Buruli Ulcer Patients Research Articles

The socioeconomic burden of Buruli Ulcer disease in the Ga West District of Ghana

Buruli ulcer (BU) is the third most common mycobacterial infection in humans after tuberculosis and leprosy. We highlight the social and economic burden of 86 BU patients studied in a Ghanaian district in 2008 which has the fifth highest BU prevalence rate in the country and is the most endemic in the Greater Accra Region. We traced patients who had received treatment for BU within the year preceding the study and interviewed them or the primary caretakers of minors mostly using a semi-structured interview guide. We found that against a background of living in abject poverty, the affected households spent on average over 80 per cent of their annual incomes on seeking health care for the disease despite the policy of free treatment for BU in government health care institutions. Beyond the direct financial costs, households incurred huge social and psychological burdens such as social stigma, isolation, and even divorce. Labor time lost due to care-seeking came close to one year for some affected patients. The extent of the burden from the disease had a relationship with care seeking patterns for the disease. We recommend that BU affected households be enrolled in the social protection programs of Ghana.KEY WORDS: Buruli ulcer, socioeconomic burden, stigma, poverty, Ghana

Geographic Distribution, Age Pattern and Sites of Lesions in a Cohort of Buruli Ulcer Patients from the Mapé Basin of Cameroon

Buruli ulcer (BU), a neglected tropical disease of the skin, caused by Mycobacterium ulcerans, occurs most frequently in children in West Africa. Risk factors for BU include proximity to slow flowing water, poor wound care and not wearing protective clothing. Man-made alterations of the environment have been suggested to lead to increased BU incidence. M. ulcerans DNA has been detected in the environment, water bugs and recently also in mosquitoes. Despite these findings, the mode of transmission of BU remains poorly understood and both transmission by insects or direct inoculation from contaminated environment have been suggested. Here, we investigated the BU epidemiology in the Mapé basin of Cameroon where the damming of the Mapé River since 1988 is believed to have increased the incidence of BU. Through a house-by-house survey in spring 2010, which also examined the local population for leprosy and yaws, and continued surveillance thereafter, we identified, till June 2012, altogether 88 RT-PCR positive cases of BU. We found that the age adjusted cumulative incidence of BU was highest in young teenagers and in individuals above the age of 50 and that very young children (<5) were underrepresented among cases. BU lesions clustered around the ankles and at the back of the elbows. This pattern neither matches any of the published mosquito biting site patterns, nor the published distribution of small skin injuries in children, where lesions on the knees are much more frequent. The option of multiple modes of transmission should thus be considered. Analyzing the geographic distribution of cases in the Mapé Dam area revealed a closer association with the Mbam River than with the artificial lake.

Towards Rational Use of Antibiotics for Suspected Secondary Infections in Buruli Ulcer Patients

BackgroundThe emerging disease Buruli ulcer is treated with streptomycin and rifampicin and surgery if necessary. Frequently other antibiotics are used during treatment.Methods/Principal FindingsInformation on prescribing behavior of antibiotics for suspected secondary infections and for prophylactic use was collected retrospectively. Of 185 patients that started treatment for Buruli ulcer in different centers in Ghana and Bénin 51 were admitted. Forty of these 51 admitted patients (78%) received at least one course of antibiotics other than streptomycin and rifampicin during their hospital stay. The median number (IQR) of antibiotic courses for admitted patients was 2 (1, 5). Only twelve patients received antibiotics for a suspected secondary infection, all other courses were prescribed as prophylaxis of secondary infections extended till 10 days on average after excision, debridement or skin grafting. Antibiotic regimens varied considerably per indication. In another group of BU patients in two centers in Bénin , superficial wound cultures were performed. These cultures from superficial swabs represented bacteria to be expected from a chronic wound, but 13 of the 34 (38%) S. aureus were MRSA.Conclusions/SignificanceA guide for rational antibiotic treatment for suspected secondary infections or prophylaxis is needed. Adherence to the guideline proposed in this article may reduce and tailor antibiotic use other than streptomycin and rifampicin in Buruli ulcer patients. It may save costs, reduce toxicity and limit development of further antimicrobial resistance. This topic should be included in general protocols on the management of Buruli ulcer.

