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Infectious keratitis is a leading cause of corneal blindness worldwide with little information known about causative etiologies in Malawi, Africa. This area is resource-limited with ophthalmologist and microbiology services. The Department of Ophthalmology at the Kamuzu College of Health Sciences in Blantyre, Malawi, is a participating site of an international corneal ulcer consortium, capriCORN (Comprehensive Analysis of Pathogens, Resistomes, and Inflammatory-markers in the CORNea). In this study, 50 patients with corneal ulcers were swabbed for pathogen identification using RNA-sequencing. Corneal trauma was reported in 41% and 19% of the patients worked in agriculture. A pathogen was identified in 58% of the cases. Fungal pathogens predominated, followed by viruses and bacteria. Aspergillus, Fusarium, HSV-1, and Gardnerella were the most common pathogens detected. 50% of patients reported treatment with an antibiotic before presentation. Pathogens unusual for infectious keratitis, such as Subramaniula asteroids, Aureobasidium pullulans, and Gardnerella vaginalis, were also detected.

ImportanceRepeated mass distribution of azithromycin has been shown to reduce childhood mortality by 14% in sub-Saharan Africa. However, the estimated effect varied by location, suggesting that the intervention may not be effective in different geographical areas, time periods, or conditions.ObjectiveTo evaluate the efficacy of twice-yearly azithromycin to reduce mortality in children in the presence of seasonal malaria chemoprevention.Design, setting, and participantsThis cluster randomized placebo-controlled trial evaluating the efficacy of single-dose azithromycin for prevention of all-cause childhood mortality included 341 communities in the Nouna district in rural northwestern Burkina Faso. Participants were children aged 1 to 59 months living in the study communities.InterventionsCommunities were randomized in a 1:1 ratio to receive oral azithromycin or placebo distribution. Children aged 1 to 59 months were offered single-dose treatment twice yearly for 3 years (6 distributions) from August 2019 to February 2023.Main outcomes and measuresThe primary outcome was all-cause childhood mortality, measured during a twice-yearly enumerative census.ResultsA total of 34 399 children (mean [SD] age, 25.2 [18] months) in the azithromycin group and 33 847 children (mean [SD] age, 25.6 [18] months) in the placebo group were included. A mean (SD) of 90.1% (16.0%) of the censused children received the scheduled study drug in the azithromycin group and 89.8% (17.1%) received the scheduled study drug in the placebo group. In the azithromycin group, 498 deaths were recorded over 60 592 person-years (8.2 deaths/1000 person-years). In the placebo group, 588 deaths were recorded over 58 547 person-years (10.0 deaths/1000 person-years). The incidence rate ratio for mortality was 0.82 (95% CI, 0.67-1.02; P = .07) in the azithromycin group compared with the placebo group. The incidence rate ratio was 0.99 (95% CI, 0.72-1.36) in those aged 1 to 11 months, 0.92 (95% CI, 0.67-1.27) in those aged 12 to 23 months, and 0.73 (95% CI, 0.57-0.94) in those aged 24 to 59 months.Conclusions and relevanceMortality in children (aged 1-59 months) was lower with biannual mass azithromycin distribution in a setting in which seasonal malaria chemoprevention was also being distributed, but the difference was not statistically significant. The study may have been underpowered to detect a clinically relevant difference.Trial registrationClinicalTrials.gov Identifier: NCT03676764.

Trachoma, caused by ocular Chlamydia trachomatis infection, is targeted for global elimination as a public health problem by 2030. To provide evidence for use of antibodies to monitor C. trachomatis transmission, we collated IgG responses to Pgp3 antigen, PCR positivity, and clinical observations from 19,811 children aged 1-9 years in 14 populations. We demonstrate that age-seroprevalence curves consistently shift along a gradient of transmission intensity: rising steeply in populations with high levels of infection and active trachoma and becoming flat in populations near elimination. Seroprevalence (range: 0-54%) and seroconversion rates (range: 0-15 per 100 person-years) correlate with PCR prevalence (r: 0.87, 95% CI: 0.57, 0.97). A seroprevalence threshold of 13.5% (seroconversion rate 2.75 per 100 person-years) identifies clusters with any PCR-identified infection at high sensitivity ( >90%) and moderate specificity (69-75%). Antibody responses in young children provide a robust, generalizable approach to monitor population progress toward and beyond trachoma elimination.

Observational studies have linked early-life antibiotic exposure to increased risk of obesity in children in high income settings. We evaluated whether neonatal antibiotic exposure led to changes in infant growth at 6 months of age in Burkina Faso. Neonates aged 8 to 27 days of age who weighed at least 2,500 g at the time of enrollment were randomized in a 1:1 fashion to a single oral 20-mg/kg dose of azithromycin or equivalent volume of placebo from April 2019 through December 2020. Weight, length, and mid-upper-arm circumference (MUAC) were measured at baseline and 6 months of age. Growth outcomes, including weight gain in grams per day, length change in millimeters per day, and changes in weight-for-age Z-score (WAZ), weight-for-length Z-score (WLZ), length-for-age Z-score (LAZ), and MUAC were compared among neonates randomized to azithromycin compared with placebo. Among 21,832 neonates enrolled in the trial, median age at enrollment was 11 days, and 50% were female. We found no evidence of a difference in weight gain (mean difference -0.009 g/day, 95% confidence interval [CI]: -0.16 to 0.14, P = 0.90), length change (mean difference 0.003 mm/day, 95% CI: -0.002 to 0.007, P = 0.23), or WAZ (mean difference -0.005 SD, 95% CI: -0.03 to 0.02, P = 0.72), WLZ (mean difference -0.01 SD, 95% CI: -0.05 to 0.02, P = 0.39), LAZ (mean difference 0.01, 95% CI: -0.02 to 0.04, P = 0.47), or MUAC (mean difference 0.01 cm, 95% CI: -0.02 to 0.04, P = 0.49). These results do not suggest that azithromycin has growth-promoting properties in infants when administered during the neonatal period. Trial registration: ClinicalTrials.gov NCT03682653.

BackgroundMaternal age is increasingly recognized as a predictor of birth outcomes. Given the importance of birth and growth outcomes for children's development, wellbeing and survival, this study examined the effect of maternal age on infant birth and growth outcomes at 6 months and mortality. Additionally, we conducted quantitative bias analysis (QBA) to estimate the role of selection bias and unmeasured confounding on the effect of maternal age on infant mortality.MethodsWe used data from randomized-controlled trials (RCTs) of 21 555 neonates in Burkina Faso conducted in 2019-2020. Newborns of mothers aged 13-19 years (adolescents) and 20-40 years (adults) were enrolled in the study 8-27 days after birth and followed for 6 months. Measurements of child's anthropometric measures were collected at baseline and 6 months. We used multivariable linear regression to compare child anthropometric measures at birth and 6 months, and logistic regression models to obtain the odds ratio (OR) of all-cause mortality. Using multidimensional deterministic analysis, we assessed scenarios in which the difference in selection probability of adolescent and adult mothers with infant mortality at 6 months increased from 0% to 5%, 10%, 15% and 20% if babies born to adolescent mothers more often died during the first week or were of lower weight and hence were not eligible to be included in the original RCT. Using probabilistic bias analysis, we assessed the role of unmeasured confounding by socio-economic status (SES).ResultsBabies born to adolescent mothers on average had lower weight at birth, lower anthropometric measures at baseline, similar growth outcomes from enrolment to 6 months and higher odds of all-cause mortality by 6 months (adjusted OR = 2.17, 95% CI 1.35 to 3.47) compared with those born to adult mothers. In QBA, we found that differential selection of adolescent and adult mothers could bias the observed effect (OR = 2.24, 95% CI 1.41 to 3.57) towards the null [bias-corrected OR range: 2.37 (95% CI 1.49 to 3.77) to 2.84 (95% CI 1.79 to 4.52)], whereas unmeasured confounding by SES could bias the observed effect away from the null (bias-corrected OR: 2.06, 95% CI 1.31 to 2.64).ConclusionsOur findings suggest that delaying the first birth from adolescence to adulthood may improve birth outcomes and reduce mortality of neonates. Babies born to younger mothers, who are smaller at birth, may experience catch-up growth, reducing some of the anthropometric disparities by 6 months of age.

