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Little is known about enteropathogen seroepidemiology among children in low-resource settings. We measured serological IgG response to eight enteropathogens ( Giardia intestinalis, Cryptosporidium parvum, Entamoeba histolytica, Salmonella enterica , enterotoxigenic Escherichia coli, Vibrio cholerae, Campylobacter jejuni , norovirus) using multiplex bead assays in cohorts from Haiti, Kenya, and Tanzania. By age 2 years, most children had evidence of exposure by IgG response to the pathogens studied. We discovered a shift in IgG distributions for many pathogens as children age, caused by boosting and waning from repeated exposures, which complicates interpretation of seroprevalence among older children. Longitudinal profiles revealed important variation in enteropathogen IgG response above seropositivity cutoffs, underscoring the importance of longitudinal designs to estimate seroincidence rates as a measure of force of infection. In longitudinal cohorts there was a linear relationship between seroprevalence and prospective seroincidence rates, suggesting the two measures provide similar information about variation in pathogen transmission.

We describe here a lateral flow-based assay (LFA) for the detection of antibodies against immunodominant antigen Pgp3 from Chlamydia trachomatis, the causative agent of urogenital chlamydia infection and ocular trachoma. Optimal signal detection was achieved when the gold-conjugate and test line contained Pgp3, creating a dual sandwich capture assay. The LFA yielded positive signals with serum and whole blood but not with eluted dried blood spots. For serum, the agreement of the LFA with the non-reference multiplex assay was 96%, the specificity using nonendemic pediatric sera was 100%, and the inter-rater agreement was κ=0.961. For whole blood, the agreement of LFA with multiplex was 81.5%, the specificity was 100%, and the inter-rater agreement was κ=0.940. The LFA was tested in a field environment and yielded similar results to those from laboratory-based testing. These data show the successful development of a lateral flow assay for detection of antibodies against Pgp3 with reliable use in field settings, which would make antibody-based testing for trachoma surveillance highly practical, especially after cessation of trachoma elimination programs.

BackgroundMathematical models predict an exponential distribution of infection prevalence across communities where a disease is disappearing. Trachoma control programs offer an opportunity to test this hypothesis, as the World Health Organization has targeted trachoma for elimination as a public health concern by the year 2020. Local programs may benefit if a single survey could reveal whether infection was headed towards elimination. Using data from a previously-published 2009 survey, we test the hypothesis that Chlamydia trachomatis prevalence across 75 Tanzanian communities where trachoma had been documented to be disappearing is exponentially distributed.Methods/findingsWe fit multiple continuous distributions to the Tanzanian data and found the exponential gave the best approximation. Model selection by Akaike Information Criteria (AICc) suggested the exponential distribution had the most parsimonious fit to the data. Those distributions which do not include the exponential as a special or limiting case had much lower likelihoods of fitting the observed data. 95% confidence intervals for shape parameter estimates of those distributions which do include the exponential as a special or limiting case were consistent with the exponential. Lastly, goodness-of-fit testing was unable to reject the hypothesis that the prevalence data came from an exponential distribution.ConclusionsModels correctly predict that infection prevalence across communities where a disease is disappearing is best described by an exponential distribution. In Tanzanian communities where local control efforts had reduced the clinical signs of trachoma by 80% over 10 years, an exponential distribution gave the best fit to prevalence data. An exponential distribution has a relatively heavy tail, thus occasional high-prevalence communities are to be expected even when infection is disappearing. A single cross-sectional survey may be able to reveal whether elimination efforts are on-track.

ImportanceThe World Health Organization recommends at least 3 annual mass drug administrations (MDAs) of azithromycin in places where the prevalence of follicular trachoma (FT) is greater than 10%. However, stopping MDA prior to 3 rounds, if monitoring indicates an absence of infection with Chlamydia trachomatis even if FT persists, may be more cost-effective.ObjectiveTo determine the prevalence of infection in communities randomized to 3 rounds of annual MDAs with azithromycin compared with communities randomized to a stopping rule, where MDA could cease if the infection rate was low. DESIGN A 1:1 community randomized trial comparing usual care with a cessation rule. The Partnership for the Rapid Elimination of Trachoma-Ziada Trial was conducted from February 1, 2010, through September 1, 2011.SettingSixteen communities in Tanzania with trachoma prevalence rates between 10% and 20%.ParticipantsA total of 100 children aged 5 years or younger randomly drawn from each community. Children had to reside in an eligible community, have no ocular condition that prevented trachoma grading or ocular specimen collection, and have a guardian who could provide consent for participation.InterventionsCessation of MDA with azithromycin if the community had no infection in their sample at 6 months or 18 months.Main outcome measureThe prevalence of C trachomatis at 18 months.ResultsNone of the intervention communities met criteria to stop MDA based on the 6-month or 18-month survey; all, as well as the usual care communities, were scheduled for a third MDA round. There was no difference in infection (2.9% vs 4.7%; P = .25) between the usual care and cessation rule communities at 18 months.Conclusions and relevanceIn this setting, communities with low (10%-20%) initial prevalence of active trachoma did not have MDA stopped before 3 annual rounds on the basis of monitoring for infection. Infection with C trachomatis in communities with average trachoma rates at 12% to 13% cannot be eliminated before 3 rounds of MDA with azithromycin.Trial registrationclinicaltrials.gov Identifier: NCT00792922.

