Optimizing Benefits While Reducing Risks of Iron in Malaria-Endemic Areas

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ABSTRACT Ensuring sufficient iron for the brain development of tens of millions of children living in malaria-endemic areas while also protecting them from infection has been an unachieved public health goal for more than a decade. Iron supplementation in these global areas is linked with increased risks of malaria and other infections. One solution to safely and effectively treat coexisting malaria and iron deficiency is to stagger the interventions, treating malaria first and delaying the start of iron until 28 days later. Preliminary data from our recent R03 pilot study demonstrate that this strategy causes the hepatic protein hepcidin to decline, allowing oral iron to be better absorbed and incorporated into hemoglobin, and also reduces the risk of infections in the short-term.11 The objective of this application is to conduct a placebo-controlled, randomized clinical trial to determine whether iron treatment begun concurrently with vs. 28 days after antimalarial treatment in Ugandan children 6- 48 months with malaria and iron deficiency results in better long-term iron status, fewer infections, and better neurobehavioral development after 12 months. The central hypothesis is that better iron incorporation and lower incidence of infectious illness observed with 28-day delayed iron in the R03 study with only 8 weeks follow-up will translate into sustained improvements iron status, lowered risk of infection, and improved cognitive and behavioral outcomes. The rationale of this study is that staggering antimalarial treatment and iron therapy protects against immediate morbidity while also optimizing long-term neurobehavioral development. Guided by strong preliminary data, the specific aims are: 1) Establish the effect of immediate vs. delayed iron treatment on long-term iron status; 2) Determine the effect of delayed iron treatment on the incidence of infectious illness; and 3) Establish the effect of delayed iron treatment on neurobehavioral development. Analysis of the gut microbiome in the delayed and immediate iron group will provide insight into potential mechanisms of any observed differences in morbidity between the groups. The translational research team is uniquely suited to assess neurobehavioral outcomes, a critical, but typically unmeasured functional outcome of a successful management approach for iron deficiency and infection. Establishment of methods to safely and effectively ensure brain iron while also protecting from infection will permit attainment of full cognitive and behavioral development for tens of millions of children worldwide suffering from iron deficiency and malaria.