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BackgroundOcular infections withChlamydia trachomatisserovars A-C cause the neglected tropical disease trachoma. As infection does not confer complete immunity, repeated infections are common, leading to long term sequelae such as scarring and blindness. Here we apply a systems serology approach to investigate whether systemic antibody features are associated with susceptibility to infection.MethodsSera from children in five trachoma endemic villages in The Gambia were assayed for 23 antibody features: IgG responses towards twoChlamydia trachomatisantigens and three serovars (elementary bodies and major outer membrane protein MOMP, serovars A-C), IgG responses towards five MOMP peptides (serovars A-C), neutralization and antibody-dependent phagocytosis. Participants were considered resistant if they subsequently developed infection only when over 70% of other children in the same compound were infected.ResultsThe antibody features assayed were not associated with resistance to infection (false discovery rate < 0.05). Anti-MOMP SvA IgG and neutralization titer were higher in susceptible individuals (p < 0.05 before multiple testing adjustment). Classification using partial least squares performed only slightly better than chance in distinguishing between susceptible and resistant participants based on systemic antibody profile (specificity 71%, sensitivity 36%).ConclusionsSystemic infection-induced IgG and functional antibody responses do not appear to be protective against subsequent infection. This may be due to confounding factors increasing both past and future exposure toC. trachomatis, or antibody-dependent enhancement. Ocular responses, IgA, avidity or cell-mediated responses may play a greater role in protective immunity than systemic IgG.

BackgroundTrachoma, caused by ocular infection with Chlamydia trachomatis, is a neglected tropical disease that can lead to blinding pathology. Current trachoma control programmes have successfully used mass drug administration (MDA) with azithromycin to clear C. trachomatis infection and reduce transmission, alongside promoting facial cleanliness for better personal hygiene and environmental improvement. In areas of low-trachoma endemicity, the relationship between C. trachomatis infection and trachomatous disease weakens, and non-chlamydial bacteria have been associated with disease signs.MethodsWe enrolled a cohort of children aged 6–10 years from three adjacent trachoma endemic villages in Kilimanjaro and Arusha regions, Northern Tanzania. Children were divided into four clinical groups based on the presence or absence of ocular C. trachomatis infection and clinical signs of trachomatous papillary inflammation (TP). To determine the impact of treatment on the ocular microbiome in these clinical groups, we performed V4-16S rRNA sequencing of conjunctival DNA from children 3–9 months pre-MDA (n = 269) and 3 months post-MDA (n = 79).ResultsChlamydia trachomatis PCR-negative, no TP children had the highest pre-MDA ocular microbiome alpha diversity, which was reduced in C. trachomatis infected children and further decreased in those with TP. Pre-MDA, Haemophilus and Staphylococcus were associated with C. trachomatis infection with and without concurrent TP, while Helicobacter was increased in those with TP in the absence of current C. trachomatis infection. Post-MDA, none of the studied children had ocular C. trachomatis infection or TP. MDA increased ocular microbiome diversity in all clinical groups, the change was of greater magnitude in children with pre-MDA TP. MDA effectively reduced the prevalence of disease causing pathogenic non-chlamydial bacteria, and promoted restoration of a normal, healthy conjunctival microbiome.ConclusionWe identified Helicobacter as a non-chlamydial bacterium associated with the clinical signs of TP. Further investigation to determine its relevance in other low-endemicity communities is required. MDA was shown to be effective at clearing C. trachomatis infection and other non-chlamydial ocular pathogens, without any detrimental longitudinal effects on the ocular microbiome. These findings suggest that azithromycin MDA may be valuable in trachoma control even in populations where the relationship between clinical signs of trachoma and the prevalence of current ocular C. trachomatis infection has become dissociated.

Class II HLA loci DRB1, DQB1 and DPB1 were typed for a total of 939 Gambian participants by locus-specific amplicon sequencing. Participants were from multiple regions of The Gambia and drawn from two studies: a family study aiming to identify associations between host genotype and trachomatous scarring (N = 796) and a cohort study aiming to identify correlates of immunity to trachoma (N = 143). All loci deviated from Hardy-Weinberg equilibrium, likely due to the family-based nature of the study: 608 participants had at least one other family member included in the study population. The most common alleles for HLA-DRB1, DQB1 and DPB1 respectively were DRB1*13:04 (18.8 %), DQB1*03:19 (27.9 %) and DPB1*01:01 (25.4 %). Participants belonged to a variety of ethnicities, including the Mandinka, Fula, Wolof and Jola ethnic groups.

Because transmission of ocular strains of Chlamydia trachomatis is greatest among preschool-aged children, limiting azithromycin distributions to this age group may conserve resources and result in less antimicrobial resistance, which is a potential advantage in areas with hypoendemic trachoma and limited resources.To determine the efficacy of mass azithromycin distributions to preschool-aged children as a strategy for trachoma elimination in areas with hypoendemic disease.In this cluster randomized clinical trial performed from November 23, 2014, until July 31, 2017, thirty rural communities in Niger were randomized at a 1:1 ratio to biannual mass distributions of either azithromycin or placebo to children aged 1 to 59 months. Participants and study personnel were masked to treatment allocation. Data analyses for trachoma outcomes were performed from October 19, 2021, through June 10, 2022.Every 6 months, a single dose of either oral azithromycin (20 mg/kg using height-based approximation for children who could stand or weight calculation for small children) or oral placebo was provided to all children aged 1 to 59 months.Trachoma was a prespecified outcome of the trial, assessed as the community-level prevalence of trachomatous inflammation-follicular and trachomatous inflammation-intense through masked grading of conjunctival photographs from a random sample of 40 children per community each year during the 2-year study period. A secondary outcome was the seroprevalence of antibodies to C trachomatis antigens.At baseline, 4726 children in 30 communities were included; 1695 children were enrolled in 15 azithromycin communities and 3031 children were enrolled in 15 placebo communities (mean [SD] proportions of boys, 51.8% [4.7%] vs 52.0% [4.2%]; mean [SD] age, 30.8 [2.8] vs 30.6 [2.6] months). The mean coverage of study drug for the 4 treatments was 79% (95% CI, 75%-83%) in the azithromycin group and 82% (95% CI, 79%-85%) in the placebo group. The mean prevalence of trachomatous inflammation-follicular at baseline was 1.9% (95% CI, 0.5%-3.5%) in the azithromycin group and 0.9% (95% CI, 0-1.9%) in the placebo group. At 24 months, trachomatous inflammation-follicular prevalence was 0.2% (95% CI, 0-0.5%) in the azithromycin group and 0.8% (95% CI, 0.2%-1.6%) in the placebo group (incidence rate ratio adjusted for baseline: 0.18 [95% CI, 0.01-1.20]; permutation P = .07).The findings of this trial do not show that biannual mass azithromycin distributions to preschool-aged children were more effective than placebo, although the underlying prevalence of trachoma was low. The sustained absence of trachoma even in the placebo group suggests that trachoma may have been eliminated as a public health problem in this part of Niger.ClinicalTrials.gov Identifier: NCT02048007.

BackgroundTo eliminate trachoma as a public health problem, the WHO recommends the SAFE strategy. As part of the SAFE strategy in the Amhara Region, Ethiopia, the Trachoma Control Program distributed over 124 million doses of antibiotic between 2007 and 2015. Despite these interventions, trachoma remained hyperendemic in many districts and a considerable level of Chlamydia trachomatis (Ct) infection was evident.MethodsWe utilised residual material from Abbott m2000 Ct diagnostic tests to sequence 99 ocular Ct samples from Amhara and investigated the role of Ct genomic variation in the continued transmission of Ct following 5 years of SAFE.FindingsSequences were typical of ocular Ct, at the whole-genome level and in tissue tropism-associated genes. There was no evidence of macrolide-resistance in this Ct population. Polymorphism in a region around ompA gene was associated with village-level TF prevalence. Additionally, greater ompA diversity at the district-level was associated with increased Ct infection prevalence.InterpretationWe found no evidence for Ct genomic variation contributing to continued transmission of Ct after treatment, adding to previous evidence that azithromycin does not drive acquisition of macrolide resistance alleles in Ct. Increased Ct infection in villages and in districts with more ompA variants requires longitudinal investigation to understand what impact this may have on treatment success and host immunity.FundingEuropean Commission; Neglected Tropical Disease Support Center; International Trachoma Initiative

Recent evidence indicates mass drug administration with azithromycin may reduce child mortality. This study uses verbal autopsy (VA) to investigate the causes of individual deaths during the Macrolides Oraux pour Réduire les Décès avec un Oeil sur la Résistance (MORDOR) trial in Malawi. Cluster randomization was performed as part of MORDOR. Biannual household visits were conducted to distribute azithromycin or placebo to children aged 1–59 months and update the census to identify deaths for VA. MORDOR was not powered to investigate mortality effects at individual sites, but the available evidence is presented here for hypothesis generation regarding the mechanism through which azithromycin may reduce child mortality. Automated VA analysis was performed to infer the likely cause of death using two major analysis programs, InterVA and SmartVA. A total of 334 communities were randomized to azithromycin or placebo, with more than 130,000 person-years of follow-up. During the study, there were 1,184 deaths, of which 1,131 were followed up with VA. Mortality was 9% lower in azithromycin-treated communities than in placebo communities (rate ratio 0.91 [95% CI: 0.79–1.05]; P = 0.20). The intention-to-treat analysis by cause using InterVA suggested fewer HIV/AIDS deaths in azithromycin-treated communities (rate ratio 0.70 [95% CI: 0.50–0.97]; P = 0.03) and fewer pneumonia deaths (rate ratio 0.82 [95% CI: 0.60–1.12]; P = 0.22). The use of the SmartVA algorithm suggested fewer diarrhea deaths (rate ratio 0.71 [95% CI: 0.51–1.00]; P = 0.05) and fewer pneumonia deaths (rate ratio 0.58 [95% CI: 0.33–1.00]; P = 0.05). Although this study is not able to provide strong evidence, the data suggest that the mortality reduction during MORDOR in Malawi may have been due to effects on pneumonia and diarrhea or HIV/AIDS mortality.