Background: Associations between repeated ocular infections with Chlamydia trachomatis in childhood and conjunctival scarring in adulthood are well established. Trachomatous scarring (TS) in children has also been observed in hyper-endemic areas, but data are scant regarding childhood scarring in areas where trachoma has been reduced to hypo-endemic levels. Methods/Principle findings: In this cross-sectional study, a random sample of children, ages 1–9 years, were selected from 38 communities in the formerly hyper-endemic district of Kongwa, Tanzania. Each participant received an ocular examination and eye-swab test for C. trachomatis infection. Conjunctival photographs were taken and analyzed at 5x magnification to determine scarring presence and severity. Community-level case clustering was assessed using intra-class correlation coefficients, and associations between TS presence and demographic/clinical factors were assessed using contingency table analyses. 1,496 children (78% of eligible) participated in this study. The mean age was 5.5 years and 51% were female. Scarring prevalence was 2.1% (95% CI: 1.5%– 3.0%). The prevalence of follicular trachoma and ocular C. trachomatis infection were 3.2% and 6.5%, respectively. Most TS cases (68.7%) fell into the mildest category, grade S1. 18.7% were grade S2; 12.6% were grade S3. No significant associations were seen between TS presence and age, sex, follicular trachoma, or active ocular C. trachomatis infection (p-values: 0.14, 0.48, 0.27, 0.15, respectively). Thirty communities (78.9%) had 0–1 TS cases, and the most seen in any single community was four cases. Three years ago, follicular trachoma prevalence averaged 4.9% in communities with 0–1 TS cases, but 7.6% in communities with 2–4 TS cases (p-value: 0.08). Conclusions: In this formerly hyper-endemic district of Tanzania, TS was rare in 1–9 year-olds and usually mild when present. Communities with higher rates of follicular trachoma in the past were more likely to have ≥2 cases of scarring, but the association was not statistically significant. [ABSTRACT FROM AUTHOR]

Background: Although facial cleanliness is part of the SAFE strategy for trachoma there is controversy over the reliability of measuring a clean face. A child’s face with no ocular and nasal discharge is clean and the endpoint of interest, regardless of the number of times it must be washed to achieve that endpoint. The issue of reliability rests on the reproducibility of graders to assess a clean face. We report the reproducibility of assessing a clean face in a field trial in Kongwa, Tanzania. Methods/Findings: Seven graders were trained to assess the presence and absence of nasal and ocular discharge on children’s faces. Sixty children ages 1–7 years were recruited from a community and evaluated independently by seven graders, once and again about 50 minutes later. Intra-and inter-observer variation was calculated using unweighted kappa statistics. The average intra-observer agreement was kappa = 0.72, and the average inter-observer agreement was kappa = 0.78. Conclusions: Intra-observer and inter-observer agreement was substantial for the assessment of clean faces using trained Tanzania staff who represent a variety of educational backgrounds. As long as training is provided, the estimate of clean faces in children should be reliable, and reflect the effort of families to keep ocular and nasal discharge off the faces. These data suggest assessment of clean faces could be added to trachoma surveys, which already measure environmental improvements, in districts. [ABSTRACT FROM AUTHOR]

Trial design: Trachoma is targeted for global elimination. Infection rates with Chlamydia trachomatis are higher in new arrivals to a community and in travelers who leave for extended periods, suggesting they are sources of re-infection. This community-randomized, clinical trial was designed to determine if a surveillance program that targeted newcomers and travelers, identified weekly, would result in more communities achieving levels of infection of ≤1%. Methods: 52 communities were randomly allocated 1:1 to the control (annual MDA alone if warranted) or intervention arm (annual MDA if warranted, plus a surveillance program to identify and treat newcomers and travelers). In each community, surveys were completed every six months on a random sample of 100 children ages 1–9 years for trachoma and infection. The primary outcome was the proportion of communities in the intervention arm, compared to the control arm, which had a prevalence of infection at ≤1% by 24 months. Registered: clinicaltrials.gov(NCT01767506). Results: Intervention communities experienced an average of 110 surveillance events per month. At 24 months, 7 (27%) of 26 intervention communities achieved a prevalence of infection ≤1% compared to 4 (15%) of the 26 control communities (odds ratio = 2·6, 95%CI = 0·56–11·9). At 24 months, the average infection prevalence in the intervention communities was 4·8, compared to 6·9 in the control communities (p = ·06). Conclusion: Despite surveillance programs for community newcomers and travelers, the proportion of intervention communities with a level of infection ≤1% was lower than expected and not significantly different from control communities. [ABSTRACT FROM AUTHOR]

