Unlocking Opportunities for Mycobacterium leprae and Mycobacterium ulcerans.

In the recent decade, scientific communities have toiled to tackle the emerging burden of drug-resistant tuberculosis (DR-TB) and rapidly growing opportunistic nontuberculous mycobacteria (NTM). Among these, two neglected mycobacteria species of the Acinetobacter family, Mycobacterium leprae and Mycobacterium ulcerans, are the etiological agents of leprosy and Buruli ulcer infections, respectively, and fall under the broad umbrella of neglected tropical diseases (NTDs). Unfortunately, lackluster drug discovery efforts have been made against these pathogenic bacteria in the recent decade, resulting in the discovery of only a few countable hits and majorly repurposing anti-TB drug candidates such as telacebec (Q203), P218, and TB47 for current therapeutic interventions. Major ignorance in drug candidate identification might aggravate the dramatic consequences of rapidly spreading mycobacterial NTDs in the coming days. Therefore, this Review focuses on an up-to-date account of drug discovery efforts targeting selected druggable targets from both bacilli, including the accompanying challenges that have been identified and are responsible for the slow drug discovery. Furthermore, a succinct discussion of the all-new possibilities that could be alternative solutions to mitigate the neglected mycobacterial NTD burden and subsequently accelerate the drug discovery effort is also included. We anticipate that the state-of-the-art strategies discussed here may attract major attention from the scientific community to navigate and expand the roadmap for the discovery of next-generation therapeutics against these NTDs.

Deep learning for AI-based diagnosis of skin-related neglected tropical diseases: A pilot study.

BACKGROUND: Deep learning, which is a part of a broader concept of artificial intelligence (AI) and/or machine learning has achieved remarkable success in vision tasks. While there is growing interest in the use of this technology in diagnostic support for skin-related neglected tropical diseases (skin NTDs), there have been limited studies in this area and fewer focused on dark skin. In this study, we aimed to develop deep learning based AI models with clinical images we collected for five skin NTDs, namely, Buruli ulcer, leprosy, mycetoma, scabies, and yaws, to understand how diagnostic accuracy can or cannot be improved using different models and training patterns. METHODOLOGY: This study used photographs collected prospectively in Côte d'Ivoire and Ghana through our ongoing studies with use of digital health tools for clinical data documentation and for teledermatology. Our dataset included a total of 1,709 images from 506 patients. Two convolutional neural networks, ResNet-50 and VGG-16 models were adopted to examine the performance of different deep learning architectures and validate their feasibility in diagnosis of the targeted skin NTDs. PRINCIPAL FINDINGS: The two models were able to correctly predict over 70% of the diagnoses, and there was a consistent performance improvement with more training samples. The ResNet-50 model performed better than the VGG-16 model. A model trained with PCR confirmed cases of Buruli ulcer yielded 1-3% increase in prediction accuracy across all diseases, except, for mycetoma, over a model which training sets included unconfirmed cases. CONCLUSIONS: Our approach was to have the deep learning model distinguish between multiple pathologies simultaneously-which is close to real-world practice. The more images used for training, the more accurate the diagnosis became. The percentages of correct diagnosis increased with PCR-positive cases of Buruli ulcer. This demonstrated that it may be better to input images from the more accurately diagnosed cases in the training models also for achieving better accuracy in the generated AI models. However, the increase was marginal which may be an indication that the accuracy of clinical diagnosis alone is reliable to an extent for Buruli ulcer. Diagnostic tests also have their flaws, and they are not always reliable. One hope for AI is that it will objectively resolve this gap between diagnostic tests and clinical diagnoses with the addition of another tool. While there are still challenges to be overcome, there is a potential for AI to address the unmet needs where access to medical care is limited, like for those affected by skin NTDs.

The development, implementation, and evaluation of an optimal model for the case detection, referral, and case management of Neglected Tropical Diseases.