The recent Macrolides Oraux pour Réduire les Décès avec un Oeil sur la Résistance (MORDOR) trial reported a reduction in child mortality following biannual azithromycin mass drug administration (MDA). Here, we investigate the financial costs and cost-effectiveness from the health provider perspective of azithromycin MDA at the MORDOR-Malawi study site. During MORDOR, a cluster-randomized trial involving biannual azithromycin MDA or placebo to children aged 1–59 months, fieldwork-related costs were collected, including personnel, transport, consumables, overheads, training, and supervision. Mortality rates in azithromycin- and placebo-treated clusters were calculated overall and for the five health zones of Mangochi district. These were used to estimate the number needed to treat to avert one death and the costs per death and disability-adjusted life year (DALY) averted. The cost per dose of MDA was $0.74 overall, varying between $0.63 and $0.94 in the five zones. Overall, the number needed to treat to avert one death was 1,213 children; the cost per death averted was $898.47, and the cost per DALY averted was $9.98. In the three zones where mortality was lower in azithromycin-treated clusters, the number needed to treat to avert one death, cost per death averted, and cost per DALY averted, respectively, were as follows: 3,070, $2,899.24, and $32.31 in Monkey Bay zone; 1,530, $1,214.42, and $13.49 in Chilipa zone; and 344, $217.98, and $2.42 in Namwera zone. This study is a preliminary cost-effectiveness analysis that indicates azithromycin MDA for reducing child mortality has the potential to be highly cost-effective in some settings in Malawi, but the reasons for geographical variation in effectiveness require further investigation.

Reductions in malaria morbidity have been reported following azithromycin mass drug administration (MDA) for trachoma. The recent Macrolides Oraux pour Reduire les Deces avec un Oeil sur la Resistance (MORDOR) trial reported a reduction in child mortality following biannual azithromycin MDA. Here, we investigate the effects of azithromycin MDA on malaria at the MORDOR-Malawi study site. A cluster-randomized double-blind placebo-controlled trial, with 15 clusters per arm, was conducted. House-to-house census was updated biannually, and azithromycin or placebo syrup was distributed to children aged 1–59 months for a total of four biannual distributions. At baseline, 12-month, and 24-month follow-up visits, a random sample of 1,200 children was assessed for malaria with thick and thin blood smears and hemoglobin measurement. In the community-level analysis, there was no difference in the prevalence of parasitemia (1.0% lower in azithromycin-treated communities; 95% CI: −8.2 to 6.1), gametocytemia (0.7% lower in azithromycin-treated communities; 95% CI: −2.8 to 1.5), or anemia (1.7% lower in azithromycin-treated communities; 95% CI: −8.1 to 4.6) between placebo and azithromycin communities. Further interrogation of the data at the individual level, both per-protocol (including only those who received treatment 6 months previously) and by intention-to-treat, did not identify differences in parasitemia between treatment arms. In contrast to several previous reports, this study did not show an effect of azithromycin MDA on malaria parasitemia at the community or individual levels.

Background As the World Health Organization seeks to eliminate trachoma by 2020, countries are beginning to control the transmission of trachomatous inflammation–follicular (TF) and discontinue mass drug administration (MDA) with oral azithromycin. We evaluated the effect of MDA discontinuation on TF1–9 prevalence at the district level. Methods We extracted from the available data districts with an impact survey at the end of their program cycle that initiated discontinuation of MDA (TF1–9 prevalence Results Of the 220 districts included, TF1–9 prevalence increased to >5% from impact to surveillance survey in 9% of districts. Regression analysis indicated that impact survey TF1–9 prevalence was a significant predictor of surveillance survey TF1–9 prevalence. The proportion of simulations with >5% TF1–9 prevalence in the surveillance survey was 2%, assuming the survey was conducted 4 years after MDA. Conclusion An increase in TF1–9 prevalence may represent disease resurgence but could also be due to measurement error. Improved diagnostic tests are crucial to elimination of TF1–9 as a public health problem.

Community-level mass treatment with azithromycin has been associated with a mortality benefit in children. However, antibiotic exposures result in disruption of the gut microbiota and repeated exposures may reduce recovery of the gut flora. We conducted a nested cohort study within the framework of a randomized controlled trial to examine associations between mass drug administration (MDA) with azithromycin and the gut microbiota of rural Malawian children aged between 1 and 59 months. Fecal samples were collected from the children at baseline and 6 months after two or four biannual rounds of azithromycin treatment. DNA was extracted from fecal samples and V4-16S rRNA sequencing used to characterize the gut microbiota. Firmicutes, Bacteroidetes, Proteobacteria and Actinobacteria were the dominant phyla while Faecalibacterium and Bifidobacterium were the most prevalent genera. There were no associations between azithromycin treatment and changes in alpha diversity, however, four biannual rounds of treatment were associated with increased abundance of Prevotella. The lack of significant changes in gut microbiota after four biannual treatments supports the use of mass azithromycin treatment to reduce mortality in children living in low- and middle-income settings.

Azithromycin mass drug administration (MDA) could reduce child mortality. However, macrolide resistance, which has generally been reported to develop after whole-community MDA for trachoma control, is a concern, and it has less commonly been studied in the context of treating children to reduce mortality. Here, we report on macrolide resistance after biannual azithromycin MDA at the Malawi site of the MORDOR study.In the MORDOR cluster-randomised trial in Malawi, 30 communities in Mangochi District were randomly selected. Communities were randomly assigned to receive azithromycin or placebo by simple randomisation without stratification. Children aged 1-59 months were administered azithromycin 20 mg/kg or placebo as an oral suspension biannually for a total of four treatments in 2015-17. 1200 children (40 children per community) were randomly selected for nasopharyngeal swabs at baseline, 12 months (6 months after the second treatment visit), and 24 months (6 months after the fourth treatment visit). Samples were processed to cultureAt baseline, 3467 (76%) of 4541 eligible children in the azithromycin group and 3107 (72%) of 4308 eligible children in the placebo group were treated. 564 nasopharyngeal swabs were taken from the azithromycin group and 563 from the placebo group, with similar numbers of swabs taken at 12 months and 24 months. In both groups at baseline, carriage ofThese findings support previous evidence from trachoma MDA programmes and suggest that monitoring of macrolide resistance should remain a key component of azithromycin interventions for reducing child mortality.BillMelinda Gates Foundation.

Background: It is unclear whether smoking increases the risk of COVID-19 hospitalisation. We first examined the association of smoking status with hospitalisation for COVID-19 compared with hospitalisation for other respiratory viral infections a year previous. Second, we examined the concordance between smoking status recorded on the electronic health record (EHR) and the contemporaneous medical notes. Methods: This case-control study enrolled adult patients (446 cases and 211 controls) at a single National Health Service trust in London, UK. The outcome variable was type of hospitalisation (COVID-19 vs. another respiratory virus a year previous). The exposure variable was smoking status (never/former/current smoker). Logistic regression analyses adjusted for age, sex, socioeconomic position and comorbidities were performed. The study protocol and analyses were pre-registered in April 2020 on the Open Science Framework. Results: Current smokers had lower odds of being hospitalised with COVID-19 compared with other respiratory viruses a year previous (ORadj=0.55, 95% CI=0.31-0.96, p=.04). There was no significant association among former smokers (ORadj=1.08, 95% CI=0.72-1.65, p=.70). Smoking status recorded on the EHR (compared with the contemporaneous medical notes) was incorrectly recorded for 168 (79.6%) controls (χ2(3)=256.5, p=2(3)=34.2, p= Conclusions: In a single UK hospital trust, current smokers had reduced odds of being hospitalised with COVID-19 compared with other respiratory viruses a year previous, although it is unclear whether this association is causal. Targeted post-discharge recording of smoking status may account for the greater EHR-medical notes concordance observed in cases compared with controls.

