Background

The World Health Organization (WHO) recommends annual mass azithromycin distribution until districts drop below 5% prevalence of trachomatous inflammation-follicular (TF). Districts with very low TF prevalence may have little or no transmission of the ocular strains of Chlamydia trachomatis that cause trachoma, and additional rounds of mass azithromycin distribution may not be useful. Here, we describe the protocol for a randomized controlled trial designed to evaluate whether mass azithromycin distribution can be stopped prior to the current WHO guidelines.

Methods

The Azithromycin Reduction to Reach Elimination of Trachoma (ARRET) study is a 1:1 community randomized non-inferiority trial designed to evaluate whether mass azithromycin distribution can be stopped in districts with baseline prevalence of TF under 20%. Communities in Maradi, Niger are randomized after baseline assessment either to continued annual mass azithromycin distribution or stopping annual azithromycin distribution over a 3-year period. We will compare the prevalence of ocular C. trachomatis (primary outcome), TF and other clinical signs of trachoma, and serologic markers of trachoma after 3 years. We hypothesize that stopping annual azithromycin distribution will be non-inferior to continued annual azithromycin distributions for all markers of trachoma prevalence and transmission.

Discussion

The results of this trial are anticipated to provide potentially guideline-changing evidence for when mass azithromycin distributions can be stopped in low TF prevalence areas. TRIAL REGISTRATION NUMBER: This study is registered at clinicaltrials.gov ( NCT04185402 ). Registered December 4, 2019; prospectively registered pre-results.

Though bulk stool remains the gold standard specimen type for enteropathogen diagnosis, rectal swabs may offer comparable sensitivity with greater ease of collection for select pathogens. This study sought to evaluate the validity and reproducibility of rectal swabs as a sample collection method for the molecular diagnosis of Giardia duodenalis. Paired rectal swab and bulk stool samples were collected from 86 children ages 0-4 years living in southwest Niger, with duplicate samples collected among a subset of 50 children. Infection was detected using a previously validated real-time PCR diagnostic targeting the small subunit ribosomal RNA gene. Giardia duodenalis was detected in 65.5% (55/84) of bulk stool samples and 44.0% (37/84) of swab samples. The kappa evaluating test agreement was 0.81 (95% CI: 0.54-1.00) among duplicate stool samples (N = 49) and 0.75 (95% CI: 0.47-1.00) among duplicate rectal swabs (N = 48). Diagnostic sensitivity was 93% (95% CI: 84-98) by bulk stool and 63% (95% CI: 49-75) by rectal swabs. When restricting to the lowest three quartiles of bulk stool quantitation cycle values (an indication of relatively high parasite load), sensitivity by rectal swabs increased to 78.0% (95% CI: 64-89, P < 0.0001). These findings suggest that rectal swabs provide less sensitive and reproducible results than bulk stool for the real-time PCR diagnosis of G. duodenalis. However, their fair sensitivity for higher parasite loads suggests that swabs may be a useful tool for detecting higher burden infections when stool collection is excessively expensive or logistically challenging.

Antibiotics are recommended by the WHO as part of the management of uncomplicated severe acute malnutrition in children. We evaluated whether azithromycin, an antibiotic with antimalarial properties, improved malarial parasitemia outcomes in children with severe acute malnutrition compared with amoxicillin, an antibiotic commonly used for severe acute malnutrition that does not have antimalarial properties. Total of 301 children were randomized (1:1) to a single oral dose of azithromycin or a 7-day course of amoxicillin and followed for 8 weeks. We found no significant evidence that children receiving azithromycin had improved parasitemia outcomes relative to amoxicillin. Although azithromycin may have advantages over amoxicillin in terms of dosing and administration for uncomplicated severe acute malnutrition, it may not yield additional benefit for malaria outcomes.

Eukaryotic parasites are significant contributors to childhood illness in Niger. While helminthiases have received national attention through mass deworming efforts, the epidemiology of intestinal protozoa in Niger remains underexamined. This study employed real-time PCR diagnostics to describe the prevalence of two schistosomes, four soil-transmitted helminths, and one protozoan parasite in Boboye Department, Dosso Region. Prevalence was assessed using bulk stool specimens collected from a population-based sample of 86 children residing in 9 communities. Anthropometric measurements were used to calculate child growth z-scores and stool consistency was graded. Helminths were absent from the study population, with the exception of a single Schistosoma haematobium infection (1/86; 1.2%). Giardia duodenalis was the only protozoa present, detected in 65% (56/86) of children. Prevalence of G. duodenalis peaked in 2-year-olds with 88% (15/17) positivity. The population was generally undernourished, though growth indices did not differ significantly between children with and without G. duodenalis infection.

