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BACKGROUND: Buruli ulcer is a neglected tropical disease caused by Mycobacterium ulcerans infection that damages the skin and subcutis. It is most prevalent in western and central Africa and Australia. Standard antimicrobial treatment with oral rifampicin 10 mg/kg plus intramuscular streptomycin 15 mg/kg once daily for 8 weeks (RS8) is highly effective, but streptomycin injections are painful and potentially harmful. We aimed to compare the efficacy and tolerability of fully oral rifampicin 10 mg/kg plus clarithromycin 15 mg/kg extended release once daily for 8 weeks (RC8) with that of RS8 for treatment of early Buruli ulcer lesions.METHODS: We did an open-label, non-inferiority, randomised (1:1 with blocks of six), multicentre, phase 3 clinical trial comparing fully oral RC8 with RS8 in patients with early, limited Buruli ulcer lesions. There were four trial sites in hospitals in Ghana (Agogo, Tepa, Nkawie, Dunkwa) and one in Benin (Pobè). Participants were included if they were aged 5 years or older and had typical Buruli ulcer with no more than one lesion (caterories I and II) no larger than 10 cm in diameter. The trial was open label, and neither the investigators who took measurements of the lesions nor the attending doctors were masked to treatment assignment. The primary clinical endpoint was lesion healing (ie, full epithelialisation or stable scar) without recurrence at 52 weeks after start of antimicrobial therapy. The primary endpoint and safety were assessed in the intention-to-treat population. A sample size of 332 participants was calculated to detect inferiority of RC8 by a margin of 12%. This study was registered with ClinicalTrials.gov, NCT01659437.FINDINGS: Between Jan 1, 2013, and Dec 31, 2017, participants were recruited to the trial. We stopped recruitment after 310 participants. Median age of participants was 14 years (IQR 10-29) and 153 (52%) were female. 297 patients had PCR-confirmed Buruli ulcer; 151 (51%) were assigned to RS8 treatment, and 146 (49%) received oral RC8 treatment. In the RS8 group, lesions healed in 144 (95%, 95% CI 91 to 98) of 151 patients, whereas lesions healed in 140 (96%, 91 to 99) of 146 patients in the RC8 group. The difference in proportion, -0·5% (-5·2 to 4·2), was not significantly greater than zero (p=0·59), showing that RC8 treatment is non-inferior to RS8 treatment for lesion healing at 52 weeks. Treatment-related adverse events were recorded in 20 (13%) patients receiving RS8 and in nine (7%) patients receiving RC8. Most adverse events were grade 1-2, but one (1%) patient receiving RS8 developed serious ototoxicity and ended treatment after 6 weeks. No patients needed surgical resection. Four patients (two in each study group) had skin grafts.INTERPRETATION: Fully oral RC8 regimen was non-inferior to RS8 for treatment of early, limited Buruli ulcer and was associated with fewer adverse events. Therefore, we propose that fully oral RC8 should be the preferred therapy for early, limited lesions of Buruli ulcer.FUNDING: WHO with additional support from MAP International, American Leprosy Missions, Fondation Raoul Follereau France, Buruli ulcer Groningen Foundation, Sanofi-Pasteur, and BuruliVac.

Buruli ulcer (BU) is a disabling and stigmatising neglected tropical disease (NTD). Its distribution and burden are unknown because of underdiagnosis and underreporting. It is caused by Mycobacterium ulcerans, an environmental pathogen whose environmental niche and transmission routes are not fully understood. The main control strategy is active surveillance to promote early treatment and thus limit morbidity, but these activities are mostly restricted to well-known endemic areas. A better understanding of environmental suitability for the bacterium and disease could inform targeted surveillance, and advance understanding of the ecology and burden of BU. We used previously compiled point-level datasets of BU and M. ulcerans occurrence, evidence for BU occurrence within national and sub-national areas, and a suite of relevant environmental covariates in a distribution modelling framework. We fitted relationships between BU and M. ulcerans occurrence and environmental predictors by applying regression and machine learning based algorithms, combined in an ensemble model to characterise the optimal ecological niche for the disease and bacterium across Africa at a resolution of 5km x 5km. Proximity to waterbodies was the strongest predictor of suitability for BU, followed potential evapotranspiration. The strongest predictors of suitability for M. ulcerans were deforestation and potential evapotranspiration. We identified patchy foci of suitability throughout West and Central Africa, including areas with no previous evidence of the disease. Predicted suitability for M. ulcerans was wider but overlapping with that of BU. The estimated population living in areas predicted suitable for the bacterium and disease was 46.1 million. These maps could be used to inform burden estimations and case searches which would generate a more complete understanding of the spatial distribution of BU in Africa, and may guide control programmes to identify cases beyond the well-known endemic areas., Author summary Like many neglected tropical diseases primarily affecting the rural poor, Buruli ulcer (BU) is under-detected and under-reported within routine health information systems. As such, the burden and distribution are not fully known, impeding appropriate targeting of health resources, control, and care for people affected. Having previously evaluated and mapped the existing evidence for BU and its causative agent M. ulcerans, we concluded that the disease was likely to occur beyond the range of known endemic areas. However, we were left with the question of where exactly these undetected cases might be occurring. Answering this question required a more fine-scale approach: BU is highly focal, presumably due to local variation in the environmental factors which determine suitability for M. ulcerans survival and transmission to humans. We used the compiled evidence and geographical datasets to build statistical models representing the relationship between environmental factors and previously reported cases. This allowed us to define the ecological niche of BU, and subsequently to identify areas across Africa where this niche was met, providing suitable conditions for the disease. We constructed separate models of suitability for M. ulcerans, using locations where its DNA had been detected in environmental sources. Unsurprisingly, suitability for M. ulcerans was predicted to be wider than, but geographically overlapping with that for BU. This implies that beyond the conditions necessary for survival of the bacterium, additional factors are required for transmission to humans. The high-resolution suitability maps we present are intended to guide case search activities which may identify endemic areas beyond the known endemic range. Data on the true prevalence of BU from targeted case searches within predicted-suitable areas will also allow us to validate and refine the models, and potentially to predict the probability of cases occurring within predicted suitable areas.