BACKGROUND: People affected by Neglected Tropical Diseases (NTDs), specifically leprosy, Buruli ulcer (BU), yaws, and lymphatic filariasis, experience significant delays in accessing health services, often leading to catastrophic physical, psychosocial, and economic consequences. Global health actors have recognized that Sustainable Development Goal 3:3 is only achievable through an integrated inter and intra-sectoral response. This study evaluated existing case detection and referral approaches in Liberia, utilizing the findings to develop and test an Optimal Model for integrated community-based case detection, referral, and confirmation. We evaluate the efficacy of implementing the Optimal Model in improving the early diagnosis of NTDs, thus minimizing access delays and reducing disease burden. METHODS: We used a participatory action research approach to develop, implement, and evaluate an Optimal Model for the case detection, referral, and management of case management NTDs in Liberia. We utilized qualitative and quantitative methods throughout the cycle and implemented the model for 12 months. RESULTS: During the implementation of our optimal model, the annual number of cases detected increased compared to the previous year. Cases were detected at an earlier stage of disease progression, however; gendered dynamics in communities shape the case identification process for some individuals. Qualitative data showed increased knowledge of the transmission, signs, symptoms, and management options among community health workers (CHW). CONCLUSION: The results provide evidence of the benefits of an integrated approach and the programmatic challenges to improve access to health services for persons affected by NTDs. The effectiveness of an integrated approach depends on a high level of collaboration, joint planning, and implementation embedded within existing health systems infrastructure.

Importance of consultations using mobile teams in the screening and treatment of neglected tropical skin diseases in Benin.

CONTEXT: Since 2013, the World Health Organization has recommended integrated control strategies for neglected tropical diseases (NTDs) with skin manifestations. We evaluated the implementation of an integrated approach to the early detection and rapid treatment of skin NTDs based on mobile clinics in the Ouémé and Plateau areas of Benin. METHODS: This descriptive cross-sectional study was performed in Ouémé and Plateau in Benin from 2018 to 2020. Consultations using mobile teams were performed at various sites selected by reasoned choice based on the epidemiological data of the National Program for the Control of Leprosy and Buruli Ulcer. All individuals presenting with a dermatological lesion who voluntarily approached the multidisciplinary management team on the day of consultation were included. The information collected was kept strictly anonymous and was entered into an Excel 2013 spreadsheet and analyzed with Stata 11 software. RESULTS: In total, 5,267 patients with various skin conditions consulted the medical team. The median age of these patients was 14 years (IQR: 7-34 years). We saw 646 (12.3%) patients presenting NTDs with skin manifestations, principally scabies, in 88.4% (571/646), followed by 37 cases of Buruli ulcer (5.8%), 22 cases of leprosy (3.4%), 15 cases of lymphatic filariasis (2.3%) and one case of mycetoma (0.2%). We detected no cases of yaws. CONCLUSION: This sustainable approach could help to decrease the burden of skin NTDs in resource-limited countries.

Changes in Inflammatory Markers in Patients Treated for Buruli Ulcer and Their Ability to Predict Paradoxical Reactions.

Mycobacterium ulcerans causes Buruli ulcer, the third most frequent mycobacterial disease after tuberculosis and leprosy. Transient clinical deteriorations, known as paradoxical reactions (PRs), occur in some patients during or after antibiotic treatment. We investigated the clinical and biological features of PRs in a prospective cohort of 41 patients with Buruli ulcer from Benin. Neutrophil counts decreased from baseline to day 90, and interleukin 6 (IL-6), granulocyte colony-stimulating factor, and vascular endothelial growth factor were the cytokines displaying a significant monthly decrease relative to baseline. PRs occurred in 10 (24%) patients. The baseline biological and clinical characteristics of the patients presenting with PRs did not differ significantly from those of the other patients. However, the patients with PRs had significantly higher IL-6 and tumor necrosis factor alpha (TNF-α) concentrations on days 30, 60, and 90 after the start of antibiotic treatment. The absence of a decrease in IL-6 and TNF-α levels during treatment should alert clinicians to the possibility of PR onset.

