Geographically structured genomic diversity of non-human primate-infecting Treponema pallidum subsp. pertenue.

Many non-human primate species in sub-Saharan Africa are infected with Treponema pallidum subsp. pertenue, the bacterium causing yaws in humans. In humans, yaws is often characterized by lesions of the extremities and face, while T. pallidum subsp. pallidum causes venereal syphilis and is typically characterized by primary lesions on the genital, anal or oral mucosae. It remains unclear whether other T. pallidum subspecies found in humans also occur in non-human primates and how the genomic diversity of non-human primate T. pallidum subsp. pertenue lineages is distributed across hosts and space. We observed orofacial and genital lesions in sooty mangabeys (Cercocebus atys) in Taï National Park, Côte d'Ivoire and collected swabs and biopsies from symptomatic animals. We also collected non-human primate bones from 8 species in Taï National Park and 16 species from 11 other sites across sub-Saharan Africa. Samples were screened for T. pallidum DNA using polymerase chain reactions (PCRs) and we used in-solution hybridization capture to sequence T. pallidum genomes. We generated three nearly complete T. pallidum genomes from biopsies and swabs and detected treponemal DNA in bones of six non-human primate species in five countries, allowing us to reconstruct three partial genomes. Phylogenomic analyses revealed that both orofacial and genital lesions in sooty mangabeys from Taï National Park were caused by T. pallidum subsp. pertenue. We showed that T. pallidum subsp. pertenue has infected non-human primates in Taï National Park for at least 28 years and has been present in two non-human primate species that had not been described as T. pallidum subsp. pertenue hosts in this ecosystem, western chimpanzees (Pan troglodytes verus) and western red colobus (Piliocolobus badius), complementing clinical evidence that started accumulating in Taï National Park in 2014. More broadly, simian T. pallidum subsp. pertenue strains did not form monophyletic clades based on host species or the symptoms caused, but rather clustered based on geography. Geographical clustering of T. pallidum subsp. pertenue genomes might be compatible with cross-species transmission of T. pallidum subsp. pertenue within ecosystems or environmental exposure, leading to the acquisition of closely related strains. Finally, we found no evidence for mutations that confer antimicrobial resistance.

Factors associated with cutaneous ulcers among children in two yaws-endemic districts in Ghana.

BACKGROUND: Yaws is a chronic relapsing disease caused by Treponema pallidum subspecies pertunue, which can result in severe disability and deformities. Children below the age of 15 years in resource-poor communities are the most affected. Several non-specific factors facilitate the continuous transmission and resurgence of the disease. Endemic communities in rural Ghana continue to report cases despite the roll out of several intervention strategies in the past years. The objective of this study was to determine the factors associated with cutaneous ulcers among children in two yaws-endemic districts in Ghana. METHODS: A community-based unmatched 1:2 case-control study was conducted among children between 1 and 15 years. Data on socio-demographic, environmental and behavioral factors were collected using a structured questionnaire. Active case search and confirmation was done using the Dual Path Platform (DPP) Syphilis Screen and Confirm test kit. Data were analyzed using STATA 15. Logistic regression was done to determine the exposures that were associated with yaws infection at 0.05 significant level. RESULTS: Sixty-two cases and 124 controls were recruited for the study. The adjusted multivariable logistic regression model showed that yaws infection was more likely among individuals who reside in overcrowded compound houses (aOR = 25.42, 95% CI: 6.15-105.09) and with poor handwashing habits (aOR = 6.46, 95% CI: 1.89-22.04). Male (aOR = 4.15, 95% CI: 1.29-13.36) and increasing age (aOR = 5.90, 95% CI: 1.97-17.67) were also associated with yaws infection. CONCLUSIONS: Poor personal hygiene, overcrowding and lack of access to improved sanitary facilities are the factors that facilitate the transmission of yaws in the Awutu Senya West and Upper West Akyem districts. Yaws was also more common among males and school-aged children. Improving living conditions, access to good sanitary facilities and encouraging good personal hygiene practices should be core features of eradication programs in endemic communities.

Spatial-temporal clustering analysis of yaws on Lihir Island, Papua New Guinea to enhance planning and implementation of eradication programs.

