Aggressive Antipyretics in CNS Malaria: A Randomized-Controlled Trial Assessing Antipyretic Efficacy and Parasite Clearance

尽管正在努力根除疟疾，但疟疾仍然是非洲的一大公共卫生挑战，每年， 约250,000名疟疾儿童经历了神经损伤并随后出现神经残疾。在其他中环 神经系统(CNS)障碍，发烧是公认的继发性神经损伤恶化的原因，前 紧张性努力是为了避免体温过高或诱导体温过低以保护神经。有证据表明 在患有中枢神经系统疟疾的儿童中，急性疾病期间体温较高是后住院的一个危险因素。 神经学后遗症。因此，积极的退热治疗可能是必要的，至少在儿童中是如此。 患有复杂疟疾的儿童，有很大的脑损伤风险。之前进行的临床试验主要是- 在患有简单疟疾和只使用一种解热药物的儿童中，玛丽亚的表现有限 在退烧方面的好处；然而，到目前为止，还没有研究检查我们对疟疾热的管理- ING双重疗法。照顾儿童的临床医生对积极退烧措施的热情 通过体外研究发现，疟疾寄生虫的复制在较高的温度下会放缓，从而遏制了疟疾 以及一项单一的临床试验，在该试验中，接受FE治疗的儿童外周寄生虫清除较慢。 别.。然而，温度和疟疾寄生虫行为之间的关系是复杂的。附加体外试验 数据表明，在高温下，未受感染的红细胞(RBC)更有可能附着在受感染的 红细胞，恶化隔离过程，增加阻碍微血管细胞的寄生虫负担。 脑血流，可能在中枢神经系统疟疾正在进行的免疫发病机制中起作用。在这个探索性的 积极退热治疗的临床试验，中枢性疟疾住院儿童将随机分为正常组 CARE(扑热息痛每6小时一次，温度为≥38.5°C)与预防性服用扑热息痛和布洛芬的对比 每6小时一次，共72小时。这项概念验证研究将确定积极的退热疗法 结果平均最高温度比平时护理的要低。HRP2的连续定量水平，一种P.fal- 寄生虫特异性蛋白，有助于估计全身寄生虫负担和中枢神经系统寄生虫隔离- 也将收集，以澄清退热药使用和体内寄生虫行为之间的关系。找到- 这项研究的INGS将确定积极退烧药用于神经保护的第三阶段临床试验 在儿科中枢神经系统应开展疟疾防治工作。这项研究将在赞比亚和马拉维进行，此前 NIH资助的合作帮助开发了开展临床所需的大量基础设施- 这种性质的Cal审判。

Despite ongoing eradication efforts, malaria remains a major public health challenge in Africa where annually, ~250,000 children with malaria experience a neurologic injury with subsequent neurodisability. In other central nervous system (CNS) disorders, fever is a recognized cause of worsening secondary neurologic injury and ex- tensive efforts are made to avoid hyperthermia or induce hypothermia for neuroprotection. Evidence indicates that among children with CNS malaria a higher temperature during the acute illness is a risk factor for post-in- fectious neurologic sequelae. As such, aggressive antipyretic therapy may be warranted, at least among chil- dren with complicated malaria who are at substantial risk of brain injury. Previous clinical trials conducted pri- marily in children with uncomplicated malaria and using only a single antipyretic medication have shown limited benefits in terms of fever reduction; however, no studies to date have examined malaria fever management us- ing dual therapies. Enthusiasm for aggressive fever reduction measures among clinicians caring for children with malaria has been curbed by in vitro findings that malaria parasite replication slows at higher temperatures and a single clinical trial in which peripheral parasite clearance was slower in children receiving treatment for fe- ver. However, the relationship between temperature and malaria parasite behavior is complex. Additional in vitro data suggest that at febrile temperatures uninfected red blood cells (RBCs) are more likely to adhere to infected RBCs, worsening the process of sequestration, increasing the parasite burden obstructing microvascular cere- bral blood flow, and perhaps contributing to ongoing immuno-pathogenesis in CNS malaria. In this exploratory clinical trial of aggressive antipyretic therapy, children hospitalized with CNS malaria will be randomized to usual care (acetaminophen every 6 hours for a temperature ≥ 38.5ºC) vs. prophylactic acetaminophen and ibuprofen every 6 hours for 72 hours. This proof-of-concept study will determine whether aggressive antipyretic therapy results in a lower mean maximum temperature relative to usual care. Serial quantitative levels of HRP2, a P. fal- ciparum-specific protein that facilitates estimates of whole body parasite burden and CNS parasite sequestra- tion, will also be collected to clarify the relationship between antipyretic use and in vivo parasite behavior. Find- ings from this study will determine whether a Phase III clinical trial of aggressive antipyretics for neuroprotection in pediatric CNS malaria should be undertaken. This study will take place in Zambia and Malawi, where prior NIH-funded collaborations have assisted in developing the substantial infrastructure needed to undertake a clini- cal trial of this nature.