Developing a Buruli ulcer community of practice in Bankim, Cameroon: A model for Buruli ulcer outreach in Africa

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Abstract

Background

In the Cameroon, previous efforts to identify Buruli ulcer (BU) through the mobilization of community health workers (CHWs) yielded poor results. In this paper, we describe the successful creation of a BU community of practice (BUCOP) in Bankim, Cameroon composed of hospital staff, former patients, CHWs, and traditional healers.

Methods and principle findings

All seven stages of a well-defined formative research process were conducted during three phases of research carried out by a team of social scientists working closely with Bankim hospital staff. Phase one ethnographic research generated interventions tested in a phase two proof of concept study followed by a three- year pilot project. In phase three the pilot project was evaluated. An outcome evaluation documented a significant rise in BU detection, especially category I cases, and a shift in case referral. Trained CHW and traditional healers initially referred most suspected cases of BU to Bankim hospital. Over time, household members exposed to an innovative and culturally sensitive outreach education program referred the greatest number of suspected cases. Laboratory confirmation of suspected BU cases referred by community stakeholders was above 30%. An impact and process evaluation found that sustained collaboration between health staff, CHWs, and traditional healers had been achieved. CHWs came to play a more active role in organizing BU outreach activities, which increased their social status. Traditional healers found they gained more from collaboration than they lost from referral.

Conclusion/ Significance

Setting up lines of communication, and promoting collaboration and trust between community stakeholders and health staff is essential to the control of neglected tropical diseases. It is also essential to health system strengthening and emerging disease preparedness. The BUCOP model described in this paper holds great promise for bringing communities together to solve pressing health problems in a culturally sensitive manner.

Author summary

Buruli ulcer (BU) is a neglected tropical disease primarily found in West Africa largely effecting the rural poor. BU has a known cause and cure, but an unknown route of transmission and a poorly understood incubation period. If not treated early and in a timely manner, BU often progresses to an advanced state requiring surgery and prolonged wound care. In the Cameroon, previous efforts to mobilize community health workers and educate community members to identify cases of BU yielded poor results. In this paper, we describe steps undertaken to create a successful BU community of practice (BUCOP) composed of community stakeholders working in concert with clinic staff. The success of the BUCOP was measured in terms of numbers of suspected BU cases referred and confirmed, a decline in treatment drop out, and sustained collaboration among stakeholders both during and following the pilot project. Pilot project success is attributed to an innovative and culturally sensitive approach to BU outreach education, increased levels of patient assistance, and mutual respect among BUCOP members for what each stakeholder contributed to BU detection, treatment, psychosocial support, and spiritual protection.

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Health worker motivation in Africa: the role of non-financial incentives and human resource management tools

Inke Mathauer, Ingo Imhoff (2006)

Background There is a serious human resource crisis in the health sector in developing countries, particularly in Africa. One of the challenges is the low motivation of health workers. Experience and the evidence suggest that any comprehensive strategy to maximize health worker motivation in a developing country context has to involve a mix of financial and non-financial incentives. This study assesses the role of non-financial incentives for motivation in two cases, in Benin and Kenya. Methods The study design entailed semi-structured qualitative interviews with doctors and nurses from public, private and NGO facilities in rural areas. The selection of health professionals was the result of a layered sampling process. In Benin 62 interviews with health professionals were carried out; in Kenya 37 were obtained. Results from individual interviews were backed up with information from focus group discussions. For further contextual information, interviews with civil servants in the Ministry of Health and at the district level were carried out. The interview material was coded and quantitative data was analysed with SPSS software. Results and discussion The study shows that health workers overall are strongly guided by their professional conscience and similar aspects related to professional ethos. In fact, many health workers are demotivated and frustrated precisely because they are unable to satisfy their professional conscience and impeded in pursuing their vocation due to lack of means and supplies and due to inadequate or inappropriately applied human resources management (HRM) tools. The paper also indicates that even some HRM tools that are applied may adversely affect the motivation of health workers. Conclusion The findings confirm the starting hypothesis that non-financial incentives and HRM tools play an important role with respect to increasing motivation of health professionals. Adequate HRM tools can uphold and strengthen the professional ethos of doctors and nurses. This entails acknowledging their professionalism and addressing professional goals such as recognition, career development and further qualification. It must be the aim of human resources management/quality management (HRM/QM) to develop the work environment so that health workers are enabled to meet their personal and the organizational goals.

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Ecology and Transmission of Buruli Ulcer Disease: A Systematic Review

Richard W. Merritt, Edward Walker, Pamela L C Small … (2010)