BACKGROUND: In the global program for the eradication of yaws, assessments of the prevalence of the disease are used to decide where to initiate mass treatment. However, the smallest administrative unit that should be used as the basis for making decisions is not clear. We investigated spatial and temporal clustering of yaws to help inform the choice of implementation unit. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed 11 years of passive surveillance data on incident yaws cases (n = 1448) from Lihir Island, Papua New Guinea. After adjusting for age, sex, and trends in health-seeking, we detected three non-overlapping spatial-temporal clusters (p < 1 × 10(-17), p = 1.4 × 10(-14), p = 1.4 × 10(-8)). These lasted from 28 to 47 months in duration and each encompassed between 4 and 6 villages. We also assessed spatial clustering of prevalent yaws cases (n = 532) that had been detected in 7 biannual active case finding surveys beginning in 2013. We identified 1 statistically significant cluster in each survey. We considered the possibility that schools that serve multiple villages might be loci of transmission, but we found no evidence that incident cases of yaws among 8- to 14-year-olds clustered within primary school attendance areas (p = 0.6846). CONCLUSIONS/SIGNIFICANCE: These clusters likely reflect transmission of yaws across village boundaries; villages may be epidemiologically linked to a degree such that mass drug administration may be more effectively implemented at a spatial scale larger than the individual village.

Targeted Treatment of Yaws With Household Contact Tracing: How Much Do We Miss?

Yaws is a disabling bacterial infection found primarily in warm and humid tropical areas. The World Health Organization strategy mandates an initial round of total community treatment (TCT) with single-dose azithromycin followed either by further TCT or active case-finding and treatment of cases and their contacts (the Morges strategy). We sought to investigate the effectiveness of the Morges strategy. We employed a stochastic household model to study the transmission of infection using data collected from a pre-TCT survey conducted in the Solomon Islands. We used this model to assess the proportion of asymptomatic infections that occurred in households without active cases. This analysis indicated that targeted treatment of cases and their household contacts would miss a large fraction of asymptomatic infections (65%-100%). This fraction was actually higher at lower prevalences. Even assuming that all active cases and their households were successfully treated, our analysis demonstrated that at all prevalences present in the data set, up to 90% of (active and asymptomatic) infections would not be treated under household-based contact tracing. Mapping was undertaken as part of the study "Epidemiology of Yaws in the Solomon Islands and the Impact of a Trachoma Control Programme," in September-October 2013.

Effectiveness of single-dose azithromycin to treat latent yaws: a longitudinal comparative cohort study.

BACKGROUND: Treatment of latent yaws is a crucial component of the WHO yaws eradication strategy to prevent relapse and the resulting transmission to uninfected children. We assessed the effectiveness of single-dose azithromycin to treat patients with latent yaws. METHODS: This population-based cohort study included children (age <20 years) living on Lihir Island, Papua New Guinea, with high-titre (rapid plasma reagin titre ≥1:8) latent or active yaws, between April, 2013, and May, 2015. Latent yaws was defined as lack of suspicious skin lesions or presence of ulcers negative for Treponema pallidum subsp pertenue on PCR, and active yaws was defined as ulcers positive for T pertenue on PCR. All children received one oral dose of 30 mg/kg azithromycin. The primary endpoint was serological cure, defined as a two-dilution decrease in rapid plasma reagin titre by 24 months after treatment. Treatment of latent yaws was taken to be non-inferior to that of active yaws if the lower limit of the two-sided 95% CI for the difference in rates was higher than or equal to -10%. This study is registered with ClinicalTrials.gov, number NCT01955252. FINDINGS: Of 311 participants enrolled, 273 (88%; 165 with latent yaws and 108 with active yaws) completed follow-up. The primary endpoint was achieved in 151 (92%) participants with latent yaws and 101 (94%) with active yaws (risk difference -2·0%, 95% CI -8·3 to 4·3), meeting the prespecified criteria for non-inferiority. INTERPRETATION: On the basis of decline in serological titre, oral single-dose azithromycin was effective in participants with latent yaws. This finding supports the WHO strategy for the eradication of yaws based on mass administration of the entire endemic community irrespective of clinical status. FUNDING: Newcrest Mining Limited and ISDIN laboratories.