Background Mass drug administration (MDA) with azithromycin is the primary strategy for global trachoma control efforts. Numerous studies have reported secondary effects of MDA with azithromycin, including reductions in childhood mortality, diarrhoeal disease and malaria. Most recently, the MORDOR clinical trial demonstrated that MDA led to an overall reduction in all-cause childhood mortality in targeted communities. There is however concern about the potential of increased antimicrobial resistance in treated communities. This study evaluated the impact of azithromycin MDA on the prevalence of gastrointestinal carriage of macrolide-resistant bacteria in communities within the MORDOR Malawi study, additionally profiling changes in the gut microbiome after treatment. For faecal metagenomics, 60 children were sampled prior to treatment and 122 children after four rounds of MDA, half receiving azithromycin and half placebo. Results The proportion of bacteria carrying macrolide resistance increased after azithromycin treatment. Diversity and global community structure of the gut was minimally impacted by treatment, however abundance of several species was altered by treatment. Notably, the putative human enteropathogen Escherichia albertii was more abundant after treatment. Conclusions MDA with azithromycin increased carriage of macrolide-resistant bacteria, but had limited impact on clinically relevant bacteria. However, increased abundance of enteropathogenic Escherichia species after treatment requires further, higher resolution investigation. Future studies should focus on the number of treatments and administration schedule to ensure clinical benefits continue to outweigh costs in antimicrobial resistance carriage. Trial registration ClinicalTrial.gov, NCT02047981. Registered January 29th 2014, https://clinicaltrials.gov/ct2/show/NCT02047981

Environmental enteric dysfunction (EED) is a subclinical condition of the gut characterized by changes in morphology and function with underlying chronic inflammatory responses. This study characterized composition and diversity of the gut microbiota in rural Malawian children with and without signs of EED. Fecal samples were collected from children aged 1–59 months. Neopterin, myeloperoxidase and alpha-1 antitrypsin concentrations were quantified by ELISA and combined to form a composite EED score using principal component analysis. DNA was extracted from fecal samples and V4-16S rRNA gene sequencing was used to characterize the gut microbiota. The concentrations of all three biomarkers decreased with increasing age, which is consistent with other studies of children living in similar low-income settings. Firmicutes, Bacteroidetes, Proteobacteria and Actinobacteria were the dominant phyla while Faecalibacterium and Bifidobacterium were the most prevalent genera. Increased alpha diversity was associated with a reduction in neopterin concentration. Microbiota composition was different between fecal samples with low and high composite EED scores; increased abundance of Succinivibrio was associated with reduced composite EED scores., Highlights • Fecal concentrations of myeloperoxidase, alpha-1 antitrypsin and neopterin decreased with age in Malawian children. • A marginal negative association was found between alpha diversity of the gut microbiota and fecal neopterin concentration. • Succinivibrio abundance was higher in children with reduced composite environmental enteric dysfunction biomarker score. • Modelling found 3 metagenomic-metabolic pathways associated with a reduced risk of high composite biomarker score., Gut microbiota; V4-16S rRNA sequencing; PICRUSt2; Environmental enteric dysfunction.

Background Gastrointestinal illness is a major cause of morbidity in travellers and is a common reason for presentation to healthcare services on return. Whilst the aetiology of imported gastrointestinal disease is predominantly infectious, outcomes are variable due to a range of phenomena such as post-infectious irritable bowel syndrome, drug resistance and occult pathology (both infectious and non-infectious). Previous studies have focussed on predictors of aetiology of gastrointestinal disease in travellers; we present a retrospective study combining both aetiological and early outcome data in a large cohort of returned travellers. Method We identified 1450 patients who attended our post-travel walk-in clinic with gastrointestinal symptoms between 2010 and 2016. Demographic, travel, clinical and laboratory data was collected through case note review. Logistic regression analysis to examine correlates of aetiology and outcome were performed in R (CRAN Project 2017). Results Of 1450 patients in our cohort 153 reported bloody diarrhoea and 1081 (74.6%) reported non-bloody diarrhoea. A definitive microbiological diagnosis was made in 310 (20.8%) of which 137 (9.4%) had a parasite identified and 111 (7.7%) had a bacterial cause identified. Factors associated with a parasitological diagnosis included history of travel to South Asia (aOR = 2.55; 95%CI 1.75–3.70, p p p p p 5iu/dL (aOR = 4.68; 95%CI 2.91–7.72, p p p p Conclusions In a cohort of returned travellers, we were able to identify multiple factors that are correlated with both aetiology and outcome of imported gastrointestinal syndromes. We predict these data will be valuable in the development of diagnostic and therapeutic pathways for patients with imported gastrointestinal infections.

Background In 2009 Ghana began to design a trachoma pre-validation surveillance plan, based on then-current WHO recommendations. The plan aimed to identify active trachoma resurgence and identify and manage trichiasis cases, through both active and passive surveillance approaches. This paper outlines and reviews the adaptations made by Ghana between 2011 and 2016. The assessment will provide a learning opportunity for a number of countries as they progress towards elimination status. Methods A mixed methods approach was taken, comprising in-depth interviews and documents review. Between January and April 2016, 20 in-depth interviews were conducted with persons involved in the operationalisation of the trachoma surveillance system from across all levels of the health system. A three-tier thematic coding framework was developed using a primarily inductive approach but also allowed for a more iterative approach, which drew on aspects of grounded theory. Results During the operationalisation of the Ghana surveillance plan there were a number of adaptations (as compared to the WHO recommendations), these included: (i) Inclusion of surveillance of active trachoma in the passive surveillance approach, as compared to trichiasis alone. Issues with case identification, challenges in implementation coverage and a non-specific reporting structure hampered effectiveness; (ii) Random selection and increase in number of sites selected for the active surveillance component. This likely lacked the spatiotemporal power to be able to identify recrudescence in a timely manner; (iii) Targeted trichiasis door-to-door case searches, led by ophthalmic nurses. An effective methodology to identify trichiasis cases but resource intensive; (iv) A buddy system between ophthalmic nurses to support technical skills in an elimination setting where it is difficult to attain diagnostic and surgical skills, due to a lack of cases. The strategy did not take into account the loss of proficiency within experienced personnel. Conclusions Ghana developed a comprehensive surveillance system that exceeded the WHO recommendations but issues with sensitivity and specificity likely led to an inefficient use of resources. Improved targeted surveillance strategies for identification of recrudescence and trichiasis case searches, need to be evaluated. Strategies must address the contextual changes that arise because of transmission decline, such as loss of surgical skills. Electronic supplementary material The online version of this article (10.1186/s40249-019-0585-x) contains supplementary material, which is available to authorized users.

Purpose: The prevalence of trichiasis is higher in females and increases markedly with age. Surveys carried out in the daytime, particularly in developing countries, are prone to find older individuals and females at home at the time of the survey. Population-level trichiasis estimates should adjust sample proportions to reflect the demographic breakdown of the population, although the most accurate method of doing this is unclear. Methods: Having obtained data from 162 surveys carried out in Ethiopia as part of the Global Trachoma Mapping Project from 2012 to 2015, we used internal validation with both Brier and Logarithmic forecast scoring to test stratification models to identify those models with the highest predictive accuracy. Selection of partitions was undertaken by both simple random sampling (SRS) and cluster sampling (CS) over 8192 selections. Results: A total of 4529 (1.9%) cases of trichiasis were identified from 241,139 individuals aged ≥15 years from a total of 4210 kebeles and 122,090 households visited. Overall, the binning method using 5-year bands from age 15 to 69 years, with coarser binning in 20-year age-bands above this age, provided the best predictive accuracy, in both SRS and CS methodologies and for both the Brier and Logarithmic scoring rules. Conclusion: The greatest predictive accuracy for trichiasis estimates was found by adjusting for sex and in 5-year age-bands from the age of 15 to 69 years and in 20-year age-bands in those aged 70 years and greater. Trichiasis surveys attempting to make population-level inferences should use this method to optimise surgery backlog estimates.

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., The COVID-19 pandemic has disrupted neglected tropical disease programs. Modelling shows the impact of this will vary across diseases. Once interventions are reintroduced, there are opportunities for mitigating the delay and accelerating progress towards the 2030 goals.

BackgroundMass drug administration (MDA) with azithromycin is the primary strategy for global trachoma control efforts. Numerous studies have reported secondary effects of MDA with azithromycin, including reductions in childhood mortality, diarrhoeal disease and malaria. Most recently, the MORDOR clinical trial demonstrated that MDA led to an overall reduction in all-cause childhood mortality in targeted communities. There is however concern about the potential of increased antimicrobial resistance in treated communities.MethodsThis study evaluated the impact of azithromycin MDA on the prevalence of gastrointestinal carriage of macrolide-resistant bacteria in communities within the MORDOR Malawi study, additionally profiling changes in the gut microbiome after treatment. For faecal metagenomics, 60 children were sampled prior to treatment and 122 children after four rounds of MDA, half receiving azithromycin and half placebo.FindingsThe proportion of bacteria carrying macrolide resistance increased after azithromycin treatment; the effect was enhanced in children treated within six months of sampling. Diversity and global community structure of the gut was minimally impacted by treatment, however abundance of several species was altered by treatment. Notably, the putative human enteropathogen Escherichia albertii was more abundant after treatment.InterpretationThe impacts of MDA with azithromycin, including increased carriage of macrolide-resistant bacteria, were enhanced in children treated more recently, suggesting effects may be transient. Increased abundance of enteropathogenic Escherichia species after treatment requires further, higher resolution investigation. Future studies should focus on the number of treatments and administration schedule to ensure clinical benefits continue to outweigh costs in antimicrobial resistance carriage.FundingBill and Melinda Gates Foundation

BackgroundIt is unclear whether smoking increases the risk of COVID-19 hospitalisation. We examined i) the association of smoking status with hospitalisation for COVID-19 compared with hospitalisation for other respiratory viral infections a year previous; and ii) concordance between smoking status recorded on the electronic health record (EHR) and the contemporaneous medical notes.MethodsThis case-control study enrolled adult patients (446 cases and 211 controls) at a single National Health Service trust in London, UK. The outcome variable was type of hospitalisation (COVID-19 vs. another respiratory virus a year previous). The exposure variable was smoking status (never/former/current smoker). Logistic regression analyses adjusted for age, sex, socioeconomic position and comorbidities were performed. The study protocol and analyses were pre-registered in April 2020 on the Open Science Framework.ResultsCurrent smokers had lower odds of being hospitalised with COVID-19 compared with other respiratory viruses a year previous (ORadj=0.55, 95% CI=0.31-0.96, p=.04). There was no significant association among former smokers (ORadj=1.08, 95% CI=0.72-1.65, p=.70). Smoking status recorded on the EHR (compared with the contemporaneous medical notes) was incorrectly recorded for 168 (79.6%) controls (χ2(3)=256.5, p=2(3)=34.2, p=ConclusionsIn a single UK hospital trust, current smokers had reduced odds of being hospitalised with COVID-19 compared with other respiratory viruses a year previous, although it is unclear whether this association is causal. Targeted post-discharge recording of smoking status may account for the greater EHR- medical notes concordance observed in cases compared with controls.