Introduction Buruli ulcer (BU) is a serious necrotizing cutaneous infection caused by Mycobacterium ulcerans [1]–[7]. Before the causative agent was specifically identified, it was clinically given geographic designations such as Bairnsdale, Searles, and Kumasi ulcer, depending on the country [8]–[11]. BU is a neglected emerging disease that has recently been reported in some countries as the second most frequent mycobacterial disease in humans after tuberculosis (TB) [12]–[14]. Large lesions often result in scarring, contractual deformities, amputations, and disabilities [2]–[4], [7], [14]–[22] (Fig. 1). Approximately 80% of the ulcers are located on the limbs, most commonly on the lower extremities yet some variation exists [3], [13], [23], [24]. In Africa, all ages and sexes are affected, but most cases of the disease occur in children between the ages of 4–15 years [5], [13], [17], [25]–[28]. 10.1371/journal.pntd.0000911.g001 Figure 1 Buruli ulcer on leg and contractual deformity on wrist and hand. (Photo by R. Kimbirauskas). BU is a poorly understood disease that has emerged dramatically since the 1980's, reportedly coupled with rapid environmental change to the landscape including deforestation, eutrophication, dam construction, irrigation, farming (agricultural and aquaculture), mining, and habitat fragmentation [3]–[7], [29], [30]. BU is a disease found in rural areas located near wetlands (ponds, swamps, marshes, impoundments, backwaters) and slow-moving rivers, especially in areas prone to flooding [3], [4], [23], [27], [29], [31]–[36] (Fig. 2). Cases have been reported from at least 32 countries in Africa (mainly west), Australia, Southeast Asia, China, Central and South America, and the Western Pacific [3], [6], [20], [28], [37], [38] (Fig. 3). A number of cases have been reported in non-endemic areas of North America and Europe as a sequel to international travel [20], [39]–[42]. 10.1371/journal.pntd.0000911.g002 Figure 2 Typical Buruli ulcer riverine endemic sites in Ghana and Benin, respectively. (Photos by M. E. Benbow and M. McIntosh, respectively). 10.1371/journal.pntd.0000911.g003 Figure 3 A global map representing countries that have reported cases of Buruli ulcer disease as of 2009 (WHO). Buruli ulcer disease is often referred to as the “mysterious disease” because the mode of transmission remains unclear, although several hypotheses have been proposed. The objectives of this article are to: 1) review the current state of knowledge on the ecology and transmission of M. ulcerans, 2) discuss traditional and non-traditional methods for investigating transmission, and 3) suggest an intellectual framework for establishing criteria for transmission. Methods Data Sources and Search Strategy Selection of the publications cited was based on the following approaches: 1) Direct knowledge of the authors of this manuscript regarding their background in the field of Buruli Ulcer research and knowledge of key papers and unpublished data; 2) Online search engines for Buruli Ulcer and Mycobacterium ulcerans (predominantly PubMed, ISI Web of Knowledge, Web of Science, Centers for Disease Control (CDC); 3) Knowledge in the field of Buruli Ulcer research in that three of the authors (Merritt, Small, Johnson) are on the WHO Technical Advisory Committee for Buruli Ulcer in Geneva, Switzerland; 4) Review of the following websites: Buruli ulcer disease maintained by WHO in Geneva, Switzerland (http://www.who.int/buruli/en), The Buruli Ulcer Disease Ecology Research Consortium (BUDERC) (https://www.msu.edu/~budiseco/index.html); and UBS Optimus Foundation (http://www.stopburuli.org). Results and Discussion The Pathogen M. ulcerans is a slow-growing environmental mycobacterium that can be isolated from primary lesions after a 5–8 week incubation period, although up to 6 months may be required [43], [44]. M. ulcerans falls into a group of closely related mycobacterial pathogens which comprise the M. marinum complex. The M. marinum complex contains mycobacterial species pathogenic for aquatic vertebrates and includes M. marinum (fish), M. pseudoschottsii (fish) and M. liflandii (frogs) [45]–[48]. All of these species are characterized by slow growth rates and low optimal growth temperatures [49]. From a genomic standpoint, the species in the M. marinum complex can be considered a single species based on the fact that they share over 97% identity in the 16sRNA gene sequence [50]. However, practical considerations have led to the establishment of separate names based on differences in host tropism and pathogenesis analogous to other mycobacterial groupings, such as the M. avium and M. tuberculosis complexes. Genomic analysis suggests that M. ulcerans evolved from an M. marinum-like ancestor [21], [51] through the acquisition of a large virulence plasmid and accumulation of multiple copies of insertion sequences, IS2404 and IS2606. The genome has undergone considerable reductive evolution through a number of mutational events including transposon insertion. As a result, the genome has accumulated over 700 pseudogenes [21], [52]. Although it has been reported that micro-aerophilic conditions enhance the growth of M. ulcerans in the BACTEC system [53], the M. ulcerans genome strain lacks both nitrate and fumarate reductase systems, suggesting that M. ulcerans is considerably handicapped in the ability to grow under low oxygen conditions compared with M. marinum. The reported discrepancy in the oxygen requirements of M. ulcerans may be due to strain differences and requires closer investigation. A mutation in crtI, a key gene in the pathway for carotinoid biosynthesis, is suggested to compromise the ability of M. ulcerans to survive in direct sunlight [52]. A number of genes in ion transport and lipid biosynthesis have been lost and the repertoire of PE, PPE genes are considerably reduced compared with M. tuberculosis or M. marinum. Taken together, these results suggest that M. ulcerans is undergoing adaptation to a different and narrower niche than M. marinum. This idea has recently gained support from experimental work in which Medaka fish were infected with M. marinum and M. ulcerans. In these studies, M. marinum produced a lethal infection in Medaka, whereas M. ulcerans was not pathogenic and declined over a 23-week infection period (L. Mosi, unpubl. data). The most important phenotypic characteristic of M. ulcerans is the low optimal growth temperature and the extremely restricted growth temperature range. M. marinum exhibits growth between 25–35°C, although the optimal growth temperature is 30–35°C [54], [55] and many M. marinum isolates are capable of growth at 37°C. In contrast, growth of M. ulcerans strains under laboratory conditions is characterized by a remarkably narrow temperature range between 28–34°C and optimal growth of most strains is found between 30–33°C [56]. The restricted growth temperature of M. ulcerans is thought to play a substantial role in the pathogenesis of BU by limiting infection to the skin. The organism has never been isolated from internal organs of human patients or from bone in cases of osteomylelitis, or from the internal organs or blood of experimentally infected animals [51], [57]–[59]. It has been recently reported that many isolates of M. ulcerans survive at 37°C for 13 days, although numbers decline after the first few days. No one has isolated or derived a strain capable of growth at 37°C [60]. The characteristic pathology of BU is mediated by a polyketide-derived macrolide exotoxin called mycolactone, which is cytotoxic and immunosuppressive [51], [61], [62]. Because of the large metabolic cost of producing mycolactone, it is likely that mycolactone plays an important role in the survival and growth of M. ulcerans in its environmental niche. Ecology and Distribution of the Pathogen and Disease Detecting M. ulcerans in the environment The slow growth rate of M. ulcerans and the complex mix of many faster growing bacteria and fungi in environmental samples have prevented direct culture on artificial media of M. ulcerans from the environment. A major breakthrough in environmental studies occurred with the development of the first PCR probes for M. ulcerans based on detection of IS2404 by Ross et al. [63]. This technique was rapidly adopted by a number of laboratories leading to identification of M. ulcerans DNA in environmental samples including detritus, soil, biofilms, water filtrates, fish, frogs, snails, insects and other invertebrates [18], [35], [64]–[75]. Although IS2404 PCR has become the gold standard for clinical diagnosis of Buruli ulcer, there are several caveats in applying these methods to environmental samples. First, PCR detects DNA, not intact organisms. The death of infected organisms will lead to the release of M. ulcerans DNA into the environment where it may stick to a number of substrates. Although in two different countries in Africa, Williamson et al. [67] found M. ulcerans DNA in 9.7% (8/82) of water filtrant samples and Vandelannoote et al. [59] found 7.7% (1/13) water samples positive for M. ulcerans, the significance of these small quantities of M. ulcerans in an environmental sample is difficult to evaluate. In southeastern Australia, M. ulcerans also has been detected in a range of environmental samples. Recently, Fyfe et al. [76], reported that 30% of selected samples including detritus, plant material, suspended solids, and soil collected from one highly-endemic area were weakly positive by quantitative PCR. However, in a low endemicity area, only 4/156 (3%) of samples (2 soil, 2 terrestrial plant) were positive. Interpretation of results from environmental PCR is complex. PCR methodology detects DNA, but it does not provide definitive proof for the presence of intact bacteria in a matrix. DNA bound to the surface of potential vectors in the water column also will be detected. However, the successful culture of M. ulcerans from an aquatic water bug collected in Benin [71] provides definitive evidence for the presence of M. ulcerans in an aquatic invertebrate. This considerable achievement was based on earlier observations using IS2404 PCR that implicated aquatic water bugs as possible reservoirs or vectors of M. ulcerans [70]. Ecological associations with disturbed water bodies Until recently, a systematic and/or quantitative approach to the ecology of M. ulcerans in the environment has received little attention, despite the fact that nearly all epidemiological studies have associated disease outbreaks with villages in close proximity to human-disturbed aquatic habitats, including both standing and moving water bodies [7], [9]–[11], [19], [20], [25], [33], [77]–[80]. Increased BU incidence has been reported in association with: 1) unprecedented flooding of lakes and rivers during heavy rainfall [9], [16], [30], [37], [81]; 2) the damming of streams and rivers to create impoundments and wetlands [4], [9], [30], [37]; 3) resorts that modify wetlands [16], [30]; 4) deforestation practices and increased agriculture leading to increased flooding [4], [9], [18], [30], [37]; 5) construction of agricultural irrigation systems [4], [30], [81]; 6) rice cultivation [4], [9]; 7); alluvial, pit and sand mining operations [30], [37], [82]; and 8) population expansion, resettlement and migration closer to water bodies [9], [16], [18], [27], [30], [37]. Indeed, many water bodies associated with increased sedimentation and eutrophication have low dissolved oxygen concentrations that may enhance the growth of M. ulcerans [53]. Hayman [9] speculated that in Australia M. ulcerans enters surface waters through deforestation, erosion and run-off contamination. He suggested that populations of M. ulcerans were washed into aquatic habitats where environmental conditions facilitated growth and proliferation, much like an algal bloom. Because most infectious diseases have a strong correlation between infective dose and incubation period for disease, Hayman [9] speculated that slow growth of M. ulcerans might be required for the bacteria to achieve population numbers sufficient to produce infection and the appearance of disease. The way in which M. ulcerans could be washed down into these habitats has never been explained, but is consistent with other reports of increased BU outbreaks associated with deforested and heavily flooded African lands [20], [33]. Further, deforestation leads to lost riparian cover, resulting in increased water temperatures that may facilitate M. ulcerans growth at optimal temperatures of 30–33°C [11], [18], [20]. Associated sedimentation (e.g., turbidity) also would provide ultraviolet light (UV) attenuation and protection for M. ulcerans biofilm near the bottom substrates and on submerged plant surfaces as proposed by Merritt et al. [30]. It has been documented that UV lowers M. ulcerans cell viability [52], and thus deforestation and high-impact agriculture may promote increased nutrients, higher temperatures, UV attenuation and lower dissolved oxygen – environmental conditions that facilitate M. ulcerans growth. Because of the association with freshwater habitats, Eddyani et al. [83] hypothesized that freshwater plankton, specifically protozoans, may act as reservoirs for M. ulcerans, or may even facilitate the multiplication of the bacteria [18]. Although the former authors did not detect M. ulcerans DNA in free-living amoebae collected BU endemic areas in Benin, this area of research definitely warrants further investigation. Landscape ecology of the disease Buruli ulcer has been widely associated with proximity to aquatic habitats. The disease is rare in the savanna regions of West Africa and drier areas of Australia. Its presence in Australia is notably costal however, where water is often saline. This association between ecosystem ecology and disease has not been quantified. Rather, the association is most often anecdotal or related to specific human risk factors (e.g., wading, swimming, fishing, bathing, washing, farming, mining, etc.) in different countries and/or regional districts (see review below). To date, there have been few ecological studies focused on statistically determining why residence near certain water bodies is associated with BU, whereas the disease is absent along others [30], [67], [68]. For example, BU is highly associated with residence along several major river systems in both Benin and Ghana [12], [14], [20], [84], [85], whereas disease is essentially non-existent in communities within a few kilometers of Lake Volta, the largest water system in Ghana, as well as along the Mono River in Benin. Williamson et al. [67] recently found that in Ghana, PCR results suggesting that M. ulcerans and/or other mycolactone producing mycobacteria are widely distributed in water bodies in endemic and non-endemic villages. In these studies, however, the identification of endemic versus non-endemic sites was based on passive surveillance. A community was considered endemic if a case had been identified in the public health center in the past three years. A community that is not listed in the health center records, in association with a case of Buruli ulcer, was considered non-endemic. A preliminary survey to validate the non-endemic status of several communities in the GA district of Ghana through active surveillance showed that Buruli ulcer cases could be indentified in nearly all of the villages visited along the Densu River in the GA district (P. C. Small, unpubl. data). In areas where much of the disease is not reported, this can lead to significant error in the designation of “non-endemic.” There have been case control studies and observational reports of disturbed landscape associations with BU disease [29], [30], [86]; however, there have only been a few recent studies to statistically quantify landscape characteristics and relationships with disease [36], [79], [81], [87]. Duker et al. [79] found that arsenic levels in soil and gold mining were significant covariates related to increased disease risk in the Amansie West district of Ghana, while Wagner et al. [36], [81] addressed larger scale land use/land cover