Community-level chlamydial serology for assessing trachoma elimination in trachoma-endemic Niger.

BACKGROUND: Program decision-making for trachoma elimination currently relies on conjunctival clinical signs. Antibody tests may provide additional information on the epidemiology of trachoma, particularly in regions where it is disappearing or elimination targets have been met. METHODS: A cluster-randomized trial of mass azithromycin distribution strategies for trachoma elimination was conducted over three years in a mesoendemic region of Niger. Dried blood spots were collected from a random sample of children aged 1-5 years in each of 24 study communities at 36 months after initiation of the intervention. A multiplex bead assay was used to test for antibodies to two Chlamydia trachomatis antigens, Pgp3 and CT694. We compared seropositivity to either antigen to clinical signs of active trachoma (trachomatous inflammation-follicular [TF] and trachomatous inflammation-intense [TI]) at the individual and cluster level, and to ocular chlamydia prevalence at the community level. RESULTS: Of 988 children with antibody data, TF prevalence was 7.8% (95% CI 6.1 to 9.5) and TI prevalence was 1.6% (95% CI 0.9 to 2.6). The overall prevalence of antibody positivity to Pgp3 was 27.2% (95% CI 24.5 to 30), and to CT694 was 23.7% (95% CI 21 to 26.2). Ocular chlamydia infection prevalence was 5.2% (95% CI 2.8 to 7.6). Seropositivity to Pgp3 and/or CT694 was significantly associated with TF at the individual and community level and with ocular chlamydia infection and TI at the community level. Older children were more likely to be seropositive than younger children. CONCLUSION: Seropositivity to Pgp3 and CT694 correlates with clinical signs and ocular chlamydia infection in a mesoendemic region of Niger. TRIAL REGISTRATION: ClinicalTrials.gov NCT00792922.

Anthropometry and Malaria among Children in Niger: A Cross-Sectional Study.

The complex relationship between malnutrition and malaria affects morbidity and mortality in children younger than 5 years, particularly in parts of sub-Saharan Africa where these conditions occur together seasonally. Previous research on this relationship has been inconclusive. Here, we examine the association between anthropometric indicators and malaria infection in a population-based sample of children younger than 5 years in Niger. This cross-sectional study is a secondary analysis of a cluster-randomized trial comparing treatment strategies for trachoma in Niger. We included children aged 6-60 months residing in the 48 communities enrolled in the trial who completed anthropometric and malaria infection assessments at the final study visit. We evaluated the association between anthropometric indicators, including height-for-age z-score (HAZ) and weight-for-age z-score (WAZ) and indicators of malaria infection, including malaria parasitemia and clinical malaria. In May 2013, we collected data from 1,649 children. Of these, 780 (47.3%) were positive for malaria parasitemia and 401 (24.3%) had clinical malaria. In models of malaria parasitemia, the adjusted odds ratio (aOR) was 1.05 (95% confidence interval [CI]: 1.00-1.10) for HAZ and 1.07 (95% CI: 0.99, 1.15) for WAZ. In models of clinical malaria, the aOR was 1.07 (95% CI: 1.02-1.11) for HAZ and 1.09 (95% CI: 1.01-1.19) for WAZ. Overall, we did not find evidence of an association between most anthropometric indicators and malaria infection. Greater height may be associated with an increased risk of clinical malaria.

The Effect of Antibiotic Selection Pressure on the Nasopharyngeal Macrolide Resistome: A Cluster-randomized Trial.

Background: Frequent use of antibiotics is thought to create selection pressure by clearing susceptible bacteria and allowing resistant bacteria to spread in a community. A cluster-randomized trial comparing 2 different frequencies of mass azithromycin distributions for trachoma provided a convenient experiment for determining the causal relationship between antibiotic consumption and antibiotic resistance. Methods: Twenty-four communities were randomized to either annual or biannual mass azithromycin distributions for trachoma. Randomization was stratified on health catchment area and trachoma prevalence. Swabs were processed for the genetic macrolide resistance determinants ermB and mefA/E in a masked fashion from a random sample of 120 preschool children before treatment and another 120 children after 2 years of mass antibiotics. Results: Macrolide resistance determinants were similar in the 12 annually and 12 biannually treated communities before treatment, with a median prevalence among preschool children of 20% (interquartile range [IQR], 10%-40%) in each group. By 24 months, macrolide resistance determinants were found more commonly in the biannually treated communities (median, 60% [IQR, 50%-80%]) than the annually treated communities (median, 40% [IQR, 20%-40%]; P < .001). Adjusting for baseline, the 24-month prevalence of macrolide resistance determinants in the biannual group was 29.4% higher than that of the annual group (95% confidence interval, 10.5%-56.7%). Conclusions: This randomized trial used direct genetic methods to confirm the causal relationship of community antibiotic consumption and antibiotic resistance. Communities randomized to less frequent use of antibiotics had a significantly lower prevalence of genetic antibiotic resistance determinants. Clinical Trials Registration: NCT00792922.