A combined effort of 11 laboratories in the WHO African region to improve quality of Buruli ulcer PCR diagnosis: The "BU-LABNET".

Buruli ulcer is one of the 20 neglected tropical diseases in the world. This necrotizing hypodermitis is a chronic debilitating disease caused by an environmental Mycobacterium ulcerans. At least 33 countries with tropical, subtropical and temperate climates have reported Buruli ulcer in African countries, South America and Western Pacific regions. Majority of cases are spread across West and Central Africa. The mode of transmission is unclear, hindering the implementation of adequate prevention for the population. Currently, early diagnosis and treatment are crucial to minimizing morbidity, costs and preventing long-term disability. Biological confirmation of clinical diagnosis of Buruli ulcer is essential before starting chemotherapy. Indeed, differential diagnosis are numerous and Buruli ulcer has varying clinical presentations. Up to now, the gold standard biological confirmation is the quantitative PCR, targeting the insertion sequence IS2404 of M. ulcerans performed on cutaneous samples. Due to the low PCR confirmation rate in endemic African countries (under 30% in 2018) for numerous identified reasons within this article, 11 laboratories decided to combine their efforts to create the network "BU-LABNET" in 2019. The first step of the network was to harmonize the procedures and ship specific reagents to each laboratory. With this system in place, implementation of these procedures for testing and follow-up was easy and the laboratories were able to carry out their first quality control with a very high success rate. It is now time to integrate other neglected tropical diseases to this platform, such as yaws or leprosy.

Quantifying Population Burden and Effectiveness of Decentralized Surveillance Strategies for Skin-Presenting Neglected Tropical Diseases, Liberia.

We evaluated programmatic approaches for skin neglected tropical disease (NTD) surveillance and completed a robust estimation of the burden of skin NTDs endemic to West Africa (Buruli ulcer, leprosy, lymphatic filariasis morbidity, and yaws). In Maryland, Liberia, exhaustive case finding by community health workers of 56,285 persons across 92 clusters identified 3,241 suspected cases. A total of 236 skin NTDs (34.0 [95% CI 29.1-38.9]/10,000 persons) were confirmed by midlevel healthcare workers trained using a tailored program. Cases showed a focal and spatially heterogeneous distribution. This community health worker‒led approach showed a higher skin NTD burden than prevailing surveillance mechanisms, but also showed high (95.1%) and equitable population coverage. Specialized training and task-shifting of diagnoses to midlevel health workers led to reliable identification of skin NTDs, but reliability of individual diagnoses varied. This multifaceted evaluation of skin NTD surveillance strategies quantifies benefits and limitations of key approaches promoted by the 2030 NTD roadmap of the World Health Organization.

A cluster randomized trial for improving mental health and well-being of persons affected by leprosy or buruli ulcer in Nigeria: A study protocol.

This protocol describes a study in which we would assess the effect of using community lay counselors, self-help groups (SHGs), and trained frontline health workers to reduce mental disorders and improve quality of life (QOL) of persons affected by leprosy or Buruli ulcer (BU). A cluster randomized controlled study design will be employed. The study will involve persons affected by leprosy or BU. Ten local government areas (clusters) with the highest number of notified leprosy or BU cases between 2014 and 2018 in Southern Nigeria will be purposively selected. The clusters will be randomized into intervention and control groups using a computer-generated list of random numbers. At baseline, data were collected using the following validated questionnaires, Patient Health Questionnaire, Generalized Anxiety Disorder questionnaire, Stigma Assessment and Reduction of Impact Scale, World Health Organization QOL BREF and Warwick-Edinburgh Mental Well-being scale among persons affected by leprosy or BU. The intervention will last for 2 years and will involve use of community lay counselors, SHGs, and appropriately trained frontline health workers in reducing mental disorders and improving QOL of persons affected by leprosy or BU. This project postulates that the reduction of burden of mental health problems and improved QOL among persons affected by leprosy or BU could be achieved through a holistic approach involving SHGs, appropriately trained community opinion leaders, and general health-care workers as well as a functional referral system. If successful, the model will be integrated into the activities of the National Tuberculosis and Leprosy Control Programme and scaled up nationwide. Trial registration: ISRCTN Registry: ISRCTN 83649248. https://trialsearch. who.int/Trial2.aspx? TrialID % ISRCTN83649248 Prospectively registered.

