Diagnostics to support mycetoma management-Development of two target product profiles.

OBJECTIVE: Mycetoma is a neglected tropical disease caused by more than 70 different microorganisms and identified by the WHO as one of the high-priority diseases for developing diagnostic tests. To ensure the production of diagnostic assays for use by clinical staff in endemic regions, target product profiles (TPPs) were designed. METHODS: We describe the development of two TPPs: one for a diagnostic test able to identify the causative agent of mycetoma and another that would determine when treatment could be stopped. The TPPs were developed by considering product use, design, performance, product configuration and costs. RESULTS: Version 1.0 TPPs for two uses were posted by WHO for a 1-month online public consultation on 25 October 2021, and the final TPP was posted online on 5 May 2022. CONCLUSION: A major difficulty encountered in developing both TPPs was the large number of agents able to cause mycetoma and the lack of specific biomarkers for most of them.

Improved rapid diagnostic tests to detect syphilis and yaws: a systematic review and meta-analysis.

BACKGROUND: Current rapid tests for syphilis and yaws can detect treponemal and non-treponemal antibodies. We aimed to critically appraise the literature for rapid diagnostic tests (RDTs) which can better distinguish an active infection of syphilis or yaws. METHODS: We conducted a systematic review and meta-analysis, searching five databases between January 2010 and October 2021 (with an update in July 2022). A generalised linear mixed model was used to conduct a bivariate meta-analysis for the pooled sensitivity and specificity. Heterogeneity was assessed using the I2 statistic. We used the Quality Assessment of Diagnostic Accuracy Studies (QUADAS) to assess the risk of bias and Grading of Recommendations, Assessment, Development and Evaluations (GRADE) to evaluate the certainty of evidence. RESULTS: We included 17 studies for meta-analyses. For syphilis, the pooled sensitivity and specificity of the treponemal component were 0.93 (95% CI: 0.86 to 0.97) and 0.98 (95% CI: 0.96 to 0.99), respectively. For the non-treponemal component, the pooled sensitivity and specificity were 0.90 (95% CI: 0.82 to 0.95) and 0.97 (95% CI: 0.92 to 0.99), respectively. For yaws, the pooled sensitivity and specificity of the treponemal component were 0.86 (95% CI: 0.66 to 0.95) and 0.97 (95% CI: 0.94 to 0.99), respectively. For the non-treponemal component, the pooled sensitivity and specificity were 0.80 (95% CI: 0.55 to 0.93) and 0.96 (95% CI: 0.92 to 0.98), respectively. CONCLUSIONS: RDTs that can differentiate between active and previously treated infections could optimise management by providing same-day treatment and reducing unnecessary treatment. PROSPERO REGISTRATION NUMBER: CRD42021279587.

Development of the Global Mycetoma Working Group.

The Global Mycetoma Working Group (GMWG) was formed in January 2018 in response to the declaration of mycetoma as a neglected tropical disease (NTD) by the World Health Assembly. The aim of the working group is to connect experts and public health practitioners around the world to accelerate mycetoma prevention activities and reduce the impact of mycetoma on patients, healthcare providers and society in the endemic regions. The working group has made tangible contributions to mycetoma programming, awareness and coordination among scientists, clinicians and public health professionals. The group's connectivity has enabled rapid response and review of NTD documents in development, has created a network of public health professionals to provide regional mycetoma expertise and has enabled mycetoma to be represented within broader NTD organizations. The GMWG will continue to serve as a hub for networking and building collaborations for the advancement of mycetoma clinical management and treatment, research and public health programming.

Integration of Management Strategies for Skin-Related Neglected Tropical Diseases.

The concept of skin neglected tropical diseases has been widely adopted into the policy and strategy of various organizations, governments, nongovernmental organizations, and health agencies. By pooling information and resources across different diseases, whose primary manifestations affect the skin, it is possible to deliver integrated surveillance and control programs and promote advocacy and reduction of disability and stigma. A further key part of the skin neglected tropical diseases program is the development and validation of training methods for front-line health workers. Networks that allow those involved in this work to share and compare expertise are being developed through various organizations.

Rifampicin and clarithromycin (extended release) versus rifampicin and streptomycin for limited Buruli ulcer lesions: a randomised, open-label, non-inferiority phase 3 trial.

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.

WhatsApp platforms in tropical public health resource-poor settings.

