Acute vs. Delayed Iron: Effect on Red Cell Iron Incorporation in Severe Malaria

描述(由申请人提供)：撒哈拉以南非洲地区每年约有100万儿童死于严重贫血。这种严重的贫血通常是由铁缺乏和疟疾感染共存引起的，但在一些研究中，标准的护理，同时铁治疗和抗疟疾治疗，在治愈深度贫血方面被证明是无效的，并促进了寄生虫的增殖。针对疟疾的促炎免疫反应下调了肠道对铁的吸收，使得在疟疾感染期间提供口服铁补充剂的效用受到质疑。本研究建议使用铁稳定同位素和随机设计来测试在抗疟疾治疗后立即开始4周或4周后开始铁治疗是否与最初给铁时更多的铁进入红细胞和改善长期血液学恢复有关。100名在乌干达坎帕拉穆拉戈医院儿科急诊病房就诊的6-36岁有疟疾临床症状的乌干达重度贫血(血红蛋白5-7.9g/dL)儿童，将在抗疟治疗后第0天(即刻组)或4周后的第28天(延迟组)被随机分成两组，立即开始铁剂治疗。儿童将在第0天、第28天和第56天在医院接受评估，并将在56天的研究期间接受每周两次的家访。拟议研究的具体目标和相应的假设是：目标1：确定抗疟疾治疗和铁治疗的顺序，从而在 首次补铁的时间。工作假设是，在儿童开始服用补充剂时，红细胞铁的掺入程度会更高。 与在抗疟疾治疗的同时开始铁治疗的儿童(即刻组)相比，在抗疟疾治疗后4周开始补铁(延迟组)，由于寄生虫更彻底的清除和炎症的消退，允许更好的铁摄取、分布和利用。目的2：确定即刻铁与延迟铁对长期血液学恢复是否有影响。工作假说是，延迟铁治疗与立即治疗相比，在第56天将与更多的血红蛋白和铁状态改善相关，这是因为延迟治疗组的寄生虫清除更彻底，从而改善了铁的吸收和使用。这项研究的结果将为抗疟疾治疗和铁治疗的最佳时机建立一个生理学框架，在此基础上可以建立未来旨在改善疟疾流行地区铁状况的干预措施，从而有助于降低发病率和死亡率，并确保数百万患有缺铁和疟疾的严重贫血儿童的神经行为全面发育。

DESCRIPTION (provided by applicant): Approximately 1 million children < 5 y living in sub-Saharan Africa die from severe anemia annually. This severe anemia frequently results from coexisting iron deficiency and malaria infection, but the standard of care, concurrent iron therapy and antimalarial treatment, has proven ineffective at curing the profound anemia and has promoted proliferation of the parasite in some studies. The pro-inflammatory immune response mounted against malaria down-regulates iron absorption in the gut, making provision of oral iron supplements during malarial infection of questionable utility. The present study proposes to use iron stable isotopes and a randomized design to test whether starting 4 weeks of iron therapy immediately after antimalarial treatment or 4 weeks later is associated with greater iron incorporation into red blood cells at the time of initial administration of iron theray and improved long-term hematological recovery. One hundred severely anemic (hemoglobin 5-7.9 g/dL) Ugandan children 6-36 mos with clinical signs of malaria who present to the Pediatric Acute Care Ward of Mulago Hospital in Kampala, Uganda, will be randomized to start iron immediately after antimalarial treatment on Day 0 (immediate group) or 4 weeks later on Day 28 (delayed group). Children will be assessed at the hospital on Day 0, Day 28 and Day 56 and will receive bi-weekly home visits for the 56-day study duration. The specific aims and corresponding hypotheses of the proposed study are: Aim 1: Identify the sequencing of antimalarial treatment and iron therapy that results in the greatest red cell iron incorporation at the time of initial iron supplement administration. The working hypothesis is that red cell iron incorporation will be greater at the time of initial supplement administration in children starting iron 4 weeks after antimalarial treatment (delayed group) compared to children starting iron concurrently with antimalarial treatment (immediate group), due to more complete parasite clearance and resolution of inflammation, permitting better iron uptake, distribution, and utilization. Aim 2: Determine whether long-term hematological recovery is impacted by immediate vs. delayed iron. The working hypothesis is that delayed iron treatment will be associated with greater hemoglobin and improved iron status at Day 56 compared to immediate treatment due to more complete parasite clearance and consequent improved iron absorption and use in the delayed group. The results of this study will establish a physiologically-based framework for the optimal timing of antimalarial treatment and iron therapy upon which future interventions aimed at improving iron status in malaria-endemic regions can be built, thus helping to reduce the morbidity and mortality and ensure the full neurobehavioral development of the millions of severely anemic children suffering from iron-deficiency and malaria.