humic and fulvic acids, which are ubiquitous in the environment and are not removed by standard DNA extraction protocols. The first confirmation that M. ulcerans was present in environmental water samples was obtained in 1997, [ 42 ] by combining the highly sensitive and specific IS2404 PCR with a method that separated sample DNA from naturally occurring inhibitors of PCR.
Three different strategies have now been used to overcome inhibition in environmental samples from M. ulcerans endemic regions. The first of these is gel chromatography. Environmental water samples are concentrated and subjected to homogenization with glass beads, followed by heat and alkaline lysis to release DNA. Total extracted DNA is then run through gel chromatography columns that separate DNA from contaminants on the basis of size. [ 35 ] Although relatively simple, the method is cumbersome and time-consuming. The second method uses paramagnetic beads linked to M. ulcerans antibodies to capture whole cells and separate them from contaminants in a magnetic field (immunomagnetic separation). [ 38 ] Antibodies are raised in laboratory animals. Captured cells are washed to remove inhibitors and then DNA is released by standard methods prior to PCR. The third approach also uses paramagnetic beads, but here the beads are linked to M. ulcerans -specific oligonucleotide probes, which capture IS2404 DNA that has been released from M. ulcerans by homogenization and alkaline lysis. The immobilized DNA is washed to remove inhibitors and used directly as a template for IS2404 PCR. The latter two methods each have limitations and advantages, but offer superior detection sensitivity and are less time-consuming than gel chromatography.DNA fingerprinting techniques for M. ulcerans
Molecular typing methods may be categorized into three broad groups on the basis of the type of macromolecules targeted for sub-typing, i.e. methods based on fatty acids, proteins and nucleic acids. Actually, the genotypic typing methods (DNA fingerprinting) that evaluate differences at the DNA level are used more commonly and have emerged as revolutionary tools for epidemiological studies.
The use of DNA fingerprinting for the identification of M. tuberculosis has greatly improved understanding of the epidemiology of tuberculosis: transmission routes of different strains have been recognized; [ 43 ] outbreaks of multidrug-resistant strains have been detected early; and the relative importance of reinfection versus reactivation can now be elucidated. [ 44 ]
Various molecular methods for fingerprinting of M. ulcerans are now being developed to facilitate studies on the epidemiology of Buruli ulcer. So far, 12 genotypes, spread over the world, have been discriminated, based on a variable number of tandem repeats and mycobacterial interspersed repetitive units. Next-Generation Sequencing will soon dramatically ameliorate subtyping and genotype differentiation.DNA sequencing
Direct comparison of some genomic DNA sequences of bacterial strains is the best means of quantitatively determining whether two strains are similar or different. Portaels et al. have analyzed the 3’-terminal region of the 16S rRNA gene sequence of 17 strains of M. ulcerans from Africa, Australia and America. [ 45 ] This analysis has revealed three subgroups that vary according to the continent of origin. Later, a fourth subgroup was discovered in China and Japan confirming the existence of an Asian type. [ 46 ]Restriction fragment length polymorphism (RFLP) RFLP based on insertion sequences
Insertion sequences (IS) are mobile genetic elements that are usually present in numerous copies within a bacterial genome. These elements can be used as probes, and because the number and location of IS elements vary, each strain will have a unique banding pattern. Molecular analysis of M. ulcerans has revealed two insertion sequences: IS2404 and IS2606. [ 34 ] Southern blot analysis to detect IS2404 and IS2606 shows inconclusive RFLP patterns between different strains. Due to the high number of copies of both elements, the banding patterns are difficult to interpret, limiting the value of the Southern blot method to type M. ulcerans isolates. [ 34 ]RFLP based on pTBN12 plasmid
Jackson et al. have used pTBN12, a well-defined plasmid, as a probe with AluI restriction fragments. [ 47 ] The probe was able to distinguish 11 RFLP patterns.Pulsed field gel electrophoresis (PFGE)
PFGE permits the generation of simplified chromosomal restriction fragment patterns without having to resort to probe hybridization methods. In this method, restriction enzymes that cut DNA infrequently are used to generate large fragments of chromosomal DNA, which are then separated by special electrophoretic procedures. Preliminary results showed that M. ulcerans genomes produce three different profiles according to the three geographical origins of the strains (Type I: Africa, Type II: Australia and Type III: North America) [ 48 ]Amplified fragment length polymorphism (AFLP)
The AFLP technique is based on the selective PCR amplification of restriction fragments from a total digest of genomic DNA. [ 49 ] This technique involves three steps: restriction of DNA and ligation of oligonucleotides and adaptors; selective amplification of sets of restriction fragments; and gel analysis of the amplification fragments. Typically 50-100 restriction fragments are amplified and detected on denaturing polyacrylamide gel. AFLP typing results in a clear distinction of M. marinum from M. ulcerans. but interspecies differentiation is not trustworthy [ 50 ]PCR typing methods
PCR is another molecular method that has become increasingly important for epidemiological studies. The technique detects and amplifies small amounts of DNA; 10-100 copies of the templates are enough to perform DNA amplification. Thus, PCR can be used to type organisms that grow slowly on laboratory media, such as M. tuberculosis. [ 51 ] PCR also can be used to detect and type pathogens in patients whose culture are negative because they have been treated. Moreover, PCR can be used to amplify the DNA from organisms that are present in tissues preserved in formalin [ 52 ] and from non-cultivable organisms (e.g. M. leprae).PCR of repetitive chromosomal elements (Rep-PCR)
Rep-PCR is a modification of the PCR technique that is more suitable for epidemiological purposes than conventional PCR. In this case, the primers are directed towards repetitive chromosomal elements such as IS6110 in M. tuberculosis and the ERIC sequence in other bacteria. [ 47 ] In M. ulcerans. the genomic sequence between the IS2404 elements has been amplified. The profiles produced by this technique categorized the strains into three subgroups related to the three different endemic regions (Africa, Australia and North America).Ribotyping
This method involves amplification of a known sequence cut by restriction enzymes, and compares restriction fragments of amplified DNA from different strains. Using this technique, the M. ulcerans genome has been found to produce three different restriction profiles related to the origin of the strains.Treatment
Preulcerative lesions are excised, and the skin is closed primarily. Ulcers are widely excised, and skin grafts applied. Continuous local heating to 40°C (e.g. by circulating water jackets) promotes healing, even without excision. Amputation of limbs is sometimes necessary. Appropriate physiotherapy is important when contracture deformities are likely to develop.
Small lesions can be treated with antibiotics alone. The current recommended regimen is rifampicin for eight weeks, with streptomycin injections given for the first four weeks, and then clarithromycin orally for the second four weeks. [ 53 ] Antibiotics are ineffective in more extensive disease and surgery is always required.Prevention
No effective prophylactic measures have been demonstrated. The Bacille Calmette-Guérin (BCG) vaccination may produce protection or delay onset of lesions for approximately 6 months [ 54 ] and may protect against severe forms of the disease such as osteomyelitis. [ 55 ]References