Summary Background Buruli ulcer can cause disfigurement and long-term loss of function. It is underdiagnosed and under-reported, and its current distribution is unclear. We aimed to synthesise and evaluate data on Buruli ulcer prevalence and distribution. Methods We did a systematic review of Buruli ulcer prevalence and used an evidence consensus framework to describe and evaluate evidence for Buruli ulcer distribution worldwide. We searched PubMed and Web of Science databases from inception to Aug 6, 2018, for records of Buruli ulcer and Mycobacterium ulcerans detection, with no limits on study type, publication date, participant population, or location. English, French, and Spanish language publications were included. We included population-based surveys presenting Buruli ulcer prevalence estimates, or data that allowed prevalence to be estimated, in the systematic review. We extracted geographical data on the occurrence of Buruli ulcer cases and M ulcerans detection from studies of any type for the evidence consensus framework; articles that did not report original data were excluded. For the main analysis, we extracted prevalence estimates from included surveys and calculated 95% CIs using Byar's method. We included occurrence records, reports to WHO and the Global Infectious Diseases and Epidemiology Network, and surveillance data from Buruli ulcer control programmes in the evidence consensus framework to grade the strength of evidence for Buruli ulcer endemicity. This study is registered with PROSPERO, number CRD42018116260. Findings 2763 titles met the search criteria. We extracted prevalence estimates from ten studies and occurrence data from 208 studies and five unpublished surveillance datasets. Prevalence estimates within study areas ranged from 3·2 (95% CI 3·1–3·3) cases per 10 000 population in Cote d'Ivoire to 26·9 (23·5–30·7) cases per 10 000 population in Benin. There was evidence of Buruli ulcer in 32 countries and consensus on presence in 12. Interpretation The global distribution of Buruli ulcer is uncertain and potentially wider than currently recognised. Our findings represent the strongest available evidence on Buruli ulcer distribution so far and have many potential applications, from directing surveillance activities to informing burden estimates. Funding AIM Initiative.

Background: There is a high burden of morbidity due to neglected tropical diseases. To help address this, the World Health Organization recommends integration of case management (CM). Here, we present a practical framework designed to identify areas that could benefit from an integrated CM strategy in Ghana. We also investigated the accessibility of primary health care (PHC) to CM cases, and the impact of this on morbidity at diagnosis. Methods: Routinely detected cases of Buruli ulcer (BU) and leprosy, and suspected lymphedema identified through morbidity surveys during mass drug administration campaigns in Ghana in 2014 were remotely georeferenced. We estimated distances from cases’ home communities to the nearest primary healthcare facility (PHC), and compared rates of reported disease, completeness of clinical information, and risk of more severe morbidity, relative to PHC accessibility. Results: We georeferenced communities of 295/350 reported leprosy cases, 240/333 BU cases, and 1,557/2383 instances of lymphedema. Overlap of these diseases was predominantly around Accra and in the Upper East Region. Rates of reported disease appeared higher in populations with higher accessibility to PHC, and leprosy cases living further from PHC had a higher risk of disability at diagnosis. Conclusions: This investigation demonstrates the feasibility and value of using routinely collected data to map CM-NTDs at low cost. The maps presented are intended to provide a resource for planning the implementation of integrated CM for NTDs in Ghana. This approach could be easily implemented by national health services in other endemic countries in the future.