Background The World Health Organization-recommended strategy for trachoma elimination as a public health problem is known by the acronym “SAFE”, where “F” stands for facial cleanliness to reduce transmission of ocular Chlamydia trachomatis infection. Accurately and reliably measuring facial cleanliness is problematic. Various indicators for measuring an unclean face exist, however, the accuracy and reliability of these indicators is questionable and their relationship to face washing practices is poorly described. Methods Clean face indicator (ocular or nasal discharge, flies on the face, and dirt on the face), trachoma clinical sign, and ocular C. trachomatis infection data were collected for 1613 children aged 0–9 years in 12 Senegalese villages as part of a cross-sectional trachoma prevalence study. Time of examination was recorded to the nearest half hour. A risk factor questionnaire containing Water, Sanitation and Hygiene (WASH) questions was administered to heads of compounds (households that shared a common doorway) and households (those who shared a common cooking pot). Results WASH access and use were high, with 1457/1613 (90.3%) children living in households with access to a primary water source within 30 min. Despite it being reported that 1610/1613 (99.8%) children had their face washed at awakening, > 75% (37/47) of children had at least one unclean face indicator at the first examination time-slot of the day. The proportion of children with facial cleanliness indicators differed depending on the time the child was examined. Dirt on the face was more common, and ocular discharge less common, in children examined after 11:00 h than in children examined at 10:30 h and 11:00 h. Conclusions Given the high reported WASH access and use, the proportion of children with an unclean face indicator should have been low at the beginning of the day. This was not observed, explained either by: the facial indicators not being reliable measures of face washing; eye discharge, nose discharge or dirt rapidly re-accumulated after face washing in children in this population at the time of fieldwork; and/or responder bias to the risk factor questionnaire. A high proportion of children had unclean face indicators throughout the day, with certain indicators varying by time of day. A reliable, standardised, practical measure of face washing is needed, that reflects hygiene behaviour rather than environmental or cultural factors. Graphical Abstract

Community-level mass treatment with azithromycin has been associated with a mortality benefit in children. However, antibiotic exposures result in disruption of the gut microbiota and repeated exposures may reduce recovery of the gut flora. We conducted a nested cohort study to examine associations between mass drug administration (MDA) with azithromycin and the gut microbiota of rural Malawian children aged between 1-59 months. Fecal samples were collected from the children prior to treatment and 6 months after two or four biannual rounds of azithromycin treatment. DNA was extracted from fecal samples and V4-16S rRNA sequencing used to characterize the gut microbiota. Firmicutes, Bacteroidetes, Proteobacteria and Actinobacteria were the dominant phyla while Faecalibacterium and Bifidobacterium were the most prevalent genera. There were no associations between azithromycin treatment and changes in alpha diversity, however, four biannual rounds of treatment were associated with increased abundance of Prevotella. The lack of significant changes in gut microbiota after four biannual treatments supports the use of mass azithromycin treatment to reduce mortality in children living in low- and middle-income settings.

BackgroundMass drug administration (MDA) with azithromycin for trachoma elimination reduces nasopharyngeal carriage of Streptococcus pneumoniae in the short term. We evaluated S. pneumoniae carried in the nasopharynx before and after a round of azithromycin MDA to determine whether MDA was associated with changes in pneumococcal population structure.MethodsWe analysed 514 pneumococcal isolates cultured from nasopharyngeal samples collected in Gambian villages that received MDA for trachoma elimination. The samples were collected during three cross-sectional surveys conducted before the third round of MDA (CSS-1) and at one (CSS-2) and six (CSS-3) months after MDA. Whole genome sequencing was conducted on randomly selected isolates. Bayesian Analysis of Population Structure (BAPS) was used to cluster related isolates by capturing variation in the core genome. Serotype and multi-locus sequence type were inferred from the genotype. The Antimicrobial Resistance Identification by Assembly (ARIBA) tool was used to identify macrolide resistance genes.ResultsTwenty-seven BAPS clusters were assigned. These consisted of 81 sequence types (STs), 15 of which were novel additions to pubMLST. Two BAPS clusters, BAPS20 (p-valueConclusionsLimited changes in pneumococcal population structure were observed after the third round of MDA suggesting treatment had little effect on the circulating lineages. An increase in macrolide resistance within one BAPS highlights the need for antimicrobial resistance surveillance in treated villages.

Trachoma is a blinding eye disease caused by the bacterium Chlamydia trachomatis. The current global elimination of trachoma initiative includes the use of mass drug distribution of azithromycin in areas where the prevalence of follicular trachoma is >10% in children aged 1-9 years. This study aims to investigate the high quality evidence of whether mass drug administration for trachoma causes the development of azithromycin resistance in S pneumoniae. Secondary objectives include (1) changes in the overall S pneumoniae prevalence and (2) concomitant development of non-macrolide resistance. Six databases were searched for articles relevant to the study question. Studies were screened and findings recorded using the PRISMA flow diagram and the Cochrane data collection checklist. Studies were only included if they included both a control and experimental group. Two risk of bias tools were used for quality appraisal of each study. After reviewing all studies, four were included in the final analysis, including one randomized control trial, two cluster-randomized trials and one prospective cohort. Findings showed decreased S pneumoniae prevalence and increased azithromycin resistant isolates following mass drug administration. This review shows that mass drug administration for trachoma can lead to a transient rise in S pneumoniae azithromycin resistance with a possible reduction in overall S pneumoniae prevalence. There is also evidence of macrolide-induced tetracycline and clindamycin resistance. The clinical impact of these findings remains unclear and further studies need to be performed to establish the significance.

Background As the World Health Organization seeks to eliminate trachoma by 2020, countries are beginning to control the transmission of trachomatous inflammation–follicular (TF) and discontinue mass drug administration (MDA) with oral azithromycin. We evaluated the effect of MDA discontinuation on TF1–9 prevalence at the district level. Methods We extracted from the available data districts with an impact survey at the end of their program cycle that initiated discontinuation of MDA (TF1–9 prevalence 5% from impact to surveillance survey in 9% of districts. Regression analysis indicated that impact survey TF1–9 prevalence was a significant predictor of surveillance survey TF1–9 prevalence. The proportion of simulations with >5% TF1–9 prevalence in the surveillance survey was 2%, assuming the survey was conducted 4 years after MDA. Conclusion An increase in TF1–9 prevalence may represent disease resurgence but could also be due to measurement error. Improved diagnostic tests are crucial to elimination of TF1–9 as a public health problem.

Summary Background The Macrolides Oraux pour Reduire les Deces avec un Oeil sur la Resistance (MORDOR) trial found that biannual mass distribution of azithromycin to children younger than 5 years in Niger reduced the primary outcome of all-cause mortality by 18%. We aimed to determine the causes of mortality among deceased children using verbal autopsy. Methods In this 2-year cluster-randomised controlled trial, 594 community clusters in Niger were randomly allocated (1:1 ratio) to receive biannual mass distributions of either oral azithromycin (approximately 20 mg per kg of bodyweight) or placebo targeted to children aged 1–59 months. Participants, study investigators, and field workers were masked to treatment allocation. Between Nov 23, 2014, and July 31, 2017, 3615 child deaths were recorded by use of biannual house-to-house censuses, and verbal autopsies were done between May 26, 2015, and May 17, 2018, to identify cause of death. Cause-specific mortality, as assessed by verbal autopsy, was a prespecified secondary outcome. This trial is completed and is registered with ClinicalTrials.gov , NCT02047981 . Findings Between Nov 23, 2014, and July 31, 2017, 303 communities (n=40 375 children at baseline) in Niger received mass azithromycin and 291 communities (n=35 747 children at baseline) received placebo. Treatment coverage was 90·3% (SD 10·6) in the azithromycin group and 90·4% (10·1) in the placebo group. No communities were lost to follow-up. In total, 1727 child deaths in the azithromycin group and 1888 child deaths in the placebo group were reported from the population censuses. Of these, the cause of death for 1566 (90·7%) children in the azithromycin group and 1735 (91·9%) children in the placebo group were ascertained by verbal autopsy interviews. In the azithromycin group, 437 (27·9%) deaths were due to malaria, 252 (16·1%) deaths were due to pneumonia, and 234 (14·9%) deaths were due to diarrhoea. In the placebo group, 493 (28·4%) deaths were due to malaria, 275 (15·9%) deaths were due to pneumonia, and 251 (14·5%) deaths were due to diarrhoea. Relative to communities that received placebo, child mortality in communities that received azithromycin was lower for malaria (incidence rate ratio 0·78, 95% CI 0·66–0·92; p=0·0029), dysentery (0·65, 0·44–0·94; p=0·025), meningitis (0·67, 0·46–0·97; p=0·036), and pneumonia (0·83, 0·68–1·00; p=0·051). The distribution of causes of death did not differ significantly between the two study groups (p=0·98). Interpretation Mass azithromycin distribution resulted in approximately a third fewer deaths in children aged 1–59 months due to meningitis and dysentery, and a fifth fewer deaths due to malaria and pneumonia. The lack of difference in the distribution of causes of death between the azithromycin and placebo groups could be attributable to the broad spectrum of azithromycin activity and the study setting, in which most childhood deaths were due to infections. Funding Bill & Melinda Gates Foundation.