BackgroundMass administration of azithromycin is an established strategy for decreasing the prevalence of trachoma in endemic areas. However, nearby untreated communities could serve as a reservoir that may increase the chances of chlamydia reinfection in treated communities.MethodsAs part of a cluster-randomized trial in Ethiopia, 60 communities were randomized to receive mass azithromycin distributions and 12 communities were randomized to no treatments until after the first year. Ocular chlamydia was assessed from a random sample of children per community at baseline and month 12. Distances between treated and untreated communities were assessed from global positioning system coordinates collected for the study.ResultsThe pretreatment prevalence of ocular chlamydia among 0 to 9 year olds was 43% (95% confidence interval [CI], 39%-47%), which decreased to 11% (95% CI, 9%-14%) at the 12-month visit. The posttreatment prevalence of chlamydia was significantly higher in communities that were closer to an untreated community after adjusting for baseline prevalence and the number of mass treatments during the year (odds ratio, 1.12 [95% CI, 1.03-1.22] for each 1 km closer to an untreated community).ConclusionsMass azithromycin distributions to wide, contiguous geographic areas may reduce the likelihood of continued ocular chlamydia infection in the setting of mass antibiotic treatments.

The relationship between malaria infection and malnutrition is complex. Using data from a randomized controlled trial of 450 children 0-5 years of age in Burkina Faso, we examined the effect of malaria infection on short-term changes in anthropometric measures, the effect of malnutrition on malaria infection, and whether age modified the effect of baseline anthropometric measures on malaria infection. Malaria infection, assessed by blood smear microscopy and weight, height, mid-upper arm circumference, height-for-age z-score, weight-for-age z-score, and weight-for-height z-score were measured at three time points: baseline, 2 weeks, and 6 months. We used generalized estimating equations adjusted for sex, age, breastfeeding, maternal education, and study treatment (azithromycin versus placebo) for all analyses. Interaction terms were used to assess effect modification by age. Among the 366 children with no malaria infection at baseline, 43 (11.6%) had malaria infection within 6 months. There were no important differences in anthropometric measures at 2 weeks and 6 months between those with and without malaria infection at baseline. There were no significant differences in prevalence of malaria infection by baseline anthropometric measures. Age (0-30 months versus 30-60 months) modified the effect of baseline weight and height on malaria infection. Among those aged 0-30 months, for each kilogram increase in weight, malaria infection increased by 27% (95% CI: 6-53%), and for each centimeter increase in height, it increased by 9% (95% CI: 1-17%), but there were no differences for those aged 30-60 months.

BackgroundSeasonal and epidemic conjunctivitis (pink eye) infections are highly contagious and impose a significant economic burden worldwide. Long-term visual impairment can occur.MethodsThis study used metagenomic deep sequencing to evaluate pathogens causing acute infectious conjunctivitis in Burkina Faso.ResultsWe found that pathogens causing conjunctivitis in Burkina Faso are diverse, with human adenoviruses responsible for a small fraction of the samples tested.ConclusionsThese results are unexpected and suggest the importance of regional surveillance.

BackgroundLow birthweight (birthweight

Mass azithromycin distribution reduces all-cause childhood mortality in some high-mortality settings in sub-Saharan Africa. Although the greatest benefits have been shown in children 1 to 5 months old living in areas with high mortality rates, no evidence of a benefit was found of neonatal azithromycin in a low-mortality setting on mortality at 6 months. We conducted a 1:1 randomized, placebo-controlled trial evaluating the effect of a single oral 20-mg/kg dose of azithromycin or matching placebo administered during the neonatal period on all-cause and cause-specific infant mortality at 12 months of age in five regions of Burkina Faso. Neonates were eligible if they were between the ages of 8 and 27 days and weighed at least 2,500 g at enrollment. Cause of death was determined via the WHO 2016 verbal autopsy tool. We compared all-cause and cause-specific mortality using binomial regression. Of 21,832 infants enrolled in the study, 116 died by 12 months of age. There was no significant difference in all-cause mortality between the azithromycin and placebo groups (azithromycin: 52 deaths, 0.5%; placebo, 64 deaths, 0.7%; hazard ratio, 0.81; 95% CI, 0.56-1.17; P = 0.30). There was no evidence of a difference in the distribution of causes of death (P = 0.40) and no significant difference in any specific cause of death between groups. Mortality rates were low at 12 months of age, and there was no evidence of an effect of neonatal azithromycin on all-cause or cause-specific mortality.

BackgroundViral conjunctivitis (pink eye) can be highly contagious and is of public health importance. There remains significant debate whether SARS-CoV-2 can present as a primary conjunctivitis. The aim of this study was to identify pathogens associated with outpatient infectious conjunctivitis during the COVID-19 Delta surge.MethodsThis prospective study was conducted in the spring and summer months of 2021. 106 patients with acute conjunctivitis who presented to the Aravind Eye Center in Madurai, India were included. One anterior nasal swab and one conjunctival swab of each eye were obtained for each enrolled patient. Samples were subsequently processed for unbiased metagenomic RNA deep sequencing (RNA-seq). Outcomes included clinical findings and codetection of other pathogens with SARS-CoV-2 in patients with conjunctivitis.ResultsAmong the 13 patients identified with human coronavirus RNA fragments in their swabs, 6 patients had SARS-CoV-2 infection, 5 patients had coinfections of SARS-CoV-2 and human adenovirus (HAdV), 1 patient had a coinfection with human coronavirus OC43 and HAdV, and 1 patient had a coinfection of Vittaforma corneae and SARS-CoV-2. 30% had bilateral disease and symptoms on presentation. Petechial hemorrhage was noted in 33% of patients with SARS-CoV-2 infection. No patients with SARS-CoV-2 or SARS-CoV-2 and HAdV infections had subepithelial infiltrates on presentation. All patients denied systemic symptoms.ConclusionsAmong the patients presented with conjunctivitis associated with human coronavirus infection, over 50% of the patients had co-infections with other circulating pathogens, suggesting the public-health importance of broad pathogen testing and surveillance in the outpatient conjunctivitis population.

BackgroundSeasonal outbreaks of infectious conjunctivitis remain a public health issue. Determination of outbreak etiologies in the context of a worldwide pandemic may provide useful information to guide public health strategies. The aim of this study was to identify pathogens associated with outpatient infectious conjunctivitis during the COVID-19 Delta surge.MethodsThis prospective study was conducted from April 2021 to September 2021. All outpatients presenting to the Aravind Eye Center (Madurai, India) with signs and symptoms consistent with acute infectious conjunctivitis were eligible. Three swabs were obtained from each participant: one from each conjunctiva and one from the anterior nares. Samples were processed for metagenomic RNA deep sequencing (RNA-seq).ResultsSamples from 106 study participants were sequenced. The most common presenting symptoms were tearing (86%) and itching (71%). Preauricular lymphadenopathy was present in 38% of participants. 20% of participants had close contacts with similar symptoms. Systemic symptoms such as coughing, runny nose, vomiting or diarrhea were uncommonly reported. 60% of all participants used some medicated eye drops upon enrollment. 75% of study participants demonstrated infection with human adenovirus D (HAdV-D). 11% of conjunctivitis was associated with SARS-CoV-2. 15% had no definitive pathogen detected. 8% of all participants had codetection of more than one pathogen on RNA-seq.ConclusionsDuring the COVID-19 Delta surge in India, HAdV-D was the most common pathogen associated with infectious conjunctivitis. SARS-CoV-2 was the second most common associated pathogen. Seasonal surveillance may be necessary for the determination of emerging and reemerging pathogens responsible for infectious conjunctivitis.