Introduction : buruli Ulcer (BU) is a chronic debilitating skin disease caused by Mycobacterium ulcerans. It is the third most widespread mycobacterium infection after tuberculosis and leprosy globally but second in Ghana; causing morbidity in immuno-competent humans. M. ulcerans infection leads to chronic ulcers, deformities and functional limitation and its virulence depend on mycolactone. BU surveillance data are not adequately analysed to effectively identify the distribution of BU disease at regional levels. BU data was therefore analysed to identify the distribution of the disease in Greater Accra Region, Ghana. Methods : data from 2011 to 2015 was extracted from the BU02 forms in the Greater Accra Region. Variables collected were sex, age, district of residence, categories of lesions, location of lesions and clinical forms. Descriptive analysis was done and expressed as frequencies and graphs using Epi info7. b>Results : a total of 496 confirmed cases were reported in the region. The mean age of the patients was 28.9±21.5years. The minimum and maximum ages were 1 year and 100 years. Yearly trends showed cases decreased from 223 (45%) in 2011 to 27 (5.4%) in 2015 with 52.2% being males and 38.3% children Conclusion : the number of reported BU cases decreased considerably over the period with most patients presenting at the late stage (Cat III) of the disease. The majority of patients are in Ga South but access health care in Ga West. Public education and national awareness about the disease should be intensified and more resources allocated to Ga West.

Background:Buruli ulcer infection is generally referred to as a re-emerging disease with the highest burden in West Africa. In Ghana, about 1000 cases are reported annually. The former Ga district (now the Ga West and Ga South municipalities) continues to report the highest proportion of the worst ulcerated wounds in Ghana, despite various interventions implemented. The aim of this study was to determine factors affecting treatment-related decision making in BU affected families. Methods: Semi-structured questionnaire interview was conducted with 33 patients (≥15 years) and seven caretakers of children aged below 15 years to determine the social and economic factors influencing BU-related health seeking decision making and types of treatment choices that are made. Results: Respondents were afflicted with varied categories of the disease (category one (30%), category two (35%) and category three (35%)). Decisions to seek health care from biomedical facilities are influenced by factors such as advice from health workers (45.0%) and advice from family members (42.5%). Only a quarter (25%) of respondents actually mentioned “financial considerations” as one of the factors that influence their decision to seek for biomedical care. Whereas there was no significant relationship between family involvement in treatment decision making and category one (p = 0.5351) lesion, there was a significant relationship between family involvement in treatment decision making and categories two (p = 0.0434) and three (p = 0.0089) lesions. Conclusion: It appears from this study that financial consideration, which has been widely cited as a cause of treatment delay may be losing its influence to social factors. With the advent of free antibiotics treatment more studies are needed to identify social factors affecting BU treatment decision making so as to redesign health promotion messages appropriately, especially those aimed at getting patients into early treatment.

Buruli ulcer, caused by Mycobacterium ulcerans, is highly endemic in West Africa. While the mode of transmission is unknown, many studies associate Buruli ulcer with different types of water exposure. We present results from the largest study to date to test for M. ulcerans in aquatic sites and identify environmental attributes associated with its presence. Environmental samples from 98 aquatic sites in the Greater Accra, Ashanti, and Volta regions of Ghana were tested for the presence of M. ulcerans DNA by polymerase chain reaction. The proportion of aquatic sites positive for M. ulcerans varied by region: Ashanti 66% (N = 39), Greater Accra 34% (N = 29), and Volta 0% (N = 30). We explored the spatial distribution of M. ulcerans positive and negative water bodies and found no significant clusters. We also determined both highly localized water attributes and broad scale remotely sensed land cover and terrain environmental characteristics associated with M. ulcerans presence through logistic regression. Our results concur with published results regarding conditions suitable for M. ulcerans growth and associations with Buruli ulcer disease burden with regards to water characteristics and disturbed environments, but differ from others with regards to spatial associations and topographic effects such as elevation and wetness. While our results suggest M. ulcerans is an environmental organism existing in a specific ecological niche, they also reveal variation in the elements defining this niche across the sites considered. In addition, despite the causal association between Buruli ulcer and M. ulcerans, we observed no significant statistical association between case reports of Buruli ulcer and presence of M. ulcerans in nearby waterbodies.

The introduction of antibiotic therapy as first-line treatment of Buruli ulcer underlines the importance of laboratory confirmation of clinical diagnosis. Because smear microscopy has very limited sensitivity, the technically demanding and more expensive IS2404 diagnostic polymerase chain reaction (PCR) has become the main method for confirmation. By optimization of the release of mycobacteria from swab specimen and concentration of bacterial suspensions before smearing, we were able to improve the detection rate of acid-fast bacilli by microscopy after Ziehl-Neelsen staining. Compared with IS2404 PCR, which is the gold standard diagnostic method, the sensitivity and specificity of microscopy with 100 concentrated specimens were 58.4% and 95.7%, respectively. We subsequently evaluated a stepwise laboratory confirmation algorithm with detection of AFB as first-line method and IS2404 PCR performed only with those samples that were negative in microscopic analysis. This stepwise approach reduced unit cost by more than 50% to $5.41, and the total costs were reduced from $917 to $433