relationships using satellite imagery, GIS, and country wide BU data from Benin. In the latter studies, Wagner et al. [36], [81] reported highest disease in communities surrounded by an agriculture matrix, and thus deforestation, with abundant wetlands and other habitats that experience frequent flooding. These were low-lying areas with complex topography far removed from urban settings [36], [81]. In another country-wide study using GIS, Brou et al. [88] found that in Côte d'Ivoire, communities near landscapes of irrigated rice and other agriculture near dams used for irrigation were related to increased risk of BU. These studies confirm previous epidemiological studies and indicate that there are quantifiable relationships between landscape features and land use that are related to BU disease. It is also clear that communities involved with these activities are at high risk for disease, yet how specific activities are associated with transmission remains unresolved. Risk factors associated with Buruli ulcer disease Recently, Jacobson and Padgett [89] systematically reviewed the risk factors associated with M. ulcerans infection throughout the world and concluded that poor wound care, failure to wear protective clothing, and living or working near water bodies were commonly identified risk factors in most studies. However, a number of epidemiological studies have identified other potential risk factors associated with M. ulcerans infection and these are summarized in Table 1. For each specific risk factor investigated, it is stated as to whether or not there was an increased or decreased risk of infection reported, or if the factor was not considered a risk factor in the analysis. Several of the commonly reported risk factors showed few consistent associations depending on the country, type of analysis conducted, use of different case definitions, and based on the control populations used [89]. For instance, in a case-control study from Ghana, Aiga et al. [25] found that swimming in rivers on a habitual basis was a significant risk factor, whereas drinking, cooking, washing clothing and bathing were not. However, in another Ghanaian study, wading, bathing, and swimming were all confirmed to be significant risk factors for BU [77]. Two studies found a decreased risk of infection with mosquito net use, while another study found no association between bed net use and infection (Table 1). However, in a case control study performed in southeastern Australia, use of insect repellent was associated with reduced risk and the reporting of mosquito bites on the forearms and lower legs was associated with increased risk [90]. Despite the association with water contact, fishermen were not found to be at high risk for the disease (Table 1). Although a review of these potential risk factors suggests that transmission of M. ulcerans might occur through direct inoculation of bacteria into the skin via contact with environmental sources, insect bites or trauma, it was clear that additional comparative studies are required to clarify the potential modes of transmission of M. ulcerans [89]. 10.1371/journal.pntd.0000911.t001 Table 1 A summary of reported risk factors associated with infection Mycobacterium ulcerans. Country Risk Factor(s) Increased Risk of Infection Decreased Risk of Infection Not Considered a Risk Factor Citation Ghana 1) Arsenic-enriched drinking water (from mining) X Duker et al. (2004) Ghana 1) Exposed skin2) Bednet and mosquito coils use3) Insect bites, cuts, scratches, and other wounds4) Exposure to riverine areas (wading and swimming)5) Association between BCG and vaccination or HIV infection6) Not wearing protective clothing7) Fishing XXX XXXX Raghunathan et al. 2005 Ghana 1) Age 2–14 years of age2) Use of water for drinking, cooking, bathing, washing3) Association with agricultural activities4) Swimming in rivers XX XX Aiga et al. 2004 Benin 1) 5–14 years of age2) Unprotected water from swamps3) BCG-vacinated patients >5 years old4) Participated in agricultural activities5) Sex XXXX X Debacker et al. 2004, 2006 Benin 1) Mosquito bed net use2) Association with agricultural activities3) Improper wound care X X X Nackers et al. 2007 Cameroon 1) Living near cocoa plantation or woods2) Wading in swamps3) Wearing protective clothing while farming4) Association with agricultural activities5) Improper wound care6) Bed nets7) Mosquito coils8) Unprotected water sources9) Fishing XXX XX XXXX Pouillot et al. 2007 Cote d′ Ivoire 1) Age group2) Wearing protective clothing during farming activities3) Washing clothes4) Swimming5) Fishing XX XXX Marston et al. 1995 Australia 1) Wearing protective clothing2) Use of insect repellent3) Most patients > 60 years old4) Washing wounds after sustaining minor skin trauma5) Exposure to mosquitoes XX XXX Quek et al. 2007 Although there have been reports of a seasonal distribution in BU cases related to rainfall-influenced patterns of village waterbody usage [32], and by season in southeastern Australia [91], other studies have not shown this relationship [12]. Recording monthly trends for BU cases over a 3-year period in Benin, Sopoh et al. [12] found consistent average monthly BU case occurrence, without an apparent seasonal trend. However, country-wide data can obscure local variation in climate and the issue of seasonal trends needs to be more closely investigated at the local level. The unknown incubation period for Buruli ulcer, which may vary from 2 weeks to 7 months [92], [93], also makes it difficult to analyze seasonal factors with Buruli ulcer occurrence. Duker et al. [4], and more recently Marion et al. [94], discussed seasonal variations and M. ulcerans infections reported from different countries and concluded that there may be a temporal relationship between BU incidences and relatively dry periods; however, it also has been reported that M. ulcerans infections occurred mainly after flooding events [9], [16], [33], [34], [95]. Environmental Reservoirs and Transmission Africa Unlike leprosy and tuberculosis, which are characterized by person-to-person transmission, it is hypothesized that M. ulcerans is acquired through environmental contact. Direct human to human transmission of M. ulcerans is extremely rare. The one reported case occurred following a human bite [96]. In this instance it was hypothesized that the patient's skin surface was contaminated with M. ulcerans from an environmental source (e.g. swamps) and driven into the skin by the playmate's bite. Non-human mammals and reptiles have been tested in the environment without positive findings [95], and several arthropods (i.e., bedbugs, black flies, mosquitoes) in Africa associated with vectoring other disease agents tested negative in early studies [18], [32]. However, few organisms of each taxonomic group were tested in these studies, and insect sampling methods were neither systematically employed nor standardized. Buruli ulcer cases in wild and domesticated animals in Africa have not been reported [97]. Portaels and colleagues [70] were first to suggest that aquatic bugs (Hemiptera) might be reservoirs of M. ulcerans in nature, and recently they described the first isolation in pure culture of M. ulcerans from a water strider (Hemiptera: Gerridae, Gerris sp.) from Benin [71]. A survey study [18] based on detection of M. ulcerans DNA in aquatic insects (Hemiptera, water bugs; Odonata, dragonfly larvae; Coleoptera, beetle larvae) collected from African BU endemic swamps confirmed their earlier findings, and suggested that small fish might also contain M. ulcerans [66], [98]–[100]. Marsollier et al. [64], [66], [98]–[100] conducted a series of laboratory studies and demonstrated that M. ulcerans could survive and show limited replication within the salivary glands of biting aquatic bugs (Naucoridae: Naucoris cimicoides). In their experimental model they demonstrated that M. ulcerans could be acquired from feeding on inoculated insect prey (a blow fly maggot), transmitted to mice via biting; and that the infected mice subsequently developed clinical BU [66]. Although there has been some controversy regarding the interpretation of this work [68], [101], [102] and subsequent follow-up studies on tracing the pathogen through the bug [103], [104], Marsollier and colleagues concluded that biting water bugs belonging to the families Naucoridae (creeping water bugs) and Belostomatidae (giant water bugs) could be considered reservoirs, and most importantly could serve as vectors in the transmission of M. ulcerans to humans in nature. More recently, Mosi et al. [101] investigated the ability of M. ulcerans to colonize aquatic bugs (Belostomatidae) collected from Africa. Using a natural infection model in which M. ulcerans-infected mosquito larvae served as prey that were then fed to the predacious bugs, Mosi and colleagues confirmed Marsollier's finding that infected belostomatid bugs could become infected with M. ulcerans via feeding. However, they concluded that transfer of bacteria through feeding was most likely to have occurred through contact with the heavily colonized raptorial arms and other external parts of the belostomatid, rather than through saliva or contact with other internal organs as originally reported [66]. Together, these experiments indeed support the hypothesis that predaceous aquatic insects may play an important role in maintaining M. ulcerans within food webs in the aquatic environment [1], [30], [68], [70] but, as detailed below, their role in actual transmission to humans remains unclear. The role of other non-insect aquatic invertebrates as intermediate hosts or environmental reservoirs for M. ulcerans has been suggested by several authors [30], [66], [70], [73], [99], and recently confirmed in more field research [67], [68]. It was experimentally confirmed that aquatic snails could be transiently colonized by M. ulcerans after feeding on M. ulcerans-containing aquatic plant biofilms [64]. Aquatic plant extracts stimulated biofilm formation, and increased the uptake of labeled metabolites by M. ulcerans in laboratory experiments [65]. In the field, Kotlowski et al. [73] recorded M. ulcerans DNA in aquatic snails from endemic regions of Ghana and Benin, and other studies have found that average estimates of M. ulcerans increased by two orders of magnitude in detritus compared to water [72]. More recently, Marsollier et al. [104] described an extracellular matrix associated with the biofilm of M. ulcerans that may confer selective advantages to the mycobacteria in colonizing various microhabitats in the environment. Based on these studies and extensive environmental studies by Williamson et al. [67], it is evident that M. ulcerans DNA can be detected within biofilm on the plant surface, and as part of decaying organic matter (detritus) both of which serve as food for certain aquatic invertebrates and fish, suggesting reservoirs and movement throughout the aquatic food web. A conceptual model, expanded and modified from Portaels et al. [70], illustrating the potential reservoirs and movement of M. ulcerans within and among aquatic environments was detailed by Merritt et al. [30] and more recently by Marion et al. [94]. Basically, M. ulcerans has been reported from mud, detritus, water filtrants, and plant biofilms, thereby allowing grazing or filtering aquatic insects (e.g., midges and mosquito larvae) or other invertebrates (snails, crustaceans, plankton) to concentrate mycobacteria through their feeding activities. Then, predatory aquatic vertebrates (i.e., some fish) and invertebrates (e.g., true bugs, beetles and dragonfly larvae) feed on other invertebrate prey or small fish, serving to move M. ulcerans from prey to biting insects. Lastly, aquatic insects capable of flight, and birds that prey on fish and/or aquatic invertebrates may potentially disseminate M. ulcerans to other aquatic environments [30]. Although the potential for different aquatic invertebrates in Africa to serve as environmental reservoirs for M. ulcerans has been clearly demonstrated, direct transmission by biting water bugs, other than by purely accidental means appears very unlikely for the following reasons. First, in Africa M. ulcerans DNA has only been detected in invertebrates that are not hematophagous. Predatory semi-aquatic Hemiptera (i.e., Naucoridae, Belostomatidae, Notonectidae) mainly feed on invertebrates (aquatic insects, Crustacea, snails) by inserting their piercing mouth parts into their prey, injecting saliva containing proteolytic enzymes, and then imbibing the liquefied prey tissues [105], [106]. Most employ an ambush strategy, waiting motionless clinging to vegetation for unsuspecting prey (Belostomatidae), while others may actively swim and pursue their prey (Naucoridae, Notonectidae) [107], [108]. Adults of most species of semi-aquatic Hemiptera possess the ability to disperse by flight, but mainly at night, and end up being attracted to electric lights during the breeding season, often correlated with the lunar cycle. Because of this, they often find their way into houses by accident [107], [108]. However, the very low disease prevalence among children less than three years of age suggests that infection does not occur in the house. When humans accidently come into contact with the bugs in the water, on aquatic vegetation, or away from water, they can be bitten [109]. However, these bugs do not actively search for humans, they do not require a blood meal or protein source to mature their eggs, nor is there any evolutionary history suggesting or supporting a vectorborne/pathogen transmission or co-evolving host/parasite relationship in the semi-aquatic Hemiptera [107], [110]. Therefore, based on the biology and behavior of predaceous aquatic insects, biting humans appears to be a rare event associated with a purely defensive reaction of these bugs [109], [111]. It should be noted, however, that the causative agent of Chagas disease (Trypanosoma cruzi) in humans is transmitted by a terrestrial hemipteran (Reduviidae), but it is through fecal contamination and not by the bite of the bug. Also, in this case the habitat of the vector (bug) is closely tied to that of its host [112]. In general, field studies on the prevalence of biting aquatic invertebrates do not support the hypothesis that biting aquatic bugs are vectors of M. ulcerans in nature; however, a recent study by Marion et al. [94] in Cameroon identified several water bug families as hosts of M. ulcerans in a Buruli ulcer endemic area. However, in Marion et al. [93], only one endemic area and one non-endemic area were evaluated, suggesting no replication, and thus, a limitation to testing how variable M. ulcerans is among endemic versus non-endemic areas/villages. This makes it difficult to compare to studies by Williamson et al. [67] and Benbow et al. [68] where multiple replicate sites were evaluated to test for M. ulcerans variability in standardized ecological samples. Benbow et al. [68] conducted the largest field study to date that examined biting water bugs in 15 disease-endemic and 12 non-disease-endemic areas of Ghana, Africa. From collections of over 22,000 invertebrates, they compared composition, abundance and invertebrate-associated M. ulcerans positivity among sites, and concluded that biting hemipterans were rare and represented a very small percentage of invertebrate communities. When endemic and non-endemic areas were compared, there were no significant differences in hemipteran abundance or invertebrate-M.ulcerans positivity rates (by PCR) between the areas, and there were no significant associations between hemipteran abundance and overall invertebrate-M.ulcerans positivity. Thus, there is little field evidence to support the assertion that biting bugs are major vectors of M. ulcerans in nature. However, as concluded by Marion et al. [94], the detection of M. ulcerans in water bugs in a specific area could possibly be used as an environmental indicator of the risk of M. ulcerans transmission to humans. Australia In Australia, infection with M. ulcerans occurs at low-levels in the wet tropical north where the