Population-Based Viral Antibody Profiles of Preschool Children in Burkina Faso.

.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.

Respiratory syncytial virus (RSV) is a major cause of serious acute lower respiratory tract infection in infants and the elderly. The lack of a licensed RSV vaccine calls for the development of vaccines with other targets and vaccination strategies. Here, we construct a recombinant protein, designated P-KFD1, comprising RSV phosphoprotein (P) and the E.-coli-K12-strain-derived flagellin variant KFD1. Intranasal immunization with P-KFD1 inhibits RSV replication in the upper and lower respiratory tract and protects mice against lung disease without vaccine-enhanced disease (VED). The P-specific CD4+ Tcells provoked by P-KFD1 intranasal (i.n.) immunization either reside in or migrate to the respiratory tract and mediate protection against RSV infection. Single-cell RNA sequencing (scRNA-seq) and carboxyfluorescein succinimidyl ester (CFSE)-labeled cell transfer further characterize the Th1 and Th17 responses induced by P-KFD1. Finally, we find that anti-viral protection depends on either interferon-γ (IFN-γ) or interleukin-17A (IL-17A). Collectively, P-KFD1 is a promising safe and effective mucosal vaccine candidate for the prevention of RSV infection.

Mass drug administration (MDA) of azithromycin to children has been found to reduce all-cause childhood mortality in some settings.1Keenan JD Bailey RL West SK et al.Azithromycin to reduce childhood mortality in sub-Saharan Africa.N Engl J Med. 2018; 378: 1583-1592Crossref PubMed Scopus (165) Google Scholar Although the underlying mechanism is unclear, presumably azithromycin MDA interrupts transmission of pathogens that cause mortality. The global child health community has subsequently debated where, when, and how to use azithromycin as part of a comprehensive child survival strategy. Patricia Pavlinac and colleagues (November, 2021)2Pavlinac PB Singa BO Tickell KD et al.Azithromycin for the prevention of rehospitalisation and death among Kenyan children being discharged from hospital: a double-blind, placebo-controlled, randomised controlled trial.Lancet Glob Health. 2021; 9: e1569-e1578Summary Full Text Full Text PDF PubMed Scopus (2) Google Scholar report the results of the Toto Bora trial—an individually randomised placebo-controlled trial that compared a 5-day course of azithromycin with placebo for prevention of mortality or rehospitalisation in children aged 1–59 months at hospital discharge. Although mortality was common in this population, Pavlinac and colleagues found no evidence of a benefit with azithromycin compared with placebo. In a Comment on the Article,3Gatimu SM Kimani RW Does mass drug administration of azithromycin reduce child mortality?.Lancet Glob Health. 2021; 9: e1485-e1486Summary Full Text Full Text PDF PubMed Scopus (1) Google Scholar Samwell Gatimu and Rachel Kimani argue that additional individually randomised trials are needed to understand the effect of azithromycin MDA on childhood mortality and its underlying mechanism. The intervention studied in the Toto Bora trial is, by design, not MDA. The goal of MDA is to interrupt transmission of pathogens and prevent morbidity by treating all members of a community simultaneously, regardless of the presence of infection. Studies with individually randomised interventions cannot evaluate the impact of MDA—a community-level intervention. The Toto Bora investigators appropriately used an individually randomised design to evaluate an individual health outcome. Children recently discharged from the hospital are at much higher risk of mortality than are children in the general population, and targeted treatment strategies could maximise the benefit of azithromycin for saving lives while minimising selection for antibiotic resistance. Childhood mortality in Kenya has dramatically declined in recent years, and azithromycin MDA for childhood mortality is not indicated according to recent WHO guidelines. Trials like Toto Bora are important to understand any role of azithromycin for specific high-risk individuals. However, they should not be confused with studies aiming to evaluate azithromycin MDA in an entire population, which have the goal of reducing population-level mortality rates.4Rose G Sick individuals and sick populations.Int J Epidemiol. 1985; 14: 32-38Crossref PubMed Scopus (2183) Google Scholar With infectious disease and MDA, an individual's exposure status is not independent of others in their community. Trials evaluating interventions involving MDA should be designed from a population perspective and use community-level randomisation. Although individually randomised trials yield important information about targeting azithromycin to reduce mortality in high-risk children from an individual perspective, they answer substantially different questions than do cluster randomised trials.5Hayes RJ Moulton LH Cluster randomised trials. Chapman and Hall/CRC, Boca Raton2017Google Scholar Individually randomised trials cannot answer mechanistic questions about effects observed in cluster randomised trials of MDA. We declare no competing interests. Azithromycin for the prevention of rehospitalisation and death among Kenyan children being discharged from hospital: a double-blind, placebo-controlled, randomised controlled trialWe did not observe a significant benefit of a 5-day course of azithromycin delivered to children younger than 5 years at hospital discharge despite the overall high risk of mortality and rehospitalisation. These findings highlight the need for more research into mechanisms and interventions for prevention of morbidity and mortality in the post-discharge period. Full-Text PDF Open Access

Mass drug administration of azithromycin: an analysis

ObjectivesChlamydia trachomatis is the most common bacterial sexually transmitted infection and is frequently asymptomatic; ocular C. trachomatis strains cause trachoma. Mass drug administration (MDA) of azithromycin for trachoma might also...