Summary Background Surgical debridement was the standard treatment for Mycobacterium ulcerans infection (Buruli ulcer disease) until WHO issued provisional guidelines in 2004 recommending treatment with antimicrobial drugs (streptomycin and rifampicin) in addition to surgery. These recommendations were based on observational studies and a small pilot study with microbiological endpoints. We investigated the efficacy of two regimens of antimicrobial treatment in early-stage M ulcerans infection. Methods In this parallel, open-label, randomised trial undertaken in two sites in Ghana, patients were eligible for enrolment if they were aged 5 years or older and had early (duration M ulcerans infection confirmed by dry-reagent-based PCR. Eligible patients were randomly assigned to receive intramuscular streptomycin (15 mg/kg once daily) and oral rifampicin (10 mg/kg once daily) for 8 weeks (8-week streptomycin group; n=76) or streptomycin and rifampicin for 4 weeks followed by rifampicin and clarithromycin (7·5 mg/kg once daily), both orally, for 4 weeks (4-week streptomycin plus 4-week clarithromycin group; n=75). Randomisation was done by computer-generated minimisation for study site and type of lesion (ulceration or no ulceration). The randomly assigned allocation was sent from a central site by cell-phone text message to the study coordinator. The primary endpoint was lesion healing at 1 year after the start of treatment without lesion recurrence or extensive surgical debridement. Analysis was by intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT00321178. Findings Four patients were lost to follow-up (8-week streptomycin, one; 4-week streptomycin plus 4-week clarithromycin, three). Since these four participants had healed lesions at their last assessment, they were included in the analysis for the primary endpoint. 73 (96%) participants in the 8-week streptomycin group and 68 (91%) in the 4-week streptomycin plus 4-week clarithromycin group had healed lesions at 1 year (odds ratio 2·49, 95% CI 0·66 to infinity; p=0·16, one-sided Fisher's exact test). No participants had lesion recurrence at 1 year. Three participants had vestibulotoxic events (8-week streptomycin, one; 4-week streptomycin plus 4-week clarithromycin, two). One participant developed an injection abscess and two participants developed an abscess close to the initial lesion, which was incised and drained (all three participants were in the 4-week streptomycin plus 4-week clarithromycin group). Interpretation Antimycobacterial treatment for M ulcerans infection is effective in early, limited disease. 4 weeks of streptomycin and rifampicin followed by 4 weeks of rifampicin and clarithromycin has similar efficacy to 8 weeks of streptomycin and rifampicin; however, the number of injections of streptomycin can be reduced by switching to oral clarithromycin after 4 weeks. Funding European Union (EU FP6 2003-INCO-Dev2-015476) and Buruli Ulcer Groningen Foundation.

Similar to other mycobacterial diseases, susceptibility to Buruli ulcer (Mycobacterium ulcerans infection) may be determined by host genetic factors. We investigated the role of SLC11A1 (NRAMP1) in Buruli ulcer because of its associations with both tuberculosis and leprosy. We enrolled 182 Buruli ulcer patients (102 with positive laboratory confirmation) and 191 healthy neighbourhood-matched controls in Ghana, and studied three polymorphisms in the SLC11A1 gene: 30 UTR TGTG ins/del, D543N G/A, and INT4 G/C. Finger prick blood samples from study subjects were dried on filter papers (FTA) and processed. D543N was significantly associated with Buruli ulcer: the odds ratio (adjusted for gender, age, and region of the participant) of the GA genotype versus the GG genotype was 2.89 (95% confidence intervals (CI): 1.41-5.91). We conclude that a genetic polymorphism in the SLC11A1 gene plays a role in susceptibility to develop Buruli ulcer, with an estimated 13% population attributable risk.

OBJECTIVES To evaluate former Buruli ulcer disease (BUD) patients to assess the factors associated with functional limitations and subsequent employment or schooling. METHODS The previously validated Buruli ulcer functional limitation score (BUFLS) questionnaire and interviews about educational and professional consequences incurred by BUD. RESULTS Of 638 participants, 362 (57%) had a functional limitation after a median period of almost 4 years after treatment for BUD. A lesion on a joint, older age, female gender, a lesion on a distal part of an extremity and a persistent wound were found to be independent risk factors for stopping work or education. The same risk factors applied to the development of a functional limitation. Both functional limitations and financial difficulties due to BUD disease often led to job loss and school dropout. CONCLUSIONS Rehabilitation programmes are urgently needed to diminish the suffering from the functional limitations and employment or schooling problems caused by BUD.

