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

摘要 确保疟疾流行地区数千万儿童大脑发育所需的足够铁 而保护他们免受感染也是十多年来未能实现的公共卫生目标。 这些全球地区的铁补充与疟疾和其他感染的风险增加有关。一 安全有效地治疗同时存在的疟疾和缺铁症的解决办法是错开干预， 首先治疗疟疾，并推迟到28天后才开始补铁。我们最近的R 03飞行员的初步数据 研究表明，这种策略导致肝蛋白铁调素下降，允许口服铁， 更好地吸收和纳入血红蛋白，也降低了短期感染的风险。11 本申请的目的是进行一项安慰剂对照、随机临床试验，以确定 在乌干达6岁以下儿童中，铁治疗是否与抗疟治疗同时开始， 48个月的疟疾和缺铁导致更好的长期铁状态，更少的感染， 12个月后的神经行为发育。核心假设是，更好的铁结合和 在R 03研究（仅8周）中，28天延迟补铁观察到的感染性疾病发生率较低 后续将转化为持续改善铁的状态，降低感染的风险，并改善 认知和行为结果。这项研究的基本原理是，惊人的抗疟治疗和 铁剂治疗可防止即刻发病，同时还可优化长期神经行为 发展在强有力的初步数据的指导下，具体目标是：1）建立即时与即时的效果。 延迟铁治疗对长期铁状态的影响; 2）确定延迟铁治疗对长期铁状态的影响。 感染性疾病的发病率; 3）确定延迟铁治疗对神经行为的影响 发展对延迟和立即补铁组的肠道微生物组的分析将提供对以下方面的深入了解： 组间观察到的任何发病率差异的潜在机制。翻译研究 团队是唯一适合评估神经行为结果，一个关键的，但通常无法衡量的功能 这是一个成功的缺铁和感染管理方法的结果。建立方法， 安全有效地确保脑铁，同时也保护免受感染，将允许达到充分的 为全球数千万患有缺铁症的儿童提供认知和行为发展 和疟疾。

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.