BACKGROUND: Mass distributions of azithromycin for trachoma have been associated with secondary benefits, including reductions in child mortality. METHODS: In the Partnership for the Rapid Elimination of Trachoma cluster-randomized trial in Niger, 24 communities were randomized to annual treatment of everyone and 24 communities were randomized to biannual treatment of children under 12 for 3 years (clinicaltrials.gov, NCT00792922). Treatment was a single dose of directly observed oral azithromycin (20 mg/kg up to 1 g in adults). Vital status was assessed during annual census and monitoring visits. In this prespecified secondary analysis, we compared the mortality rate among children 6 months to less than 5 years of age by treatment arm using negative binomial regression. RESULTS: Among children 6 months to less than 5 years of age, 404 deaths occurred during the study period. The mortality rate was 35.6 deaths per 1000 person-years (231 deaths, 95% CI: 30.9-40.9) in the annual arm and 29.0 deaths per 1000 person-years (173 deaths, 95% CI: 24.8-33.8) in the biannual arm. The mortality rate ratio comparing children in the biannual arm to the annual arm was 0.81 (95% CI: 0.66-1.00, P = 0.07; primary outcome). The mortality rate ratio comparing children who died from infectious causes in the biannual arm to the annual arm was 0.73 (95% CI: 0.57-0.94; P = 0.02). No adverse events were reported. CONCLUSIONS: This secondary analysis of a cluster-randomized trial found a nonsignificant 19% decrease in mortality among children 6 months to less than 5 years of age who received biannual azithromycin compared with children who received annual azithromycin. This study was conducted in a high mortality, trachoma-endemic area; thus, results may be specific to this environment only. In addition, the trial was neither designed nor powered to detect a mortality effect, and we cannot rule out the possibility that mortality differences resulted from bias.

Introduction To date, eleven countries have been validated as having eliminated trachoma as a public health problem, including Ghana in 2018. Surveillance for recrudescence is needed both pre- and post-validation but evidence-based guidance on appropriate strategies is lacking. We explored two potential surveillance strategies in Ghana. Methodology/principal findings Amongst randomly-selected communities enrolled in pre-validation on-going surveillance between 2011 and 2015, eight were identified as having had trachomatous-inflammation follicular (TF) prevalence ≥5% in children aged 1–9 years between 2012 and 2014. These eight were re-visited in 2015 and 2016 and neighbouring communities were also added (“TF trigger” investigations). Resident children aged 1–9 years were then examined for trachoma and had a conjunctival swab to test for Chlamydia trachomatis (Ct) and a dried blood spot (DBS) taken to test for anti-Pgp3 antibodies. These investigations identified at least one community with evidence of probable recent Ct ocular transmission. However, the approach likely lacks sufficient spatio-temporal power to be reliable. A post-validation surveillance strategy was also evaluated, this reviewed the ocular Ct infection and anti-Pgp3 seroprevalence data from the TF trigger investigations and from the pre-validation surveillance surveys in 2015 and 2016. Three communities identified as having ocular Ct infection >0% and anti-Pgp3 seroprevalence ≥15.0% were identified, and along with three linked communities, were followed-up as part of the surveillance strategy. An additional three communities with a seroprevalence ≥25.0% but no Ct infection were also followed up (“antibody and infection trigger” investigations). DBS were taken from all residents aged ≥1 year and ocular swabs from all children aged 1–9 years. There was evidence of transmission in the group of communities visited in one district (Zabzugu-Tatale). There was no or little evidence of continued transmission in other districts, suggesting previous infection identified was transient or potentially not true ocular Ct infection. Conclusions/significance There is evidence of heterogeneity in Ct transmission dynamics in northern Ghana, even 10 years after wide-scale MDA has stopped. There is added value in monitoring Ct infection and anti-Ct antibodies, using these indicators to interrogate past or present surveillance strategies. This can result in a deeper understanding of transmission dynamics and inform new post-validation surveillance strategies. Opportunities should be explored for integrating PCR and serological-based markers into surveys conducted in trachoma elimination settings., Author summary The goal for trachoma programmes is elimination of trachoma as a public health problem. This means that ongoing low-level eye-to-eye transmission of the causative bacterium, Chlamydia trachomatis (Ct), is acceptable. Countries need to implement a suitable surveillance system to identify any return to higher transmission levels. The best methodology for doing this is not known. We first explored the approach used by Ghana in its standard programme, which involved monitoring a limited number of randomly selected communities for evidence of active (inflammatory) trachoma visible in children’s eyes on examination by trained observers. Although this strategy led to identification of at least one community that had probably had recent Ct transmission, the approach is unlikely to consistently identify places where return to higher levels of transmission is a risk. We also explored using information on infection (detected in eye swabs) and antibodies to Ct (detected in the blood) to identify communities at risk. We found evidence of both persistent eye-to-eye Ct transmission and areas where infection was transient and has now gone away. We conclude that the use of infection and antibody data for surveillance of trachoma appears promising.

© 2017 The Author(s). The frequency and duration of Chlamydia trachomatis (Ct) ocular infections decrease with age, suggesting development of partial immunity. However, there is a lack of clear correlates of immunity to Ct infection in humans. We screened sera from a cohort of Gambian children followed for six-months against a Ct-proteome microarray. At genome sequence level, we detected signatures of selection from a population of ocular Ct isolates from Guinea-Bissau. Together these approaches allowed us to highlight the focus of humoral responses and hypothesise new modes of pathogen immune evasion. Children who were susceptible to frequent and/or prolonged Ct infection had a less focussed antibody response, including preferential recognition of forty-two antigens. There was evidence of positive and purifying selection across the genome, but little balancing selection. In contrast, most antigens that were associated with susceptibility were under neutral selection. These data suggest an evasion strategy in which Ct presents a large panel of irrelevant antigens to the immune system to block or misdirect protective responses. Development of a focused immune response, possibly induced through vaccination, may be an effective strategy to promote protection to Ct infection.

Background Helminthic and protozoan infections are common, particularly in low- or middle-income countries. Although an association between parasite carriage and markers of poor growth have been shown in some studies, systematic reviews have suggested only a modest impact of clearing carriage. The prevalence of these pathogens and the effect that they have on growth in preschool children has never been investigated in Malawi. Methods One hundred ninety-three children aged 0–72 months were randomly recruited from rural villages in the Mangochi district of Malawi. Formol-ether concentration was performed on stool and the samples examined with a light microscope. Anthropometric data was taken for each child and the haemoglobin measured with a point of care test. Results The mean age of the children was 2 years 4 months. Overall prevalence of intestinal parasite infection was 37.3%. Protozoa were found in 28.5% of children, while helminths were found in 8.8%. The most commonly found organisms were Giardia lambia (12.4%), Entamoeba coli (10.4%) and Hookworm species (3.6%). Stunting was seen in 47.8% of children, 12.9% were underweight and 5.0% were wasted. No significant association was found between markers of poor growth and infection with any intestinal parasite. Conclusions We found that prevalence of helminth infection was low in preschool children living in the Mangochi district compared to international standards. However a significant proportion of the preschool population are infected with protozoa, particularly Giardia lambia. In this cohort, despite a significant prevalence of stunting, helminth infection was not significantly associated with any markers of poor growth. The significance of protozoal carriage and contribution to growth restriction in this context creates further avenues for future research.

Background Mass drug administration (MDA) with azithromycin is a cornerstone of the trachoma elimination strategy. Although the global prevalence of active trachoma has declined considerably, prevalence persists or even increases in some communities and districts. To increase understanding of MDA impact, we investigated the prevalence of active trachoma and ocular C. trachomatis prevalence, organism load, and circulating strains at baseline and one-year post-MDA in The Gambia and Senegal. Methods Pre- and one-year post-MDA, children aged 0–9 years were examined for clinical signs of trachoma in six Gambian and 12 Senegalese villages. Ocular swabs from each child’s right conjunctiva were tested for evidence of ocular C. trachomatis infection and organism load (ompA copy number), and ompA and multi-locus sequence typing (MLST) was performed. Results A total of 1171 children were examined at baseline and follow-up in The Gambia. Active trachoma prevalence decreased from 23.9% to 17.7%, whereas ocular C. trachomatis prevalence increased from 3.0% to 3.8%. In Senegal, 1613 and 1771 children were examined at baseline and follow-up, respectively. Active trachoma prevalence decreased from 14.9% to 8.0%, whereas ocular C. trachomatis prevalence increased from 1.8% to 3.6%. Higher organism load was associated with having active trachoma and severe inflammation. Sequence typing demonstrated that all Senegalese samples were genovar A, whereas Gambian samples were a mix of genovars A and B. MLST provided evidence of clustering at village and household levels and demonstrated differences of strain variant frequencies in Senegal, indicative of an “outbreak”. MLST, including partial ompA typing, provided greater discriminatory power than complete ompA typing. Conclusions We found that one round of MDA led to an overall decline in active trachoma prevalence but no impact on ocular C. trachomatis infection, with heterogeneity observed between villages studied. This could not be explained by MDA coverage or number of different circulating strains pre- and post-MDA. The poor correlation between active trachoma and infection prevalence supports the need for further work on alternative indicators to clinical signs for diagnosing ocular C. trachomatis infection. MLST typing has potential molecular epidemiology utility, including better understanding of transmission dynamics, although relationship to whole-genome sequence variability requires further exploration.