climate is similar to sub-Saharan Africa [113]–[115]. However, more than 80% of Australia's cases of Buruli ulcer in the past 15 years have been in the temperate southeastern state of Victoria [93]. In comparison to Africa, people in Victoria have less direct contact with the environment, yet in two well-described outbreaks, 1.2–6.0% of the entire resident population in the outbreak areas developed Buruli ulcer [35], [116]. Visitors may also be at risk, and in one case, contact with an endemic town for just one day appeared to be sufficient to develop Buruli ulcer up to 7 months later [35]. In attempting to understand possible modes of transmission, two competing models have been proposed to explain this pattern of limited environmental contact, brief exposure, and high attack rates. Hayman [9] proposed that transmission by aerosol could partially explain outbreaks of M. ulcerans disease and an opportunity arose to test this hypothesis during a three year period when a large cluster of Buruli ulcer cases occurred in East Cowes, Phillip Island. This outbreak was significant in that only part of the town was affected, and there was a newly created wetland and a golf course at the center of the affected area. The golf course used a mixture of ground water and recycled water for irrigation and run-off from the golf course was likely to have drained towards the new wetland, connecting the two systems. Many of the case-patients lived close to the wetland or the golf course, supporting the concept of transmission by drifting aerosols from contaminated irrigation water [116]–[119]. Initially, no method existed for detection of M. ulcerans in environmental samples. However, as part of the outbreak investigation, Ross et al. [63] discovered IS2404, a high copy number insertion sequence in M. ulcerans. A PCR method using IS2404 as a target sequence has rapidly become the diagnostic method of choice for Buruli ulcer due to its high sensitivity, specificity, and its speed compared with traditional culture methods. IS2404 PCR was then adapted for application to environmental samples, and positive results were obtained from the wetland and golf course irrigation system-the first direct evidence that M. ulcerans DNA is present in environmental samples. IS2404 PCR also can be used as a preliminary test for the presence of M. ulcerans in Africa, but aquatic mycobacteria associated with disease in fish and West African clawed frogs (Xenopus tropicalis) also contain IS2404. For this reason, IS2404 lacks sufficient specificity for use as sole criteria for M. ulcerans in Africa. To date, there is no evidence from Australia of the presence of IS2404 in any other environmental mycobacterium. The above findings supported the hypothesis that the golf course irrigation system and nearby wetland at Phillip Island had become contaminated with M. ulcerans, although transmission by aerosol itself was not directly assessed [72], [120]. Drainage of the wetland, reduction in recycled water use, cleaning of the irrigation equipment at the golf course, and subsequent separation of ground water from recycled water were collectively associated with fewer cases in the following years. Buruli ulcer linked to Phillip Island is now rare; however, disease activity in at least one other Victorian endemic area also declined over a similar time frame without a specific intervention, making it difficult to conclude that the environmental alterations made at Phillip Island were directly responsible for the decline in cases. During the same period several possums (Australian native tree-dwelling marsupials) with Buruli ulcer were identified at Phillip Island [18], the significance of which will be discussed further below. In 2002, a new outbreak commenced in a small town on the Bellarine Peninsula about 60 km to the west of Phillip Island, also in coastal Victoria, southeastern Australia. More than 100 people who either live in or have visited Point Lonsdale have now been diagnosed with Buruli ulcer [35]. Several other towns on the Bellarine Peninsula have been linked to cases, but in lower numbers thus far. Although Point Lonsdale also has a golf course, it is not centrally located, and does not use recycled water. In 2004, intense local mosquito activity seemed to be associated in time with new cases of BU and Buruli lesions were observed on ankles and elbows, and on the back where gaps in clothing could allow access for mosquitoes. In one case, Buruli ulcer developed on the ear of a child who was only briefly present in the outbreak area. The child's mother suspected a mosquito bite as the initiating event [35]. These observations led to a series of studies aimed at assessing a possible role for mosquitoes in the transmission of M. ulcerans. Using an improved real-time quantitative IS2404 PCR environmental screening method [74], more than 11,000 adult mosquitoes captured at Point Lonsdale were tested, and M. ulcerans DNA was identified in or on an estimated 4.3/1,000 mosquitoes. Most PCR positive mosquito pools were Aedes camptorhynchus (Thomson), the most common species on the Bellarine peninsula; however, M. ulcerans DNA also was detected in one or more pools of four other species [35]. PCR amplification and sequence analysis of one variable number tandem repeat (VNTR) locus confirmed that mosquitoes were carrying M. ulcerans DNA, indistinguishable from that of the human outbreak strain [74], [121]. A review of notifiable diseases in Victoria in the period 2002-8, demonstrated a statistically significant correlation between notifications of Buruli ulcer and Ross River Virus/Barmah Forest Virus infections (RRV/BFV) – both of which are transmitted by mosquitoes – but there was no correlation with any other non-mosquito borne notifiable disease [122]. A case-control study, conducted on the Bellarine Peninsula including Point Lonsdale, showed that the odds of being diagnosed with Buruli ulcer were at least halved in respondents who frequently used insect repellent, wore long trousers outdoors, and immediately washed minor skin wounds, and were at least doubled for those who received mosquito bites on the lower legs or lower arms. In a multivariate model, after adjusting for age and location, use of insect repellent and being bitten by mosquitoes on the lower legs were found to be independently associated with Buruli ulcer risk [90]. In laboratory experiments using a green fluorescent protein (GFP) labeled M. ulcerans mutant, in which GFP was linked to the mycolactone toxin polyketide synthase promoter, it was shown that when fed as a single pulse to live mosquito larvae, M. ulcerans-GFP was able to persist through 4 larval instars in the mouth parts and midgut of the insect. This was not observed with a closely related M. marinum-GFP mutant that did not produce mycolactone [123]. This permissive effect of mycolactone on allowing M. ulcerans to selectively colonize aquatic insects also was observed in experiments using aquatic water bugs [66], [100], [104]. However, other investigators found equal colonization with mycolactone negative and wild type strains [101], and this earlier selective effect was not observed in a study on M. ulcerans colonization of mosquitoes conducted by Wallace et al. [124].The latter study found a nearly 100% infection rate was obtained when wild type M. ulcerans, an isogenic mycolactone-negative M. ulcerans, and M. marinum (a non-toxin producing potential progenitor of M. ulcerans) were used to infect mosquito larva. These findings are in line with the fact that mosquito larvae do not discriminately feed on specific bacteria or other foods unless ingestion is mediated by particle size [125], [126]. Differences in experimental conditions and bacterial strains used may help to explain these conflicting findings. Collectively, the above transmission research conducted in southeastern Australia lends support to mosquitoes as being a possible vector of the pathogen for Buruli Ulcer disease in this region of the country (see Bradford Hill guidelines for a critical assessment, below). More recently, it also has been discovered that that 38% of ringtail possums (Pseudocheirus peregrinus (Boddaert)) and 24% of brushtail possums (Trichosurus vulpecula Flannery) captured at Point Lonsdale had laboratory-confirmed M. ulcerans skin lesions and/or M. ulcerans PCR positive feces (Fyfe et al. [76]). The exact sequence of events linking mosquitoes, humans, contaminated possum excreta and infected possums has yet to be determined, but direct or indirect mosquito transmission from a possum reservoir presents a parallel model with aerosol transmission from contaminated environmental water sources. Neither the aerosol nor mosquito transmission hypothesis in temperate Australia is incompatible with transmission by direct contact with the environment or by other vectors not yet examined. Future research on the biological relationships within each model will help to resolve the relative probability and plausibility of either mode. Criteria for Establishing the Role of Insect Vectors of M. ulcerans Stringent criteria exist in biomedical research for indicting the roles of living agents as biologically significant reservoirs and/or vectors of pathogens. The application of these criteria to the transmission of M. ulcerans presents a significant challenge. The above review reveals that various routes of transmission may occur, varying amongst epidemiological setting and geographic region, and that there may be some role for living agents as reservoirs and as vectors of M. ulcerans, in particular aquatic insects, adult mosquitoes or other biting arthropods. It is also clear that the exact mode of transmission, if indeed there is a single mode, remains unknown. We briefly discuss the process by which a vector is incriminated to the point of as much certainty as is possible, and then discuss the application of this process to indictment of insect vectors for transmission of M. ulcerans. If Buruli ulcer is a vectored disease, intervention might be designed to reduce the possibility of transmission since there are possibilities other than suppressing vector populations. Vector incrimination traditionally involves satisfying a set of criteria analogous to Koch's postulates, summarized by Barnett [127] as follows: (1) the vector must be shown to acquire the pathogen from an identified source such as an infected vertebrate host or other reservoir, and thereafter become infected with the pathogen; (2) the vector must be shown convincingly to have close associations with infected hosts, including humans, in time and space; (3) individual vectors collected in endemic settings must repeatedly be found infected with the pathogen; and (4) efficient transmission to competent vertebrate hosts must be demonstrated experimentally, under well controlled conditions, by individual vectors, such as by bite or other means of direct contact. These criteria accommodate mechanical transmission if infection includes recovery of the pathogen from the vector's body, without making any assumptions about replication of the pathogen on or in the vector. Further, they do not preclude the possibility of parallel modes of transmission other than vectors. For example, the causative agent of plague, Yersinia pestis, has a flea vector and during sporadic outbreaks is transmitted by flea bites; but these bacteria also are transmitted during epidemics in aerosols generated by sneezing of pneumonically-infected humans or animals such as cats, which is probably the predominant mode of transmission in epidemics [128]. Similarly, human infection with the causative agent of tularemia, Franciscella tularensis, may occur through direct contact with contaminated water, by aerosols, by contact with blood or infected tissues of animals, or by bites of infected ticks, deer flies, or mosquitoes [129], [130]. The causative agent of Rift Valley fever, a Phlebovirus in the family Bunyaviridae, is transmitted amongst infected vertebrate reservoirs (mainly ungulates) by mosquitoes; however, many human infections occur upon exposure to infected animal blood at the time of slaughter, by aerosolization, as well as by mosquito bites [131]. Another useful illustration is that of Chlamydia trachomatis, the causative agent of trachoma, where the transmission to human eyes has been definitively associated with contact by Musca sorbens flies (Diptera: Muscidae) that breed in human feces in various parts of Africa [132]. Despite this observation, other mechanisms of transmission for this disease are known, such as person-to-person contact with contaminated fingers and wash towels [133], [134]. In two of the above examples (plague and Rift Valley fever), the pathogen has a close biological relationship with, and dependency upon, insect vectors; neither pathogen could persist in nature without infecting their respective vectors. For tularemia and trachoma, vectors are not essential to pathogen persistence in nature, even though fly control in the latter case was shown to reduce incidence of disease in humans [135]. However, it is unlikely in the case of tularemia and trachoma that even highly effective fly control could eliminate human infection in endemic areas owing to other modes of transmission [133]. Therefore, using a critical approach to address the issue of insect vector incrimination for M. ulcerans, one must be cognizant of the relative biological dependency of this bacterium on an insect vector, and the potential for facultative and facilitative relationships between these bacteria and various insect “hosts” to exist which may be ancillary or even spurious to the essential and normal transmission modes. The most thorough examination of the role of an insect vector for transmission of M. ulcerans stems from investigations of aquatic, predaceous Hemiptera (true bugs) as reviewed above, which go far in addressing and meeting Barnett's criteria. It is important to recognize that the vast number of studies of M. ulcerans in environmental samples provide qualitative, indirect evidence of M. ulcerans based on very sensitive methods for detecting M. ulcerans DNA. Such studies revealed repeatedly that natural infection by M. ulcerans in field-collected bugs occurred, but it was tempered by detection of M. ulcerans in many other aquatic insects [18], [67]. Thus, definitive incrimination of a single species or group of closely-related aquatic and semi-aquatic Hemiptera to the exclusion of other insects was not initially established. Other studies suggested natural contamination of the surfaces of these insects with M. ulcerans and suggested that M. ulcerans growth could occur as biofilms on the external appendages of such ‘bugs’ [101]. Thus, although aquatic and semi-aquatic Hemiptera and other insects found to harbor M. ulcerans in nature might provide habitat for the bacteria, along with numerous other living and non-living surfaces where biofilms could form [104], this is insufficient evidence for indicating an obligatory or even facultative vectorial role to these insects. Although the experiments reported by Marsollier et al. [64], [66], [98]–[100] suggested modest bacterial replication in internal tissues of bugs, acquisition of bacterial infection from a live source (infected fly maggots meant to simulate an infected prey item), and transmission to mice, this evidence does not establish natural infection coupled with transmission to humans. Finally, there has been no epidemiological association established between spatial and temporal distribution of contacts with aquatic Hemiptera, or bites by them, and development of Buruli ulcer in humans [68]. As reviewed above, the common understanding of the feeding habitats of aquatic and semi-aquatic Hemiptera does not include feeding on humans. More likely, infection in aquatic insects is associated with exposure to M. ulcerans in detritus and on biofilms formed on submerged materials, leading to a generalized distribution of M. ulcerans and M. ulcerans DNA in aquatic environments. In this particular scenario, despite the body of research on the topic, Barnett's criteria have not yet been fulfilled satisfactorily. The recent research by Wallace et al. [124], whilst firmly documenting growth of M. ulcerans in mosquito larvae and transtadial infection after the molt, showed that infection did not persist upon metamorphosis to the adult stage. Thus, the link between presence of M. ulcerans in aquatic environments in which larval mosquitoes are found and adult mosquito infection with M. ulcerans, was not confirmed experimentally. However, these studies did show that M. ulcerans DNA could be detected on surface components of some adult mosquitoes. This brings up an important issue regarding experimental design and suggests that interpretation of PCR results obtained from whole insect lysates must be cautiously interpreted. These findings suggest that further research is required to confirm the association between mosquito bites, adult mosquito infection, and incidence of Buruli ulcer in humans in Australia (reviewed above), where a link between mosquito feeding on infected possums and transmission of the agent via the same species of mosquitoes was proposed (Fyfe et al.