Mathematical Modeling of Programmatic Requirements for Yaws Eradication.

Yaws is targeted for eradication by 2020. The mainstay of the eradication strategy is mass treatment followed by case finding. Modeling has been used to inform programmatic requirements for other neglected tropical diseases and could provide insights into yaws eradication. We developed a model of yaws transmission varying the coverage and number of rounds of treatment. The estimated number of cases arising from an index case (basic reproduction number [R0]) ranged from 1.08 to 3.32. To have 80% probability of achieving eradication, 8 rounds of treatment with 80% coverage were required at low estimates of R0 (1.45). This requirement increased to 95% at high estimates of R0 (2.47). Extending the treatment interval to 12 months increased requirements at all estimates of R0. At high estimates of R0 with 12 monthly rounds of treatment, no combination of variables achieved eradication. Models should be used to guide the scale-up of yaws eradication.

Yaws: towards the WHO eradication target.

In 2012 WHO declared a target to eradicate yaws by 2020. The cornerstone of this strategy is community mass treatment with azithromycin. Initial studies suggest this is a very effective tool that may be capable of interrupting transmission. Alongside this there has been progress in the development and validation of diagnostic tests for yaws. Several new challenges have also emerged, in particular, evidence that Haemophilus ducreyi can cause phenotypically similar ulcers in yaws endemic communities, and evidence for a possible non-human primate reservoir. The 2020 eradication target remains ambitious and more challenges should be expected on the journey.

Yaws, a non-venereal treponemal infection. Still endemic in some parts of the world.

Yaws is an infection that mainly affects the poorest populations living in humid tropical areas. We reviewed the literature on yaws, the most common non-venereal treponemal infection, using the standard Prescrire methodology. Yaws is often transmitted directly from person to person. It starts as a single lesion, later leading to multiple contagious lesions. Yaws mainly affects children. The infection remains asymptomatic for several years. In about 10% of cases, late reactivation leads to bone lesions, deformities and disability. Diagnosis of yaws is based on the clinical and epidemiological context. Serological tests cannot distinguish between yaws and syphilis or other non-venereal treponematoses. Curative treatment consists of a single injection of benzathine benzylpenicillin. The results of a randomised trial suggest that a single oral dose of azithromycin is as effective as penicillin. In India, yaws was successfully eradicated through a programme based on providing information to the population at risk, screening and treatment.

Climate and New World periosteal reaction patterns: implications for migration routes into the western hemisphere.

The presence of the diseases yaws and bejel are indicated by periosteal reaction patterns. The distributions of these two diseases in ancient North American human populations show evidence of climatic influence. Those ancient populations lacking either yaws or bejel (the null periosteal reaction pattern) can be found in the coldest parts of the Cold Winter Regions. Those populations with yaws (the poly-ostotic periosteal reaction) can be found in the milder portions of the Cold Winter Regions. The populations with bejel (the pauci-ostotic periosteal reaction) are found either outside of or marginal to Cold Winter Regions. The Bering Strait area is considered to be the gateway to the ancient New World. The cold climates present in this area should have influenced the routes available for the diseases to spread from population to population or by migration of infected populations into the Western Hemisphere. It is suggested that the coastal route with its milder maritime climate was the route taken by yaws when it entered the New World. The presence of bejel in ancient North America presents a conundrum. The climate would have blocked the spread of the disease from Siberia to Alaska in either Late Glacial or Holocene times. This suggests that our present view of migration routes is incomplete.

Nonvenereal treponematoses: yaws, endemic syphilis, and pinta.

The nonvenereal treponematoses--yaws, endemic syphilis, and pinta--constitute a major health concern for many third world countries. These diseases are caused by an organism that is morphologically and antigenically identical to the causative agent of venereal syphilis, Treponema pallidum. Nonvenereal treponematoses differ significantly in their modes of transmission, epidemiology, and clinical presentation from venereal syphilis. Like venereal syphilis, they have a chronic relapsing course and have prominent cutaneous manifestations. Recently, several cases of imported yaws and endemic syphilis have been described in Europe. With the escalating U.S. military presence in many remote areas of the world and ever-increasing world-wide travel, the diagnosis of the nonvenereal treponematoses must be considered in appropriate clinical and historical situations.

