Thinking Deeper About Important Mass Treatment Trials

To the Editor—We congratulate Keenan and colleagues [1] on their large and important study of >5500 children aged 1–5 years in rural Ethiopia followed up 26 months after 4914 received a single dose of azithromycin in a mass treatment trial for trachoma, in which they found significant reductions in all-cause child mortality. Their findings illustrate the importance of thinking beyond a single disease affected by interventions. Indeed, it should push us to think well beyond just mortality to underlying morbidities that may influence mortality from other diseases and also have dire lifelong consequences. For example, malnutrition can predispose to deaths from pneumonia or malaria. Furthermore, malnourished children who survive may have lifelong developmental consequences, including impaired cognition, productivity, and overall potential [2]. Because malnutrition can result from intestinal infections that may be substantially reduced by azithromycin, these profound impacts are critical to recognize and quantify. Only with such broader considerations and further study can we adequately assess the true impact of potentially simple interventions. Such were the discoveries that children given a single dose or course of albendazole in randomized, placebo-controlled trials had improved growth and cognitive function, hence elucidating the importance of soil-transmitted helminths to child development [3–8], reminiscent of the broader benefits of reducing child mortality found when children were given vitamin A supplementation to prevent xerophthalmia [9]. We must explore the same for common intestinal protozoa and bacterial infections (near ubiquitous in many areas) that may likewise be critical to early childhood development as well as longer-term outcomes. It would be interesting, for example, if differences emerge in anthropometry (especially height-for-age z scores) or if the all-cause mortality includes differences in specific mortality from malaria or pneumonia in studies such as that of Keenan et al. Such further work may not only document causality but also provide innovative approaches to reducing the huge human burden of impaired physical and cognitive development that currently plagues nearly one-third of all children in developing areas of the world. Although annual global child mortality has fallen to 7.6 million (still >20 000 each day!), fully 178 million children are moderately to severely stunted, implying serious (and urgent) concern for brain development in these vulnerable children [10].