In order to deliver equal healthcare access to resource-poor settings, sustainable, cost-effective systems of communication should be used. As mobile phone use increases, remote care can be delivered via teledermatology using Apps. This commentary covers how WhatsApp could be used by dermatologists seeking to deliver healthcare in this context.

Molecular strain typing of the yaws pathogen, Treponema pallidum subspecies pertenue.

Yaws is a neglected tropical disease caused by the bacterium Treponema pallidum subspecies pertenue. The disease primarily affects children under 15 years of age living in low socioeconomic conditions in tropical areas. As a result of a renewed focus on the disease owing to a recent eradication effort initiated by the World Health Organization, we have evaluated a typing method, adapted from and based on the enhanced Centers for Disease Control and Prevention typing method for T. pallidum subsp. pallidum, for possible use in epidemiological studies. Thirty DNA samples from yaws cases in Vanuatu and Ghana, 11 DNA samples extracted from laboratory strains, and 3 published genomic sequences were fully typed by PCR/RFLP analysis of the tpr E, G, and J genes and by determining the number of 60-bp repeats within the arp gene. Subtyping was performed by sequencing a homonucleotide "G" tandem repeat immediately upstream of the rpsA gene and an 84-bp region of tp0548. A total of 22 complete strain types were identified; two strain types in clinical samples from Vanuatu (5q11/ak and 5q12/ak), nine strain types in clinical samples from Ghana (3q12/ah, 4r12/ah, 4q10/j, 4q11/ah, 4q12/ah, 4q12/v, 4q13/ah, 6q10/aj, and 9q10/ai), and twelve strain types in laboratory strains and published genomes (2q11/ae, 3r12/ad, 4q11/ad, 4q12/ad, 4q12/ag, 4q12/v, 5r12/ad, 6r12/x, 6q11/af, 10q9/r, 10q12/r, and 12r12/w). The tpr RFLP patterns and arp repeat sizes were subsequently verified by sequencing analysis of the respective PCR amplicons. This study demonstrates that the typing method for subsp. pallidum can be applied to subsp. pertenue strains and should prove useful for molecular epidemiological studies on yaws.

Buruli ulcer in Nigeria: results of a pilot case study in three rural districts.

BACKGROUND: Buruli ulcer (BU), also known as Mycobacterium ulcerans disease, is the third most common mycobacterial disease worldwide. Although BU disease has been diagnosed among Nigerians in neighbouring West African countries, data on the burden of the disease in Nigeria itself are scanty. This study aimed to assess the magnitude and epidemiology of BU in the South South region of Nigeria. METHODS: We conducted a cross-sectional survey in the Ogoja territory (comprising 31 communities). We undertook sensitisation programmes centred on BU in 10 of the communities. Participants were asked to identify community members with long-standing ulcers, who were then invited for evaluation. We also contacted traditional healers to refer their clients who had non-healing ulcers. All suspected cases had a full clinical evaluation and laboratory testing. Confirmed cases were given treatment in a referral hospital in the territory. RESULTS: We diagnosed 41 clinical BU cases; 36 (87.8 %) of which were confirmed by quantitative polymerase chain reaction (qPCR). These 36 PCR-confirmed cases were diagnosed in a total population of 192,169 inhabitants. Therefore, the estimated crude prevalence of BU was 18.7 per 100,000 population, varying from 6.0 to 41.4 per 100,000 in the districts surveyed. The majority (66.7 %) of the cases were females. About 92 % of the BU lesions were located on the patients' extremities. No differences were observed between the sexes in terms of the location of the lesions. The age of the patients ranged from four to 60 years, with a median age of 17 years. All 35 (100 %) patients who consented to treatment completed chemotherapy as prescribed. Of the treated cases, 29 (82.9 %) needed and received surgery. All cases healed, but 29 (82.9 %) had some limitations in movement. Healing with limitations in movement occurred in 18/19 (94.7 %) and 8/10 (80.0 %) of patients with lesions >15 cm (Category III) and 6-15 cm in diameter (Category II), respectively. The median duration of treatment was 130 (87-164) days for children and 98 (56-134) days for adults (p = 0.15). CONCLUSIONS: In Nigeria, BU is endemic but its severity is underestimated-at least in the study setting. There is a need to identify and map BU endemic regions in Nigeria. A comprehensive BU control programme is also urgently needed.