The reliability and validity of the earlier developed Buruli ulcer functional limitation score (BUFLS) questionnaire was assessed. Of 638 former Buruli ulcer patients (of 678 individuals examined), sufficient items on daily activities ( 13 of the 19) were applicable to calculate a score. To determine the validity, the functional limitation scores of the 638 individuals were compared with the global impression of the limitations, range of motion (ROM), and the social impact (change of occupation or education) of Buruli ulcer. To determine inter-observer reliability, the functional limitation score was reassessed in 107 participants within one and three weeks after the first interview by another interviewer and interpreter. Both global impression and ROM correlated well with the functional limitation scores ( 0.66 and 0.61). The inter-observer reliability of 107 participants as measured by an intra-class correlation coefficient of 0.86 was very good. The functional limitation scores measured in the second assessment were significantly higher than in the first assessment. This should be taken into account when the functional limitation score is used for the individual patient. The BUFLS can be used as for between group comparisons of endpoints in clinical trials and in the planning of resources. tations. 5 A reduction in the range of motion (ROM) was found in 58% of the former Buruli ulcer patients in Ghana when using a goniometer. Instead of measuring the physical limitations in ROM of joints, a simple and functional scoring system to assess nature and severity of the impairment on carrying out daily activities as a result of Buruli ulcer has been proposed. 6 Based on frequency endorsement and applicability, a ques- tionnaire with 19 items of daily activities was developed. The questionnaire has a good internal consistency ( 0.89). 7,8 In this study, the validity and reliability of this questionnaire was analyzed.

Buruli ulcer, a disease with long-term consequences, is emerging in west Africa. Thus, a functional limitation scoring system is needed to assess its nature and severity. A list of daily activities was developed for this disease. Following treatment of Buruli ulcer, persons in Benin (n = 47) and Ghana (n = 41) were investigated. Nineteen items were identified with good internal consistency. Participants (median age = 14 years) could not perform 23% of their daily activities. Twenty-nine participants did not have any functional limitation. The average limitation score was 31% in Benin and 15% in Ghana (P = 0.006). The mean limitation score in participants without visible contractures (n = 65) was 13%, whereas patients with visible contractures (n = 20) or an amputation (n = 3) had a score of more than 50%. Validity and reliability should be further analyzed to optimize the scale for use in individual evaluation, as an end point in intervention trials, and in planning of resources needed for the care of patients with functional limitations.

Background Buruli ulcer is considered a re-emerging disease in West Africa where it has suffered neglect over the years, though children below the age of 16 years are the worst affected in most endemic regions. Due to delayed health seeking, the disease leads to disabilities resulting from amputation and loss of vital organs like the eye leading to school dropout and other social and economic consequences for the affected family. Early treatment with antibiotics is effective; however, this involves daily oral and intramuscular injection at distant health facilities for 56 days making it a challenge among poor rural folks living on daily subsistence work. The mode of transmission of Buruli ulcer is not known and there is no effective preventive vaccine for Buruli ulcer. Thus the only effective control tool is early case detection and treatment to reduce morbidity and associated disabilities that occurs as a result of late treatment. It is therefore essential to implement interventions that remove impediments that limit early case detection; access to early effective treatment and this paper reports one such effort where the feasibility of social interventions to enhance Buruli ulcer control was assessed. Methods This was a qualitative study using in-depth interviews to generate information to ascertain the benefit or otherwise of the intervention implemented. Clinical records of patients to generate data to determine the feasibility and effectiveness of social interventions in the fight against Buruli ulcer was examined. In all, 56 in-depth interviews (28 at baseline and 28 at evaluation) were conducted for this report. Results At full implementation, treatment default and dropout reduced significantly from 58.8% and 52.9% at baseline to 1.5% and 1.5% respectively. The number of early case detection went up significantly. Affected families were happy with social interventions such as provision of transportation and breakfast to patients on daily basis. Families were happy with the outpatient services provided under the intervention where no patient was admitted into the hospital. Conclusion The study showed that with a little more investment in early case detection, diagnosis and treatment, coupled with free transportation and breakfast for patients, most of the cases could be treated effectively with the available antibiotics to avoid disability and complications from the disease.

Background Previous 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 Findings For 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. Conclusions These 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., Author Summary Sero-epidemiological analyses revealed that a higher proportion of sera from individuals living in the Buruli ulcer (BU) endemic Densu River Valley of Ghana contain Mycobacterium ulcerans 18 kDa small heat shock protein (shsp)-specific IgG than sera from inhabitants of the Volta Region, which was regarded so far as BU non-endemic. However, follow-up studies in the Volta Region showed that the individual with the highest anti-18 kDa shsp-specific serum IgG titer of all participants from the Volta Region had a BU lesion. Identification of more BU patients in the Volta Region by subsequent active case search demonstrated that sero-epidemiology can help identify low endemicity areas. Endemic and non-endemic communities along the Densu River Valley differed neither in sero-prevalence nor in positivity of environmental samples in PCR targeting M. ulcerans genomic and plasmid DNA sequences. A lower risk of developing M. ulcerans disease in the non-endemic communities may either be related to host factors or a lower virulence of local M. ulcerans strains.