Comparison of 8 weeks standard treatment (rifampicin plus clarithromycin) vs. 4 weeks standard plus amoxicillin/clavulanate treatment [RC8 vs. RCA4] to shorten Buruli ulcer disease therapy (the BLMs4BU trial): study protocol for a randomized controlled multi-centre trial in Benin.

BACKGROUND: Buruli ulcer (BU) is a neglected tropical disease caused by Mycobacterium ulcerans that affects skin, soft tissues, and bones, causing long-term morbidity, stigma, and disability. The recommended treatment for BU requires 8 weeks of daily rifampicin and clarithromycin together with wound care, physiotherapy, and sometimes tissue grafting and surgery. Recovery can take up to 1 year, and it may pose an unbearable financial burden to the household. Recent in vitro studies demonstrated that beta-lactams combined with rifampicin and clarithromycin are synergistic against M. ulcerans. Consequently, inclusion of amoxicillin/clavulanate in a triple oral therapy may potentially improve and shorten the healing process. The BLMs4BU trial aims to assess whether co-administration of amoxicillin/clavulanate with rifampicin and clarithromycin could reduce BU treatment from 8 to 4 weeks. METHODS: We propose a randomized, controlled, open-label, parallel-group, non-inferiority phase II, multi-centre trial in Benin with participants stratified according to BU category lesions and randomized to two oral regimens: (i) Standard: rifampicin plus clarithromycin therapy for 8 weeks; and (ii) Investigational: standard plus amoxicillin/clavulanate for 4 weeks. The primary efficacy outcome will be lesion healing without recurrence and without excision surgery 12 months after start of treatment (i.e. cure rate). Seventy clinically diagnosed BU patients will be recruited per arm. Patients will be followed up over 12 months and managed according to standard clinical care procedures. Decision for excision surgery will be delayed to 14 weeks after start of treatment. Two sub-studies will also be performed: a pharmacokinetic and a microbiology study. DISCUSSION: If successful, this study will create a new paradigm for BU treatment, which could inform World Health Organization policy and practice. A shortened, highly effective, all-oral regimen will improve care of BU patients and will lead to a decrease in hospitalization-related expenses and indirect and social costs and improve treatment adherence. This trial may also provide information on treatment shortening strategies for other mycobacterial infections (tuberculosis, leprosy, or non-tuberculous mycobacteria infections). TRIAL REGISTRATION: ClinicalTrials.gov NCT05169554 . Registered on 27 December 2021.

Mycobacterial skin infection.

PURPOSE OF REVIEW: The aim of this article is to review the most recent evidences concerning mycobacterial skin infections, limiting the period of literature research to 2020--2021. RECENT FINDINGS: Mycobacterial skin infections include a heterogeneous group of cutaneous diseases.Cutaneous tuberculosis is usually the result of hematogenous dissemination or spread from underlying foci and it must be distinguished from tuberculids, resulting from the immunological reaction to Mycobacterium tuberculosis antigens. Leprosy prevalence was drastically reduced after introduction of multidrug therapy in the 1980 s, but cases are still reported due to underdiagnosis, and animal and environmental reservoirs. Recent advances concentrate in the diagnostic field. Specific guidelines for the treatment of nontuberculous mycobacteria skin infections are missing and surgical procedures may be required. Prognosis is better as compared to nontuberculous mycobacteria lung disease. Rapid laboratory-confirmed diagnosis of Buruli ulcer may be achieved by the IS2404 PCR. Among new drugs, telacebec is promising in terms of potency, shorter duration and tolerability in animal studies. A clinical trial in humans is planned. SUMMARY: Mycobacterial cutaneous lesions are nonpathognomonic and clinical suspicion must be confirmed by culture or molecular detection. Long-course multidrug treatment is required based on susceptibility tests. Surgical intervention may also be required. Rehabilitation and psychosocial support reduce long-term physical and mental consequences mostly in Buruli ulcer and leprosy.