BackgroundOcular rosacea is common and is often managed with long-term antibiotic treatment. Doxycycline is the most commonly selected antibiotic for the treatment of rosacea. As there is no established standard of care treatment dose for rosacea, prescribed doses of doxycycline vary widely. The FDA classifies 40 mg daily dose of doxycycline for ocular rosacea as sub-microbial in comparison to an antibiotic dose of 200 mg daily. However, this "sub-microbial" dose has never been evaluated in patients with ocular rosacea, and even the sub-microbial dose has potential to alter systemic mucosa flora. Here, we present a randomized controlled trial using RNA sequencing to fully characterize the impact of sub-microbial antibiotic dosing of doxycycline on antimicrobial resistance and bacterial composition of the ocular and gut flora.MethodsIn a triple-masked parallel randomized control trial, patients with ocular rosacea will be randomized to three arms: a 40-mg dose of doxycycline, a 200-mg antibiotic dose of doxycycline, or placebo. Collected rectal and lower eyelid samples will be compared for frequency of antimicrobial resistance genetic determinants and microbiome diversity. A subjective ocular surface disease index survey and objective tear breakup time measurement will be determined.DiscussionThese results will enhance our understanding of the overall systemic impact of long-term systemic sub-microbial antibiotic dosing for the treatment of chronic recurrent ocular inflammatory diseases.Trial registrationThis trial was registered on ClinicalTrials.org (NCT05296837) on March 22, 2022.

BackgroundTransmission by unreported cases has been proposed as a reason for the 2013-2016 Ebola virus (EBOV) epidemic decline in West Africa, but studies that test this hypothesis are lacking. We examined a transmission chain within social networks in Sukudu village to assess spread and transmission burnout.MethodsNetwork data were collected in 2 phases: (1) serological and contact information from Ebola cases (n = 48, including unreported); and (2) interviews (n = 148), including Ebola survivors (n = 13), to identify key social interactions. Social links to the transmission chain were used to calculate cumulative incidence proportion as the number of EBOV-infected people in the network divided by total network size.ResultsThe sample included 148 participants and 1522 contacts, comprising 10 social networks: 3 had strong links (>50% of cases) to the transmission chain: household sharing (largely kinship), leisure time, and talking about important things (both largely non-kin). Overall cumulative incidence for these networks was 37 of 311 (12%). Unreported cases did not have higher network centrality than reported cases.ConclusionsAlthough this study did not find evidence that explained epidemic decline in Sukudu, it excluded potential reasons (eg, unreported cases, herd immunity) and identified 3 social interactions in EBOV transmission.

BackgroundTo facilitate mass distribution of azithromycin, trachoma control programmes use height instead of weight to determine dose for children 6 months to 15 years old. WHO has recommended azithromycin distribution to children 1-11 months old to reduce mortality in high mortality settings under carefully monitored conditions. Weight was used to determine dose in children 1-5 months old in studies of azithromycin distribution for child survival, but a simplified approach using age or height for all aged 1-11 months old could increase programme efficiency in real-world settings.MethodsThis secondary analysis used data from two cluster randomised trials of azithromycin distribution for child mortality in Niger and Burkina Faso. An exhaustive search algorithm was developed to determine the optimal dose for different age groups, using tolerance limits of 10-20 mg/kg for children 1-2 months old and 15-30 mg/kg for children 3-11 months old. Height-based dosing was evaluated against the existing trachoma dosing pole and with a similar exhaustive search.ResultsThe optimal two-tiered age-based approach suggested a dose of 80 mg (2 mL) for children 1-2 months old and 160 mg (4 mL) for children 3-11 months old. Under this schedule, 89%-93% of children would have received doses within tolerance limits in both study populations. Accuracy was 93%-94% with a three-tiered approach, which resulted in doses of 80 mg (2 mL), 120 mg (3 mL) and 160 mg (4 mL) for children 1-2, 3-4 and 5-11 months old, respectively. For children 1-5 months old, the existing height pole would result in 70% of doses within tolerance limits. The optimisation identified height-based dosing options with 95% accuracy, although this would require changes to the existing dosing pole as well as additional training to measure infants lying flat.ConclusionsOverall, an age-based approach with two age tiers resulted in high accuracy while considering both concerns about overdosing in this young population and simplicity of field operations.

BackgroundRecurrent conjunctivitis epidemics are prevalent worldwide. Aetiologies are often undetermined.MethodsWe surveyed conjunctivitis researchers about perceived trends in prevalence, incidence and aetiologies of conjunctivitis epidemics.ResultsOf the 155 participants, 7% endorsed globally variable and dynamic microbial aetiologies of conjunctivitis epidemics. Increased incidence of conjunctivitis epidemics over the last decade were reported by 21% of respondents. Peak seasons differed between the northern and southern hemispheres.ConclusionsThere is regional equipoise regarding the increasing incidence and emerging underlying aetiologies of epidemic conjunctivitis. Further investigation of global surveillance and microbial characterization of conjunctivitis outbreaks could improve prevention and outcomes.

We analyzed samples obtained at baseline and 24 months in a mass azithromycin administration trial in Niger using quantitative polymerase chain reaction. In villages randomized to azithromycin, Shigella was the only pathogen reduced at 24 months (prevalence ratio, 0.36 [95% confidence interval: .17-.79]; difference in log quantity, -.42 [-.75 to -.10]).

PurposeDevelop computer vision models for image-based differentiation of bacterial and fungal corneal ulcers and compare their performance against human experts.DesignCross-sectional comparison of diagnostic performance.ParticipantsPatients with acute, culture-proven bacterial or fungal keratitis from 4 centers in South India.MethodsFive convolutional neural networks (CNNs) were trained using images from handheld cameras collected from patients with culture-proven corneal ulcers in South India recruited as part of clinical trials conducted between 2006 and 2015. Their performance was evaluated on 2 hold-out test sets (1 single center and 1 multicenter) from South India. Twelve local expert cornea specialists performed remote interpretation of the images in the multicenter test set to enable direct comparison against CNN performance.Main outcome measuresArea under the receiver operating characteristic curve (AUC) individually and for each group collectively (i.e., CNN ensemble and human ensemble).ResultsThe best-performing CNN architecture was MobileNet, which attained an AUC of 0.86 on the single-center test set (other CNNs range, 0.68-0.84) and 0.83 on the multicenter test set (other CNNs range, 0.75-0.83). Expert human AUCs on the multicenter test set ranged from 0.42 to 0.79. The CNN ensemble achieved a statistically significantly higher AUC (0.84) than the human ensemble (0.76; P < 0.01). CNNs showed relatively higher accuracy for fungal (81%) versus bacterial (75%) ulcers, whereas humans showed relatively higher accuracy for bacterial (88%) versus fungal (56%) ulcers. An ensemble of the best-performing CNN and best-performing human achieved the highest AUC of 0.87, although this was not statistically significantly higher than the best CNN (0.83; P = 0.17) or best human (0.79; P = 0.09).ConclusionsComputer vision models achieved superhuman performance in identifying the underlying infectious cause of corneal ulcers compared with cornea specialists. The best-performing model, MobileNet, attained an AUC of 0.83 to 0.86 without any additional clinical or historical information. These findings suggest the potential for future implementation of these models to enable earlier directed antimicrobial therapy in the management of infectious keratitis, which may improve visual outcomes. Additional studies are ongoing to incorporate clinical history and expert opinion into predictive models.

BackgroundBiannual mass azithromycin administration reduces all-cause childhood mortality in some sub-Saharan African settings, with the largest effects in children aged 1-5 months. Azithromycin has not been distributed to children

Trachoma is an infectious disease characterized by repeated exposures to Chlamydia trachomatis (Ct) that may ultimately lead to blindness. Efficient identification of communities with high infection burden could help target more intensive control efforts. We hypothesized that IgG seroprevalence in combination with geospatial layers, machine learning, and model-based geostatistics would be able to accurately predict future community-level ocular Ct infections detected by PCR. We used measurements from 40 communities in the hyperendemic Amhara region of Ethiopia to assess this hypothesis. Median Ct infection prevalence among children 0-5 years old increased from 6% at enrollment, in the context of recent mass drug administration (MDA), to 29% by month 36, following three years without MDA. At baseline, correlation between seroprevalence and Ct infection was stronger among children 0-5 years old (ρ = 0.77) than children 6-9 years old (ρ = 0.48), and stronger than the correlation between active trachoma and Ct infection (0-5y ρ = 0.56; 6-9y ρ = 0.40). Seroprevalence was the strongest concurrent predictor of infection prevalence at month 36 among children 0-5 years old (cross-validated R2 = 0.75, 95% CI: 0.58-0.85), though predictive performance declined substantially with increasing temporal lag between predictor and outcome measurements. Geospatial variables, a spatial Gaussian process, and stacked ensemble machine learning did not meaningfully improve predictions. Serological markers among children 0-5 years old may be an objective tool for identifying communities with high levels of ocular Ct infections, but accurate, future prediction in the context of changing transmission remains an open challenge.

