Acute vs. delayed iron therapy: effect on iron status, anemia and cognition

描述(申请人提供)：疟疾和缺铁在非洲儿童中经常共存。这两种情况都是贫血和认知障碍的主要原因。然而，疟疾儿童缺铁的治疗是有问题的。铁是恶性疟原虫生存所必需的。在治疗疟疾时进行铁剂治疗可能会导致寄生虫清除延迟，并增加随后感染疟疾的风险。相反，疟疾引起的炎症会导致铁代谢的改变(肠道铁吸收减少，网状内皮系统铁捕获)，这种变化可持续2周，有可能降低口服补铁剂的疗效。一些研究表明，铁的封存是疟疾贫血病理生理学的重要组成部分，但很少有人评估铁封存对发育中的大脑的影响。我们正在进行一项关于患有严重疟疾的乌干达儿童队列中认知障碍发病机制的研究(5R01NS055349)。在这一疟疾队列中，我们在本研究中建议评估立即和延迟治疗缺铁对短期和长期铁状态(目标1)、后续疟疾风险(目标2)和长期神经行为功能(目标3)的影响，并确定调节这些影响的潜在机制。在目标1中，铁缺乏的严重疟疾儿童将被随机接受立即或延迟一个月的铁质治疗。分别于治疗前、治疗后1、6、12个月检测血红蛋白、铁状态(锌锌蛋白、铁蛋白、转铁蛋白)、红细胞生成素(促红细胞生成素、网织红细胞计数)和炎症反应(肝素、铁蛋白、α-酸性糖蛋白、细胞因子)，并进行组间比较。在目标2中，将对疟疾发病进行积极监测，并将在一年的随访期内比较立即铁剂治疗和延迟铁剂治疗的儿童的疟疾发病率。在目标3中，对特定受缺铁影响的行为的评估将被添加到目前研究中实施的详细认知测试中，在注册时以及6个月和12个月后。患有脑型疟疾的儿童的脑脊液蛋白质组也将在缺铁和不缺铁的儿童中进行比较。我们预计，这项研究将在我们理解疟疾-铁相互作用如何影响儿童贫血、疟疾风险和神经行为发育方面取得重大进展，并将为未来疟疾流行地区的大规模补铁试验提供基础。 与公共卫生有关：疟疾和缺铁在非洲儿童中经常并存，是贫血和认知障碍的主要原因。目前的研究将评估将铁治疗推迟到疟疾相关炎症减轻后是否会改善非洲儿童的铁状况、血红蛋白水平以及认知和行为结果。这项研究的信息将指导非洲未来的铁和疟疾干预计划。

DESCRIPTION (provided by applicant): Malaria and iron deficiency frequently coexist in African children. Both conditions are major causes of anemia and cognitive impairment. However, treatment of iron deficiency in children with malaria is problematic. Iron is essential for P. falciparum survival. Iron therapy at the time of malaria treatment may lead to delayed parasite clearance and an increased risk of subsequent malaria. Conversely, malaria- induced inflammation leads to changes in iron metabolism (reduced intestinal iron absorption, iron trapping in the reticuloendothelial system) that can persist for >2 weeks, potentially reducing the efficacy of oral iron supplements^'^. Several studies suggest that sequestering of iron is an important component in the pathophysiology of malarial anemia, but few have assessed the effect that iron sequestration has on the developing brain. We have an ongoing study (5R01NS055349) on the pathogenesis of cognitive impairment in a cohort of Ugandan children with severe malaria. Within this malaria cohort, we propose in the present study to evaluate the effects of immediate vs. delayed treatment of iron deficiency on short and long-term iron status (Aim 1), risk of subsequent malaria (Aim 2), and long-term neurobehavioral function (Aim 3), and to identify potential mechanisms that mediate these effects. In Aim 1, children with severe malaria who are iron-deficient will be randomized to receive immediate or 1-month-delayed iron treatment. Hemoglobin, iron status (ZnPP, ferritin, TfR), erythropoiesis (erythropoietin, reticulocyte count) and inflammation (hepcidin, ferritin, alphal-acid glycoprotein, cytokines) will then be measured at baseline and 1, 6 and 12 months later and compared between treatment groups. In Aim 2, cctive surveillance for malaria episodes will be performed, and number of malaria episodes will be compared in children with immediate vs. delayed iron treatment over the 1-year period of follow-up. In Aim 3, evaluation of behaviors specifically affected by iron deficiency will be added to the detailed cognitive testing administered in the current study at enrollment and 6 and 12 months later. The CSF proteome in children with cerebral malaria will also be compared in those with and without iron deficiency. We expect that this study will constitute a major advance in our understanding of how malaria-iron interactions influence anemia, malaria risk and neurobehavioral development in children, and will provide a foundation for future large-scale iron supplementation trials in malaria endemic areas. PUBLIC HEALTH RELEVANCE: Malaria and iron deficiency frequently coexist in African children and are major causes of anemia and cognitive impairment. The present study will assess whether delaying iron treatment until after malaria- related inflammation is reduced leads to improved iron status, hemoglobin level and cognitive and behavioral outcomes in children in Africa. Information from this study will guide future iron and malaria intervention programs in Africa.