Reconstructive surgery for sequellae of Mycobacterium ulcerans infection (Buruli ulcer) of the upper limb.

INTRODUCTION: Infection by Mycobacterium ulcerans constitutes a neglected tropical disease whose prevalence seems to have overrun those of cutaneous tuberculosis and leprosy. Its aggressivity depends on a mycolactone toxin. Lesions may involve skin, tendon and bone with a large spectrum of manifestations: non-ulcerative (papules, nodules, plaques), ulcerative and oedematous presentations as well as osteomyelitis with muscular contraction and ankylosis. Upper limbs account for more than two thirds of the infection sites. Surgical treatment may involve tendon transpositions, partial and total skin grafts. Amputation is relegated to extreme cases. MATERIAL AND METHODS: Selected iconography from patients during the last 15 years is presented. At least 1500 cases had partial skin grafts (anterior thigh). Total skin grafts (inguinal region) were used in about 200 cases. Complex lesions involved 9 ilioinguinal flaps (5 boys, 4 girls, mean age 11.2 years, range 2-16 years), 5 tendon transfers (4 boys, one girl, mean age 15.4 years, range 12-19 years) and 3 resections of the first carpal row (2 girls, 1 boy, mean age 8 years, range 4-15 years). RESULTS AND DISCUSSION: Out of 9 ilioinguinal flaps mild, marginal necrosis was the only complication in 2 patients without flap loss. Mean hospital stay was 26.44 days (range, 18-41 days), with return to full weight-bearing after a mean of 12 weeks (range 9-25 weeks) after discharge. Functional thumb opposition to allow pencil prehension was achieved in all three cases of resection of first carpal row resection without postoperative complications.

Novel Diagnostics for Kaposi Sarcoma and Other Skin Diseases in Resource-Limited Settings.

In resource-limited settings, point-of-care diagnostic devices have the potential to reduce diagnostic delays and improve epidemiologic surveillance of dermatologic conditions. We outline novel-point-of care diagnostics that have recently been developed for dermatologic conditions that primarily affect patients living in resource-limited settings, namely, Kaposi sarcoma, cutaneous leishmaniasis, leprosy, Buruli ulcer, yaws, onchocerciasis, and lymphatic filariasis. All of the technologies described in this article are prototypes, and some have undergone field testing. These devices still require validation in real-world settings and effective pricing to have a major impact on dermatologic care in resource-limited settings.

Bacille Calmette Guérin (BCG) and new TB vaccines: Specific, cross-mycobacterial and off-target effects.

The Bacille Calmette Guérin (BCG) vaccine was developed over a century ago and has become one of the most used vaccines without undergoing a modern vaccine development life cycle. Despite this, the vaccine has protected many millions from severe and disseminated forms of tuberculosis (TB). In addition, BCG has cross-mycobacterial effects against non-tuberculous mycobacteria and off-target (also called non-specific or heterologous) effects against other infections and diseases. More recently, BCG's effects on innate immunity suggest it might improve the immune response against viral respiratory infections including SARS-CoV-2. New TB vaccines, developed over the last 30 years, show promise, particularly in prevention of progression to disease from TB infection in young adults. The role of BCG in the context of new TB vaccines remains uncertain as most participants included in trials have been previously BCG immunised. BCG replacement vaccines are in efficacy trials and these may also have off-target effects.