BackgroundAzithromycin is a broad-spectrum antibiotic that has moderate antimalarial activity and has been shown to reduce all-cause mortality when biannually administered to children under five in high mortality settings in sub-Saharan Africa. One potential mechanism for this observed reduction in mortality is via a reduction in malaria transmission.MethodsWe evaluated whether a single oral dose of azithromycin reduces malaria positivity by rapid diagnostic test (RDT). We conducted an individually randomized placebo-controlled trial in Burkina Faso during the high malaria transmission season in August 2020. Children aged 8 days to 59 months old were randomized to a single oral dose of azithromycin (20 mg/kg) or matching placebo. At baseline and 14 days following treatment, we administered a rapid diagnostic test (RDT) to detect Plasmodium falciparum and measured tympanic temperature for all children. Caregiver-reported adverse events and clinic visits were recorded at the day 14 visit.ResultsWe enrolled 449 children with 221 randomized to azithromycin and 228 to placebo. The median age was 32 months and 48% were female. A total of 8% of children had a positive RDT for malaria at baseline and 11% had a fever (tympanic temperature ≥ 37.5 °C). In the azithromycin arm, 8% of children had a positive RDT for malaria at 14 days compared to 7% in the placebo arm (P = 0.65). Fifteen percent of children in the azithromycin arm had a fever ≥ 37.5 °C compared to 21% in the placebo arm (P = 0.12). Caregivers of children in the azithromycin group had lower odds of reporting fever as an adverse event compared to children in the placebo group (OR 0.41, 95% CI 0.18-0.96, P = 0.04). Caregiver-reported clinic visits were uncommon, and there were no observed differences between arms (P = 0.32).ConclusionsWe did not find evidence that a single oral dose of azithromycin reduced malaria positivity during the high transmission season. Caregiver-reported fever occurred less often in children receiving azithromycin compared to placebo, indicating that azithromycin may have some effect on non-malarial infections. Trial registration Clinicaltrials.gov NCT04315272, registered 19/03/2020.

PurposeTo develop and evaluate an automated, portable algorithm to differentiate active corneal ulcers from healed scars using only external photographs.DesignA convolutional neural network was trained and tested using photographs of corneal ulcers and scars.ParticipantsDe-identified photographs of corneal ulcers were obtained from the Steroids for Corneal Ulcers Trial (SCUT), Mycotic Ulcer Treatment Trial (MUTT), and Byers Eye Institute at Stanford University.MethodsPhotographs of corneal ulcers (n = 1313) and scars (n = 1132) from the SCUT and MUTT were used to train a convolutional neural network (CNN). The CNN was tested on 2 different patient populations from eye clinics in India (n = 200) and the Byers Eye Institute at Stanford University (n = 101). Accuracy was evaluated against gold standard clinical classifications. Feature importances for the trained model were visualized using gradient-weighted class activation mapping.Main outcome measuresAccuracy of the CNN was assessed via F1 score. The area under the receiver operating characteristic (ROC) curve (AUC) was used to measure the precision-recall trade-off.ResultsThe CNN correctly classified 115 of 123 active ulcers and 65 of 77 scars in patients with corneal ulcer from India (F1 score, 92.0% [95% confidence interval (CI), 88.2%-95.8%]; sensitivity, 93.5% [95% CI, 89.1%-97.9%]; specificity, 84.42% [95% CI, 79.42%-89.42%]; ROC: AUC, 0.9731). The CNN correctly classified 43 of 55 active ulcers and 42 of 46 scars in patients with corneal ulcers from Northern California (F1 score, 84.3% [95% CI, 77.2%-91.4%]; sensitivity, 78.2% [95% CI, 67.3%-89.1%]; specificity, 91.3% [95% CI, 85.8%-96.8%]; ROC: AUC, 0.9474). The CNN visualizations correlated with clinically relevant features such as corneal infiltrate, hypopyon, and conjunctival injection.ConclusionsThe CNN classified corneal ulcers and scars with high accuracy and generalized to patient populations outside of its training data. The CNN focused on clinically relevant features when it made a diagnosis. The CNN demonstrated potential as an inexpensive diagnostic approach that may aid triage in communities with limited access to eye care.

PurposeThe purpose of this article was to evaluate the impact of sample collection order on the diagnostic yield of metagenomic deep sequencing (MDS) for determining the causative pathogen in infectious keratitis.MethodsWe performed a cross-sectional diagnostic test evaluation among subjects with infectious keratitis at Aravind Eye Hospital in Madurai, India. All subjects underwent corneal scrapings of the affected eye to obtain potassium hydroxide smear, Gram stain, bacterial culture, and fungal culture, in this order. The order of MDS specimen collection relative to smear and culture samples was randomized and served as the primary predictor. Outcomes included the normalized copy number of pathogenic RNA detected by MDS, the proportion of MDS samples that were diagnostic, and the agreement of MDS results with cultures.ResultsMDS samples from 46 subjects with corneal ulcers were evaluated. MDS was positive in 33 subjects (76%) and had 74% overall agreement with culture results. There was no association between order of MDS sample collection and normalized copy number of genetic material detected (P = 0.62) or the likelihood of MDS positivity (P = 0.46). However, the likelihood of agreement between MDS and cultures decreased when MDS corneal swabs were collected after other diagnostic corneal scrapings (P = 0.05).ConclusionsThe overall yield of MDS for detecting the cause of infectious keratitis was not affected by sample collection order. However, diagnostic agreement between MDS and cultures decreased when MDS samples were collected after other specimens. Additional investigation is warranted to determine whether this represents increased sensitivity of MDS compared with cultures or higher susceptibility to contaminants.

BackgroundIn a prior study at the start of the pandemic, we reported reduced numbers of Google searches for the term "conjunctivitis" in the United States in March and April 2020 compared with prior years. As one explanation, we conjectured that reduced information-seeking may have resulted from social distancing reducing contagious conjunctivitis cases. Here, after 1 year of continued implementation of social distancing, we asked if there have been persistent reductions in searches for "conjunctivitis," and similarly for other communicable disease terms, compared to control terms.ObjectiveThe aim of this study was to determine if reduction in searches in the United States for terms related to conjunctivitis and other common communicable diseases occurred in the spring-winter season of the COVID-19 pandemic, and to compare this outcome to searches for terms representing noncommunicable conditions, COVID-19, and to seasonality.MethodsWeekly relative search frequency volume data from Google Trends for 68 search terms in English for the United States were obtained for the weeks of March 2011 through February 2021. Terms were classified a priori as 16 terms related to COVID-19, 29 terms representing communicable conditions, and 23 terms representing control noncommunicable conditions. To reduce bias, all analyses were performed while masked to term names, classifications, and locations. To test for the significance of changes during the pandemic, we detrended and compared postpandemic values to those expected based on prepandemic trends, per season, computing one- and two-sided P values. We then compared these P values between term groups using Wilcoxon rank-sum and Fisher exact tests to assess if non-COVID-19 terms representing communicable diseases were more likely to show significant reductions in searches in 2020-2021 than terms not representing such diseases. We also assessed any relationship between a term's seasonality and a reduced search trend for the term in 2020-2021 seasons. P values were subjected to false discovery rate correction prior to reporting. Data were then unmasked.ResultsTerms representing conjunctivitis and other communicable conditions showed a sustained reduced search trend in the first 4 seasons of the 2020-2021 COVID-19 pandemic compared to prior years. In comparison, the search for noncommunicable condition terms was significantly less reduced (Wilcoxon and Fisher exact tests, P

BackgroundThe chlamydial major outer membrane protein, encoded by the ompA gene, is a primary target for chlamydial vaccine research. However, human studies of ompA-specific immunity are limited, and prior studies have been limited in differentiating re-infection from persistent infection. The purpose of this study was to assess whether children living in trachoma-endemic communities with re-infections of ocular chlamydia were more likely to be infected with a different or similar genovar.Methodology and findingsThe study included 21 communities from a trachoma-hyperendemic area of Ethiopia that had been treated with a mass azithromycin distribution for trachoma. Conjunctival swabbing was offered to all children younger than 5 years of age at baseline (i.e., pre-treatment), and then at follow-up visits 2 and 6 months later. Swabs were subjected to polymerase chain reaction (PCR) to detect C. trachomatis. A random sample of 359 PCR-positive swabs, stratified by study visit and study community, was chosen for ompA sequencing. In addition, ompA sequencing was performed on all swabs of 24 children who experienced chlamydial re-infection (i.e., positive chlamydial test before treatment, negative test 2 months following mass distribution of azithromycin, and again a positive test 6 months post-treatment). ompA sequencing was successful for 351 of 359 swabs of the random sample and 44 of 48 swabs of the re-infection sample. In the random sample, ompA types clustered within households more than would be expected by chance. Among the 21 re-infected children with complete ompA data, 14 had the same ompA type before and after treatment.ConclusionThe high frequency of ompA concordance suggests incomplete genovar-specific protective immunity and the need for multiple antigens as vaccine targets.