Background Buruli ulcer (BU), caused by Mycobacterium ulcerans infection, is a debilitating disease of the skin and underlying tissue. The first phase of a BU prevention and treatment programme (BUPaT) was initiated from 2005–2008, in the Ga-West and Ga-South municipalities in Ghana to increase access to BU treatment and to improve early case detection and case management. This paper assesses achievements of the BUPaT programme and lessons learnt. It also considers the impact of the programme on broader interests of the health system. Methods A mixed-methods approach included patients' records review, review of programme reports, a stakeholder forum, key informant interviews, focus group discussions, clinic visits and observations. Principal Findings Extensive collaboration existed across all levels, (national, municipality, and community), thus strengthening the health system. The programme enhanced capacities of all stakeholders in various aspects of health services delivery and demonstrated the importance of health education and community-based surveillance to create awareness and encourage early treatment. A patient database was also created using recommended World Health Organisation (WHO) forms which showed that 297 patients were treated from 2005–2008. The proportion of patients requiring only antibiotic treatment, introduced in the course of the programme, was highest in the last year (35.4% in the first, 23.5% in the second and 42.5% in the third year). Early antibiotic treatment prevented recurrences which was consistent with programme aims. Conclusions To improve early case management of BU, strengthening existing clinics to increase access to antibiotic therapy is critical. Intensifying health education and surveillance would ultimately increase early reporting and treatment for all cases. Further research is needed to explain the role of environmental factors for BU contagion. Programme strategies reported in our study: collaboration among stakeholders, health education, community surveillance and regular antibiotic treatment can be adopted for any BU-endemic area in Ghana., Author Summary Buruli ulcer (BU), caused by Mycobacterium ulcerans infection, is a debilitating disease of the skin and underlying tissue which starts as a painless nodule, oedema or plaque and could develop into painful and massive ulcers if left untreated. Using a combination of quantitative and qualitative methods, the study assessed the effectiveness of the BUPaT programme to improve early detection and management of BU in an endemic area in Ghana. The results of the study showed extensive collaboration across all levels, (national, municipality and community), which contributed to strengthening the programme. Health staff were trained to manage all BU cases. School teachers, municipal environmental staff and community surveillance volunteers were trained to give the right health messages, screen for detection of early cases and refer for medical treatment. WHO-recommended antibiotics improved treatment and cure, particularly for early lesions, and prevented recurrences. Improving access to antibiotic treatment is critical for early case management. Health education is required to emphasise the effectiveness of treatment with antibiotics to reduce deformities and the importance of seeking medical treatment for all skin lesions. Further research is needed to explain the role of environmental factors in BU contagion.

We have evaluated the clinical efficacy of the combination of oral rifampin at 10 mg/kg of body weight and intramuscular streptomycin at 15 mg/kg for 8 weeks (RS8), as recommended by the WHO, in 160 PCR-confirmed cases ofMycobacterium ulceransdisease. In 152 patients (95%) with all forms of disease from early nodules to large ulcers, with or without edema, the lesions healed without recourse to surgery. Eight patients whose ulcers were healing poorly had skin grafting after completion of antibiotics. There were no recurrences among 158 patients reviewed at the 1-year follow-up. The times to complete healing ranged from 2 to 48 weeks, according to the type and size of the lesion, but the average rate of healing (rate of reduction in ulcer diameter) varied widely. Thirteen subjects had positive cultures forM. ulceransduring or after treatment, but all the lesions healed without further antibiotic treatment. Adverse events were rare. These results confirm the efficacy of RS8 delivered in a community setting.

We have studied the evolution of the gamma interferon (IFN-γ) and interleukin 10 (IL-10) responses afterMycobacterium ulceranssonicate stimulation of whole blood from patients with earlyM. ulceranslesions during treatment with rifampin and streptomycin for 8 weeks. Among the 26 patients, secretion of IFN-γ increased during treatment, with a significant increase at 4 weeks and a further increase after 8 weeks overall. The increase was more rapid in patients with large or ulcerative lesions, becoming significant by 4 weeks. For small lesions, there was only a minor increase, which did not reach significance. There was no significant change in the median IL-10 response during antibiotic therapy, and there was no inverse correlation between IFN-γ and IL-10 responses. These results demonstrate that an IFN-γ secretory response toM. ulceransdeveloped, independently of IL-10 secretion, in patients whoseM. ulceransdisease healed during antibiotic therapy.