Evaluation of the national tuberculosis surveillance and response systems, 2018 to 2019: National Tuberculosis, Leprosy and Buruli Ulcer Control Programme, Abuja, Nigeria.

INTRODUCTION: Nigeria is among the countries with high Tuberculosis (TB) burden by global rating signifying the relevance of TB surveillance system evaluation in improving performance and capacity of the existing system. Hence, this evaluation was conducted in order to determine the gaps and proffer solution to enhance the TB surveillance system performance. METHODS: questionnaires were administered to eight key informants using face-to-face interview method; data obtained was analyzed. Total number of TB cases and estimated number of cases for year 2018 was obtained. Percentage of positive cases using the GeneXpert test for 6 months (January to June 2019) was obtained. Available documents and publications on the National Tuberculosis, Leprosy and Buruli Ulcer Control Programme (NTBLCP) were also sought for information. RESULTS: the NTBLCP has over 5,300 TB service points and 1,602 microscopy Centre's distributed across the country. Acceptance for the standard TB case definition was 100%, forms used are easy to fill and diagnosis is laboratory-based requiring specialized trainings for laboratory personnel. The system had 25% sensitivity, high data quality with 100% timeliness. The TB surveillance system is representative of all ages. The system was first designed as TB and Leprosy Control Programme but later Buruli ulcer was incorporated into the Programme. First quarter supervisory visits are skipped due to late funding and delayed budget approval. Major share of the funding comes from donor partners. CONCLUSION: the system is useful, representative, acceptable, has good data quality, timely, and sensitive. The system is stable but needs to be funded more by the government. There is need for early funding and budget approval to avoid skipping of supervisory visits due to funding challenges. The system is not simple due the various test that need to be conducted before, during and after treatment to detect and verify that the patient is cured. We recommend continuous training of health workers, routine monitoring and evaluation, integration of TB care and prevention into other health services programmes like HIV/AIDS and active case search at all levels to increase the sensitivity of the system. Speed up the process of integration of NTBLCP surveillance system with IDSR for data harmonization in the country.

Impact of common skin diseases on children in rural Côte d'Ivoire with leprosy and Buruli ulcer co-endemicity: A mixed methods study.

BACKGROUND: Skin-related neglected tropical diseases (skin NTDs) occur against a background of a very high prevalence of common skin diseases in sub-Saharan Africa. In this study, we examined the knowledge, attitude and practices (KAP) and the impact of common skin diseases in children living in a leprosy and Buruli ulcer (BU) co-endemic district in a west African country of Côte d'Ivoire, in order to help inform disease control efforts for skin NTDs. METHODS AND PRINCIPLE FINDINGS: Fourteen focus group discussions (FGDs) with schoolchildren, 5 FGDs with parents of a child affected with skin disease(s), and 27 in-depth semi-structured interviews with key personnel were conducted. The Children's Dermatology Quality of Life Index (CDLQI) questionnaire was applied to 184 schoolchildren with skin diseases. We found that there was ignorance or neglect towards skin diseases in general, due to their high prevalence and also the perceived minimal impact on children's daily lives. While the median score for the CDLQI questionnaire was 5 (IQR 2-9) out of 30, a range of scores was observed. Symptoms such as pruritus and experiencing bullying by classmates contributed to reduction in their quality of life. Poor hygiene was considered as a major cause of skin diseases. CONCLUSIONS/SIGNIFICANCE: Despite their high impact on affected populations, we observed a high level of ignorance and neglect toward common skin diseases. There is a critical need to increase awareness of skin diseases, or skin health promotion, which supports changing of the health-seeking behaviour for skin conditions. This will aid in early detection and treatment of the skin NTDs, in addition to providing benefits for those affected by other skin diseases. Educational opportunities should be utilized to their utmost. One would be associated with water, sanitation, and hygiene (WASH) strategies, but careful messages need to be developed and delivered.

