The authors have declared that no competing interests exist.
The WHO yaws eradication strategy consists of one round of total community treatment (TCT) of single-dose azithromycin with coverage of > 90%.The efficacy of the strategy to reduce the levels on infection has been demonstrated previously in isolated island communities in the Pacific region. We aimed to determine the efficacy of a single round of TCT with azithromycin to achieve a decrease in yaws prevalence in communities that are endemic for yaws and surrounded by other yaws-endemic areas.
Surveys for yaws seroprevalence and prevalence of skin lesions were conducted among schoolchildren aged 5–15 years before and one year after the TCT intervention in the Abamkrom sub-district of Ghana. We used a cluster design with the schools as the primary sampling unit. Among 20 eligible primary schools in the sub district, 10 were assigned to the baseline survey and 10 to the post-TCT survey. The field teams conducted a physical examination for skin lesions and a dual point-of-care immunoassay for non-treponemal and treponemal antibodies of all children present at the time of the visit. We also undertook surveys with non-probabilistic sampling to collect lesion swabs for etiology and macrolide resistance assessment.
At baseline 14,548 (89%) of 16,287 population in the sub-district received treatment during TCT. Following one round of TCT, the prevalence of dual seropositivity among all children decreased from 10.9% (103/943) pre-TCT to 2.2% (27/1211) post-TCT (OR 0.19; 95%CI 0.09–0.37). The prevalence of serologically confirmed skin lesions consistent with active yaws was reduced from 5.7% (54/943) pre-TCT to 0.6% (7/1211) post-TCT (OR 0.10; 95% CI 0.25–0.35). No evidence of resistance to macrolides against
A single round of high coverage TCT with azithromycin in a yaws affected sub-district adjoining other endemic areas is effective in reducing the prevalence of seropositive children and the prevalence of early skin lesions consistent with yaws one year following the intervention. These results suggest that national yaws eradication programmes may plan the gradual expansion of mass treatment interventions without high short-term risk of reintroduction of infection from contiguous untreated endemic areas.
In this study, we provided a single round of total community treatment (TCT) with azithromycin to the population of a sub-district in Ghana (16,287 people) that is endemic for yaws and surrounded by other yaws-endemic communities to determine whether a sustained decrease in yaws prevalence could be achieved up to one year after the intervention. The efficacy of TCT was assessed by performing a clinical evaluation and serological testing of any yaws-like lesions found as well as serological screening of asymptomatic schoolchildren aged 5–15 years pre-TCT and at one year post-TCT. The results indicate that after a single round of high coverage TCT (89%) with azithromycin, the prevalence of active and latent yaws was significantly reduced. We also found that the use of a dual point-of-care immunoassay to detect non-treponemal and treponemal antibodies among school-going children is a practical alternative to laboratory-based serological testing to evaluate the effectiveness of yaws interventions in resource-poor settings.
Yaws is a chronic, relapsing, neglected tropical disease caused by
Primary yaws lesions develop at the site of initial inoculation after an incubation period of 9–90 days. These lesions are initially papules, which can develop into papillomata and eventually ulcerate, and are most frequently found on the lower legs and ankles and, less frequently, on the skin of the upper limbs and elsewhere on the body. If left untreated, the disease may progress to the secondary stage, which is characterized by multiple skin lesions as well as osteitis and periostitis of the bones underlying the skin lesions. Untreated disease may spontaneously resolve clinically and enter a period of latency prior to the development of non-infectious gummas of the skin, cartilage and bone, resulting in the destructive, often disfiguring, lesions of late yaws [
During the 1950s and 1960s, the World Health Organization (WHO) and the United Nations Children’s Fund (UNICEF) led a global campaign to eradicate the disease by providing mass treatment to affected communities using single intramuscular injections of long-acting penicillin. The strategy was based on the need to screen at least 90% of the population, treat the entire reservoir of treponemal infection (including those with clinical disease, latent infection and contacts) and to perform periodic surveys at 6–12 months to identify and treat missed, new and imported cases [
In 2012, the finding that a single oral dose of azithromycin was as effective as injectable penicillin for the treatment of yaws [
In 2015, the first empirical data of the impact of mass treatment with azithromycin on disease transmission became available. A study carried out in Lihir, Papua New Guinea (PNG) demonstrated that mass treatment with azithromycin to the population of yaws-endemic island communities resulted in a significant decrease in the prevalence of clinically early yaws lesions and a decrease in reactive serological markers for the disease [