Mass Azithromycin and Malaria Parasitemia in Niger: Results from a Community-Randomized Trial.

Studies designed to determine the effects of mass administration of azithromycin on trachoma have suggested that mass azithromycin distributions may also reduce the prevalence of malaria. These studies have typically examined the impact of a small number of treatments over short durations. In this prespecified substudy of a cluster-randomized trial for trachoma, we compared malaria parasitemia prevalence in 24 communities in Niger randomized to receive either annual or biannual mass azithromycin distributions over 3 years. The 12 communities randomized to annual azithromycin received three treatments during the high-transmission season, and the 12 communities randomized to biannual azithromycin received a total of six treatments: three during the high-transmission season and three during the low-transmission season. Blood samples were taken to assess malariometric indices among children in all study communities at a single time point during the high-transmission season after 3 years of the intervention. No significant differences were identified in malaria parasitemia, parasite density, or hemoglobin concentration between the annual and biannual treatment arms. When compared with annual mass azithromycin alone, additional mass azithromycin distributions given during the low-transmission season did not significantly reduce the subsequent prevalence of malaria parasitemia or parasite density after 3 years, as measured during the high-transmission season.

Short-term forecasting of the prevalence of clinical trachoma: utility of including delayed recovery and tests for infection.

BACKGROUND: The World Health Organization aims to control blinding trachoma by 2020. Decisions on whether to start and stop mass treatments and when to declare that control has been achieved are currently based on clinical examination data generated in population-based surveys. Thresholds are based on the district-level prevalence of trachomatous inflammation-follicular (TF) in children aged 1-9 years. Forecasts of which districts may and may not meet TF control goals by the 2020 target date could affect resource allocation in the next few years. METHODS: We constructed a hidden Markov model fit to the prevalence of two clinical signs of trachoma and PCR data in 24 communities from the recent PRET-Niger trial. The prevalence of TF in children in each community at 36 months was forecast given data from earlier time points. Forecasts were scored by the likelihood of the observed results. We assessed whether use of TF with additional TI and PCR data rather than just the use of TF alone improves forecasts, and separately whether incorporating a delay in TF recovery is beneficial. RESULTS: Including TI and PCR data did not significantly improve forecasts of TF. Forecasts of TF prevalence at 36 months by the model with the delay in TF recovery were significantly better than forecasts by the model without the delay in TF recovery (p = 0.003). A zero-inflated truncated normal observation model was better than a truncated normal observation model, and better than a sensitivity-specificity observation model. CONCLUSION: The results in this study suggest that future studies could consider using just TF data for forecasting, and should include a delay in TF recovery. TRIAL REGISTRATION: Clinicaltrials.gov NCT00792922.

Short-term Forecasting of the Prevalence of Trachoma: Expert Opinion, Statistical Regression, versus Transmission Models.

BACKGROUND: Trachoma programs rely on guidelines made in large part using expert opinion of what will happen with and without intervention. Large community-randomized trials offer an opportunity to actually compare forecasting methods in a masked fashion. METHODS: The Program for the Rapid Elimination of Trachoma trials estimated longitudinal prevalence of ocular chlamydial infection from 24 communities treated annually with mass azithromycin. Given antibiotic coverage and biannual assessments from baseline through 30 months, forecasts of the prevalence of infection in each of the 24 communities at 36 months were made by three methods: the sum of 15 experts' opinion, statistical regression of the square-root-transformed prevalence, and a stochastic hidden Markov model of infection transmission (Susceptible-Infectious-Susceptible, or SIS model). All forecasters were masked to the 36-month results and to the other forecasts. Forecasts of the 24 communities were scored by the likelihood of the observed results and compared using Wilcoxon's signed-rank statistic. FINDINGS: Regression and SIS hidden Markov models had significantly better likelihood than community expert opinion (p = 0.004 and p = 0.01, respectively). All forecasts scored better when perturbed to decrease Fisher's information. Each individual expert's forecast was poorer than the sum of experts. INTERPRETATION: Regression and SIS models performed significantly better than expert opinion, although all forecasts were overly confident. Further model refinements may score better, although would need to be tested and compared in new masked studies. Construction of guidelines that rely on forecasting future prevalence could consider use of mathematical and statistical models. TRIAL REGISTRATION: Clinicaltrials.gov NCT00792922.

Does mass azithromycin distribution impact child growth and nutrition in Niger? A cluster-randomized trial.