The MORDOR trial in Niger, Malawi, and Tanzania found that biannual mass distribution of azithromycin to children younger than 5 years led to a 13.5% reduction in all-cause mortality (NCT02048007). To help elucidate the mechanism for mortality reduction, we report IgG responses to 11 malaria, bacterial, and protozoan pathogens using a multiplex bead assay in pre-specified substudy of 30 communities in the rural Niger placebo-controlled trial over a three-year period (n = 5642 blood specimens, n = 3814 children ages 1-59 months). Mass azithromycin reduces Campylobacter spp. force of infection by 29% (hazard ratio = 0.71, 95% CI: 0.56, 0.89; P = 0.004) but serological measures show no significant differences between groups for other pathogens against a backdrop of high transmission. Results align with a recent microbiome study in the communities. Given significant sequelae of Campylobacter infection among preschool aged children, our results support an important mechanism through which biannual mass distribution of azithromycin likely reduces mortality in Niger.

BackgroundWHO promotes the SAFE strategy for the elimination of trachoma as a public health programme, which promotes surgery for trichiasis (ie, the S component), antibiotics to clear the ocular strains of chlamydia that cause trachoma (the A component), facial cleanliness to prevent transmission of secretions (the F component), and environmental improvements to provide water for washing and sanitation facilities (the E component). However, little evidence is available from randomised trials to support the efficacy of interventions targeting the F and E components of the strategy. We aimed to determine whether an integrated water, sanitation, and hygiene (WASH) intervention prevents the transmission of trachoma.MethodsThe WASH Upgrades for Health in Amhara (WUHA) was a two-arm, parallel-group, cluster-randomised trial in 40 rural communities in Wag Hemra Zone (Amhara Region, Ethiopia) that had been treated with 7 years of annual mass azithromycin distributions. The randomisation unit was the school catchment area. All households within a 1·5 km radius of a potential water point within the catchment area (as determined by the investigators) were eligible for inclusion. Clusters were randomly assigned (at a 1:1 ratio) to receive a WASH intervention either immediately (intervention) or delayed until the conclusion of the trial (control), in the absence of concurrent antibiotic distributions. Given the nature of the intervention, participants and field workers could not be masked, but laboratory personnel were masked to treatment allocation. The WASH intervention consisted of both hygiene infrastructure improvements (namely, construction of a community water point) and hygiene promotion by government, school, and community leaders, which were implemented at the household, school, and community levels. Hygiene promotion focused on two simple messages: to use soap and water to wash your or your child's face, and to always use a latrine for defecation. The primary outcome was the cluster-level prevalence of ocular chlamydia, measured annually using conjunctival swabs in a random sample of children aged 0-5 years from each cluster at 12, 24, and 36 month timepoints. Analyses were done in an intention-to-treat manner. This trial is ongoing and is registered at ClinicalTrials.gov, NCT02754583.FindingsBetween Nov 9, 2015, and March 5, 2019, 40 of 44 clusters assessed for eligibility were enrolled and randomly allocated to the trial groups (20 clusters each, with 7636 people from 1751 households in the intervention group and 9821 people from 2211 households in the control group at baseline). At baseline, ocular chlamydia prevalence among children aged 0-5 years was 11% (95% CI 6 to 16) in the WASH group and 11% (5 to 18) in the control group. At month 36, ocular chlamydia prevalence had increased in both groups, to 32% (24 to 41) in the WASH group and 31% (21 to 41) in the control group (risk difference across three annual monitoring visits, after adjustment for prevalence at baseline: 3·7 percentage points; 95% CI -4·9 to 12·4; p=0·40). No adverse events were reported in either group.InterpretationAn integrated WASH intervention addressing the F and E components of the SAFE strategy did not prevent an increase in prevalence of ocular chlamydia following cessation of antibiotics in an area with hyperendemic trachoma. The impact of WASH in the presence of annual mass azithromycin distributions is currently being studied in a follow-up trial of the 40 study clusters. Continued antibiotic distributions will probably be important in areas with persistent trachoma.FundingNational Institutes of Health-National Eye Institute.TranslationFor the Amharic translation of the abstract see Supplementary Materials section.

BackgroundAzithromycin has recently been shown to reduce all-cause childhood mortality in sub-Saharan Africa. One potential mechanism of this effect is via the anti-malarial effect of azithromycin, which may help treat or prevent malaria infection. This study evaluated short- and longer-term effects of azithromycin on malaria outcomes in children.MethodsChildren aged 8 days to 59 months were randomized in a 1:1 fashion to a single oral dose of azithromycin (20 mg/kg) or matching placebo. Children were evaluated for malaria via thin and thick smear and rapid diagnostic test (for those with tympanic temperature ≥ 37.5 °C) at baseline and 14 days and 6 months after treatment. Malaria outcomes in children receiving azithromycin versus placebo were compared at each follow-up timepoint separately.ResultsOf 450 children enrolled, 230 were randomized to azithromycin and 220 to placebo. Children were a median of 26 months and 51% were female, and 17% were positive for malaria parasitaemia at baseline. There was no evidence of a difference in malaria parasitaemia at 14 days or 6 months after treatment. In the azithromycin arm, 20% of children were positive for parasitaemia at 14 days compared to 17% in the placebo arm (P = 0.43) and 7.6% vs. 5.6% in the azithromycin compared to placebo arms at 6 months (P = 0.47).ConclusionsAzithromycin did not affect malaria outcomes in this study, possibly due to the individually randomized nature of the trial. Trial registration This study is registered at clinicaltrials.gov (NCT03676751; registered 19 September 2018).

BackgroundThe World Health Organization (WHO) recommends annual mass azithromycin distribution until districts drop below 5% prevalence of trachomatous inflammation-follicular (TF). Districts with very low TF prevalence may have little or no transmission of the ocular strains of Chlamydia trachomatis that cause trachoma, and additional rounds of mass azithromycin distribution may not be useful. Here, we describe the protocol for a randomized controlled trial designed to evaluate whether mass azithromycin distribution can be stopped prior to the current WHO guidelines.MethodsThe Azithromycin Reduction to Reach Elimination of Trachoma (ARRET) study is a 1:1 community randomized non-inferiority trial designed to evaluate whether mass azithromycin distribution can be stopped in districts with baseline prevalence of TF under 20%. Communities in Maradi, Niger are randomized after baseline assessment either to continued annual mass azithromycin distribution or stopping annual azithromycin distribution over a 3-year period. We will compare the prevalence of ocular C. trachomatis (primary outcome), TF and other clinical signs of trachoma, and serologic markers of trachoma after 3 years. We hypothesize that stopping annual azithromycin distribution will be non-inferior to continued annual azithromycin distributions for all markers of trachoma prevalence and transmission.DiscussionThe results of this trial are anticipated to provide potentially guideline-changing evidence for when mass azithromycin distributions can be stopped in low TF prevalence areas. TRIAL REGISTRATION NUMBER: This study is registered at clinicaltrials.gov ( NCT04185402 ). Registered December 4, 2019; prospectively registered pre-results.