Nonvenereal treponematoses: yaws, endemic syphilis, and pinta

The nonvenereal treponematoses--yaws, endemic syphilis, and pinta--constitute a major health concern for many third world countries. These diseases are caused by an organism that is morphologically and antigenically identical to the causative agent of venereal syphilis, Treponema pallidum. Nonvenereal treponematoses differ significantly in their modes of transmission, epidemiology, and clinical presentation from venereal syphilis. Like venereal syphilis, they have a chronic relapsing course and have prominent cutaneous manifestations. Recently, several cases of imported yaws and endemic syphilis have been described in Europe. With the escalating U.S. military presence in many remote areas of the world and ever-increasing world-wide travel, the diagnosis of the nonvenereal treponematoses must be considered in appropriate clinical and historical situations.

[Resurgence of yaws in Central African Republic. Role of the Pygmy population as a reservoir of the virus]. / Résurgence du pian en République centrafricaine. Rôle de la population pygmée comme réservoir de virus.

The authors present the results of a clinical (framboesia) and serological (TPHA and VDRL) investigation aimed at defining the reservoir of virus of yaws in the Lobaye area (southwest of CAR) out of which the disease spreads in spite of previous mass treatment campaigns. The Lobaye focus is still active because we found among the pediatric population under the age of 15 years, 5.6% contagious skin lesion and 19.6% VDRL+. In this area with contact between nomadic Pygmies and sedentary ethnic groups, the observed level of clinical and serological attacks suggested that the pygmie population, as previously described, makes up the principal focus of yaws. For every 1 case found through clinical examination, 3.5 cases VDRL+ and 4.8 cases TPHA+ are found through serological examination. This proportion indicates that clinical screening alone is not sufficient to evaluate the endemic yaws level in a population.

Research: the prerequisite for innovative strategies and technologies.

The search for new strategies and technologies for the control of yaws, a genuine but much neglected tropical disease problem, has been largely unsuccessful. This disease, with conspicuous early symptoms and a late crippling pathology, attracted the attention of the first generation of tropical doctors. As soon as specific therapy became available in the early part of the 20th century, mass treatment campaigns were started. The availability and efficacy of penicillin led some to anticipate yaws eradication; this expectation was not met but rather induced a false sense of security. After varying intervals resurgences occurred in several endemic regions. It is important to analyze this failure so that mistakes and underestimated or overlooked factors can be identified. On the whole, the main difficulty has been a lack of interest in a presumably disappearing disease and a consequent failure to take advantage of the benefits offered by recent advances in basic biomedical technology. Solid clinical, epidemiologic, and sociocultural data in connection with mass treatment and control are still needed. Research of high quality, with continuous assessment in the field, is a prerequisite for innovative strategies and technologies.

Yaws in Ghana.

The final results of a three-year campaign against yaws in the Republic of Ghana, which was introduced in an attempt to reduce an unusually high prevalence, are summarized. The campaign started in January 1981 and officially ended in December 1983. Serious economic and technical constraints slowed the progress of work after the first year and reduced the total population covered. In spite of the shortcomings, the program provided penicillin treatment to 77,818 patients with active yaws (4.04% of those examined during the campaign) as well as chemoprophylaxis for an additional 1,556,360 contacts. The campaign staff compiled detailed information on the epidemiology of yaws in Ghana. A second attack phase using simple equipment and vehicles such as motorcycles and bicycles could be implemented with greater efficiency and could reduce costs.

Feasibility of eradicating yaws.

The elimination of yaws from large geographic areas provides evidence that global elimination of person-to-person yaws transmission is feasible. The failure to reach that goal to date is the result of managerial rather than technical deficiencies. If the eradication of yaws can be accomplished, it should be done to reduce the suffering that is associated with the disease. In addition, a positive benefit-cost ratio is likely to be realized within a period of decades, and in areas endemic for yaws, its elimination could well provide a basis for the development of a strong system of primary health care. The decision to eliminate yaws must be made deliberately by the World Health Assembly with full knowledge of the implication of not making such a decision. A positive decision would result in enriched lives for countless potential victims of yaws and save the world money in the long term.