To the Editor: Buruli ulcer (BU), a neglected tropical disease caused by Mycobacterium ulcerans, is characterized by necrosis of subcutaneous tissue, leading to chronic, painless, and progressive ulcers. Without proper treatment, BU results in severe and permanent disability in more than a quarter of patients. Most patients are children 30 countries (1). The World Health Organization (WHO) has described the epidemiology, clinical features, diagnosis, and treatment of BU (1–3). In 1967, Gray et al. described 4 BU cases in the Benue River Valley in Nigeria (4). The authors also reported unpublished cases of the disease in Banbur, Adamawa State, in the upper part of the Benue River Valley. In 1976, Oluwasanmi et al. described 24 BU cases in and around Ibadan (5). Since then, there has been no official report of BU in Nigeria. However, unofficial reports indicate that the disease is still present in the country. For example, between 1998 and 2000, BU cases from the Leprosy and Tuberculosis Hospital in Moniaya-Ogoja, Cross River State, were bacteriologically confirmed at the Institute of Tropical Medicine in Belgium (6). More recently, patients from Nigeria have been treated in the neighboring countries of Benin (7) and Cameroon (8). To clarify the BU situation in Nigeria, the government, with technical assistance from WHO, carried out a rapid assessment in the southern and southeastern states of the country, where cases had been previously reported. Preassessment sensitization workshops for health workers within the selected states were held in June and July 2006. The assessment took place November 15–19, 2006. The team, which was made up of international experts and national and state health officials, was divided into 2 groups. Group A visited Akwa Ibom and Cross Rivers States, and group B visited Anambra, Ebonyi, and Enugu States. Based on the WHO case definitions (1), 14 of 37 patient examined were considered likely to have BU (9 active and 5 inactive cases); 9 were children

Mycobacterium ulcerans disease is common in some humid tropical areas, particularly in parts of West Africa, and current management is by surgical excision of skin lesions ranging from early nodules to extensive ulcers (Buruli ulcer). Antibiotic therapy would be more accessible to patients in areas of Buruli ulcer endemicity. We report a study of the efficacy of antibiotics in converting early lesions (nodules and plaques) from culture positive to culture negative. Lesions were excised either immediately or after treatment with rifampin orally at 10 mg/kg of body weight and streptomycin intramuscularly at 15 mg/kg of body weight daily for 2, 4, 8, or 12 weeks and examined by quantitative bacterial culture, PCR, and histopathology for M. ulcerans . Lesions were measured during treatment. Five lesions excised without antibiotic treatment and five lesions treated with antibiotics for 2 weeks were culture positive, whereas three lesions treated for 4 weeks, five treated for 8 weeks, and three treated for 12 weeks were culture negative. No lesions became enlarged during antibiotic treatment, and most became smaller. Treatment with rifampin and streptomycin for 4 weeks or more inhibited growth of M. ulcerans in human tissue, and it provides a basis for proceeding to a trial of antibiotic therapy as an alternative to surgery for early M. ulcerans disease.

We studied hospital records of 750 consecutive Buruli ulcer patients in a highly endemic area in Amansie West, Ghana. Although more Buruli ulcer lesions were found on the right side of the body, comparison of lesions on arms and legs showed a bilaterally symmetrical distribution. Upper and lower extremities were affected equally by Buruli ulcers, if correction was made for differences in body surface area. Patients from outside the Amansie West district presented significantly more often with ulcerated lesions, which were more often located on a joint, than patients who lived in Amansie West, suggesting that longer travel distance might have caused delay. Our observations of a bilaterally symmetrical distribution of lesions on extremities and equal upper and lower extremity involvement are compatible with a mode of transmission that involves passive exposure of exposed body parts. An asymmetrical distribution of lesions was found in an earlier study, suggesting transmission by vegetation near the ground, through activities like farming or play. Perhaps, transmission in or near water, e.g. by bites of infected aquatic insects, might favour the pattern of distribution of lesions that we found. (C) 2004 Royal Society of Tropical Medicine and Hygiene. Published by Elsevier Ltd. All rights reserved.

Buruli ulcer disease (BUD), caused byMycobacterium ulcerans, follows an indolent course of initial progression to ulceration accompanied by extensive tissue damage. It has been suggested that healing disease stages are accompanied by a protective immune response. We hypothesized that interleukin-4 (IL-4)- or IL-10-induced downregulation of Th-1 responses plays a key role in the progression of early BUD and that healing is accompanied by an augmented Th-1 response. Gamma interferon (IFN-γ), IL-4, and IL-10 responses were measured after in vitro stimulation with phytohemagglutinin (PHA) and tuberculin purified protein derivative (PPD) of whole blood from 39 (23 early- and 16 late-stage) BUD patients and 39 healthy control subjects in Ghana. Additionally, 30 patients with active or treated tuberculosis (TB) serving as PPD-responsive positive controls were studied. Early-stage BUD patients produced significantly lower levels of IFN and IFN-γ/IL-4 ratios compared to late-stage BUD patients after PHA stimulation. Compared to that of controls, IFN-γ production after tuberculin stimulation was significantly higher in late-stage but not in early-stage BUD patients (P= 0.009). IL-10 and IL-4 levels did not differ between BUD patients and controls, although active TB patients had significantly higher IL-10 production levels than did treated TB patients. Multivariate analysis showed no confounding factors. In conclusion, Th-1 down regulation in early BUD appears to reverse in later stages of BUD, although an association with IL-10 or IL-4 production does not emerge from our data. Here we show differences in Th-1-type cytokine production between early- and late-stage BUD that might reflect an improved immune defense over time.