BackgroundLow birthweight is a major contributor to infant mortality. We evaluated the association between antenatal care (ANC) attendance and low birthweight among newborns in 5 regions of Burkina Faso.MethodsWe utilized data from the baseline assessment of a randomized controlled trial evaluating azithromycin distribution during the neonatal period for prevention of infant mortality. Neonates were eligible for the trial if the weighed at least 2500 g at enrollment and were 8-27 days of age. Data on ANC attendance and birthweight was extracted from each child's carnet de santé, a government-issued health card on which pregnancy and birth-related data are recorded. We used linear and logistic regression models adjusting for potentially confounding variables to evaluate the relationship between ANC attendance (as total number of visits and ≥ 4 antenatal care visits) and birthweight (continuously and categorized into

ObjectiveTo determine whether a water, sanitation and hygiene intervention could change hygiene behaviours thought to be important for trachoma control.MethodsWe conducted a cluster-randomized trial in rural Ethiopia from 9 November 2015 to 5 March 2019. We randomized 20 clusters to an intervention consisting of water and sanitation infrastructure and hygiene promotion and 20 clusters to no intervention. All intervention clusters received a primary-school hygiene curriculum, community water point, household wash station, household soap and home visits from hygiene promotion workers. We assessed intervention fidelity through annual household surveys.FindingsOver the 3 years, more wash stations, soap and latrines were seen at households in the intervention clusters than the control clusters: risk difference 47 percentage points (95% confidence interval, CI: 41-53) for wash stations, 18 percentage points (95% CI: 12-24) for soap and 12 percentage points (95% CI: 5-19) for latrines. A greater proportion of people in intervention clusters reported washing their faces with soap (e.g. risk difference 21 percentage points; 95% CI: 15-27 for 0-5 year-old children) and using a latrine (e.g. risk difference 9 percentage points; 95% CI: 2-15 for 6-9 year-old children). Differences between the intervention and control arms were not statistically significant for many indicators until the programme had been implemented for at least a year; they did not decline during later study visits.ConclusionThe community- and school-based intervention was associated with improved hygiene access and behaviours, although changes in behaviour were slow and required several years of the intervention.

Of 61 355 visits by children

BackgroundCurrent guidelines recommend community-wide mass azithromycin for trachoma, but a targeted treatment strategy could reduce the volume of antibiotics required.MethodsIn total, 48 Ethiopian communities were randomized to mass, targeted, or delayed azithromycin distributions. In the targeted arm, only children aged 6 months to 5 years with evidence of ocular chlamydia received azithromycin, distributed thrice over the following year. The primary outcome was ocular chlamydia at months 12 and 24, comparing the targeted and delayed arms (0-5 year-olds, superiority analysis) and the targeted and mass azithromycin arms (8-12 year-olds, noninferiority analysis, 10% noninferiority margin).ResultsAt baseline, the mean prevalence of ocular chlamydia in the 3 arms ranged from 7% to 9% among 0-5 year-olds and from 3% to 9% among 8-12 year-olds. Averaged across months 12-24, the mean prevalence of ocular chlamydia among 0-5 year-olds was 16.7% (95% confidence interval [CI]: 9.0%-24.4%) in the targeted arm and 22.3% (95% CI: 11.1%-33.6%) in the delayed arm (P = .61). The final mean prevalence of ocular chlamydia among 8-12 year-olds was 13.5% (95% CI: 7.9%-19.1%) in the targeted arm and 5.5% (95% CI: 0.3%-10.7%) in the mass treatment arm (adjusted risk difference 8.5 percentage points [pp] higher in the targeted arm, 95% CI: 0.9 pp-16.1 pp higher).ConclusionsAntibiotic treatments targeted to infected preschool children did not result in significantly less ocular chlamydia infections compared with untreated communities and did not meet noninferiority criteria relative to mass azithromycin distributions. Targeted approaches may require treatment of a broader segment of the population in areas with hyperendemic trachoma.

Background/aimsAlthough tremendous progress towards the 2020 goal of global elimination of trachoma as a public health problem has been made, it will not be achieved. Future targets are now being considered. One option is changing the goal to eradication. We surveyed trachoma experts to assess beliefs related to trachoma eradication and determine perceived obstacles to achieving it.MethodsWe conducted a survey at the beginning of a trachoma eradication session at the 2019 Coalition for Operational Research on Neglected Tropical Diseases meeting in National Harbor, Maryland, USA. We asked respondents what the most important goal of azithromycin mass drug administration was for trachoma (control, elimination of infection or eradication) and if and when they believed trachoma eradication would occur. We then asked what the biggest obstacles were to global eradication.ResultsFifty-six surveys were returned (95%). Most (91%) participants reported that the most important goal of azithromycin mass drug administration was control or elimination of infection, and 24% of participants reported that global eradication was not possible. Of the 76% who reported a year by which they believed trachoma could be eradicated, most fell between 2040 and 2050. Commonly cited barriers to global eradication included lack of surveillance tools to confirm eradication or monitor for infection recrudescence (32%) and lack of resources (23%).ConclusionsDevelopment of alternative indicators for trachoma surveillance and continued investment in trachoma programmes, particularly focused support in the most heavily affected populations, might increase enthusiasm for the feasibility of eradication.

BackgroundTremendous progress towards elimination of trachoma as a public health problem has been made. However, there are areas where the clinical indicator of disease, trachomatous inflammation-follicular (TF), remains prevalent. We quantify the progress that has been made, and forecast how TF prevalence will evolve with current interventions. We also determine the probability that a district is a transmission-hotspot based on its TF prevalence (ie, reproduction number greater than one).MethodsData on trachoma prevalence come from the GET2020 global repository organized by the World Health Organization and the International Trachoma Initiative. Forecasts of TF prevalence and the percent of districts with local control is achieved by regressing the coefficients of a fitted exponential distribution for the year-by-year distribution of TF prevalence. The probability of a district being a transmission-hotspot is extrapolated from the residuals of the regression.ResultsForecasts suggest that with current interventions, 96.5% of surveyed districts will have TF prevalence among children aged 1-9 years

Due to the COVID-19 pandemic, many key neglected tropical disease (NTD) activities have been postponed. This hindrance comes at a time when the NTDs are progressing towards their ambitious goals for 2030. Mathematical modelling on several NTDs, namely gambiense sleeping sickness, lymphatic filariasis, onchocerciasis, schistosomiasis, soil-transmitted helminthiases (STH), trachoma, and visceral leishmaniasis, shows that the impact of this disruption will vary across the diseases. Programs face a risk of resurgence, which will be fastest in high-transmission areas. Furthermore, of the mass drug administration diseases, schistosomiasis, STH, and trachoma are likely to encounter faster resurgence. The case-finding diseases (gambiense sleeping sickness and visceral leishmaniasis) are likely to have fewer cases being detected but may face an increasing underlying rate of new infections. However, once programs are able to resume, there are ways to mitigate the impact and accelerate progress towards the 2030 goals.

PurposeTo critically evaluate the potential impact of the coronavirus disease (COVID-19) pandemic on global ophthalmology and VISION 2020.DesignPerspective supplemented with epidemiologic insights from available online databases.MethodsWe extracted data from the Global Vision Database (2017) and Global Burden of Disease Study (2017) to highlight temporal trends in global blindness since 1990, and provide a narrative overview of how COVID-19 may derail progress toward the goals of VISION 2020.ResultsOver 2 decades of VISION 2020 advocacy and program implementation have culminated in a universal reduction of combined age-standardized prevalence of moderate-to-severe vision impairment (MSVI) across all world regions since 1990. Between 1990 and 2017, low-income countries observed large reductions in the age-standardized prevalence per 100,000 persons of vitamin A deficiency (25,155 to 19,187), undercorrected refractive disorders (2,286 to 2,040), cataract (1,846 to 1,690), onchocerciasis (5,577 to 2,871), trachoma (506 to 159), and leprosy (36 to 26). Despite these reductions, crude projections suggest that more than 700 million persons will experience MSVI or blindness by 2050, principally owing to our growing and ageing global population.ConclusionsDespite the many resounding successes of VISION 2020, the burden of global blindness and vision impairment is set to reach historic levels in the coming years. The impact of COVID-19, while yet to be fully determined, now threatens the hard-fought gains of global ophthalmology. The postpandemic years will require renewed effort and focus on vision advocacy and expanding eye care services worldwide.