PCR Typing of Mycobacterium ulcerans Lineages Based on Large Sequence Polymorphisms

Genetic fine typing of Mycobacterium ulcerans, the causative agent of the neglected tropical disease Buruli ulcer, has long been hampered by the remarkable genetic homogeneity of patient isolates. However, large sequence polymorphisms (LSPs), mainly originating from insertional-deletional genomic events, allow the differentiation between major lineages of M. ulcerans and other mycolactone producing mycobacteria (MPMs). Here, we describe an LSP-based rapid PCR typing scheme for these mycobacteria. Application of this approach to a selection of mycobacterial strains isolated from Buruli ulcer patients in Japan shows that they belong to the M. ulcerans Asian haplotype.

Rapid Assessment Survey of The Prevalence of Buruli Ulcer in The Health District of South Maniema, Maniema Province, The Democratic Republic of The Congo

Background: Buruli ulcer (BU) is endemic in more than 30 countries worldwide. Africa is the most affected continent with 16 confirmed endemic countries and 7 suspected or potential endemic countries. In the Democratic Republic of the Congo, a survey in 2004 showed the presence of suspected cases of BU in five of the country’s 11 provinces. The current survey was carried out in 2010 to confirm the endemicity of BU is the southern part of the Maniema Province and to provide support for case management and control measures if necessary. Method: The method of the survey was based on the protocol of rapid prevalence assessment survey (RPAS), proposed by the Buruli ulcer control Program of the World Health Organization (WHO) Regional Office for Africa to confirm BU endemic in countries. It included: awareness campaign and sensitization of health workers and communities in suspected endemic areas, followed by clinical screening of patients with suspected BU lesions and sampling of suspicious lesions by swab or fine needle aspiration (FNA) for laboratory confirmation of diagnosis, mainly by PCR. WHO-recommended treatment is proposed for cases which clinical features were in favor of the diagnosis of Buruli ulcer. Results: The survey in the Southern part of Maniema province targeted six of the nine health zones of Kasongo district. The three other health zones in the district were not be visited for accessibility and security reasons. A total of 66 suspected cases of Buruli ulcer were found at the Hospital of Kindu and in the six visited health zones. The lab tests with Ziehl-Nielsen (ZN) technique have confirmed 9 cases of BU. PCR tests confirmed eight cases of BU, including three who were not positive to the ZN tests. This makes a total of 12 BU patients confirmed by ZN and/or PCR and gives a proportion of laboratory confirmation of 18%. Discussions: Based on the results of this survey all health zones in South Maniema were classified as Buruli ulcer endemic areas, because of the same geo-climatic features that characterize all of them. These findings are similar to those of previous studies in the same province. The low confirmation rate of BU suspected cases by laboratory tests (18%) could be explained by the fact that many of the suspicious lesions which were sampled were very old wounds and had been evolving for several years. The WHO Regional Office for Africa has developed a plan of surveys, using the same rapid assessment protocol to confirm the endemicity of Buruli ulcer in other suspected endemic provinces of the DRC and in other member states of WHO African Region.

Corticosteroid-Induced Immunosuppression Ultimately Does Not Compromise the Efficacy of Antibiotherapy in Murine Mycobacterium ulcerans Infection