[76]). An analysis of blood host choice by mosquitoes, documenting blood feeding on both possums and humans in the area where human cases of Buruli ulcer are occurring, would be required as one element of satisfying Barnett's criterion #2. At best, Barnett's criteria for vector incrimination have not been completely satisfied for a mosquito vector role, but more compelling data may be forthcoming on this matter in the future. A second approach to vector incrimination involves application of the Bradford Hill guidelines for establishing causation of infection and disease in epidemiological/ecological contexts [136]. Rather than rely upon experimental evidence, the Bradford Hill guidelines emphasize epidemiological/ecological association and use of logical inference to build up support and evidence for a strong conclusion of cause and effect, where A represents the “cause” and B the “effect” in the relationships under study [137]. The result is an “evidence hierarchy” that can be used in formal deduction [138], and represents an interdisciplinary approach to causal investigation in disease ecology. Here, “A” would be contact between an insect vector infected with M. ulcerans, and “B” would be human infection with M. ulcerans. The guidelines are qualitative in nature and do not require the clear endpoints of Barnett's criteria, yet represent a logical approach to the problem of cause and effect under epidemiological circumstances [139]. They are as follows (Table 2): 10.1371/journal.pntd.0000911.t002 Table 2 Listing of Hill's guidelines (Bradford Hill guidelines, Hill 1965) for associating a role of insect vectors of pathogens causing human disease. Term Descriptor/Qualifier 1. Plausibility Plausible, rational given knowledge of the biology of the putative vector, biology of the pathogen, and epidemiology of the disease. Specious associations would contraindicate a positive association. 2. Temporality The insect vector must show a temporal association with infection in humans; in particular, infected vectors should be found in endemic areas immediately before human cases occur. 3. Strength The association of the putative insect vector with human cases must be strong in time and space and in an epidemiological context. Correlation analysis supports the conclusion of strength if the correlation is positive. 4. Biological Gradient Prevalence of human cases should co-vary with prevalence of infection in the insect population. 5. Consistency Confirmed human cases should consistently be associated with infected insect vectors in time and space. 6. Alternate Explanations Explanations other than those related to a role of an insect vector should be considered and ruled out, or validated. 7. Experimentation Role of an insect species as a vector should be validated through experimental analysis with adequate controls and with realism in experimental design. 8. Specificity Infection with M. ulcerans in humans occurs when, and only when, a bite by an infected insect occurs first. 9. Coherence The association of human infection with insect transmission must cohere to knowledge of similar relationships in other similar associations. (1) Plausibility. The cause and effect association of A and B must be plausible, that is, rational and lacking in speciousness. By this is meant that the association reflects the common understanding of the normal behavior and other attributes of both A and B, bringing the appropriate factors together in such a way that abnormally implausible (i.e., irrational) explanations must be discounted. In formal philosophy, plausibility must be demonstrated by sets of binary outcomes whose relationships are clearly defined propositions which can be resolved by the application of logical discourse [140]. Although plausibility can be formulated axiomatically, it cannot be analyzed statistically. It is important, therefore, not to confuse “plausible” with “probable” as the latter allows for rare and unusual circumstances and events to be explanatory under the right circumstances, whereas the former involves a rigorous, but non-probabilistic analytical process. Put more simply, plausibility addresses qualitatively how likely or unlikely it is that A results in B. A common problem in epidemiological scenarios that confronts plausibility is the issue of clusters of cases of infection (e.g., [134]), which may or may not have spatial associations with other nearby cases or with the landscape qualities near those cases [136]. In the case of Buruli ulcer and vector transmission of M. ulcerans, it is not implausible that Hemiptera and human cases are associated in time and space, but it is not plausible that there is a direct, causal relationship between the pair except in rare, accidental circumstances. Hence, there is insufficient evidence to conclude that biting hemipterans are a significant vector of M. ulcerans, although they may act as environmental reservoirs. (2) Temporality. If A results in B, then A must consistently precede B in temporal sequence. For Buruli ulcer, there is no evidence that bites of particular insects consistently precede development of patent M. ulcerans infection in humans, although there is evidence that mosquito bites are associated with increased risk [90]. The problem with this guideline is the prolonged period of time between exposure and development of symptoms in Buruli ulcer disease. However, if bites from true bugs always preceded disease, patients are likely to remember these due to the painful nature of a naucorid or belostomatid bite, in contrast to bites by mosquitoes that often go unnoticed. (3) Strength. Is the “strength” of the association great? For example, is there a statistically significant correlation between A and B in space and or time? The association between contact with water sources and M. ulcerans infection in humans is reasonably strong, but between insect bites and infection it is not for hemipterans, nor yet firmly established for mosquitoes in Australia and virtually non-existent for mosquitoes in Africa. (4) Biological gradient or dose-response relationship. Infection in B should increase proportionately as A increases. This principle can operate at the dose-response level, as in a toxicological series; or at the population level, as when, e.g., more dengue virus infected mosquitoes results in more human cases of infection with that virus in space and time. The relationship may not be linear, thus confounding the interpretation of the relationship. There is no evidence that higher infection rate of M. ulcerans in aquatic insects results in higher incidence of infection in humans, although there is evidence that adult mosquitoes caught in highly endemic area in southeastern Australia are more likely to be PCR positive than those caught in areas with lower endemicity [35]. (5) Consistency. Episodes and research data where A and B show spatial and temporal associations commensurate with the other Bradford Hill guidelines must consistently reveal the association to be a positive one. Consistency could be revealed by meta-analysis of many data sets or through replicated, longitudinal studies across time and space. If scenarios emerge in which B occurs, but A does not in space and time, then doubt emerges regarding the veracity of the association. Although there are vignettes, correlations, and observations regarding insect vectors of M. ulcerans, there is no clear consistency among epidemiological scenarios to currently support the notion that insects are the predominant vector in most geographic regions. Consistent data are lacking for the ubiquitous role of vectors in the M. ulcerans transmission system. (6) Consideration of alternate explanations and analogous situations. Explanations other than causation due to A must be carefully weighed as alternatives. Causation may be inferred by analogous correspondence with other scenarios. For Buruli ulcer, a wide range of alternate explanations for transmission exists, such as human behavior linkages involving activities that increase direct skin contacts with contaminated water and inoculation with infective doses of M. ulcerans through lesions. However, as we have seen, several diseases with insect vector associations have alternative transmission modes, such as tularemia, plague, Rift Valley fever, and trachoma. Thus, it is plausible that there are multiple modes of transmission in Buruli ulcer, with certain modes more likely given specific environmental and socio-cultural contexts. (7) Experimentation. If experimental manipulations are feasible and can be structured realistically, then outcomes of the treatment regime conferred upon B (such as exposure to the effects of A) must reflect the association in a positive way. Often, however, Bradford Hill guidelines are utilized because experiments are either not possible, or not sufficiently rigorous or realistic. Experimental data on insect-M. ulcerans relationships have been reviewed above. There seems to be a sufficient body of work with sufficient variation in outcomes that the treatment manipulations do not lead to easily generalized conclusions on the association. Furthermore, it is often difficult to find true replication for large-scale experiments (e.g., treating replicate ponds with a specific chemical agent to test of changes in M. ulcerans), making it difficult to rigorously evaluate and experimentally test complex dynamics related to multiple modes of transmission of M. ulcerans within the environment. (8) Specificity. In this guideline, B follows A, but B does not follow when other plausible explanatory factors and events occur in temporal or spatial association. It is one of the most difficult of the guidelines to satisfy and comes closest to a strict criterion, usually because of incomplete information, multiple causes of B, random effects, and systematic errors of measurement. The review of the literature on cause and effect between insects and Buruli ulcer cases indicates a paucity of data to prove specificity. Furthermore, there are few studies relating disease incidence and insect abundance in time and space especially in Africa, and none of the alternate explanations for transmission reviewed above, such as through aerosols (9), have been discounted. The current available data points to a multiple transmission model for Buruli ulcer, indicating that the Buruli ulcer disease system lacks specificity with regard to vector insects, with the possible exception of southeastern Australia. Therefore, more complete and rigorous qualitative assessments of data are critical to provide evidence for consistency and specificity with regard to the role of vectors and reservoirs in transmission of M. ulcerans. (9) Coherence. The association of B with A must cohere to knowledge of similar relationships in other similar associations. For M. ulcerans, insect transmission is quite unusual, as the remainder of the M. marinum group does not depend upon invertebrate vectors for transmission and infection in fish hosts. Furthermore, there is no scientific precedent for transmission of any disease agent from the direct bites of hemipteran bugs, nor is there precedent for biological transmission of any bacterial pathogen by mosquitoes known. Thus, coherence is overall not strong. However, although closely related to M. marinum, M. ulcerans is a distinct species with a genomic signature indicating it has diverged from its free-living ancestor and now occupies a specialized niche environment. Either a vertebrate gastrointestinal tract (e.g. possums) or insects may provide this unknown microenvironment. In summary, neither the application of Barnett's strict criteria nor the Bradford Hill guidelines support conclusively that bites by M. ulcerans-infected insects' result in human infection with M. ulcerans. However, further research will reveal if any associations might result in higher risk of infection under certain circumstances. Infection with anthrax bacteria, Bacillus anthracis, provides a useful comparison, not as a directly transferable model, but rather as a model for conceptualization of how insects, like mosquitoes, may have ancillary roles in bacterial transmission when other transmission modes also exist [141]. In that system, infection occurs in animals endemically and sporadically. When they are stressed (as in a drought), they become susceptible to low dosages of bacterial spores in soil. As animals die, colonization of necrophilic flies during decomposition results in infection locally and increased bacterial sporulation and more animal cases occur as a result (the so-called “case multipliers” effect of insects). As more animals become infected, an insect-mediated dispersal of bacteria occurs by biting flies such as deer flies and horse flies, whose mouthparts can become contaminated with bacteria during blood feeding (the so-called “space multiplier” effect of insects). The role of flies in both modes furthers epizootics of anthrax. Although these two processes are unlikely to occur for Buruli ulcer, which appears to be mainly an endemic disease, the scenario for anthrax establishes a model by which insects might be envisioned to have ancillary roles in transmission for M. ulcerans as well. Conclusions Recommended research directions on Buruli ulcer disease As stated in the beginning of this review, Buruli ulcer disease has been referred to as the “mysterious disease” because the exact mode(s) of transmission, in the strictest sense, remain unclear, although several hypotheses have been proposed. We have reviewed the hypotheses and reported on studies that provide good evidence of probable reservoirs for the disease, particularly in Australia. An intellectual framework for establishing criteria for transmission followed this. Finally, we recommend that the following research studies be conducted to help better understand transmission of M. ulcerans in nature: 1) in depth studies of human behavior patterns in African endemic villages to better understand exposure to the pathogen in the environment; 2) a search for mammalian and/or other animal reservoirs and potential arthropod vectors in Africa; 3) understanding the relationship between mosquitoes, humans and infected possums who frequently share the same habitats in Australia; 4) laboratory competency studies with Australian mosquitoes using local strains of MU to determine whether transmission could occur vertically (larvae to adult) or horizontally (adult feeds on possum and then on humans); 5) further field and laboratory experiments on vector transmission and vector competence to confirm current hypotheses and experimental evidence on arthropod transmission; and 6) the development of new and innovative studies aimed at satisfying Hill's Criteria to provide strong and logically defendable evidence about the true mode, or modes, of Buruli ulcer transmission in nature. 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Integrated Control and Management of Neglected Tropical Skin Diseases

