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

描述（由申请人提供）：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，治疗患有疟疾的儿童缺铁是有问题的。铁对恶性疟原虫的生存至关重要。在疟疾治疗期间进行铁疗法可能导致寄生虫清除延迟，并增加随后发生疟疾的风险。相反，疟疾引起的炎症会导致铁代谢的变化（肠道铁吸收减少，铁被困在网状内皮系统中），这种变化可持续50 ~ 2周，可能会降低口服铁补充剂的功效^'^。一些研究表明，铁的隔离是疟疾贫血病理生理的一个重要组成部分，但很少有人评估铁的隔离对发育中的大脑的影响。我们有一项正在进行的研究（5R01NS055349），研究乌干达严重疟疾儿童队列中认知障碍的发病机制。在这个疟疾队列中，我们建议在本研究中评估铁缺乏的即时治疗和延迟治疗对短期和长期铁状态（Aim 1）、后续疟疾风险（Aim 2）和长期神经行为功能（Aim 3）的影响，并确定介导这些影响的潜在机制。在第1阶段，患有严重疟疾的缺铁儿童将随机接受立即或延迟1个月的铁治疗。然后在基线和1、6和12个月后测量血红蛋白、铁状态（ZnPP、铁蛋白、TfR）、红细胞生成（促红细胞生成素、网织红细胞计数）和炎症（hepcidin、铁蛋白、α -酸糖蛋白、细胞因子），并比较治疗组之间的差异。在目标2中，将对疟疾发作进行主动监测，并在1年随访期间比较接受立即和延迟铁治疗的儿童的疟疾发作次数。在Aim 3中，对铁缺乏具体影响的行为的评估将被添加到当前研究中在入组时以及6个月和12个月后进行的详细认知测试中。脑型疟疾患儿脑脊液蛋白质组也将在缺铁和不缺铁患儿中进行比较。我们期望这项研究将为我们理解疟疾-铁相互作用如何影响儿童贫血、疟疾风险和神经行为发育提供重大进展，并为未来在疟疾流行地区进行大规模补铁试验提供基础。

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.