BackgroundBuruli ulcer (BU) is a necrotizing disease of the skin, subcutaneous tissue and bone caused by Mycobacterium ulcerans. It has been suggested that the immune response developed during the recommended rifampicin/streptomycin (RS) antibiotherapy is protective, contributing to bacterial clearance. On the other hand, paradoxical reactions have been described during or after antibiotherapy, characterized by pathological inflammatory responses. This exacerbated inflammation could be circumvented by immunosuppressive drugs. Therefore, it is important to clarify if the immune system contributes to bacterial clearance during RS antibiotherapy and if immunosuppression hampers the efficacy of the antibiotic regimen.Methodology/Principal FindingsWe used the M. ulcerans infection footpad mouse model. Corticosteroid-induced immunosuppression was achieved before experimental infection and maintained during combined RS antibiotherapy by the administration of dexamethasone (DEX). Time-lapsed analyses of macroscopic lesions, bacterial burdens, histology and immunohistochemistry were performed in M. ulcerans-infected footpads. We show here that corticosteroid-immunosuppressed mice are more susceptible to M. ulcerans, with higher bacterial burdens and earlier ulceration. Despite this, macroscopic lesions remised during combined antibiotic/DEX treatment and no viable bacteria were detected in the footpads after RS administration. This was observed despite a delayed kinetics in bacterial clearance, associated with a local reduction of T cell and neutrophil numbers, when compared with immunocompetent RS-treated mice. In addition, no relapse was observed following an additional 3 month period of DEX administration.Conclusions/SignificanceThese findings reveal a major role of the RS bactericidal activity for the resolution of M. ulcerans experimental infections even during immunosuppression, and support clinical investigation on the potential use of corticosteroids or other immunosuppressive/anti-inflammatory drugs for the management of BU patients undergoing paradoxical reactions.

Buruli-Ulcer Induced Disability in Ghana: A Study at Apromase in the Ashanti Region

Objectives. To describe trends and category of disabilities caused by Buruli ulcer disease. Design. This retrospective study was set up to quantify information on the disability trends caused by Buruli ulcer (BU) using data on patients attending BU and chronic ulcer clinics from 2004 to 2009, at Global Evangelical Mission Hospital, Apromase. Methods. Data was retrieved from the WHO BU1 form, case registry book, surgical theatre register, and BU patients' records book of the hospital. Disability was measured as the incapability of patients to perform one or more daily activities due to his/her state of BU disease before treatment. Results. A total of 336 positive BU cases comprising 181 males (53.9%) were recorded of which 113 (33.6%) cases of disabilities were identified. A mean age of 52.5 (±1.32) years was recorded. For the trend of disabilities, the year 2009 recorded the highest (N = 34, 31.0%). The lesions were mostly located at the lower limbs (N = 65, 57.5%) region of the patients. Lesions with diameter >15 cm were the major (59.3%) category of lesions. Conclusion. Trend of disability reveals proportional increase over the years from 2004 to 2009. Contracture at the knee and ankle joints was the commonest disability recorded.

Sero-Epidemiology as a Tool to Screen Populations for Exposure to Mycobacterium ulcerans

BackgroundPrevious analyses of sera from a limited number of Ghanaian Buruli ulcer (BU) patients, their household contacts, individuals living in BU non-endemic regions as well as European controls have indicated that antibody responses to the M. ulcerans 18 kDa small heat shock protein (shsp) reflect exposure to this pathogen. Here, we have investigated to what extent inhabitants of regions in Ghana regarded as non-endemic for BU develop anti-18 kDa shsp antibody titers.Methodology/Principal FindingsFor this purpose we determined anti-18 kDa shsp IgG titers in sera collected from healthy inhabitants of the BU endemic Densu River Valley and the Volta Region, which was so far regarded as BU non-endemic. Significantly more sera from the Densu River Valley contained anti-18 kDa shsp IgG (32% versus 12%, respectively). However, some sera from the Volta Region also showed high titers. When interviewing these sero-responders, it was revealed that the person with the highest titer had a chronic wound, which was clinically diagnosed and laboratory reconfirmed as active BU. After identification of this BU index case, further BU cases were clinically diagnosed by the Volta Region local health authorities and laboratory reconfirmed. Interestingly, there was neither a difference in sero-prevalence nor in IS2404 PCR positivity of environmental samples between BU endemic and non-endemic communities located in the Densu River Valley.ConclusionsThese data indicate that the intensity of exposure to M. ulcerans in endemic and non-endemic communities along the Densu River is comparable and that currently unknown host and/or pathogen factors may determine how frequently exposure is leading to clinical disease. While even high serum titers of anti-18 kDa shsp IgG do not indicate active disease, sero-epidemiological studies can be used to identify new BU endemic areas.