Oriol Mitjà, Michael Marks, Laia Bertran … (2017)

Introduction Neglected tropical diseases (NTDs) are communicable diseases that occur under conditions of poverty and are concentrated almost exclusively in impoverished populations in the developing world. NTDs affect more than 1000 million people in tropical and subtropical countries, costing developing economies billions of dollars every year. Effective control of NTDs can be achieved with the use of large-scale delivery of single-dose preventive chemotherapy (PC) or intensified disease management (IDM) or both, as is the case for some diseases such as lymphatic filariasis, trachoma, and yaws. Several NTDs exhibit significant cutaneous manifestations that are associated with long-term disfigurement and disability, including Buruli ulcer (BU); cutaneous leishmaniasis (CL); leprosy; mycetoma; yaws; hydrocele and lymphoedema (resulting from lymphatic filariasis); and depigmentation, subcutaneous nodules, severe itching, and hanging groin (resulting from onchocerciasis). Skin examination offers an opportunity to screen people in the communities or children in schools to identify multiple conditions in a single visit. This common approach to skin diseases justifies the integrated delivery of health care interventions to both increase cost-effectiveness and expand coverage. WHO’s Department of Control of NTDs (WHO/NTD) plans to promote an integrated strategy for the skin NTDs requiring IDM. Targeting skin NTDs also provides a platform for treatment of common skin conditions and, therefore, has wider public health benefits. An informal panel of experts (writing this manuscript) was established to help develop guidance in support of the new WHO strategic direction and to develop a proposal for a change in policy for the integrated control and management of the skin NTDs. A symposium at the 2015 ASTMH meeting[1] initiated a discussion of opportunities around integration of surveillance and control of NTDs that affect the skin, but this paper moves these ideas forward and includes some initial recommendations about how these opportunities could be realised. We aim to provide specific pragmatic information and actual recommendations about potential surveillance and management approaches. Burden of Skin NTDs Skin NTDs are frequently co-endemic in many countries, districts, and communities (Table 1). [2–9] While none of the skin NTDs are significant causes of mortality, they are responsible for a large number of disability-adjusted life years (DALYs) lost.[10] For example, contractures and resulting disability in BU, advanced lymphoedema and hydrocele in LF, the consequences of permanent nerve damage in leprosy, amputations in mycetoma, and bone involvement in yaws can lead to debilitating deformities and difficulty in securing employment.[11] 10.1371/journal.pntd.0005136.t001 Table 1 Characteristics of skin NTDs. Causative agent Mode of transmission Natural reservoir Geographic distribution by continent/region (Major affected countries) Key manifestation Complications Peak age (male: female ratio) Incidence (annual) year 6–13 WHO target by 2020 WHA resolution Buruli ulcer Mycobacterium ulcerans Unknown Contaminated water West and Central Africa, Western Pacific Skin ulcer Severe scarring with limb contractures 5–15 (2:1) 2,200 Control WHA57.1 (2004) Cutaneous leishmaniasis Leishmania spp. Sand fly vectors Rodents, Hyraxes Middle East, West and East Africa, Mediterranean basin, and South-America Skin ulcer, papules, nodules or plaques, Disseminated skin disease and significant facial destruction All ages (1:1) 700,000 Control WHA60.13 (2007) Filarial lymphoedema Filariae such as Wuchereria bancrofti Anopheles, Culex and Aedes mosquitoes Human Worldwide distribution Lower limb oedema Lymphoedema and elephantiasis Adults (ND) 970,000 Elimination as public health problem WHA50.29 (1997) Onchocerciasis complications Onchocerca volvulus Blackfly Simulium vectors Human West, Central and East Africa, foci in Latin America Itchy papules, vesicles, pustules, papulonodules or plaques Subcutaneous nodules; hanging groin Impetigo Physical appearance, nuisance, psychological impact, stigma Children and adults (ND) Adults (ND) NA Elimination in selected countries in Africa NA Leprosy Mycobacterium leprae Mycobacterium lepromatosis Probably respiratory route Human Worldwide distribution (India, Brazil, Bangladesh, Indonesia, DRC, Ethiopia and Nigeria) Skin patches/nodules, Thickened nerves, Sensory and/or motor disturbance Peripheral neuropathy and permanent damage of the limbs, eyes and nose 5–15 and 20–40 (1.5:1) 215,000 Elimination as public health problem WHA51.15 (1998) Mycetoma Fungal or bacterial species Inoculation via contaminated thorn or splinter Soil Worldwide distribution (Sudan, Mexico and India) Subcutaneous mass with sinuses and discharge Local destruction of subcutaneous tissue All ages (3:1 to 5:1) Unknown Control WHA69.21 (2016) Yaws Treponema pallidum ssp. pertenue Direct contact Human West and Central Africa and South Pacific Skin ulcer Involvement of the bones and joints 2–15 (1.5:1) 60,000 Eradication WHA31.58 (1978) In addition, skin NTDs result in stigmatization, discrimination, and psychological distress, which contribute to suffering and may affect health-seeking behaviours and adherence to treatment.[12] Finally, the economic impact of accessing care and rehabilitative measures can be substantial.[13] Policy Change In May 2013, the World Health Assembly (WHA) adopted resolution WHA66.12, which calls on Member States to intensify and integrate control measures to improve the health of NTD-affected populations.[14] Individual NTDs have WHA mandates, including the control of morbidity due to BU, CL, filarial lymphoedema, the elimination of onchocerciasis, the achievement of elimination of leprosy as a public health problem, and the eradication of yaws. In May 2016, the WHA adopted a resolution on mycetoma that called for the need to develop diagnostic tests and simpler treatment as well as enhanced surveillance.[15] For many years, vertical disease programmes were established to deal with priority diseases, but, increasingly, there has been a move to integrate programmes into general health services. WHO’s Department of Control of NTDs currently promotes intervention-based approaches rather than disease-specific approaches. Each vertical disease program is resource intensive, and resources are not maximized when they are fragmented. Integrating interventions should allow a common approach for case detection and community-based diagnosis, resulting in increased program efficiency through sharing of resources. We propose a new approach to neglected tropical skin diseases, in which seven diseases are grouped together. Integration is defined here to mean combining activities of two or more diseases at the same time and in the same communities with the aim of increasing efficiency. Each country and region may adapt the strategy to the prevailing local or regional co-endemicity of these diseases. The following are reasons why a policy change to the integrated approach for skin NTDs is feasible. Skin examination is an opportunity to identify multiple conditions in a single visit. Skin diseases can be suspected and diagnosed clinically by appropriately trained individuals, including community health workers and village volunteers. The case-management strategy of the skin diseases targeted is similar, including detection and diagnosis by skin examination, with or without confirmation of the diagnosis by laboratory test, and treatment by the use of effective medicines (oral treatment and/or injection) or morbidity and disability management. Benefits and Challenges The proposed integrated strategy may provide many benefits and opportunities: Increased effectiveness and efficiency. Increased impact of resources improving the opportunity and justification for investment. Increased access to timely diagnosis of cases from the communities thus enhancing disease surveillance. Alleviation of poverty as a result of morbidity caused by NTDs. Improved knowledge, capacity, and motivation of health workers and village volunteers who may see only a few or none of these diseases in single vertical programmes. Sustained awareness and knowledge of both declining and emerging diseases to enhance surveillance. Development of regional centres of excellence. Improvement in skin health overall. Despite the potential benefits, the following potential challenges should be acknowledged: Loss of vertical programmes may lead to loss of specialized expertise. Lack of adequately trained staff. Staff attrition after training. Referral centres may be unable to cope with the increased demand for skin NTD services. Risk of developing a new vertical programme, which remains poorly integrated with the existing health care system. Description of Integrated IDM NTD Implementation We propose three main linked activities in support of this integrated strategy (Box 1): firstly, identification of areas of geographic overlap; secondly, the use of training packages for the identification of multiple skin conditions; finally, integrated active case detection and use of pathways for diagnosis and management in the local community as far as possible, with referral to local health centres and district hospitals as required. Box 1. Integrated IDM-NTDs Implementation Approach Initial assessment of disease burden: conduct surveys to identify endemic areas for targeting intensified interventions. Training: validate a training program based on standardised clinical diagnostic schemes and organise training for trainers, health workers, and village volunteers. Development of an integrated control strategy for each district: suggest interventions to meet the specific needs of each district, depending on which diseases are identified in the initial assessment and survey. Social mobilisation: create demand for and a means of participating in interventions, and address specific aspects and concerns related to the diseases. Active case detection: implement active case finding in schools and communities. Case management: establish a referral pathway to undertake early diagnosis and treatment. Health facility mapping and strengthening: mapping health facilities in endemic areas to guide the needed improvements in infrastructure, equipment, and supplies to ensure optimum quality care of patients. Assessment of disease burden The first step of the integrated approach is to establish the presence or absence of disease in each district for the purpose of deciding the specific intervention(s) that might be required. Initial mapping could be based on a combination of routine surveillance data and specific population-based surveys. These data can be used to classify the Implementation Unit (IU) as a whole as being endemic or nonendemic. Usually the district level is identified as the IU, covering a population of 100,000–250,000, but the choice should be guided by feedback received from lower administrative levels (i.e., if the skin NTD is very focal, a lower administrative level such as sub-district may be chosen as the IU). Passive surveillance data in health care facilities normally includes the patient’s village of residence, which constitutes the basic mapping unit and allows identification of IUs with current or historical cases of the skin NTDs.[16] However, hidden or unknown cases would not be identified through this approach. Counts from sub-IU regions or point locations of cases during active case-finding can be collected by mobile teams visiting villages in affected areas. Rapid assessment procedures are also emerging as useful tools that provide estimates of the probability of local prevalence (e.g., prob[prevalence > 0.1]) for each IU rather than estimates of the local prevalence itself.[17] Training of health workers and village volunteers The success of an integrated approach will rely on well trained health workers and village volunteers being able to correctly identify multiple skin conditions. It is, therefore, necessary to develop, validate, and implement structured training programmes for those who will be conducting the field work as well as for the staff who will be training them. Simplified algorithms (Table 2) have shown reasonable sensitivity and specificity in diagnosing a limited range of skin conditions when compared to diagnoses made by dermatologists[18,19], but further work is needed to expand these algorithms to cover the full range of common skin conditions and skin NTDs. Simple integrated pictorial guides can also be developed to help health workers and village volunteers. Structured teledermatology resources could provide a system of support.[20] Data collection could be augmented through the use of electronic data collection tools and cloud-based data management, which have proven powerful in large-scale mapping projects.[21] 10.1371/journal.pntd.0005136.t002 Table 2 An example of key diagnostic signs for identification of targeted diseases. Key sign identified by HCW or village volunteer Diagnostic criteria utilised by HCW or referral centre Common differential diagnosis Skin ulcer Presence of ulcerative lesions with or without crusts Buruli ulcer, Cutaneous leishmaniasis, Yaws, Tropical ulcer, Stasis or venous ulcer Presence of chronic nodules or papillomatous lesions associated with ulceration Edges raised or indurated in CL and yaws; edges undermined in BU Subcutaneous mass Indurated painless swelling or mass involving the foot Mycetoma, Chromoblastomycosis, Buruli ulcer nodule or plaque, Skin cancer, Kaposi’s sarcoma, Onchocercal nodule History of penetrating injury at the same site or walking barefoot in mycetoma Sinus tracts, chronic discharge and grains in mycetoma Well-demarcated firm subcutaneous nodule(s) overlying a bony prominence (e.g., iliac crest, trochanters, ribs, sacrum) in onchocerciasis Swelling of limb or legs Painless non-pitting swelling Filarial lymphoedema, Podoconiosis, TB lymphadenitis, Leprosy oedema, Buruli ulcer oedema, Congestive heart failure oedema Skin patch Presence of a hypopigmented patch Leprosy, Pityriasis versicolor, Pityriasis alba, Vitiligo Reduced sensation within the patch in leprosy Enlarged nerves in leprosy Chronic duration (>3 months) HCW, health care worker. Conduct active case detection Scale-up of case detection activities is critical to effectively reduce the burden and transmission of skin NTDs. Even in NTDs where mass drug administration (MDA) is the initial stage of control interventions—such as yaws—as disease prevalence comes down, incident disease will still occur, for which individual diagnosis and treatment will be required to prevent resurgence.