In this study, we aimed to assess the impact of a single round of TCT with azithromycin using two markers of infection among school-going children in the target communities before and one year after the intervention. We measured the prevalence of dually seropositive for non-treponemal and treponemal serological markers, and the prevalence of active yaws-like lesions among children. A secondary objective was to establish the etiology of active yaws-like lesions among schoolchildren using sensitive molecular techniques and to assess the occurrence of mutations associated with azithromycin resistance among
The study protocol was approved by the ethics committee of the Ghana Health Service, Ministry of Health (GHS-ERC-05/01/13). Written informed consent was obtained from parents and where they were unable to provide consent, teachers provided written consent on their behalf, which is normal practice for mass treatments campaigns in Ghana. Prior to the initiation of mass treatment with azithromycin, information sessions were held with the regional directorate of health services, the district political authorities and communities about the study in order to gain their support. The local radio was used to inform the entire district about the mass treatment campaign. Health workers and village volunteers distributed the WHO yaws picture booklets [
We conducted a prospective observational study in the Abamkrom sub-district, West Akim district of the Eastern Region of Ghana between October 2013 and December 2014. The sub-district is highly endemic for yaws (
Prior to the implementation of the study, the health workers and village volunteers were trained on the objectives of the study, recognition of yaws-like lesions, implementation and data collection tools. The TCT programme was conducted by 13 teams of two trained volunteers drawn from affected communities who were supervised by local health-care workers or members of the national yaws eradication programme. During a five-day period in November–December 2013, the teams offered azithromycin tablets (purchased by WHO from Medopharm, Chennai, India) at a single oral dose of 30 mg/kg per body weight (maximum 2 g) to all members of the 36 targeted communities aged 6 months and above at no cost to the participants. The tablets (500g strength) were administered to the eligible population according to age as described in the WHO Morges Strategy document [
We used cluster sampling with individual schools as the cluster unit. Eligibility for inclusion was met by 20 primary schools with a population larger than 100 children among 24 schools located in the sub-district. The schools were randomly assigned to either the pre- or post- TCT evaluation surveys. Therefore, the sets of schools for pre- and post- TCT surveys were mutually exclusive and schools could not be chosen repeatedly for more than one survey. Every child present at the time of our visit to the schools selected was invited to participate in the study.
The primary outcome was prevalence of
In October 2013, before the mass treatment campaign (November–December 2013), we conducted a baseline assessment survey in 10 randomly selected primary schools and every child present, 943 children in total, was enrolled. One year after the intervention (November–December 2014), every child from a further group of 10 randomly selected schools, 1211 children in total, were selected for an identical post-intervention assessment of impact survey.
During both assessments, all children were examined clinically for skin lesions consistent with early infectious yaws (i.e. skin papilloma, chronic solitary or multiple skin ulcerations) and a specimen of capillary blood was collected from all, symptomatic and asymptomatic, participants to perform a point-of-care immunoassay for antibody to yaws infection. All children with active yaws-like lesions detected during either the initial or post-TCT assessments or those who were asymptomatic but had a dually non-treponemal and treponemal antibody-positive result on initial field screening were treated with a single dose of azithromycin (30 mg/kg) and followed up for adverse events.
A point-of-care immunoassay, developed for the serological diagnosis of syphilis, that can simultaneously detect both non-treponemal and treponemal antibodies (DPP Syphilis Screen and Confirm Assay, Chembio Diagnostic Systems, Medford, NY, USA) [
We conducted clinical surveys to collect lesion swabs for PCR testing before and one year after TCT. Due to the low number of
Children with suspected yaws had their lesions photographed and specimens taken directly from the largest papilloma or ulcer after cleansing with sterile saline using either a sterile plastic curette (Ear Curette, Sklar Instruments, West Chester, PA, USA) or sterile dacron-tipped swabs (Medical Wire & Equipment, Corsham, UK) for PCR testing.
Scrapings from papillomata and swabs taken from the bases of skin ulcerations were expressed into 1.2 ml of Assay-Assure nucleic acid transport medium (Thermo Fisher Scientific, Waltham, MA, USA). All specimens were stored frozen at −20°C before shipping, on dry ice, to the WHO Collaborating Centre for Reference & Research in Syphilis Serology at the Centers for Disease Control in Atlanta, GA, USA. Genomic DNA was extracted from 350 μl aliquots of assay-assure samples using the iPrep PureLink gDNA blood kits (Life Technologies, Grand Island, NY, USA) and iPrep purification instrument.