Objective:In the present study, we aimed to compare anthropometric indicators as predictors of mortality in a community-based setting.Design:We conducted a population-based longitudinal study nested in a cluster-randomized trial. We assessed weight, height and mid-upper arm circumference (MUAC) on children 12 months after the trial began and used the trial’s annual census and monitoring visits to assess mortality over 2 years.Setting:Niger.Participants:Children aged 6–60 months during the study.Results:Of 1023 children included in the study at baseline, height-for-age Z-score, weight-for-age Z-score, weight-for-height Z-score and MUAC classified 777 (76·0 %), 630 (61·6 %), 131 (12·9 %) and eighty (7·8 %) children as moderately to severely malnourished, respectively. Over the 2-year study period, fifty-eight children (5·7 %) died. MUAC had the greatest AUC (0·68, 95 % CI 0·61, 0·75) and had the strongest association with mortality in this sample (hazard ratio = 2·21, 95 % CI 1·26, 3·89, P = 0·006).Conclusions:MUAC appears to be a better predictor of mortality than other anthropometric indicators in this community-based, high-malnutrition setting in Niger.

The putative vector of trachoma, Musca sorbens, prefers to lay its eggs on human faeces on the ground. This study sought to determine whether M. sorbens females were attracted to volatile odours from human faeces in preference to odours from the faeces of other animals, and to determine whether specific volatile semiochemicals mediate selection of the faeces. Traps baited with the faeces of humans and local domestic animals were used to catch flies at two trachoma-endemic locations in The Gambia and one in Ethiopia. At all locations, traps baited with faeces caught more female M. sorbens than control traps baited with soil, and human faeces was the most successful bait compared with soil (mean rate ratios 44.40, 61.40, 10.50 [P, Author summary Musca sorbens, also known as the Bazaar Fly, visits people’s faces to feed on ocular and nasal discharge. While feeding, M. sorbens can transmit Chlamydia trachomatis, the bacterium that causes the infectious eye disease trachoma. Around 1.9 million people worldwide are visually impaired or blind from this disease. Although it is believed that M. sorbens transmits trachoma, very few studies have looked at ways to control this fly. A large-scale trial has shown that control of fly populations with insecticide reduces active trachoma disease prevalence. Odour-baited traps for the suppression of disease vector populations are an attractive option as there is no widespread spraying of insecticide; however, highly attractive baits are critical to their success. Here, we demonstrate that the preference of these flies for breeding in human faeces is probably mediated by odour cues, and we isolate chemicals in the odour of human faeces that cause a response in the antennae of M. sorbens. These compounds may play a role in the specific attractiveness of human faeces to these flies, perhaps by being present in greater amounts or at favourable ratios. These may be developed into a chemical lure for odour-baited trapping to suppress M. sorbens populations.

Background: Trachoma, a neglected tropical disease, is the leading infectious cause of blindness and visual impairment worldwide. Host responses to ocular chlamydial infection resulting in chronic inflammation and expansion of non-chlamydial bacteria are hypothesized risk factors for development of active trachoma and conjunctival scarring.Methods: Ocular swabs from trachoma endemic populations in The Gambia were selected from archived samples for 16S sequencing and host conjunctival gene expression. We recruited children with active trachoma and adults with conjunctival scarring, alongside corresponding matched controls.Findings: In children, active trachoma was not associated with significant changes in the ocular microbiome. Haemophilus enrichment was associated with antimicrobial responses but not linked to active trachoma. Adults with scarring trachoma had a reduced ocular bacterial diversity compared to controls, with increased relative abundance of Corynebacterium. Increased abundance of Corynebacterium in scarring disease was associated with innate immune responses to the microbiota, dominated by altered mucin expression and increased matrix adhesion.Interpretation: In the absence of current Chlamydia trachomatis infection, changes in the ocular microbiome associate with differential expression of antimicrobial and inflammatory genes that impair epithelial cell health. In scarring trachoma, expansion of non-pathogenic bacteria such as Corynebacterium and innate responses are coincident, warranting further investigation of this relationship. Comparisons between active and scarring trachoma supported the relative absence of type-2 interferon responses in scarring, whilst highlighting a common suppression of re-epithelialization with altered epithelial and bacterial adhesion, likely contributing to development of scarring pathology.

Purpose: The clinical sign trachomatous inflammation - follicular (TF) is used to monitor indication for and response to mass azithromycin distribution in trachoma-endemic communities. Here, we assess the relationship between TF, trachomatous inflammation - intense (TI), and infection with ocular Chlamydia trachomatis over time during annual mass azithromycin distribution. Methods: We used data from a cluster-randomized trial of mass azithromycin distribution for trachoma control in a mesoendemic region of Niger. This study includes 24 communities that received 3 years of annual mass azithromycin distribution. TF, TI, and ocular chlamydia infection were monitored among children aged 0-5 years. We assessed the correlation between the prevalence of ocular chlamydia infection and 1) TF and 2) TI prevalence over time. Results: At baseline, ocular chlamydia prevalence was 21.2% (95% CI 14.3-28.1%), TF prevalence was 27.7% (95% CI 21.2-34.2%), and TI prevalence was 8.3% (95% CI 5.2-11.5%). The prevalence of all three measures decreased significantly over time (P < 0.001). At baseline, ocular chlamydia infection prevalence was strongly correlated with both TF (rho = 0.78, P < 0.0001) and TI (rho = 0.76, P < 0.0001). The correlation between ocular chlamydia infection and both TF and TI was weak at months 12 and 24. At 36 months, when TF prevalence had dropped below 10%, ocular chlamydia infection and TF were moderately correlated (rho = 0.70, P= 0.0002). Conclusions: Both TF and TI are good indicators of infection prevalence prior to mass azithromycin distribution. However, this relationship may be affected by repeated rounds of mass azithromycin distribution.

Background Biannual mass azithromycin administration to preschool children reduces all-cause mortality, but the mechanism for the effect is not understood. Azithromycin has activity against malaria parasites, and malaria is a leading cause of child mortality in the Sahel. The effect of biannual versus annual azithromycin distribution for trachoma control on serological response to merozoite surface protein 1 (MSP-119), a surrogate for malaria incidence, was evaluated among children in Niger. Methods Markers of malaria exposure were measured in two arms of a factorial randomized controlled trial designed to evaluate targeted biannual azithromycin distribution to children under 12 years of age compared to annual azithromycin to the entire community for trachoma control (N = 12 communities per arm). Communities were treated for 36 months (6 versus 3 distributions). Dried blood spots were collected at 36 months among children ages 1–5 years, and MSP-119 antibody levels were assessed using a bead-based multiplex assay to measure malaria seroprevalence. Results Antibody results were available for 991 children. MSP-119 seropositivity was 62.7% in the biannual distribution arm compared to 68.7% in the annual arm (prevalence ratio 0.91, 95% CI 0.83 to 1.00). Mean semi-quantitative antibody levels were lower in the biannual distribution arm compared to the annual arm (mean difference − 0.39, 95% CI − 0.05 to − 0.72). Conclusions Targeted biannual azithromycin distribution was associated with lower malaria seroprevalence compared to that in a population that received annual distribution. Trial Registration Clinicaltrials.gov NCT00792922

Introduction Skin diseases represent a significant public health problem in most low and middle income settings. Nevertheless, there is a relative paucity of high-quality epidemiological data on the prevalence of these conditions. Materials/Methods We conducted two cross-sectional population-based skin-surveys of children (6 months to 9 years old) in the Bijagós Archipelago of Guinea-Bissau during the dry season (February-March 2018) and the wet season (June-July 2018). Following a period of training, a nurse performed a standardised examination for communicable dermatoses for each participant. We calculated the prevalence of each skin condition and investigated demographic associations. Results 1062 children were enrolled in the dry season survey of whom 318 (29.9%) had at least one skin diseases. The most common diagnosis was tinea capitis (154/1062, 14.5% - 95% CI 12.5–16.8%) followed by tinea corporis (84/1062, 7.9% - 95% CI 6.4–9.7%), pyoderma (82/1062, 7.7% - 95% CI 6.2–9.5%) and scabies (56/1062. 5.2% - 95%CI 4.0–6.8%). 320 children were enrolled in the wet season survey of whom 121 (37.8%) had at least one skin problem. Tinea capitis remained the most common diagnosis (79/320, 24.7% - 95% CI 20.1–29.9%), followed by pyoderma (38/320, 11.9% - 95% CI 8.6–16.1%), tinea corporis (23/320, 7.2% - 95% 4.7–10.7%) and scabies (6/320, 1.9% - 95% CI 0.8–4.2%). Conclusions Our study, which utilised robust population-based cluster random sampling methodology, demonstrates the substantial disease burden caused by common communicable dermatoses in this setting. Given these findings, there is a need to consider common dermatoses as part of Universal Health Coverage to deliver ‘skin-health for all’., Author summary Skin conditions are very common in many low and middle income settings but there have been relatively few surveys of skin disease conducted using the best epidemiological approaches. We performed two cross-sectional population-based skin-surveys of children in the Bijagós Archipelago, Guinea-Bissau, using gold-standard sampling methodologies. Skin conditions were extremely common and almost 30% of children had at least one common, infectious skin condition in both surveys. Fungal skin and scalp infections were the most common conditions followed by bacterial skin infections. Our survey demonstrates that common, easily treatable skin conditions are responsible for a high burden of disease in this population. Skin-health should be considered a key component of the Universal Health Coverage agenda.