Background: Trachomatous trichiasis (TT), inturned eyelashes from repeated infection with Chlamydia trachomatis, is the leading infectious cause of blindness in the world. Though surgery will correct entropion caused by trachoma, uptake of TT surgery remains low. In this case-control study, we identify barriers that prevent TT patients from receiving sight-saving surgery. Methodology/Principal Findings: Participants were selected from a database of TT cases who did (acceptors) and did not (non-acceptors) have surgery as of August 2015. We developed an in-home interview questionnaire, using open and closed-ended questions on perceived barriers to accessing surgical services. We compared responses between the acceptors and non-acceptors, examining differences in reasons for and against surgery, sources of TT information, and suggestions for improving surgical delivery. 167 participants (mean age 61 years, 79.7% females) were interviewed. Compared to acceptors, non-acceptors were more likely to report they had no one to accompany them to surgery (75.3% vs. 42.6%, p<0.0001), they could manage TT on their own (69.9% vs. 31.5%, p<0.0001), and the surgery camp was too far (53.4% vs. 28.7%, p = 0.001). Over 90% of both acceptors and non-acceptors agreed on the benefits of having surgery. Fear of surgery was the biggest barrier stated by both groups. Despite this fear, acceptors were more likely than non-acceptors to also report fear of losing further vision without surgery. Conclusions/Significance: Barriers included access issues, familial and/or work responsibilities, the perception that self-management was sufficient, and lack of education about surgery. Fear of surgery was the biggest barrier facing both acceptors and non-acceptors. Increasing uptake will require addressing how surgery is presented to community residents, including outlining treatment logistics, surgical outcomes, and stressing the risk of vision loss. [ABSTRACT FROM AUTHOR]

Purpose: To examine the relationship between ocular Chlamydia trachomatis infection and follicular trachoma (TF) in children prior to and following multiple rounds of annual mass drug administration (MDA) with azithromycin. Methodology/principal findings: Thirty-two communities with endemic trachoma in Kongwa District, Tanzania, were offered annual MDA as part of a district-wide trachoma control program. Presence of ocular C. trachomatis infection and TF were assessed in 3,200 randomly sampled children aged five years and younger, who were examined prior to each MDA. Infection was detected using the Amplicor CT/NG assay and TF was identified by clinical examination using the World Health Organization (WHO) simplified grading system. The association between chlamydial infection and TF in children was evaluated at baseline prior to any treatment, and 12 months after each of three annual rounds of mass treatment. Factors associated with infection were examined using generalized estimating equation models. At baseline, the overall prevalence of chlamydial infection and TF was 22% and 31%, respectively. Among children with clinical signs of TF, the proportion of those with infection was 49% prior to treatment and declined to 30% after three MDAs. The odds of infection positivity among children with clinical signs of TF decreased by 26% (OR 0.74, 95% CI 0.65 to 0.84, p = <0.01) with each MDA, after adjusting for age. For children aged under one year, who did not receive treatment, the relationship was unchanged. Conclusions/significance: The association between ocular C. trachomatis infection and TF weakened in children with each MDA, as both infection and clinical disease prevalence declined. However, there was still a significant proportion of TF cases with infection after three rounds of MDA. New strategies are needed to assess this residual infection for optimal treatment distribution. [ABSTRACT FROM AUTHOR]