Trachoma is the world’s most frequent cause of blindness from an infectious agent. The disease caused by infection is associated with lack of access to sanitation and low hygiene standards. Trachoma is controlled through the Surgery, Antibiotics, Facial cleanliness, and Environmental improvement (SAFE) strategy, which delivers azithromycin (AZM) mass drug administration (MDA) in endemic areas. The putative vector Musca sorbens principally reproduce in human faecal matter left in the environment due to open defecation. Ivermectin (IVM) is on the WHO’s essential medicines list and is administered as preventative chemotherapy against two neglected tropical diseases (NTDs)—onchocerciasis, as an annual or bi-annual treatment, and lymphatic filariasis, as an annual treatment in combination with albendazole. Ivermectin has a known inhibitive effect on insects that reproduce in dung. To assess if IVM could be a viable vector control tool against M. sorbens, this study evaluates existing data from trachoma, onchocerciasis and lymphatic filariasis mass drug administration (MDA) operations in Ethiopia. Persistent and recrudescent trachoma in evaluation units (EUs) were examined for whether AZM MDA in EUs was accompanied by IVM MDA, and whether co-administration was associated with greater likelihood of trachoma control. Results show an association suggesting that EUs that received both IVM and AZM MDA benefit from improved control of trachoma in persistent or recrudescent areas, when compared to EUs that received AZM MDA. This initial investigation supports the potential for ivermectin’s use to support SAFE. Findings warrant further work to validate ivermectin’s impact on M. sorbens reproduction through controlled lab and field-based studies.

Definitions for coronavirus disease 2019 reinfection, relapse and PCR re-positivity

The effects of azithromycin mass drug administration (MDA) on trachoma and yaws have been addressed. However, the secondary effects of azithromycin MDA remain unclear. This study aimed to explore the secondary effects of azithromycin MDA. PubMed, Embase, Cochrane Library, Web of Science, and ClinicalTrials.gov were searched from conception to January 5, 2022. Studies on secondary effects of azithromycin MDA were included. A total of 34 studies were included. Six of them reported on child mortality, 10 on malaria, and 20 on general morbidity and condition. Azithromycin MDA reduced child mortality, and quarterly MDA may be most beneficial for reducing child mortality. The effect of azithromycin MDA on malaria was weak. No association was observed between azithromycin MDA and malaria parasitemia (rate ratio: 0.71, 95% confidence interval: 0.43-1.15). Azithromycin MDA was associated with a lower risk of respiratory tract infections and diarrhea. Additionally, it was associated with a lower risk of fever, vomiting, and headache. The carriage of pathogenic organisms such as Streptococcus pneumoniae and gut Campylobacter species was reduced. However, these secondary effects of azithromycin MDA appeared to last only a few weeks. Moreover, no association was observed between azithromycin MDA and nutritional improvement in children. In conclusion, azithromycin MDA had favorable secondary effects on child mortality and morbidity. However, the effects were short term.

BackgroundAs new interventions to reduce childhood mortality are identified, careful consideration must be given to identifying populations that could benefit most from them. Promising reductions in childhood mortality reported in a large cluster randomized trial of mass drug administration (MDA) of azithromycin (AZM) prompted the development of visually compelling, easy-to-use tools that synthesize country-specific data on factors that would influence both potential AZM benefit and MDA implementation success.Methodology/Principal FindingsWe assessed the opportunity to reduce mortality and the feasibility of implementing such a program, creating Opportunity and Feasibility Indices, respectively. Countries with high childhood mortality were included. A Country Ranking Index combined key variables from the previous two Indices and applied a scoring system to identify high-priority countries. We compared four scenarios with varying weights given to each variable.Twenty-five countries met inclusion criteria. We created easily visualized tools to display the results of the Opportunity and Feasibility Indices. The Opportunity Index revealed substantial variation in the opportunity for an MDA of AZM program to reduce mortality, even among countries with high overall childhood mortality. The Feasibility Index demonstrated that implementing such a program would be most challenging in the countries that could see greatest benefit. Based on the Country Ranking Index, Equatorial Guinea would benefit the most from the MZA of AZM in three of the four scenarios we tested.Conclusions/SignificanceThese visually accessible tools can be adapted or refined to include other metrics deemed important by stakeholders, and provide a quantitative approach to prioritization for intervention implementation. The need to explicitly state metrics and their weighting encourages thoughtful and transparent decision making. The objective and data-driven approach promoted by the three Indices may foster more efficient use of resources.