Buruli Ulcer: Treatment Challenges at Three Centres in Ghana

Aims. This retrospective study was to identify some challenges in the treatment of Buruli ulcer (BU) and present a proposed treatment regime. Materials and Methods. Information from patients medical records, hospital database, and follow-up findings on BU treatment procedures from 1994 to 1998 and from 2004 to 2007 at three research sites in Ghana were reviewed to determine the treatment challenges encountered. Data needed were recorded and analyzed, and results presented using SPSS version 17.0. Results. A total of 489 BU patients information was selected for the study. A majority (56.90%, n = 278) of the patients were children (0–14 years), with a mean age of 12.8 years. Significant challenges in BU treatment in Ghana identified included sequelae (P = 0.041 ), delayed treatment (P = 0.012 ), and high treatment cost (P = 0.044 ). Duration of hospital stay was clearly correlated with the time spent at home prior to admission; spearman's rank correlation coefficient was 0.72 (95% CI 0.42–0.87). Conclusion. Delays in seeking treatment among BU patients were the main factor which resulted in most of the other factors contributing to the challenges in treatment. A combination of psychosocial and biomedical approach was proposed as holistic method to alleviate the challenges in BU treatment.

ガーナ共和国アシャンティ州におけるブルーリ潰瘍と国民健康保険制度の実態

The objectives of this paper are to grasp the current status of an endemic disease in the Republic of Ghana known as Buruli ulcer(BU) and to clarify relationships between the National Health Insurance Scheme(NHIS) and the health care system. As for the method of the study, I have adopted field investigations conducted in Ghana in March, 2009 and August, 2011. All the counter-measurements on BU taken either by the very government or international NGOs have been administered and controlled the disease in accordance with the National Buruli ulcer Control Programme(NBUCP) under the guidance of Global Buruli ulcer Initiative which was established in Geneva, Switzerland in 1998 as an advisory committee of the World Health Organization. BU patients can receive treatments free. The government sponsored NBUCP and direct and indirect donations from various NGOs provide the cost of medical treatments. The Ghanian NHIS of 2003 aimed to ease and improve the health situations of the people. Some of serious endemic diseases like BU, however, are excluded from the schemes. While the NHIS remains ineffective to the diseases like BU, the burden of treatment costs puts the strain on NBUCP. The field researches indicate that the budgets provided by the NBUCP often faile to cover the fundamental medical supplies like bandages. This causes to give an extra burden on the already constrained hospital budgets. Only reliefs the hospitals can rely on are the international aids which often determine the fate of the national disease control. The research reveals that the region's health system remains unsound. Ghana represents such realities of West Africa as a whole.

Household Perceptions, Treatment-Seeking Behaviors and Health Outcomes for Buruli Ulcer Disease in a Peri-Urban District in Ghana

Buruli ulcer (BU) has been associated with very unimaginable outcomes. It is flesh eating, disfiguring and economically dehydrating. Yet the disease is still mostly shrouded in mystery. Consequently, people have different perceptions about it and hence adopt different treatment behaviorss towards it; notwithstanding the free treatment for it. The purpose of this paper is to identify and examine respondents’ perceptions and the influence these have on their health seeking behaviorss. Eighty-six BU patients who had been treated or were being treated of BU in the Ga West District Health Center in Ghana were sampled for this study. A structured questionnaire and a qualitative in-depth interview guide were used to elicit the data. Some of the interviewees held the belief that the disease is caused by their adversaries, including witches. More than half of the respondents, however, did not have any idea about the disease and thought it is just the work of God. The first point of call for health care for most of the patients studied was herbalists or else they used herbs. Nearly a quarter of them also engaged in self medication, including the use of ‘pain killers’ and ointments, since they took the first signs for ordinary boils. Perceptions of the cause of the disease influenced health seeking behaviors, which further influenced treatment outcomes. A lot of education is needed on the symptoms of the disease, including encouraging early seeking of care at the District Health Center.

Histopathological Changes and Clinical Responses of Buruli Ulcer Plaque Lesions during Chemotherapy: A Role for Surgical Removal of Necrotic Tissue?