We examined whether baseline mortality risk, as a function of child age and site, modified the azithromycin mortality-reduction effect in the Macrolide Oraux pour Réduire les Décès avec un Oeil sur la Résistance (MORDOR) clinical trial. We used the Cox proportional hazards model with an interaction term. Three models were examined representing three sources for the baseline-risk covariate: two using sources external to MORDOR and the third leveraging data within MORDOR. All three models provided moderate evidence for the effect becoming stronger with increasing baseline mortality (P = 0.02, 0.02, and 0.07, respectively) at the rate of approximately 6-12% additional mortality reduction per doubling of baseline mortality. Etiological and programmatic implications of these findings are discussed.

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

Background

Burkina Faso has a seasonal malnutrition pattern, with higher malnutrition prevalence during the rainy season when crop yields are low. We investigated the association between dietary diversity and nutritional status among children aged 6-59 mo during the low crop yield season in rural Burkina Faso to assess the role of dietary diversity during the lean season on childhood nutritional status.

Methods

Caregivers reported the dietary diversity of the past 7 d, consisting of 11 food groups, summed into a scale. Anthropometric measurements were taken from all children. Height-for-age (HAZ), weight-for-height (WHZ) and weight-for-age (WAZ) z-scores were calculated based on 2006 WHO standards. Stunting, wasting and underweight were defined as HAZ, WHZ and WAZ <-2 SD, respectively. Multivariable regression models adjusting for potential confounders including household food insecurity and animal ownership were used to assess the relationship between anthropometric indices and dietary diversity.

Results

Of 251 children enrolled in the study, 20.6% were stunted, 10.0% wasted and 13.9% underweight. Greater dietary diversity was associated with greater HAZ (SD 0.14, 95% CI 0.04 to 0.25) among all children. There was no association between dietary diversity and wasting or mid-upper arm circumference in this study.

Conclusions

Increasing dietary diversity may be an approach to reduce the burden of stunting and chronic malnutrition among young children in regions with seasonal food insecurity.

Background

Given the high risk of infectious mortality among children with severe acute malnutrition (SAM), the World Health Organization recommends routine administration of a broad-spectrum antibiotic like amoxicillin as part of the management of uncomplicated SAM. However, evidence for the efficacy of amoxicillin to improve nutritional recovery or reduce mortality has been mixed. With a long half-life and evidence of efficacy to reduce mortality in high-risk populations, azithromycin is a potential alternative to amoxicillin in the management of SAM. In this pilot study, we aim to compare the efficacy of azithromycin to amoxicillin to improve nutritional outcomes in children with uncomplicated SAM.

Methods

This pilot randomized controlled trial will enroll 300 children with uncomplicated SAM from 6 Centre de Santé et de Promotion Sociale in the Boromo health district in Burkina Faso. Eligible children are randomized to receive a single directly observed dose of oral azithromycin or a 7-day course of oral amoxicillin in addition to the standard package of care for uncomplicated SAM. Enrolled children are followed weekly until nutritional recovery, and all children return for a final study visit at 8 weeks after enrollment. Anthropometric indicators, vital status, and clinical outcomes are monitored at each visit and compared by arm. Primary feasibility outcomes include enrollment potential, refusals, loss to follow-up, and completeness of data collection. The primary clinical outcome is weight gain (g/kg/day) over the 8-week study period.

Discussion

This pilot trial will establish the feasibility of conducting a full-scale randomized controlled trial to evaluate alternative antibiotics in this setting and provide preliminary evidence for the efficacy of azithromycin compared to amoxicillin to improve outcomes for children with SAM.

Trial registration

This trial was first registered on clinicaltrials.gov on 26 June 2018 ( NCT03568643 ).

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

Mass azithromycin distribution has been shown to reduce all-cause mortality in preschool children in sub-Saharan Africa. However, substantial heterogeneity in the apparent effect has been noted across geographic settings, suggesting a greater relative benefit in higher mortality settings. Here, we evaluated the relationship between the underlying mortality rate and the efficacy of azithromycin for the prevention of child mortality using data from multiple sites in Ethiopia, Malawi, Niger, and Tanzania. Between regions, we find no strong evidence of effect modification of the efficacy of azithromycin distribution for the prevention of child mortality by the underlying mortality rate (P = 0.12), although a modest effect is consistent with our findings. Higher mortality settings could be prioritized, however, because of the larger number of deaths which could be averted with azithromycin distribution.