Commentary on: Keenan JD, Bailey RL, West Sk, et al . Azithromycin to reduce childhood mortality in sub-Saharan Africa. N Engl J Med 2018;378:1583–92. A recent study by Keenan and...

High prevalence of pre-existing serological cross-reactivity against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in sub-Saharan Africa

Exudative cutaneous ulcers (CU) in yaws-endemic areas are associated with Treponema pallidum subsp. pertenue (TP) and Haemophilus ducreyi (HD), but one-third of CU cases are idiopathic (IU). Using mass drug administration (MDA) of azithromycin, a yaws eradication campaign on Lihir Island in Papua New Guinea reduced but failed to eradicate yaws; IU rates remained constant throughout the campaign. To identify potential etiologies of IU, we obtained swabs of CU lesions (n = 279) and of the skin of asymptomatic controls (AC; n = 233) from the Lihir Island cohort and characterized their microbiomes using a metagenomics approach. CU bacterial communities were less diverse than those of the AC. Using real-time multiplex PCR with pathogen-specific primers, we separated CU specimens into HD-positive (HD+), TP+, HD+TP+, and IU groups. Each CU subgroup formed a distinct bacterial community, defined by the species detected and/or the relative abundances of species within each group. Streptococcus pyogenes was the most abundant organism in IU (22.65%) and was enriched in IU compared to other ulcer groups. Follow-up samples (n = 31) were obtained from nonhealed ulcers; the average relative abundance of S. pyogenes was 30.11% in not improved ulcers and 0.88% in improved ulcers, suggesting that S. pyogenes in the not improved ulcers may be azithromycin resistant. Catonella morbi was enriched in IU that lacked S. pyogenes As some S. pyogenes and TP strains are macrolide resistant, penicillin may be the drug of choice for CU azithromycin treatment failures. Our study will aid in the design of diagnostic tests and selective therapies for CU.IMPORTANCE Cutaneous ulcers (CU) affect approximately 100,000 children in the tropics each year. While two-thirds of CU are caused by Treponema pallidum subspecies pertenue and Haemophilus ducreyi, the cause(s) of the remaining one-third is unknown. Given the failure of mass drug administration of azithromycin to eradicate CU, the World Health Organization recently proposed an integrated disease management strategy to control CU. Success of this strategy requires determining the unknown cause(s) of CU. By using 16S rRNA gene sequencing of swabs obtained from CU and the skin of asymptomatic children, we identified another possible cause of skin ulcers, Streptococcus pyogenes Although S. pyogenes is known to cause impetigo and cellulitis, this is the first report implicating the organism as a causal agent of CU. Inclusion of S. pyogenes into the integrated disease management plan will improve diagnostic testing and treatment of this painful and debilitating disease of children and strengthen elimination efforts.

Anti–SARS-CoV-2 Antibody Responses in Patients With IBD Treated With Biologics: Are We Finding CLARITY?

Background.Trials have demonstrated that azithromycin mass drug administration (MDA) to children 1–59 months old reduces mortality, but increases antimicrobial resistance (AMR). The World Health Organization recommends that programs include mortality and AMR monitoring. Niger is expanding the azithromycin MDA for child survival program nationwide.Methods.To establish program monitoring and leverage the infrastructure to evaluate other community health interventions, AVENIR II is designed as a cluster-randomized adaptive platform trial with monitoring and re-randomization every 2 years. The initial focus is to monitor under-5 mortality, AMR, implementation, and safety as the program expands in Niger. All eligible primary health center catchment areas (Centre de Santé Intégrés, CSIs) will be included in biannual oral azithromycin MDA to children 1–59 months old. A subset will be randomized to delay MDA for the first 2 years, after which they will receive MDA and another subset will be randomized to stop MDA for the next 2 years. The proportion randomized to delay or stop will be determined using an adaptive algorithm including: 1) results of prior azithromycin MDA mortality trials, 2) expert opinion on the appropriate ethical balance between delivering the program and monitoring AMR, and 3) statistical power to detect a programmatically relevant difference between arms. We anticipate 5–10% of CSIs will be randomized to delay or stop at each randomization. Mortality and AMR will be monitored at baseline and every 2 years. Implementation and safety outcomes will be monitored continuously. To enable ongoing monitoring while ensuring program access, CSIs receiving MDA will be re-randomized using the adaptive algorithm updated with new mortality results and no CSI will go without MDA for more than 2 years. In this platform design, additional arms may be added or dropped based on information from other studies, updates to guidelines, or preferences of Niger policymakers, and other interventions may be evaluated.Discussion.The risk of AMR has led to caution in the implementation of azithromycin MDA. We present a design that enables continued rigorous evaluation of program impact on key outcomes, with flexibility to evaluate other interventions as well.Trial registration.clinicaltrials.gov (NCT06358872), registered April 2024

Safety of integrated mass drug administration of azithromycin, albendazole and ivermectin versus standard treatment regimens: a cluster-randomised trial in Ethiopia