BackgroundBuruli ulcer (BU) caused by Mycobacterium ulcerans is a necrotizing skin disease usually starting with a subcutaneous nodule or plaque, which may ulcerate and progress, if untreated, over months and years. During the currently recommended antibiotic treatment with rifampicin/streptomycin plaque lesions tend to ulcerate, often associated with retarded wound healing and prolonged hospital stays.Methodology/Principal FindingsIncluded in this study were twelve laboratory reconfirmed, HIV negative BU patients presenting with plaque lesions at the CDTUB in Allada, Benin. Punch biopsies for histopathological and immunohistochemical analysis were taken before start of treatment and after four to five weeks of treatment. Where excision or wound debridement was clinically indicated, the removed tissue was also analyzed. Based on clinical judgment, nine of the twelve patients enrolled in this study received limited surgical excision seven to 39 days after completion of chemotherapy, followed by skin grafting. Lesions of three patients healed without further intervention. Before treatment, plaque lesions were characterized by a destroyed subcutis with extensive necrosis without major signs of infiltration. After completion of antibiotic treatment partial infiltration of the affected tissue was observed, but large necrotic areas remained unchanged.Conclusion/SignificanceOur histopathological analyses show that ulceration of plaque lesions during antibiotic treatment do not represent a failure to respond to antimycobacterial treatment. Based on our results we suggest formal testing in a controlled clinical trial setting whether limited surgical excision of necrotic tissue favours wound healing and can reduce the duration of hospital stays.

Outcome of Buruli ulcer patients

Outcome of Buruli ulcer patients

Mycolactone Diffuses into the Peripheral Blood of Buruli Ulcer Patients - Implications for Diagnosis and Disease Monitoring

Background Mycobacterium ulcerans, the causative agent of Buruli ulcer (BU), is unique among human pathogens in its capacity to produce a polyketide-derived macrolide called mycolactone, making this molecule an attractive candidate target for diagnosis and disease monitoring. Whether mycolactone diffuses from ulcerated lesions in clinically accessible samples and is modulated by antibiotic therapy remained to be established.Methodology/Principal FindingPeripheral blood and ulcer exudates were sampled from patients at various stages of antibiotic therapy in Ghana and Ivory Coast. Total lipids were extracted from serum, white cell pellets and ulcer exudates with organic solvents. The presence of mycolactone in these extracts was then analyzed by a recently published, field-friendly method using thin layer chromatography and fluorescence detection. This approach did not allow us to detect mycolactone accurately, because of a high background due to co-extracted human lipids. We thus used a previously established approach based on high performance liquid chromatography coupled to mass spectrometry. By this means, we could identify structurally intact mycolactone in ulcer exudates and serum of patients, and evaluate the impact of antibiotic treatment on the concentration of mycolactone.Conclusions/SignificanceOur study provides the proof of concept that assays based on mycolactone detection in serum and ulcer exudates can form the basis of BU diagnostic tests. However, the identification of mycolactone required a technology that is not compatible with field conditions and point-of-care assays for mycolactone detection remain to be worked out. Notably, we found mycolactone in ulcer exudates harvested at the end of antibiotic therapy, suggesting that the toxin is eliminated by BU patients at a slow rate. Our results also indicated that mycolactone titres in the serum may reflect a positive response to antibiotics, a possibility that it will be interesting to examine further through longitudinal studies.

Factors enhancing the control of Buruli ulcer in the Bomfa communities, Ghana

This study examines factors that may enhance the control and holistic treatment of Buruli ulcer in an endemic area of the Ashanti Region in Ghana. A total of 189 Buruli ulcer patients from the Bomfa sub-district were treated at the Global Evangelical Mission Hospital, Apromase-Ashanti, Ghana, from January to December 2005. Diagnosis was based on clinical findings and confirmed by any two positives of Ziehl-Neelson test for acid fast bacilli, polymerase chain reaction and histopathology. Children up to age 14 made up 43.4% of the cases; male: female ratio was 3:2. The mean duration of hospitalization was 77 days and hospital stay was significantly correlated with the time spent at home with the disease prior to admission; also, 76.7% of the cases were late ulcers. Of the 189 patients, 145 (i.e. 76.7%) were treated with antibiotics and surgery which involved excision, skin grafting with or without contracture release. A follow-up survey after the introduction of the psychosocial approach recorded fewer (85) new Buruli ulcer (BU) cases of which, the majority (78.8%, 67) were nodules and only 21.2% (18) were ulcers. Health education plays a major role in the holistic treatment of BU. This paper proposes a further study in other endemic areas on the treatment of BU with emphasis on psychosocial approach for holistic treatment.