BackgroundTrachoma, a neglected tropical disease, is the leading infectious cause of blindness and visual impairment worldwide. Host responses to ocular chlamydial infection resulting in chronic inflammation and expansion of non-chlamydial bacteria are hypothesised risk factors for development of active trachoma and conjunctival scarringMethodsOcular swabs from trachoma endemic populations in The Gambia were selected from archived samples for 16S sequencing and host conjunctival gene expression. We recruited children with active trachoma and adults with conjunctival scarring, alongside corresponding matched controls.FindingsIn children, active trachoma was not associated with significant changes in the ocular microbiome.Haemophilusenrichment was associated with antimicrobial responses but not linked to active trachoma. Adults with scarring trachoma had a reduced ocular bacterial diversity compared to controls, with increased relative abundance ofCorynebacterium. Increased abundance ofCorynebacteriumin scarring disease was associated with innate immune responses to the microbiota, dominated by altered mucin expression and increased matrix adhesion.InterpretationIn the absence of currentC. trachomatisinfection, changes in the ocular microbiome associate with antimicrobial and inflammatory responses that impair epithelial cell health. In scarring trachoma, expansion of ‘non-pathogenic’ bacteria such asCorynebacteriumand innate responses are coincident, warranting further investigation of this relationship. Comparisons between active and scarring trachoma supported the relative absence of type-1 interferon responses in scarring, whilst highlighting a common suppression of re-epithelialisation with altered epithelial and bacterial adhesion, likely contributing to development of scarring pathology.

IntroductionScabies is highly endemic among impoverished populations and has been recently included in the WHO’s list of neglected tropical diseases (NTDs). Community support and behavioural changes are essential for the success of control interventions. This study aimed to explore beliefs, prevention attitudes and health care-seeking behaviours towards scabies in the Bijagós Archipelago of Guinea-Bissau.MethodsData were collected through two methods. Community key informants (community members, community health workers, healthcare workers and traditional healers) were interviewed using snowball sampling. A questionnaire covering perceptions, attitudes and practices was administered to community members using random cluster sampling. Thematic analysis of qualitative data was applied to identify themes. Descriptive statistics were used for quantitative data analysis.ResultsThere was a satisfactory awareness about scabies, but perceptions about disease causation and transmission were imprecise. Misconceptions about personal hygiene as the primary measure for scabies prevention were recurrent. Some participants recognised the importance of early treatment to interrupt transmission. Treatment of close contacts was not considered important. Costs were the main determining factor for treatment choice between traditional healer and the local health centre. Late presentation and delayed treatment were common and associated with poverty and stigmatisation. Scabies impaired quality of life by affecting social interactions, health, fitness to work and school attendance.ConclusionsThere is a need to improve education, recognition, management and affordable access to treatment. Community education, healthcare workers’ training and skin NTDs integrated control programmes should address the challenges highlighted in this study.Authors SummaryScabies is a common skin infection in low income settings. We conducted a study in Guinea-Bissau to explore the knowledge, attitudes and practices about scabies. We conducted interviews with healthcare workers, traditional healers and community members and additionally used an oral-administered questionnaire with a larger sample of community residents. Most individuals had knowledge of scabies and were aware that person to person transmission occurred. However personal and environmental hygiene were both incorrectly identified as particularly important in the transmission of scabies. Cost played a major role in determining where individuals sought care and both poverty and disease associated stigma resulted in delays seeking care. There is a need to improve community and health care worker education about scabies and improve affordable access to treatment.

Mass drug administration (MDA) with azithromycin may reduce under-5 child mortality (U5M) in sub-Saharan Africa. Here, we conducted a pooled analysis of all published cluster-randomized trials evaluating the effect of azithromycin MDA on child mortality. We pooled data from cluster-randomized trials randomizing communities to azithromycin MDA versus control. We calculated mortality rates in the azithromycin and control arms in each study, and by country for multisite studies including multiple countries. We conducted a two-stage individual community data meta-analysis to estimate the effect of azithromycin for prevention of child mortality. Three randomized controlled trials in four countries (Ethiopia, Malawi, Niger, and Tanzania) were identified. The overall pooled mortality rate was 15.9 per 1,000 person-years (95% confidence interval [CI]: 15.5–16.3). The pooled mortality rate was lower in azithromycin-treated communities than in placebo-treated communities (14.7 deaths per 1,000 person-years, 95% CI: 14.2–15.3 versus 17.2 deaths per 1,000 person-years, 95% CI: 16.5–17.8). There was a 14.4% reduction in all-cause child mortality in communities receiving azithromycin MDA (95% CI: 6.3–21.7% reduction, P = 0.0007). All-cause U5M was lower in communities receiving azithromycin MDA than in control communities, suggesting that azithromycin MDA could be a new tool to reduce child mortality in sub-Saharan Africa. However, heterogeneity in effect estimates suggests that the magnitude of the effect may vary in time and space and is currently not predictable.

1.ABSTRACTMalawi has successfully leveraged multiple delivery platforms to scale-up and sustain the implementation of preventive chemotherapy (PCT) for the control of morbidity caused by soil-transmitted helminths (STH). Sentinel monitoring demonstrates this strategy has been successful in reducing STH infection in school-age children, although our understanding of the contemporary epidemiological profile of STH across the broader community remains limited. As part of a multi-site trial evaluating the feasibility of interrupting STH transmission across three countries, this survey aimed to describe the baseline demographics and the prevalence, intensity and associated risk factors of STH infection in Mangochi district, southern Malawi. Between October-December 2017, a household census was conducted across the catchment area of seven primary healthcare facilities, enumerating 131,074 individuals across 124 villages. A cross-sectional survey was then conducted between March-May 2018 in the enumerated area as a baseline for a cluster randomised trial. An age-stratified random sample of 6,102 individuals were assessed for helminthiasis by Kato-Katz and completed a detailed risk-factor questionnaire. The age-cluster weighted prevalence of any STH infection was 7.8% (95% C.I. 7.0%-8.6%) comprised predominantly of hookworm species and of entirely low-intensity infections. The presence and intensity of infection was significantly higher in men and in adults. Infection was negatively associated with risk factors that included increasing levels of relative household wealth, higher education levels of any adult household member, current school attendance, or recent deworming. In this setting of relatively high coverage of sanitation facilities, there was no association between hookworm and reported access to sanitation, handwashing facilities, or water facilities. These results describe a setting that has reduced the prevalence of STH to a very low level and confirms many previously recognised risk-factors for infection. Expanding the delivery of anthelmintics to groups where STH infection persist could enable Malawi to move past the objective of elimination of morbidity, and towards the elimination of STH.2.AUTHOR SUMMARYThe major public health strategy to control soil-transmitted helminths (STH) is preventive chemotherapy, whereby those at greatest risk of morbidity – children and women of childbearing age - are presumptively treated with a safe, effective and inexpensive anthelminthic drug. In Malawi, this has been successfully sustained for nearly a decade through annual school-based deworming, in addition to integration within child health campaigns and routine antenatal care. Routine surveillance of schoolchildren demonstrates that STH has been reduced to very low levels in this age group, but few community-based epidemiological surveys have been conducted to investigate STH in the broader population. In this survey, we observed that while infection with STH has been reduced to low levels overall, it is much higher in adults and particularly in males, with the odds of being infected greater in those from less wealthy households or from households with lower levels of adult education. These results underline that while preventive chemotherapy has likely been key to reductions in STH; sub-populations not routinely targeted by preventive chemotherapy, and the most disadvantaged members of society, continue to be disproportionately affected. We propose that evaluation of more comprehensive control strategies – such as entire-community deworming – could overcome these limitations, and present a route to STH elimination.