[22] Different approaches to active case detection may be used. House-to-house screening strategies yield the highest number of newly detected cases, though this strategy can be expensive and difficult to sustain. Alternative strategies include mobile teams visiting villages to screen all attendees at a central location or the use of an incentive-based approach, in which case detection is done by trained health workers detecting cases in their health centre catchment areas. In sub-Saharan Africa, trained village volunteers have also been instrumental in the detection and referral of diseases such as Buruli ulcer, Guinea worm, and leprosy.[23,24] A large network of village volunteers has also been pivotal in the Indian yaws elimination program and the program to eliminate visceral leishmaniasis.[25] Social mobilization activities will be needed prior to the start of active case detection programs. Communication efforts will focus on informing and enhancing knowledge among the general public to engage people and strengthen their participation in case finding activities. Other social mobilization avenues, including mass media, will provide a common platform by which to address social aspects associated with these diseases such as stigma and discrimination. Referral pathways It will be important to establish clear referral pathways for people with positive findings on screening for both suspected targeted diseases and non-targeted conditions, some of which can be managed at frontline health care level. Cases of skin NTDs will most often be detected at the community level by health workers or volunteers and then referred to the nearest health facility for management. Cases that cannot be managed at the primary health facility will be referred to the peripheral hospital. At this level, diagnosis and management of minor complications like skin grafting should be done. Complex cases should be referred to specialist referral centres. Community-based rehabilitation programs will need to be strengthened to support the increased case load. Improvements in the public health system are required to make treatment available and accessible at all levels. Clinical diagnosis and laboratory confirmation Clinical signs are of variable sensitivity in these diseases, so well-trained staff and diagnostic tests have an important role on diagnosis. The manifestations of leprosy have overlapping clinical features with many other skin diseases.[4] Chronic skin ulcers that fail to heal are a common presentation for all three: BU, CL, and yaws (Fig 1).[2,3,6] Skin ulcers may also result from polymicrobial infections, Haemophilus ducreyi,[13] and neuropathy (due to leprosy, diabetes) or vascular disease. Lower limb swelling of filarial lymphoedema may be mistaken for podoconiosis, TB lymphadenitis, or systemic diseases such as heart failure (Fig 2).[7] The main differential diagnoses of mycetoma are chromoblastomycosis and skin cancer.[5] 10.1371/journal.pntd.0005136.g001 Fig 1 Common skin ulcerative lesions related to neglected tropical diseases. (A) Buruli ulcer with undermined hanging edge, (B) Ill-defined ulcerated infiltrated granulomatous-looking lesions on dorsum of the hand in cutaneous leishmaniasis, (C) Early-stage yaws ulcer with raised edge and “raspberry” type appearance of the central granulation tissue, (D) Multiple yellow-crusted ulcers on the arms in secondary yaws. Images credit: Kingsley Asiedu (A,D), Oriol Mitjà (C), Jorge Postigo (B). 10.1371/journal.pntd.0005136.g002 Fig 2 Common skin neglected tropical diseases lesions. (A) Mycetoma with few active sinuses, grains, and discharge, (B) Bilateral lymphoedema of both legs in the late stage of lymphatic filariasis, (C) Hypopigmented anaesthetic macules with infiltrated edge of borderline tuberculoid leprosy. Images credit: Ahmed Fahal (A), CDC Public Health Image library (B), Rie Yotsu (C). Skin ulcer The diagnosis of skin ulcers in the tropics remains problematic as clinical features alone are insufficient to make a decision on treatment. PCR diagnostic platforms in reference laboratories are used for confirmation of many conditions, but these facilities are remote from the communities where the diseases occur. Sampling procedures like swabbing for detection of Mycobacterium ulcerans,[26] and Treponema pallidum subsp. pertenue[27] can be performed in the field. Routine diagnosis of CL is based on detection of Leishmania spp. DNA in the biopsy of skin lesions;[28] however, it is also possible to perform DNA analysis on impression smears from ulcerated CL lesions that can be collected in the field.[29] The main disadvantage of PCR is that sample transfer mechanisms from the field to reference laboratories for testing are generally slow, resulting in delays and dropout during the diagnostic process. Point-of-care tests (POCT) are available to aid clinicians to determine the etiology of skin ulcers before the patient leaves the clinical setting. Fluorescent thin layer chromatography (fTLC) is a simple and low-cost technique that can be used for detection of mycolactone in skin swabs from BU lesions at a peripheral hospital laboratory using a small bench analyser;[30] however, this test is still in the development stage. The Dual Path Platform (DPP) yaws rapid test kit, which is based on simultaneous detection of antibodies to treponemal and nontreponemal antigens, allows for serological diagnosis of yaws in the field.[31,32] Subcutaneous mass Multiple diagnostic tools are usually required to determine the extent of infections and to identify the causative agents of mycetoma and guide treatment. Ultrasound examination, fine-needle aspiration and deep-seated surgical biopsy need to be performed if feasible. The ultrasound and examination of aspirated material can be POCTs. Surgical biopsies can be processed for tissue histopathological examination, microbiology, and molecular studies. Individuals suspected of having mycetoma will need to be referred for further imaging to determine the extent of disease. Formal diagnosis of onchocerciasis is by skin snips to detect Onchocerca volvulus microfilariae. Ultrasound of suspected onchocercal nodules may reveal dead or live adult worms. Limb swelling Filarial lymphoedema is clinically difficult to distinguish from podoconiosis, but a diagnostic algorithm exists. Clinical diagnosis is accurate in settings where only podoconiosis is endemic; in settings where the two diseases may overlap, the combination of clinical history, physical examination, and blood tests for antifilarial antibody (Wb123 assay) have been used to reach a diagnosis.[33] Skin patch The diagnosis of leprosy is usually made clinically, which requires health workers to be trained to recognise the varied presentations of the disease including the immune-mediated leprosy reactional states. Skin biopsy is not routinely performed and needs to be interpreted in conjunction with the clinical features. In two leprosy referral centres in Brazil, slit skin smears were only positive in 59%[34] of patients and have not been a recommended part of leprosy programmes since 1998. Patients with suspected leprosy will need to be referred for further assessment and diagnostic procedures where necessary. Individuals suspected of having leprosy need to be assessed for nerve function impairment, and this needs to be repeated regularly during treatment and beyond. Treatment If skin NTDs are diagnosed and treated early, disabilities and disfigurements are preventable. In addition, simple skin-directed therapy can contribute to enhanced resolution and reduction in morbidity. Specific interventions Once a presumptive diagnosis is established, patients need to be referred for confirmatory diagnosis or testing and treatment except for yaws, which can be immediately treated at the time of detection using single-dose oral drugs (Table 3). Nonopioid analgesics are usually sufficient for managing mild pain related to skin lesions; however, more severe pain may complicate some diseases (e.g., neuropathic pain in leprosy or pain related to erythema nodosum leprosum). For yaws, treatment of all household contacts is necessary, even if they have no symptoms. The treatment of contacts of leprosy patients remains controversial and raises ethical issues around disclosure of diagnosis. 10.1371/journal.pntd.0005136.t003 Table 3 Recommended diagnosis and management of suspected skin lesions. Field assessment Initial management Laboratory tools Medical treatment Supportive measures Treatment of contacts Surgery Prevention of disabilities and rehabilitation Buruli ulcer Clinical Swabbing, registration and referral PCR of skin swab samples fTLC under development Oral rifampin + injectable streptomycin or oral clarithromycin for 8 weeks Wound dressing No Yes Yes Cutaneous leishmaniasis Clinical Swabbing, registration and referral Microscopy and PCR of skin swab Depends on species. Local or systemic therapy. Wound dressing No No No Filarial lymphoedema Clinical Registration and referral ICT antigen test (usually negative), and antifilarial antibodies Oral diethylcarbamazine for 12 days ± doxycycline for 4 to 6 weeks Skin barrier function improvement measures No Yes Yes Oncocerciasis Clinical Registration and referral Skin snips. Serological and antigen tests under development Oral ivermectin Pruritic rash -treatment for any itching and secondary infection If in endemic area Yes for nodules or hanging groin No Leprosy Clinical Registration and referral Slit skin smear or skin biopsy material Multidrug antibiotic therapy for 6 or 12 months. Home-based self-inspections and appropriate footwear Single dose rifampicin is being piloted but is not policy Yes Yes Mycetoma Clinical Registration and referral Microscopy examination and culture of grains/biopsy Depends on species. Long term antibiotic or antifungal. Skin barrier function improvement measures No Yes Yes Yaws Clinical Swabbing, and immediate treatment DPP test and PCR of skin swab Single oral dose of azithromycin (2nd line: injectable benzathine penicillin) Wound dressing Single dose azithromycin No No fTLC, fluorescent thin layer chromatography; ICT, immunochromatography, DPP, dual path platform yaws assay. Surgery is only occasionally needed for these diseases. In BU, antibiotic therapy (oral or injectable) is largely replacing surgical excision of tissue in active disease; surgery followed by physical therapy may be required for preventing contractures. In leprosy, surgery has long been used to correct functional and stigmatising cosmetic impairments. Early localised mycetoma lesions are amenable to surgical cure with a lower recurrence rate. Problematic onchocercal nodules can be excised, and hanging groin in onchoceriasis is amenable to surgery to reduce psychological distress. Clinical wound care and repair of skin barrier function Importantly, integrated but nonspecific interventions can be implemented for case morbidity management that can benefit patients with skin NTDs sharing similar basic pathologies. Wound management is a common approach for most skin NTDs; hence, the provision of appropriate dressings and training of health workers is important for a satisfactory outcome. Effective wound management requires access to water and simple, cheap non-adherent dressings, which keep wounds clean, protected from trauma, improve healing rates of damaged skin, and potentially prevent transmission. Skin barrier function improvement measures (e.g., washing, emollients, and compression shoes) minimize the risk of further damage in filarial lymphoedema.[35,36] Provision of simple exercise regimens with or without compression can also improve lymphoedema. The use of shoes is beneficial in the fight against several skin NTDs, and there are likely to be additional benefits such as protection against tetanus, tungiasis, and soil-transmitted helminths. Future Directions An integrated approach to the skin NTDs has the potential to reduce transmission, delays in diagnosis, and associated morbidity of these conditions and promote skin health for all. An integrated approach also has the potential to reduce costs for both patients and health systems. The WHO Department of Control of NTDs should take the lead in coordinating global efforts with the support of donors and partners, focusing on key areas (Box 2). Publication of this policy paper aims to trigger public debate about the approach and to encourage new funding to be targeted towards management of these important NTDs. Box 2. Next Steps Advocacy Increasing awareness of skin NTDs and their impact on affected communities. Promoting integrated management schemes and their potential benefits to society and donors. Networking technical and professional groups, donors, NGOs, endemic countries, and different disease control programmes. Policy Gaining consensus and support from all major stakeholders including the Ministries of Health on the way forward for implementation. Promoting a common management strategy of these diseases at community and health facility levels and resources required at each level. Research Validating a clinical algorithm for identification of skin NTDs using key symptoms and signs. Developing common clinical and laboratory diagnostic platforms for these diseases, which are practical in the field. Mapping to identify their overlap to allow integrated coordinated control and treatment activities as well as health system strengthening for service delivery. Piloting the integrated approach in one or several regions. Better understanding of the epidemiology of these diseases including transmission and interaction with poverty and water, sanitation, and hygiene (WASH). Understand community resilience and program factors that strengthen community participation. Integration of surveillance and interventions will not be possible without considerable political support, at a number of levels. There will be very real challenges to integration, including relationships with donors, potential changes to NTD management structures, and complexities in health care worker training among many others, and any of these challenges could derail efforts to achieving integrated management. Strong relationships will be required between governments, international agencies, implementing partners, and donors, with a clear plan of action supported by an evidence base to move forward an agenda of integration.