The co-infection of Buruli ulcer and cutaneous leishmaniasis in Sudanese patient: An association by choice or by chance?

Buruli ulcer and cutaneous leishmaniasis both have the similar cutaneous clinical presentation. Therefore, relying on clinical diagnosis can be challenging. We present a case of 45 years old woman diagnosed with cutaneous leishmaniasis, confirmed by skin biopsy. She received different modalities of anti-leishmanial treatment (fluconazole 450mg daily for 4 weeks, sodium stibogluconate (SSG) followed by thermal therapy, SSG/IV 20mg/kg for 30 days combined with paromomycin 15mg/kg IM for 17 days). These treatments were associated with partial improvement of the ulcer and failure of healing. A second biopsy demonstrated the presence of Mycobacterium ulcerans and hence the diagnosis of Buruli ulcer as a cause of the delayed healing of the ulcer. M. ulcerans releases a toxin known as mycolactone, which decreases immune system function and results in tissue death. M. ulcerans, is regarded as the third most prevalent Mycobacterium after M. tuberculosis and M. leprae. Treatment with streptomycin intramuscular injections 1g daily and rifampicin 600mg daily for 8 weeks was associated with complete healing of the ulcer. To our knowledge, this is the first report that describes the co-infection of Buruli ulcer and cutaneous leishmaniasis in Sudan.

Pharmacologic management of Mycobacterium ulcerans infection.

INTRODUCTION: Pharmacological treatment of Buruli ulcer (Mycobacterium ulcerans infection; BU) is highly effective, as shown in two randomized trials in Africa. AREAS COVERED: We review BU drug treatment - in vitro, in vivo and clinical trials (PubMed: '(Buruli OR (Mycobacterium AND ulcerans)) AND (treatment OR therapy).' We also highlight the pathogenesis of M. ulcerans infection that is dominated by mycolactone, a secreted exotoxin, that causes skin and soft tissue necrosis, and impaired immune response and tissue repair. Healing is slow, due to the delayed wash-out of mycolactone. An array of repurposed tuberculosis and leprosy drugs appears effective in vitro and in animal models. In clinical trials and observational studies, only rifamycins (notably, rifampicin), macrolides (notably, clarithromycin), aminoglycosides (notably, streptomycin) and fluoroquinolones (notably, moxifloxacin, and ciprofloxacin) have been tested. EXPERT OPINION: A combination of rifampicin and clarithromycin is highly effective but lesions still take a long time to heal. Novel drugs like telacebec have the potential to reduce treatment duration but this drug may remain unaffordable in low-resourced settings. Research should address ulcer treatment in general; essays to measure mycolactone over time hold promise to use as a readout for studies to compare drug treatment schedules for larger lesions of Buruli ulcer.

Integrated approach in the control and management of skin neglected tropical diseases in three health districts of Côte d'Ivoire.

BACKGROUND: Neglected tropical diseases (NTDs) comprise 20 communicable diseases that are prevalent in rural poor and remote communities with less access to the health system. For effective and efficient control, the WHO recommends that affected countries implement integrated control interventions that take into account the different co-endemic NTDs in the same community. However, implementing these integrated interventions involving several diseases with different etiologies, requiring different control approaches and driven by different vertical programs, remains a challenge. We report here the results and lessons learned from a pilot test of this integrated approach based on integrated screening of skin diseases in three co-endemic health districts of Côte d'Ivoire, a West African country endemic for Buruli ulcer, leprosy and yaw. METHOD: This cross-sectional study took place from April 2016 to March 2017 in 3 districts of Côte d'Ivoire co-endemic for BU, leprosy and yaws. The study was carried out in 6 stages: identification of potentially co-endemic communities; stakeholder training; social mobilization; mobile medical consultations; case detection and management; and a review meeting. RESULTS: We included in the study all patients with skin signs and symptoms at the screening stage who voluntarily accepted screening. In total, 2310 persons screened had skin lesions at the screening stage. Among them, 07 cases were diagnosed with Buruli ulcer. There were 30 leprosy cases and 15 yaws detected. Other types of ulcerations and skin conditions have been identified and represent the majority of cases detected. We learned from this pilot experience that integration can be successfully implemented in co-endemic communities in Côte d'Ivoire. Health workers are motivated and available to implement integrated interventions instead of interventions focused on a single disease. However, it is essential to provide capacity building, a minimum of drugs and consumables for the care of the patients identified, as well as follow-up of identified patients, including those with other skin conditions. CONCLUSIONS: The results of this study show that the integration of activities can be successfully implemented in co-endemic communities under the condition of staff capacity building and minimal care of identified patients.