Introduction A number of neglected tropical diseases are targeted for elimination or eradication. An effective surveillance system is critical to determine if these goals have been achieved and maintained. Trachoma has two related but morphologically different presentations that are monitored for elimination, the active infectious form of trachoma and trachomatous trichiasis (TT), the progression of the disease. There are a number of lessons learnt from the Guinea worm surveillance system that are particularly compatible for TT surveillance and the onchocerciasis surveillance system which can provide insights for surveillance of the infectious form of trachoma. Methods/Principal findings A literature search of peer-reviewed published papers and grey literature was conducted using PUBMED and Google Scholar for articles relating to dracunculiasis or Guinea worm, onchocerciasis and trachoma, along with surveillance or elimination or eradication. The abstracts of relevant papers were read and inclusion was determined based on specified inclusion and exclusion criteria. The credibility and bias of relevant papers were also critically assessed using published criteria. A total of 41 papers were identified that were eligible for inclusion into the review. The Guinea worm programme is designed around a surveillance-containment strategy and combines both active and passive surveillance approaches, with a focus on village-based surveillance and reporting. Although rumour reporting and a monetary incentive for the identification of confirmed Guinea worm cases have been reported as successful for identifying previously unknown transmission there is little unbiased evidence to support this conclusion. More rigorous evidence through a randomised controlled trial, influenced by motivational factors identified through formative research, would be necessary in order to consider applicability for TT case finding in an elimination setting. The onchocerciasis surveillance strategy focuses on active surveillance through sentinel surveillance of villages and breeding sites. It relies on an entomological component, monitoring infectivity rates of black flies and an epidemiological component, tracking exposure to infection in humans. Challenges have included the introduction of relatively complex diagnostics that are not readily available in onchocerciasis endemic countries and target thresholds, which are practically unattainable with current diagnostic tests. Although there is utility in monitoring for infection and serological markers in trachoma surveillance, it is important that adequate considerations are made to ensure evidence-based and achievable guidelines for their utility are put in place. Conclusions/Significance The experiences of both the Guinea worm and onchocerciasis surveillance strategies have very useful lessons for trachoma surveillance, pre- and post-validation. The use of a monetary reward for identification of TT cases and further exploration into the use of infection and serological indicators particularly in a post-validation setting to assist in identifying recrudescence would be of particular relevance. The next step would be a real-world evaluation of their relative applicability for trachoma surveillance., Author summary The design of a surveillance system needs to be carefully thought out to ensure it provides sufficient evidence to determine if a disease or infection is eliminated or eradicated. If inappropriate it can lead to on-going transmission and resurgence of infection or disease or the unnecessary continuation of interventions, wasting valuable resources. Guinea worm is a disease that is painful and debilitating, for which there is no drug or vaccine. The aim is to eradicate the disease and as such the Guinea worm programme is designed around a strategy of identification of cases and their containment to prevent onward transmission. Onchocerciasis if left untreated can lead to blindness. The aim is to eliminate the disease through the interruption of transmission. A literature review was conducted to determine available evidence and identify lessons that can be learnt from the surveillance of both diseases for the design of trachoma surveillance strategies in the endgame. The potential utility of rumour reporting and a monetary incentive for the identification of a confirmed case of Guinea worm could be explored for trichiasis case finding. Trichiasis is the progression of trachoma and leads to significant ocular morbidity. The introduction of tests for infection and antibodies and the utility of sentinel surveillance as utilised for onchocerciasis are interesting considerations for active trachoma surveillance post-validation and has potential to identify recrudescence cost-effectively. The experiences of both the Guinea worm and onchocerciasis surveillance strategies have very useful lessons that can be trialled for trachoma surveillance. However, their real-world applicability and implications for trachoma need to be evaluated before any changes in guidelines are proposed.

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., Author summary Trachoma programs currently use the clinical sign of trachomatous inflammation-follicular (TF) to guide community treatment decisions and evaluate response to mass drug administration with azithromycin. These programs rely on clinical grading that poorly correlates with infection with the causative agent of trachoma, Chlamydia trachomatis (Ct), in low prevalence areas. Serologic measures of Ct may provide additional information about exposure and transmission patterns. Here, we evaluated the relationship between serologic markers of Ct, infection, and TF at the individual and community levels to evaluate the utility of serology for measuring trachoma in a mesoendemic region of Niger. We found that serologic markers correlated with both infection and TF, indicating that inclusion of serologic markers may be useful to guide trachoma decision making.

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.

Purpose The purpose of this study was to assess whether non-chlamydial bacterial infection is associated with progression of trachomatous scarring in adults. Methods This was a cohort study involving 800 participants in northern Tanzania who underwent clinical examination, photography, and conjunctival swab collection for microbiology over a 24-month period. Samples for microbiology were inoculated onto blood and chocolate agar, and Chlamydia trachomatis was detected by PCR. Progression was determined by comparison of baseline to 24-month photographs. Results C. trachomatis was detected in only four participants at baseline. At 24 months, 617 participants (77.1%) were followed up. Of those seen at 24 months, 452 could be reliably assessed. Definite scarring progression (progressors) was seen in 345 (55.9%); there was no progression (nonprogressors) in 107 (17.3%). Using combined baseline and 12-month microbiology results, progressors had significantly higher levels of commensal and pathogenic bacterial organisms detected compared with nonprogressors. After adjusting for age, baseline scarring, and ethnicity, there was weak evidence (P = 0.07) that the bacteria category was associated with scarring progression (commensal organisms only: odds ratio [OR] = 1.61; 95% confidence interval [CI]: 0.90 to 2.89; pathogenic organisms either with or without commensal: OR = 2.39; 95% CI: 1.10 to 5.16). Conclusion The findings were consistent with the possibility that trachomatous scarring in adults is associated with the presence of non-chlamydial bacterial organisms, particularly pathogenic organisms. C. trachomatis was detected very infrequently and may not be an important factor in the pathogenesis of scarring progression in adults. This has implications for trachoma control programs, which largely concentrate on reducing C. trachomatis levels and transmission.

We hypothesized that mass distribution of a broad-spectrum antibiotic agent to preschool children would reduce mortality in areas of sub-Saharan Africa that are currently far from meeting the Sustainable Development Goals of the United Nations.In this cluster-randomized trial, we assigned communities in Malawi, Niger, and Tanzania to four twice-yearly mass distributions of either oral azithromycin (approximately 20 mg per kilogram of body weight) or placebo. Children 1 to 59 months of age were identified in twice-yearly censuses and were offered participation in the trial. Vital status was determined at subsequent censuses. The primary outcome was aggregate all-cause mortality; country-specific rates were assessed in prespecified subgroup analyses.A total of 1533 communities underwent randomization, 190,238 children were identified in the census at baseline, and 323,302 person-years were monitored. The mean (±SD) azithromycin and placebo coverage over the four twice-yearly distributions was 90.4±10.4%. The overall annual mortality rate was 14.6 deaths per 1000 person-years in communities that received azithromycin (9.1 in Malawi, 22.5 in Niger, and 5.4 in Tanzania) and 16.5 deaths per 1000 person-years in communities that received placebo (9.6 in Malawi, 27.5 in Niger, and 5.5 in Tanzania). Mortality was 13.5% lower overall (95% confidence interval [CI], 6.7 to 19.8) in communities that received azithromycin than in communities that received placebo (P0.001); the rate was 5.7% lower in Malawi (95% CI, -9.7 to 18.9), 18.1% lower in Niger (95% CI, 10.0 to 25.5), and 3.4% lower in Tanzania (95% CI, -21.2 to 23.0). Children in the age group of 1 to 5 months had the greatest effect from azithromycin (24.9% lower mortality than that with placebo; 95% CI, 10.6 to 37.0). Serious adverse events occurring within a week after administration of the trial drug or placebo were uncommon, and the rate did not differ significantly between the groups. Evaluation of selection for antibiotic resistance is ongoing.Among postneonatal, preschool children in sub-Saharan Africa, childhood mortality was lower in communities randomly assigned to mass distribution of azithromycin than in those assigned to placebo, with the largest effect seen in Niger. Any implementation of a policy of mass distribution would need to strongly consider the potential effect of such a strategy on antibiotic resistance. (Funded by the Bill and Melinda Gates Foundation; MORDOR ClinicalTrials.gov number, NCT02047981 .).

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.

In a large community-randomized trial, biannual azithromycin distributions significantly reduced postneonatal childhood mortality in sub-Saharan African sites. Here, we present a prespecified secondary analysis showing that much of the protective effect was in the first 3 months postdistribution. Distributing more frequently than biannually could be considered if logistically feasible. Clinical Trials Registration. NCT02047981.

Repeated oral azithromycin distribution targeted only to children has proven effective in reducing the ocular Chlamydia that causes trachoma. Here, we assess whether an enhanced coverage target of at least 90% of children is superior to the World Health Organization recommendation of at least 80%. Twenty-four trachoma-endemic communities in Matamèye, Niger, were randomized to a single day of azithromycin distribution aiming for at least 80% coverage or up to 4 days of treatment and > 90% coverage of children under age 12. All distributions were biannual. Children < 5 years of age and adults > 15 years were monitored for ocular Chlamydia infection by polymerase chain reaction every 6 months for 36 months in children and at baseline and 36 months in adults. Ocular Chlamydia prevalence in children decreased from 24.9% (95% confidence interval [CI] 15.9–33.8%) to 4.4% (95% CI 0.6–8.2%, P < 0.001) at 36 months in the standard coverage arm and from 15.6% (95% CI 10.0–21.2%) to 3.3% (95% CI 1.0–5.5%; P < 0.001) in the enhanced coverage arm. Enhanced coverage reduced ocular Chlamydia prevalence in children more quickly over time compared with standard (P = 0.04). There was no difference between arms at 36 months in children (2.4% lower with enhanced coverage, 95% CI 7.7–12.5%; P = 0.60). No infection was detected in adults at 36 months. Increasing antibiotic coverage among children from 80% to 90% may yield only short term improvements for trachoma control programs. Targeting treatment to children alone may be sufficient for trachoma control in this setting.