Background: The World Health Organization recommends at least 3 annual antibiotic mass drug administrations (MDA) where the prevalence of trachoma is >10% in children ages 1–9 years, with coverage at least at 80%. However, the additional value of higher coverage targeted at children with multiple rounds is unknown. Trial Design: 2×2 factorial community randomized, double blind, trial. Trial methods: 32 communities with prevalence of trachoma ≥20% were randomized to: annual MDA aiming for coverage of children between 80%–90% (usual target) versus aiming for coverage>90% (enhanced target); and to: MDA for three years versus a rule of cessation of MDA early if the estimated prevalence of ocular C. trachomatis infection was less than 5%. The primary outcome was the community prevalence of infection with C. trachomatis at 36 months. Results: Over the trial's course, no community met the MDA cessation rule, so all communities had the full 3 rounds of MDA. At 36 months, there was no significant difference in the prevalence of infection, 4.0 versus 5.4 (mean adjusted difference = 1.4%, 95% CI = −1.0% to 3.8%), nor in the prevalence of trachoma, 6.1 versus 9.0 (mean adjusted difference = 2.6%, 95% CI = −0.3% to 5.3%) comparing the usual target to the enhanced target group. There was no difference if analyzed using coverage as a continuous variable. Conclusion: In communities that had pre-treatment prevalence of follicular trachoma of 20% or greater, there is no evidence that MDA can be stopped before 3 annual rounds, even with high coverage. Increasing coverage in children above 90% does not appear to confer additional benefit. [ABSTRACT FROM AUTHOR]

Trachoma programs have dramatically reduced the prevalence of the ocular chlamydia that cause the disease. Some have hypothesized that immunity to the infection may be reduced because of program success in reducing the incidence of infection, and transmission may then increase. Longitudinal studies of multiple communities would be necessary to test this hypothesis. Here, we quantify transmission using an estimated basic reproduction number based on 32 communities during the first, second, and third years of an antibiotic treatment program. We found that there is little to no increase in the basic reproduction number over time. The estimated linear trend in the basic reproduction number, , was found to be −0.025 per year, 95% CI −0.167 to 0.117 per year. We are unable to find evidence supporting any loss of immunity over the course of a 3-year program. This is encouraging, as it allows the possibility that repeated mass antibiotic distributions may eliminate infection from even the most severely affected areas. [ABSTRACT FROM AUTHOR]

Purpose: To determine the sensitivity, specificity, and field utility of the Cepheid GeneXpert Chlamydia trachomatis (CT) Assay (GeneXpert) for ocular chlamydia infection compared to Roche Amplicor CT assay (Amplicor). Methods: In a trachoma-endemic community in Kongwa Tanzania, 144 children ages 0 to 9 were surveyed to assess clinical trachoma and had two ocular swabs taken. One swab was processed at Johns Hopkins University, Baltimore MD, using Amplicor, (Roche Molecular Diagnostics) and the other swab was processed at a field station in Kongwa using the GeneXpert Chlamydia trachomatis/Neisseria gonorrhoeae assay (Cepheid). The sensitivity and specificity of GeneXpert was compared to the Amplicor assay. Results: Of the 144 swabs taken the prevalence of follicular trachoma by clinical exam was 43.7%, and by evidence of infection according to Amplicor was 28.5%. A total of 17 specimens (11.8%) could not be processed by GeneXpert in the field due to lack of sample volume, other specimen issues or electricity failure. The sensitivity of GeneXpert when compared to Amplicor was 100% and the specificity was 95%. The GeneXpert test identified more positives in individuals with clinical trachoma than Amplicor, 55% versus 52%. Conclusion: The GeneXpert test for C. trachomatis performed with high sensitivity and specificity and demonstrated excellent promise as a field test for trachoma control. [ABSTRACT FROM AUTHOR]

Background: Defining endpoints for trachoma programs can be a challenge as clinical signs of infection may persist in the absence of detectable bacteria. Antibody-based tests may provide an alternative testing strategy for surveillance during terminal phases of the program. Antibody-based assays, in particular ELISAs, have been shown to be useful to document C. trachomatis genital infections, but have not been explored extensively for ocular C. trachomatis infections. Methodology/Principal Findings: An antibody-based multiplex assay was used to test two C. trachomatis antigens, pgp3 and CT694, for detection of trachoma antibodies in bloodspots from Tanzanian children (n = 160) collected after multiple rounds of mass azithromycin treatment. Using samples from C. trachomatis-positive (by PCR) children from Tanzania (n = 11) and control sera from a non-endemic group of U.S. children (n = 122), IgG responses to both pgp3 and CT694 were determined to be 91% sensitive and 98% specific. Antibody responses of Tanzanian children were analyzed with regard to clinical trachoma, PCR positivity, and age. In general, children with more intense ocular pathology (TF/TI = 2 or most severe) had a higher median antibody response to pgp3 (p = 0.0041) and CT694 (p = 0.0282) than those with normal exams (TF/TI = 0). However, 44% of children with no ocular pathology tested positive for antibody, suggesting prior infection. The median titer of antibody responses for children less than three years of age was significantly lower than those of older children. (p<0.0001 for both antigens). Conclusions/Significance: The antibody-based multiplex assay is a sensitive and specific additional tool for evaluating trachoma transmission. The assay can also be expanded to include antigens representing different diseases, allowing for a robust assay for monitoring across NTD programs. [ABSTRACT FROM AUTHOR]