The specimen DNAs were originally screened with TaqMan-based real-time 4-plex polymerase chain reaction (PCR) targeting
All DNA samples were tested for
In addition, serum samples were obtained from venous blood collected from all children with active lesions, for laboratory-based testing. These were stored frozen at −20°C and transported on dry ice to the WHO Collaborating Centre for Reference & Research in Syphilis Serology, where they were tested using a quantitative rapid plasma reagin (RPR) test (Alere North America, Inc., Orlando, FL, USA) and a
Data were entered in Microsoft Access software, version 15.0 (Microsoft, Redmond, WA, USA) at the Ministry of Health, Ghana. The integrity of the data was verified by using a double data entry process. The primary outcome was change in prevalence of dual seropositivity following TCT, secondary outcomes were changes in rates of prevalence of suspected cases with lesions and change in prevalence of cases with lesion and seropositivity. We calculated that a sample size for the pre- and post-TCT surveys of at least 854 schoolchildren aged 5–15 years (EPI INFO 2000 sample size calculator) was required to detect a reduction by 45% in yaws seroprevalence among students before and after TCT intervention with a 95% confidence interval (CI) and 80% power. A design effect of 2 for the cluster sampling method was used to calculate the power [
We calculated prevalence rates and 95% confidence intervals using the clustered sandwich estimator to control the variability of clusters. We evaluated the changes in yaws seroprevalence, and prevalence of yaws-like lesions among the schoolchildren sampled before and one year after TCT using logistic regression models controlling the variance-covariance matrix (VCE) corresponding to the parameter estimates. We reported the standard errors of parameter estimates as the square root of the variances of the VCE. For these, we use the option cluster in the calculus of Odds Ratios with the logistic regression models. We calculated Odds Ratios (post- compared to pre- TCT) for positive serology or clinical findings. The differences in the prevalence rates were considered statistically significant when two-sided p-values were less than 0.05. The statistical analysis was performed with Stata StataCorp. 2017 (Stata Statistical Software: Release 15. College Station, TX: StataCorp LLC)
During the 5-day community-based mass treatment campaign, 14 548 (89%) of 16,287 residents in the sub-district received a single oral dose of azithromycin. Individuals who were not eligible for treatment (977, 6.0%), or absent during the mass treatment (762, 4.7%) accounted for 10.7%. of the total population (16 287) of the sub-district. There were no severe adverse events attributable to the study drug; only 45 (0.3%) of the 14 548 participants treated reported mild to moderate self-limiting adverse events including abdominal discomfort, nausea and vomiting.
Of the 943 children examined at schools before the community-based mass treatment campaign, 487 (51.6%) were male, and a similar proportion of males was found among those examined at schools after the TCT (632 /1211, 52.2%). The mean (SD) age of the pre-TCT schoolchildren (10.5 [2.5] years) compared with that of the post-TCT children (9.4 [3.6] years) was not significantly different.