BACKGROUND: Antibiotic use on animals demonstrates improved growth regardless of whether or not there is clinical evidence of infectious disease. Antibiotics used for trachoma control may play an unintended benefit of improving child growth. METHODOLOGY: In this sub-study of a larger randomized controlled trial, we assess anthropometry of pre-school children in a community-randomized trial of mass oral azithromycin distributions for trachoma in Niger. We measured height, weight, and mid-upper arm circumference (MUAC) in 12 communities randomized to receive annual mass azithromycin treatment of everyone versus 12 communities randomized to receive biannual mass azithromycin treatments for children, 3 years after the initial mass treatment. We collected measurements in 1,034 children aged 6-60 months of age. PRINCIPAL FINDINGS: We found no difference in the prevalence of wasting among children in the 12 annually treated communities that received three mass azithromycin distributions compared to the 12 biannually treated communities that received six mass azithromycin distributions (odds ratio = 0.88, 95% confidence interval = 0.53 to 1.49). CONCLUSIONS/SIGNIFICANCE: We were unable to demonstrate a statistically significant difference in stunting, underweight, and low MUAC of pre-school children in communities randomized to annual mass azithromycin treatment or biannual mass azithromycin treatment. The role of antibiotics on child growth and nutrition remains unclear, but larger studies and longitudinal trials may help determine any association.

Importance of including borderline cases in trachoma grader certification.

We assessed trachoma grading agreement among field graders using photographs that included the complete spectrum of disease and compared it with cases where there was consensus among experienced graders. Trained photographers took photographs of children's conjunctiva during a clinical trial in Ethiopia. We calculated κ-agreement statistics using a complete set of 60 cases and then recalculated the κ using a consensus set where cases were limited to those cases with agreement among experienced graders. When the complete set of 60 cases was used, agreement was moderate (κ = 0.61, 95% confidence interval [95% CI] = 0.56-0.67). When the consensus set was used, agreement improved significantly (κ = 0.75, 95% CI = 0.68-0.80). The κ of the consensus set was higher than the complete set by 0.14 (95% CI = 0.12-0.16) (P < 0.001). If testing sets remove difficult-to-grade cases, agreement in trachoma grading may be higher than actually seen in population-based trachoma surveys.

Impact of mass azithromycin distribution on malaria parasitemia during the low-transmission season in Niger: a cluster-randomized trial.

We assessed the effect of mass azithromycin treatment on malaria parasitemia in a trachoma trial in Niger. Twenty-four study communities received treatment during the wet, high-transmission season. Twelve of the 24 communities were randomized to receive an additional treatment during the dry, low-transmission season. Outcome measurements were conducted at the community-level in children < 1-72 months of age in May-June 2011. Parasitemia was higher in the 12 once-treated communities (29.8%, 95% confidence interval [CI] = 21.5-40.0%) than in the 12 twice-treated communities (19.5%, 95% CI = 13.0-26.5%, P = 0.03). Parasite density was higher in once-treated communities (354 parasites/µL, 95% CI = 117-528 parasites/µL) than in twice-treated communities (74 parasites/µL, 95% CI = 41-202 parasites/µL, P = 0.03). Mass distribution of azithromycin reduced malaria parasitemia 4-5 months after the intervention. The results suggest that drugs with antimalaria activity can have long-lasting impacts on malaria during periods of low transmission.

The easiest children to reach are most likely to be infected with ocular Chlamydia trachomatis in trachoma endemic areas of Niger.

BACKGROUND: Control programs for trachoma use mass antibiotic distributions to treat ocular Chlamydia trachomatis in an effort to eliminate this disease worldwide. To determine whether children infected with ocular Chlamydia are more likely to present later for examination than those who are uninfected, we compare the order of presentation for examination of children 0-5 years, and the presence of ocular Chlamydia by PCR in 4 villages in Niger where trachoma is endemic. METHODS: We conducted a cluster-randomized, controlled trial where 48 randomly selected villages in Niger are divided into 4 study arms of different mass treatment strategies. In a substudy of the main trial, we randomly selected 1 village from each of the 4 study arms (4 total villages) and we evaluated the odds of ocular Chlamydia versus the rank order of presentation for examination and laboratory assessment before treatment was offered. FINDINGS: We found the odds of harboring ocular Chlamydia dropped by more than 70% from the first child examined to the last child examined (OR 0.27, 95% CI 0.13-0.59, P = 0.001) in the 4 randomly selected villages. We found the odds of active trachoma dropped by 80% from the first child examined to the last child examined (OR 0.20, 95% CI 0.10-0.4, P<0.0001) in the 48 villages in the main trial. INTERPRETATION: This study demonstrates that even if the WHO recommended 80% treatment coverage is not reached in certain settings, children 0-5 years with the greatest probability of ocular Chlamydia have higher odds of receiving attention because they are the first to present. These results suggest there may be diminishing returns when using scarce resources to track down the last few children in a mass treatment program. TRIAL REGISTRATION: ClinicalTrials.gov NCT00792922.