BackgroundBiannual distribution of azithromycin to children 1-59 months old reduced mortality by 14% in a cluster-randomized trial. The World Health Organization has proposed targeting this intervention to the subgroup of children 1-11 months old to reduce selection for antimicrobial resistance. Here, we describe a trial designed to determine the impact of age-based targeting of biannual azithromycin on mortality and antimicrobial resistance.MethodsAVENIR is a cluster-randomized, placebo-controlled, double-masked, response-adaptive large simple trial in Niger. During the 2.5-year study period, 3350 communities are targeted for enrollment. In the first year, communities in the Dosso region will be randomized 1:1:1 to 1) azithromycin 1-11: biannual azithromycin to children 1-11 months old with placebo to children 12-59 months old, 2) azithromycin 1-59: biannual azithromycin to children 1-59 months old, or 3) placebo: biannual placebo to children 1-59 months old. Regions enrolled after the first year will be randomized with an updated allocation based on the probability of mortality in children 1-59 months in each arm during the preceding study period. A biannual door-to-door census will be conducted to enumerate the population, distribute azithromycin and placebo, and monitor vital status. Primary mortality outcomes are defined as all-cause mortality rate (deaths per 1000 person-years) after 2.5 years from the first enrollment in 1) children 1-59 months old comparing the azithromycin 1-59 and placebo arms, 2) children 1-11 months old comparing the azithromycin 1-11 and placebo arm, and 3) children 12-59 months in the azithromycin 1-11 and azithromycin 1-59 arms. In the Dosso region, 50 communities from each arm will be followed to monitor antimicrobial resistance. Primary resistance outcomes will be assessed after 2 years of distributions and include 1) prevalence of genetic determinants of macrolide resistance in nasopharyngeal samples from children 1-59 months old, and 2) load of genetic determinants of macrolide resistance in rectal samples from children 1-59 months old.DiscussionAs high-mortality settings consider this intervention, the results of this trial will provide evidence to support programmatic and policy decision-making on age-based strategies for azithromycin distribution to promote child survival.Trial registrationThis trial was registered on January 13, 2020 (clinicaltrials.gov: NCT04224987 ).

BackgroundProgress towards elimination of trachoma as a public health problem has been substantial, but the coronavirus disease 2019 (COVID-19) pandemic has disrupted community-based control efforts.MethodsWe use a susceptible-infected model to estimate the impact of delayed distribution of azithromycin treatment on the prevalence of active trachoma.ResultsWe identify three distinct scenarios for geographic districts depending on whether the basic reproduction number and the treatment-associated reproduction number are above or below a value of 1. We find that when the basic reproduction number is 1, significant delays can occur. In most districts, 1 y of COVID-related delay can be mitigated by a single extra round of mass drug administration. However, supercritical districts require a new paradigm of infection control because the current strategies will not eliminate disease.ConclusionsIf the pandemic can motivate judicious, community-specific implementation of control strategies, global elimination of trachoma as a public health problem could be accelerated.

BackgroundThe COVID-19 pandemic has disrupted planned annual antibiotic mass drug administration (MDA) activities that have formed the cornerstone of the largely successful global efforts to eliminate trachoma as a public health problem.MethodsUsing a mathematical model we investigate the impact of interruption to MDA in trachoma-endemic settings. We evaluate potential measures to mitigate this impact and consider alternative strategies for accelerating progress in those areas where the trachoma elimination targets may not be achievable otherwise.ResultsWe demonstrate that for districts that were hyperendemic at baseline, or where the trachoma elimination thresholds have not already been achieved after three rounds of MDA, the interruption to planned MDA could lead to a delay to reaching elimination targets greater than the duration of interruption. We also show that an additional round of MDA in the year following MDA resumption could effectively mitigate this delay. For districts where the probability of elimination under annual MDA was already very low, we demonstrate that more intensive MDA schedules are needed to achieve agreed targets.ConclusionThrough appropriate use of additional MDA, the impact of COVID-19 in terms of delay to reaching trachoma elimination targets can be effectively mitigated. Additionally, more frequent MDA may accelerate progress towards 2030 goals.

BackgroundDelays in care-seeking for childhood illness may lead to more severe outcomes. We evaluated whether community distance from a primary healthcare facility was associated with decreased healthcare utilization in a rural district of northwestern Burkina Faso.MethodsWe conducted passive surveillance of all government-run primary healthcare facilities in Nouna District, Burkina Faso from March 1 through May 31, 2020. All healthcare visits for children under 5 years of age were recorded on a standardized form for sick children. We recorded the age, sex, and community of residence of the child as well as any diagnoses and treatments administered. We calculated healthcare utilization per 100 child-months by linking the aggregate number of visits at the community level to the community's population of children under 5 months per a census that was conducted from August 2019 through February 2020. We calculated the distance between each community and its corresponding healthcare facility and assessed the relationship between distance and the rate of healthcare utilization.ResultsIn 226 study communities, 12,676 primary healthcare visits were recorded over the three-month period. The median distance between the community and primary healthcare facility was 5.0 km (IQR 2.6 to 6.9 km), and median number of healthcare visits per 100 child-months at the community level was 6.7 (IQR 3.7 to 12.3). The rate of primary healthcare visits declined with increasing distance from clinic (Spearman's rho - 0.42, 95% CI - 0.54 to - 0.31, P

IntroductionFacial hygiene promotion and environmental improvements are central components of the global trachoma elimination strategy despite a lack of experimental evidence supporting the effectiveness of water, sanitation and hygiene (WASH) measures for reducing trachoma transmission. The objective of the WUHA (WASH Upgrades for Health in Amhara) trial is to evaluate if a comprehensive water improvement and hygiene education programme reduces the prevalence of ocular chlamydia infection in rural Africa.Methods and analysisForty study clusters, each of which had received at least annual mass azithromycin distributions for the 7 years prior to the start of the study, are randomised in a 1:1 ratio to the WASH intervention arm or a delayed WASH arm. The WASH package includes a community water point, community-based hygiene promotion workers, household wash stations, household WASH education books, household soap distribution and a primary school hygiene curriculum. Educational activities emphasise face-washing and latrine use. Mass antibiotic distributions are not provided during the first 3 years but are provided annually over the final 4 years of the trial. Annual monitoring visits are conducted in each community. The primary outcome is PCR evidence of ocular chlamydia infection among children aged 0-5 years, measured in a separate random sample of children annually over 7 years. A secondary outcome is improvement of the clinical signs of trachoma between the baseline and final study visits as assessed by conjunctival photography. Laboratory workers and photo-graders are masked to treatment allocation.Ethics and disseminationStudy protocols have been approved by human subjects review boards at the University of California, San Francisco, Emory University, the Ethiopian Food and Drug Authority, and the Ethiopian Ministry of Innovation and Technology. A data safety and monitoring committee oversees the trial. Results will be disseminated through peer-reviewed publications and presentations.Trial registration number(http://www.clinicaltrials.gov): NCT02754583; Pre-results.

Locally tailored interventions for neglected tropical diseases (NTDs) are becoming increasingly important for ensuring that the World Health Organization (WHO) goals for control and elimination are reached. Mathematical models, such as those developed by the NTD Modelling Consortium, are able to offer recommendations on interventions but remain constrained by the data currently available. Data collection for NTDs needs to be strengthened as better data are required to indirectly inform transmission in an area. Addressing specific data needs will improve our modelling recommendations, enabling more accurate tailoring of interventions and assessment of their progress. In this collection, we discuss the data needs for several NTDs, specifically gambiense human African trypanosomiasis, lymphatic filariasis, onchocerciasis, schistosomiasis, soil-transmitted helminths (STH), trachoma, and visceral leishmaniasis. Similarities in the data needs for these NTDs highlight the potential for integration across these diseases and where possible, a wider spectrum of diseases.