The prevalence rate of dual seropositivity in the DPP test decreased significantly, from 103/943 (10.9% 95% CI 6.5–17.5) among children in the pre-TCT survey to 27/1211 (2.2%, 95%CI 1.3–3.7; OR 0.19, 95%CI 0.09–0.37) in the post-TCT survey (
Burden of disease | Pre-TCT number (%) | 95% CI | Post-TCT number (%) | 95% CI | Odds Ratio (95% CI) |
---|---|---|---|---|---|
Yaws seroprevalence (dually-positive DPP rapid test) | 103/943 (10.9%) | (6.5%-17.5%) | 27/1211 (2.2%) | (1.3%-3.7%) | 0.19 (0.09–0.37) |
Prevalence of skin lesions | 337/943 (35.7%) | (30.8%-40.9%) | 223/1211 (18.4%) | (14.1%-23.6%) | 0.41 (0.31–0.52) |
Prevalence of yaws-like lesions with a dually positive DPP rapid test | 54/943 (5.7%) | (3.2%-9.9%) | 7/1211 (0.6%) | (0.2%-1.6%) | 0.10 (0.25–0.35) |
The results of PCR testing obtained from the children with active lesions in the extended intervention area pre- TCT are shown in
Pattern of seroreactivity | Pre-TCT | |||
---|---|---|---|---|
PCR negative no.−/total(%) | ||||
TPPA+/RPR+ | 20/57 (35.1%) | 6/57 (10.5%) | 7/57 (12.3%) | 24/57 (42.1%) |
TPPA+/RPR- | 1/8 (12.5%) | 1/8 (12.5%) | 2/8 (25.0%) | 4/8 (50.0%) |
TPPA−/ RPR+ | 0 | 0 | 0 | 0 |
TPPA−/RPR- | 1/93 (1.1%) | 0 | 29/93 (31.2%) | 63/93 (67.7%) |
Total | 22/158 (13.9%) | 7/158 (4.4%) | 38/158 (24.1%) | 91/158 (57.6%) |
PCR analysis | Pre-TCT | Post-TCT | OR (95% CI) |
---|---|---|---|
T. pertenue-PCR + no.+/total (%) | 3/53 (5.7%) | 0/49 (0.0%) | NA |
12/53 (22.6%) | 14/49 (28.6%) | 0.73 (0.27–1.96) | |
0/53 (0.0%) | 0/49 (0.0%) | NA | |
Macrolide resistant |
0/3 (0.0%) | 0/0 (0.0%) | NA |
PCR negative no.+/total (%) | 39/53 (73.6%) | 35/49 (71.4%) | 1.11 (0.42–2.91) |
Of the 158 blood samples collected pre-TCT from children with active lesions that underwent serological testing at the CDC laboratory (
Our study demonstrates that the provision of mass azithromycin administration given as a single oral dose of 30 mg/kg, up to a maximum dose of 2 g, is effective in reducing both the rates of seropositivity and the presence of serologically positive skin lesions consistent with yaws. Our results support the findings of earlier publications from PNG [
One year after TCT, we recorded a reduction in the prevalence of active yaws-like skin lesions among schoolchildren living in the targeted communities which was consistent with a reduction of passively detected suspected yaws cases in the same sub-district area (from 103 cases in 2012 to 20 in 2014) recorded in the routine reporting system (DHIMS2) of the Ministry of Health. Although the sample size was extremely small, we were unable to detect
The population coverage that was achieved in the Ghanaian population reported here (89%) was slightly higher than that achieved in the PNG study (84%) [
Recent studies on yaws conducted in PNG [
Our study has some limitations. First, the use of school-going children as a sampling methodology may introduce bias because the poorest children, who are at most risk of the disease, may not attend school. However, school-sampling is generally considered a good and convenient sub-population sample for other NTDs and routine surveillance data from DHIMS2 confirmed the overall decrease of yaws-like cases seen in the sub-district one year after the mass treatment. Further studies to compare the impact of interventions on school versus community-based populations are clearly indicated. Second, we selected two different groups of schools for pre- and post-TCT assessments, rather than returning to the original schools to determine the impact of TCT on the children who were seen initially. We considered that the additional survey for clinical and serological screening, and treatment of positive cases, that these schools would receive was effectively an additional public health intervention that is not a normal part of the larger interventions that the study aimed to evaluate. We therefore randomly selected a different group of schools for the post-TCT evaluation one year later to avoid measuring the potential impact of a double treatment. Third, the DPP point-of-care test that was used in this study lacks some sensitivity at low titres compared with conventional laboratory-based testing [
It seems clear, from the results of this intervention study, that yaws-like lesions caused by
In conclusion, our findings provide additional evidence that one round of TCT with azithromycin with high coverage ~ 90%, as part of the WHO Morges Strategy, is highly effective in providing a sustained and significant decrease in the prevalence of yaws 12 months after mass treatment from endemic communities, even if they adjoin other untreated endemic areas. Because 6-monthly resurveys using field staff may be costly, perhaps, if the initial coverage is >90%, in some places, a practical approach is to use trained village volunteers for ongoing active community surveillance and health promotion activities for yaws, especially, in the post-TCT phase similar to the experience of the guinea worm eradication programme [
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The authors would like to thank all the health workers, community leaders, schoolteachers and schoolchildren in the Abamkrom sub-district, West Akim District of the Eastern Region of Ghana for their cooperation and support for the study. We thank Mr Alexei Mikhailov, Department of Control of Neglected Tropical Diseases, World Health Organization, Geneva, Switzerland for creating the maps. The findings and conclusions in this paper are those of the authors and do not necessarily represent the views of their respective institutions.