A cluster-randomized controlled trial evaluating the effects of mass azithromycin treatment on growth and nutrition in Niger.

Antimicrobials are used primarily to treat infectious disease, but they have other effects. Here, we assess anthropometry measurements in children 6-60 months in 24 communities randomized to one or two mass azithromycin distributions over a 1-year period in Niger. We compared the prevalence of wasting, low mid-upper arm circumference, stunting, and underweight in communities in the two treatment arms. We were unable to prove that there was a difference in the prevalence of wasting in the 12 communities that received one mass azithromycin distribution versus the 12 communities that received two mass azithromycin distributions (odds ratio = 0.75, 95% confidence interval = 0.46-1.23). Likewise, we were unable to detect a difference in the two treatment arms for low mid-upper arm circumference, stunting, and underweight. There may not be an association between antibiotic use and improved growth in humans, or this trial was not powerful enough to detect an association if it exists.

Community risk factors for ocular Chlamydia infection in Niger: pre-treatment results from a cluster-randomized trachoma trial.

BACKGROUND: Trachoma control programs utilize mass azithromycin distributions to treat ocular Chlamydia trachomatis as part of an effort to eliminate this disease world-wide. But it remains unclear what the community-level risk factors are for infection. METHODS: This cluster-randomized, controlled trial entered 48 randomly selected communities in a 2×2 factorial design evaluating the effect of different treatment frequencies and treatment coverage levels. A pretreatment census and examination established the prevalence of risk factors for clinical trachoma and ocular chlamydia infection including years of education of household head, distance to primary water source, presence of household latrine, and facial cleanliness (ocular discharge, nasal discharge, and presence of facial flies). Univariate and multivariate associations were tested using linear regression and Bayes model averaging. FINDINGS: There were a total of 24,536 participants (4,484 children aged 0-5 years) in 6,235 households in the study. Before treatment in May to July 2010, the community-level prevalence of active trachoma (TF or TI utilizing the World Health Organization [WHO] grading system) was 26.0% (95% CI: 21.9% to 30.0%) and the mean community-level prevalence of chlamydia infection by Amplicor PCR was 20.7% (95% CI: 16.5% to 24.9%) in children aged 0-5 years. Univariate analysis showed that nasal discharge (0.29, 95% CI: 0.04 to 0.54; P = 0.03), presence of flies on the face (0.40, 95% CI: 0.17 to 0.64; P = 0.001), and years of formal education completed by the head of household (0.07, 95% CI: 0.07 to 0.13; P = 0.03) were independent risk factors for chlamydia infection. In multivariate analysis, facial flies (0.26, 95% CI: 0.02 to 0.49; P = 0.03) and years of formal education completed by the head of household (0.06, 95% CI: 0.008 to 0.11; P = 0.02) were associated risk factors for ocular chlamydial infection. INTERPRETATION: We have found that the presence of facial flies and years of education of the head of the household are risk factors for chlamydia infection when the analysis is done at the community level. TRIAL REGISTRATION: ClinicalTrials.gov NCT00792922.

How much is not enough? A community randomized trial of a Water and Health Education programme for Trachoma and Ocular C. trachomatis infection in Niger.

SUMMARY OBJECTIVE: To determine the impact after 2 years of a water and health education (W/HE) programme on ocular Chlamydia trachomatis infection and trachoma. METHODS: We randomized 12 trachoma-endemic communities in Maradi, Niger 1:1 to W/HE intervention and control arms and collected data on 10 of the 12 villages. In the intervention villages, at least one clean water well was constructed, and a 3 month, modest health education programme was provided immediately prior to the 2 year survey. We censused all households, and 557 children ages 1-5 years were randomly selected as sentinel children and examined at baseline and at one and 2 years from baseline. Trachoma was clinically assessed and a swab taken and analyzed for C. trachomatis. Tetracycline eye ointment was provided to all children in either arm during the surveys who had signs of trachoma. RESULTS: Infection with C. trachomatis declined slightly, and not significantly, in the children in the control villages over the 2 years, from 15% to 11%. The decline in infection was more pronounced, and significant, in the children in the intervention villages, from 26% to 15%. However, the change in infection rates in the intervention villages was not significantly different from the change in infection rates in the control villages (P = 0.39, and 0.11 for change from baseline to 1 year and 2 year, respectively). There was also no difference in the change in overall trachoma rates between the two arms. CONCLUSION: These data suggest that the provision of water plus a modest health education programme did not result in a significant difference in trachoma or ocular C. trachomatis infection in endemic communities in Niger. A more substantial health education intervention is likely necessary to produce change.