Recently, [Klis et al.][1] conducted an audit of Buruli ulcer case record forms of patients managed under routine care conditions in a Buruli ulcer treatment center and showed a surprisingly high rate (54%) of noncompliance with therapy ([1][2]). Incomplete adherence to treatment has been identified

Summary Objective In view of technical and financial limitations in areas of endemicity, the current practice and recommendations for the laboratory diagnosis of Buruli ulcer disease (BUD) may have to be reconsidered. We reviewed diagnostic results in order to explore options for a modified, more practicable, cost-effective and timely approach to the laboratory diagnosis of BUD. Methods Diagnostic specimens from 161 clinically diagnosed BUD patients from four different treatment centres in Ghana were subjected to laboratory analysis. The positivity rates of the laboratory assays were compared. Results The number of laboratory-confirmed clinically diagnosed BUD cases with one positive confirmative test was 20% higher than that with two positive confirmative tests. The specificity of microscopy (MIC) and PCR was 96.6% and 100%, respectively. Subsequent analysis of specimens from surgically excised pre-ulcerative tissue-by-tissue MIC and tissue PCR rendered 65% laboratory-confirmed BUD cases. Subsequent analysis of diagnostic swabs from ulcerative lesions by swab smear MIC and swab PCR rendered 70% of laboratory-confirmed BUD cases. Conclusions The specificity of the diagnostic tests used in this study suggests that one positive diagnostic test may be considered sufficient for the laboratory confirmation of BUD. Subsequent application of different diagnostic tests rendered a laboratory confirmation of 65% pre-ulcerative and of 70% ulcerative lesions. Implementation of a stepwise, subsequent analysis of diagnostic specimens will result in considerable cost saving compared with simultaneous testing of specimens by several diagnostic assays. Objectifs Vu les limitations techniques et financieres dans les zones endemiques, la pratique actuelle et les recommandations pour le diagnostic de laboratoire de la maladie de l'ulcere de Buruli (UB) pourraient etre a revoir. Nous avons analyse des resultats de diagnostic afin de d'investiguer des options pour un diagnostic de laboratoire modifie pour l'UB qui soit plus pratique, avec un bon rapport cout/efficacite et une approche plus opportune. Methodes Des specimens de 161 patients UB cliniquement diagnostiques dans quatre centres de traitement differents du Ghana ont ete analyses en utilisant des tests de laboratoire et les taux de positivite ont ete compares. Resultats Le nombre de cas d'UB cliniquement diagnostiques et confirmes par un seul test positif de laboratoire etait 20% plus eleve que celui par deux tests positifs de laboratoire. La specificite de la microscopie et de la PCR etait de 96,6% et 100% respectivement. Une analyse subsequente par microscopie et par PCR, de specimens provenant d'excision de tissu en state pre ulcere a revele 65% de cas d'UB confirmes au laboratoire. L'analyse subsequente par microscopie et par PCR sur des prelevements sur tiges de coton de lesions ulcerees a revele 70% de cas d'UB confirmes au laboratoire. Conclusions La specificite des tests de diagnostic utilises dans cette etude suggere qu'un seul test positif peut etre considere suffisant pour la confirmation de laboratoire de l'UB. L'application subsequente de differents tests de laboratoire a permis une confirmation de laboratoire pour 65% de cas de lesions en stade pre ulcere et 70% de cas de lesions ulcerees. L'implementation d'une analyse par etape des specimens permettra de reduire considerement les couts par rapport au test simultane des specimens par plusieurs tests de diagnostic. Objetivo En vista de las limitaciones tecnicas y economicas existentes en las areas endemicas, deberia reconsiderarse la practica y recomendaciones actuales para el diagnostico en laboratorio de la ulcera de Buruli (UB). Hemos revisado los resultados del diagnostico en laboratorio de la UB, con el fin de explorar opciones para un nuevo enfoque mas practico, costo-efectivo y oportuno. Metodos Se analizaron 161 especimenes de pacientes con diagnostico clinico de UB de cuatro centros diferentes en Ghana. Se comparo la tasa de positividad de las muestras. Resultados El numero de casos clinicos de UB confirmados por laboratorio con una prueba positiva confirmatoria fue un 20% mas alta que con dos pruebas confirmatorias. La especificidad de la microscopia y la PCR fue del 96.6% y 100% respectivamente. Analisis subsiguientes de especimenes diagnosticos de frotis de lesiones ulcerosas mediante microscopia y PCR dieron un 70% de los casos de UB previamente confirmados en el laboratorio. Conclusiones La especificidad de las pruebas diagnosticas utilizadas en este estudio sugiere que una prueba diagnostica positiva puede considerarse como suficiente para la confirmacion en laboratorio de la UB. La aplicacion subsiguiente de diferentes tecnicas diagnosticas tuvo una confirmacion del 65% para lesiones pre-ulcerativas y un 70% para las ulcerativas. La implementacion de un analisis escalonado de los especimenes diagnosticos resultaria en un ahorro considerable, comparado con una evaluacion simultanea de los especimenes utilizando diferentes pruebas diagnosticas.