Mycobacterium ulcerans DNA Not Detected in Faecal Samples from Buruli Ulcer Patients: Results of a Pilot Study

It has recently been shown that in a Buruli ulcer (BU) endemic region of southeastern Australia, significant numbers of possums (native tree-dwelling marsupials) have clinical BU disease. Furthermore, based on quantitative PCR (qPCR) analysis, animals with BU lesions (and some without) shed M. ulcerans DNA in their faeces, indicative of bacterial loads of up to 108 organisms/gram. These findings led us to propose that humans might also harbour M. ulcerans in their gastrointestinal tract and shed the bacterium in their faeces. We conducted a pilot study and collected faecal swabs from 26 patients with confirmed BU and 31 healthy household controls. Faecal samples were also collected from 10 healthy controls from non-endemic regions in Ghana. All 67 specimens were negative when tested by IS2404 PCR. The detection sensitivity of this method was ≥104 bacteria per gram (wet-weight) of human faecal material. We conclude that the human gastrointestinal tract is unlikely to be a significant reservoir of M. ulcerans.

BURDEN OF BURULI ULCER: HOW AFFECTED HOUSEHOLDS IN A GHANAIAN DISTRICT COPE

Buruli Ulcer (BU) is economically burdensome and socially stigmatising. We examined the burden of BU and the strategies commonly adopted by households in a Ghanaian district to cope with it. Respondents for the study were conveniently sampled using data from a BU unit within the District Health Centre. Adult BU patients and caretakers of minor patients (aged less than 15) who had reported for care within the past year were interviewed. A semi- structured questionnaire was used for the interviews. The staff in-charge of an international NGO with services to BU patients in the district was also interviewed. The disease was associ- ated with poor rural households with mean annual incomes of the equivalent of USD 490.70 or less. Other costs and stigma associated with the disease posed a great burden on the already poor households we studied. Households adopt coping strategies, including sale of assets, reduction in farm sizes, and avoiding people, all of which are potentially risky for future sustainability.

Geographic Expansion of Buruli Ulcer Disease, Cameroon

Geographic Expansion of Buruli Ulcer Disease, Cameroon

Geographic Expansion of Buruli Ulcer Disease, Cameroon

Geographic Expansion of Buruli Ulcer Disease, Cameroon

Mycobacterium ulcerans infections cause progressive muscle atrophy and dysfunction, and mycolactone impairs satellite cell proliferation

Clinical observations from Buruli ulcer (BU) patients in West Africa suggest that severe Mycobacterium ulcerans infections can cause skeletal muscle contracture and atrophy leading to significant impairment in function. In the present study, male mice C57BL/6 were subcutaneously injected with M. ulcerans in proximity to the right biceps muscle, avoiding direct physical contact between the infectious agent and the skeletal muscle. The histological, morphological, and functional properties of the muscles were assessed at different times after the injection. On day 42 postinjection, the isometric tetanic force and the cross-sectional area of the myofibers were reduced by 31% and 29%, respectively, in the proximate-infected muscles relative to the control muscles. The necrotic areas of the proximate-infected muscles had spread to 7% of the total area by day 42 postinjection. However, the number of central nucleated fibers and myogenic regulatory factors (MyoD and myogenin) remained stable and low. Furthermore, Pax-7 expression did not increase significantly in mycolactone-injected muscles, indicating that the satellite cell proliferation is abrogated by the toxin. In addition, the fibrotic area increased progressively during the infection. Lastly, muscle-specific RING finger protein 1 (MuRF-1) and atrogin-1/muscle atrophy F-box protein (atrogin-1/MAFbx), two muscle-specific E3 ubiquitin ligases, were upregulated in the presence of M. ulcerans. These findings confirmed that skeletal muscle is affected in our model of subcutaneous infection with M. ulcerans and that a better understanding of muscle contractures and weakness is essential to develop a therapy to minimize loss of function and promote the autonomy of BU patients.