Human genetics of Buruli ulcer.

Buruli ulcer, the third most common mycobacterial disease worldwide, is caused by Mycobacterium ulcerans and characterized by devastating necrotizing skin lesions. Susceptibility to Buruli ulcer is thought to depend on host genetics, but very few genetic studies have been performed. The identification of a microdeletion on chromosome 8 in a familial form of severe Buruli ulcer suggested a monogenic basis of susceptibility. The role of common host genetic variants in Buruli ulcer development has been investigated in only three candidate-gene studies targeting genes involved in mycobacterial diseases. A recent genome-wide association study suggested a probable role for long non-coding RNAs and strengthened the contribution of autophagy as a major defense mechanism against mycobacteria. In this review, we summarize the history, epidemiological and clinical aspects of Buruli ulcer, focusing particularly on genetic findings relating to susceptibility to this disease. Finally, we discuss exciting new genetic avenues arising, in particular, from studies of mouse models, and the need for different disciplines to work together, to benefit from the extensive work on other mycobacterial diseases, mostly tuberculosis and leprosy. We are convinced that such pooling of effort will lead to the development of efficient novel strategies for combatting Buruli ulcer.

Cell-mediated and serology-based tests for Mycobacterium ulcerans disease: A systematic review and meta-analysis.

Buruli ulcer (BU) is a subcutaneous necrotic infection of the skin caused by Mycobacterium ulcerans. It is the third most common human mycobacterial disease after tuberculosis (TB) and leprosy. The available methods for detection of the bacilli in lesions are microscopic detection, isolation and cultivation of the bacterium, histopathology, and polymerase chain reaction (PCR). These methods, although approved by the World Health Organization (WHO), have infrastructural and resource challenges in medical centres and cell-mediated immunity (CMI) and/or serology-based tests have been suggested as easier and more appropriate for accurate assessment of the disease, especially in remote or underdeveloped areas. This study systematically reviewed and conducted a meta-analysis for all research aimed at developing cell-mediated immunity (CMI) and/or serology-based tests for M. ulcerans disease. Information for this review was searched through PubMed and Web of Science databases and identified up to June 2019. References from relevant articles and reports from the WHO Annual Meeting of the Global Buruli Ulcer Initiative were also used. Twelve studies beginning in 1952, that attempted to develop CMI and/or serology-based tests for the disease were identified. These studies addressed issues of specificity and sensitivity in context of antigen composition as well as study heterogeneity and bias. The two main types of antigenic preparations considered were pathogen-derived and recombinant protein preparations. There was slight difference in test performance when M. ulcerans recombinant proteins [positivity: 67.5%; 32.5%] or pathogen-derived [positivity: 76.0%; 24.0%] preparations were used as test antigens among BU patients. However, pathogen-derived preparations were better at differentiating between patients and control groups [odds ratio (OR) of 27.92, 95%CI: 5.05-154.28]. This was followed by tests with the recombinant proteins [OR = 1.23, 95%CI: 0.27-5.62]. Overall, study heterogeneity index, I2 was 92.4% (p = 0.000). It is apparent from this review that standardisation is needed in any future CMI and/or serology-based tests used for M. ulcerans disease.