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

急性与延迟铁治疗：对铁状态、贫血和认知的影响

基本信息

批准号：
8520359
负责人：
CHANDY C. JOHN
金额：
$ 3.81万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2014-07-31
项目状态：
已结题

项目摘要

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.

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。铁是恶性疟原虫生存所必需的。疟疾治疗时的铁疗法可能会导致寄生虫清除延迟并增加随后患疟疾的风险。相反，疟疾诱导的炎症导致铁代谢的变化（肠铁吸收减少，网状内皮系统中的铁捕获），其可持续>2周，潜在地降低口服铁补充剂的功效。一些研究表明，铁螯合是疟疾贫血的病理生理学的重要组成部分，但很少有评估铁螯合对发育中的大脑的影响。我们有一项正在进行的研究（5 R 01 NS 055349）在乌干达儿童严重疟疾的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立即与延迟治疗缺铁对短期和长期铁状态（目标1），随后的疟疾风险（目标2）和长期神经行为功能（目标3）的影响，并确定介导这些影响的潜在机制。在目标1中，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（铁调素、铁蛋白、α-酸性糖蛋白、细胞因子），并在治疗组之间进行比较。在目标2中，将对疟疾发作进行主动监测，并将在1年随访期内比较立即与延迟铁剂治疗的儿童中疟疾发作的数量。在目标3中，将在入组时以及6个月和12个月后，在本研究中进行的详细认知测试中增加对铁缺乏症特别影响的行为的评估。脑型疟疾患儿的CSF蛋白质组也将与缺铁和非缺铁儿童进行比较。我们希望这项研究将成为我们了解疟疾-铁相互作用如何影响儿童贫血，疟疾风险和神经行为发育的重大进展，并将为未来在疟疾流行地区进行大规模铁补充试验提供基础。公共卫生相关性：疟疾和缺铁在非洲儿童中经常共存，是贫血和认知障碍的主要原因。本研究将评估将铁治疗推迟到疟疾相关炎症减少后是否会导致非洲儿童铁状况、血红蛋白水平以及认知和行为结果的改善。这项研究的信息将指导非洲未来的铁和疟疾干预计划。