The World Health Organization (WHO) recommends continuing azithromycin mass drug administration (MDA) for trachoma until endemic regions drop below 5% prevalence of active trachoma in children aged 1-9 years. Azithromycin targets the ocular strains of Chlamydia trachomatis that cause trachoma. Regions with low prevalence of active trachoma may have little if any ocular chlamydia, and, thus, may not benefit from azithromycin treatment. Understanding what happens to active trachoma and ocular chlamydia prevalence after stopping azithromycin MDA may improve future treatment decisions. We systematically reviewed published evidence for community prevalence of both active trachoma and ocular chlamydia after cessation of azithromycin distribution. We searched electronic databases for all peer-reviewed studies published before May 2020 that included at least 2 post-MDA surveillance surveys of ocular chlamydia and/or the active trachoma marker, trachomatous inflammation-follicular (TF) prevalence. We assessed trends in the prevalence of both indicators over time after stopping azithromycin MDA. Of 140 identified studies, 21 met inclusion criteria and were used for qualitative synthesis. Post-MDA, we found a gradual increase in ocular chlamydia infection prevalence over time, while TF prevalence generally gradually declined. Ocular chlamydia infection may be a better measurement tool compared to TF for detecting trachoma recrudescence in communities after stopping azithromycin MDA. These findings may guide future trachoma treatment and surveillance efforts.

The MORDOR study, a masked, community-level randomized clinical trial conducted in Niger, Malawi and Tanzania (2015 to 2017), showed that biannual administration of single-dose azithromycin to preschool children reduced all-cause mortality. We sought to evaluate its impact on causes of death in children aged 1-59 months in Tanzania. A random sampling of 614 communities was conducted in Kilosa District, Tanzania, with simple random assignment of communities to receive either azithromycin or placebo. In these communities, a census was carried out every 6 months and children aged 1-59 months received biannual (every 6 months), single-dose azithromycin (~20mg/kg) or placebo depending on community assignment, over a 2-year period. Mortality was determined at the time of the biannual census. For child deaths, a verbal autopsy was performed to ascertain the cause using a standardized diagnostic classification. A total of 190- (0.58 /100 person-years) and 200 deaths (0.59/100 person-years) were reported in the azithromycin and placebo arms, respectively. Malaria, pneumonia and diarrhea, accounted for 71% and 68% of deaths in the respective arms. Overall, the mortality was not different by treatment arm, nor were the distribution of causes of death after adjusting for community clustering. The cause-specific mortality for diarrhea/pneumonia was no different over time. In children aged 1-5 months, 32 deaths occurred in the placebo arm and 25 deaths occurred in the azithromycin arm; 20 (62.5%) deaths in the placebo- and 10 (40%) in the azithromycin arm were attributed to diarrhea or pneumonia. Neither differences in the number of deaths nor the diarrhea/pneumonia attribution was statistically significant after adjusting for community clustering. In conclusion, azithromycin was not associated with a significant decline in deaths by specific causes compared to placebo. The non-significant lower rates of diarrhea or pneumonia in children

Biannual mass azithromycin distribution reduces all-cause child mortality in some settings in sub-Saharan Africa; however, adverse events and short-term infectious outcomes following treatment have not been well characterized. Children aged 0-59 months were recruited in Nouna Town, Burkina Faso, and randomized 1:1 to a single directly observed oral 20 mg/kg dose of azithromycin or placebo. At 14 days after treatment, caregivers were interviewed about adverse event symptoms their child experienced since treatment and if they had sought health care for their child. All children had tympanic temperature measured at the 14-day visit. We compared adverse events and clinic visits using logistic regression models between azithromycin- and placebo-controlled children. Of 450 children enrolled, 230 were randomized to azithromycin and 220 to placebo. On average, children were aged 28 months, and 50.9% were female. Caregivers of 20% of children reported that their child experienced at least one adverse event, with no significant difference between study arms (19.9% azithromycin; 20.0% placebo, logistic regression P = 0.96). Vomiting was more often reported by caregivers of azithromycin-treated children than by those of placebo-treated children (7.2% azithromycin, 1.9% placebo, logistic regression P = 0.01). There were no significant differences in other adverse events or clinic visits. Adverse events following a single oral dose of azithromycin in preschool children were rare and mild. Azithromycin administration appears safe in this population.

Conjunctival examination for trachomatous inflammation-follicular (TF) guides public health decisions for trachoma. Smartphone cameras may allow remote conjunctival grading, but previous studies have found low sensitivity. A random sample of 412 children aged 1-9 years received an in-person conjunctival examination and then had conjunctival photographs taken with 1) a single-lens reflex (SLR) camera and 2) a smartphone coupled to a 3D-printed magnifying attachment. Three masked graders assessed the conjunctival photographs for TF. Latent class analysis was used to determine the sensitivity and specificity of each grading method for TF. Single-lens reflex photo-grading was 95.0% sensitive and 93.6% specific, and smartphone photo-grading was 84.1% sensitive and 97.6% specific. The sensitivity of the smartphone-CellScope device was considerably higher than that of a previous study using the native smartphone camera, without attachment. Magnification of smartphone images with a simple attachment improved the grading sensitivity while maintaining high specificity in a region with hyperendemic trachoma.

We evaluated the potential antiviral effects of azithromycin on the nasopharyngeal virome of Nigerien children who had received multiple rounds of mass drug administration. We found that the respiratory burden of non-severe acute respiratory syndrome coronaviruses was decreased with azithromycin distributions. Clinical Trials Registration. NCT02047981.

BackgroundOur understanding of the different effects of targeted versus nontargeted violence on Ebola virus (EBOV) transmission in Democratic Republic of the Congo (DRC) is limited.MethodsWe used time-series data of case counts to compare individuals in Ebola-affected health zones in DRC, April 2018-August 2019. Exposure was number of violent events per health zone, categorized into Ebola-targeted or Ebola-untargeted, and into civilian-induced, (para)military/political, or protests. Outcome was estimated daily reproduction number (Rt) by health zone. We fit linear time-series regression to model the relationship.ResultsAverage Rt was 1.06 (95% confidence interval [CI], 1.02-1.11). A mean of 2.92 violent events resulted in cumulative absolute increase in Rt of 0.10 (95% CI, .05-.15). More violent events increased EBOV transmission (P = .03). Considering violent events in the 95th percentile over a 21-day interval and its relative impact on Rt, Ebola-targeted events corresponded to Rt of 1.52 (95% CI, 1.30-1.74), while civilian-induced events corresponded to Rt of 1.43 (95% CI, 1.21-1.35). Untargeted events corresponded to Rt of 1.18 (95% CI, 1.02-1.35); among these, militia/political or ville morte events increased transmission.ConclusionsEbola-targeted violence, primarily driven by civilian-induced events, had the largest impact on EBOV transmission.

BackgroundMass distribution of azithromycin to preschool children twice yearly for 2 years has been shown to reduce childhood mortality in sub-Saharan Africa but at the cost of amplifying macrolide resistance. The effects on the gut resistome, a reservoir of antimicrobial resistance genes in the body, of twice-yearly administration of azithromycin for a longer period are unclear.MethodsWe investigated the gut resistome of children after they received twice-yearly distributions of azithromycin for 4 years. In the Niger site of the MORDOR trial, we enrolled 30 villages in a concurrent trial in which they were randomly assigned to receive mass distribution of either azithromycin or placebo, offered to all children 1 to 59 months of age every 6 months for 4 years. Rectal swabs were collected at baseline, 36 months, and 48 months for analysis of the participants' gut resistome. The primary outcome was the ratio of macrolide-resistance determinants in the azithromycin group to those in the placebo group at 48 months.ResultsOver the entire 48-month period, the mean (±SD) coverage was 86.6±12% in the villages that received placebo and 83.2±16.4% in the villages that received azithromycin. A total of 3232 samples were collected during the entire trial period; of the samples obtained at the 48-month monitoring visit, 546 samples from 15 villages that received placebo and 504 from 14 villages that received azithromycin were analyzed. Determinants of macrolide resistance were higher in the azithromycin group than in the placebo group: 7.4 times as high (95% confidence interval [CI], 4.0 to 16.7) at 36 months and 7.5 times as high (95% CI, 3.8 to 23.1) at 48 months. Continued mass azithromycin distributions also selected for determinants of nonmacrolide resistance, including resistance to beta-lactam antibiotics, an antibiotic class prescribed frequently in this region of Africa.ConclusionsAmong villages assigned to receive mass distributions of azithromycin or placebo twice yearly for 4 years, antibiotic resistance was more common in the villages that received azithromycin than in those that received placebo. This trial showed that mass azithromycin distributions may propagate antibiotic resistance. (Funded by the Bill and Melinda Gates Foundation and others; ClinicalTrials.gov number, NCT02047981.).