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Contributors

Paschal Kum Awah: Role: ConceptualizationRole: InvestigationRole: MethodologyRole: Project administrationRole: SupervisionRole: Writing – original draftRole: Writing – review & editing

Alphonse Um Boock: Role: ConceptualizationRole: Funding acquisitionRole: Project administrationRole: SupervisionRole: Writing – review & editing

Ferdinand Mou: Role: Data curationRole: Formal analysisRole: InvestigationRole: ValidationRole: Writing – review & editing

Joseph Tohnain Koin: Role: InvestigationRole: Writing – review & editing

Evaristus Mbah Anye: Role: InvestigationRole: Writing – review & editing

Djeunga Noumen: Role: ConceptualizationRole: Project administrationRole: Supervision

Mark Nichter:

ORCID: http://orcid.org/0000-0002-4112-3010

Role: ConceptualizationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: SupervisionRole: Writing – original draftRole: Writing – review & editing

Pamela L. C. Small: Role: Editor

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Journal ID (nlm-ta): PLoS Negl Trop Dis

Journal ID (iso-abbrev): PLoS Negl Trop Dis

Journal ID (publisher-id): plos

Journal ID (pmc): plosntds

Title: PLoS Neglected Tropical Diseases

Publisher: Public Library of Science (San Francisco, CA USA )

ISSN (Print): 1935-2727

ISSN (Electronic): 1935-2735

Publication date (Electronic): 27 March 2018

Publication date Collection: March 2018

Volume: 12

Issue: 3

Electronic Location Identifier: e0006238

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[1 ] Department of Anthropology, Faculty of Art, Letters and Social Sciences, University of Yaoundé I, Yaoundé, Cameroon

[2 ] Program Unit FAIRMED, Bern, Switzerland

[3 ] Monitoring & Evaluation Unit FAIRMED, Yaoundé, Cameroon

[4 ] Bankim Health District, Ministry of Health, Adamaoua Region, Cameroon

[5 ] School of Anthropology, University of Arizona, Tucson, United States of America

University of Tennessee, UNITED STATES

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The authors have declared that no competing interests exist.

¶ Membership of Stop Buruli Consortium are listed in the Acknowledgments.

* E-mail: Nichtermark@ 123456gmail.com

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Mark Nichter http://orcid.org/0000-0002-4112-3010

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Publisher ID: PNTD-D-17-01462

DOI: 10.1371/journal.pntd.0006238

PMC ID: 5889189

PubMed ID: 29584724

SO-VID: cc73af83-6935-4be8-b393-8d3f8cb5efbe

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This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Date received : 14 September 2017

Date accepted : 13 January 2018

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Figures: 2, Tables: 7, Pages: 20

Funding

Funded by: funder-id http://dx.doi.org/10.13039/501100008391, UBS Optimus Foundation;

Award Recipient : Alphonse Um Boock

This research was funded by the Optimus Foundation as part of the Stop Buruli Initiative. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Publication Update 2018-04-06

Data Availability All relevant data are within the paper and its Supporting Information files.

Developing a Buruli ulcer community of practice in Bankim, Cameroon: A model for Buruli ulcer outreach in Africa

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