Challenges and key research questions for yaws eradication.

Yaws is endemic in west Africa, southeast Asia, and the Pacific region. To eradicate yaws by 2020, WHO has launched a campaign of mass treatment with azithromycin. Progress has been made towards achievement of this ambitious goal, including the validation of point-of-care and molecular diagnostic tests and piloting of the strategy in several countries, including Ghana, Vanuatu, and Papua New Guinea. Gaps in knowledge need to be addressed to allow refinement of the eradication strategy. Studies exploring determinants of the spatial distribution of yaws are needed to help with the completion of baseline mapping. The finding that Haemophilus ducreyi causes lesions similar to yaws is particularly important and further work is needed to assess the effect of azithromycin on these lesions. The integration of diagnostic tests into different stages of the eradication campaign needs investigation. Finally, studies must be done to inform the optimum mass-treatment strategy for sustainable interruption of transmission.

Yaws.

INTRODUCTION: Yaws, caused by Treponema pallidum ssp. pertenue, is endemic in parts of West Africa, Southeast Asia and the Pacific. The WHO has launched a campaign based on mass treatment with azithromycin, to eradicate yaws by 2020. SOURCES OF DATA: We reviewed published data, surveillance data and data presented at yaws eradication meetings. AREAS OF AGREEMENT: Azithromycin is now the preferred agent for treating yaws. Point-of-care tests have demonstrated their value in yaws. AREAS OF CONTROVERSY: There is limited data from 76 countries, which previously reported yaws. Different doses of azithromycin are used in community mass treatment for yaws and trachoma. GROWING POINTS: Yaws eradication appears an achievable goal. The programme will require considerable support from partners across health and development sectors. AREAS TIMELY FOR DEVELOPING RESEARCH: Studies to complete baseline mapping, integrate diagnostic tests into surveillance and assess the impact of community mass treatment with azithromycin are ongoing.

Epidemiology of yaws: an update.

Yaws, a neglected tropical disease, is targeted for eradication by 2020 through large-scale mass-treatment programs of endemic communities. A key determinant for the success of the eradication campaign is good understanding of the disease epidemiology. We did a review of historical trends and new information from endemic countries, with the aim of assessing the state of knowledge on yaws disease burden. Transmission of yaws is now present in Africa, Asia, and the South Pacific. At least 12 countries are known to harbor yaws cases and 21 to 42 million people live in endemic areas. Between 2008 and 2012 more than 300,000 new cases were reported to the World Health Organization. Yaws presented high geographical variation within a country or region, high seasonality for incidence of active disease, and evidence that low standards of hygiene predispose to suffering of the disease. Key data issues include low levels of reporting, potential misdiagnosis, and scarce documentation on prevalence of asymptomatic infections. Currently available data most likely underestimates the magnitude of the disease burden. More effort is needed in order to refine accuracy of data currently being reported. A better characterization of the epidemiology of yaws globally is likely to positively impact on planning and implementation of yaws eradication.

Detection of Mycolactone A/B in Mycobacterium ulcerans-Infected Human Tissue.

BACKGROUND: Mycobacterium ulcerans disease (Buruli ulcer) is a neglected tropical disease common amongst children in rural West Africa. Animal experiments have shown that tissue destruction is caused by a toxin called mycolactone. METHODOLOGY/PRINCIPAL FINDINGS: A molecule was identified among acetone-soluble lipid extracts from M. ulcerans (Mu)-infected human lesions with chemical and biological properties of mycolactone A/B. On thin layer chromatography this molecule had a retention factor value of 0.23, MS analyses showed it had an m/z of 765.6 [M+Na(+)] and on MS:MS fragmented to produce the core lactone ring with m/z of 429.4 and the polyketide side chain of mycolactone A/B with m/z of 359.2. Acetone-soluble lipids from lesions demonstrated significant cytotoxic, pro-apoptotic and anti-inflammatory activities on cultured fibroblast and macrophage cell lines. Mycolactone A/B was detected in all of 10 tissue samples from patients with ulcerative and pre-ulcerative Mu disease. CONCLUSIONS/SIGNIFICANCE: Mycolactone can be detected in human tissue infected with Mu. This could have important implications for successful management of Mu infection by antibiotic treatment but further studies are needed to measure its concentration.