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个重大公共卫生挑战，每年， 约250，000名患有疟疾的儿童经历了神经损伤，随后出现神经残疾。在其他中央 神经系统（CNS）疾病，发热是继发性神经损伤恶化的公认原因， 为了避免体温过高或诱导体温过低以保护神经，人们进行了大量的努力。证据表明 在患有中枢神经系统疟疾的儿童中，急性疾病期间的体温较高是住院后的一个风险因素， 传染性神经系统后遗症因此，积极的退热治疗可能是必要的，至少在儿童中是如此。 患有复杂性疟疾的人有很大的脑损伤风险。先前进行的临床试验 在患有无并发症疟疾的儿童中，仅使用单一的解热药物显示出有限的 在减少发热方面的好处;然而，迄今为止还没有研究检查疟疾发热管理我们- 双重治疗。在照顾儿童的临床医生中积极采取积极的退烧措施 体外研究发现，疟疾寄生虫的复制在较高的温度下会减慢， 以及一项临床试验，在该试验中，接受fe治疗的儿童外周寄生虫清除较慢， ver.然而，温度和疟原虫行为之间的关系是复杂的。另外的体外 数据表明，在发热温度下，未感染的红细胞（RBC）更容易粘附在感染的红细胞上。 红细胞，恶化的过程隔离，增加寄生虫负担阻碍微血管cere- 脑血流量，并可能有助于持续免疫发病机制中枢神经系统疟疾。在这个探索性的 一项积极的解热治疗的临床试验，患有CNS疟疾的住院儿童将被随机分配到常规治疗组， 护理（对乙酰氨基酚，每6小时一次，温度≥ 38.5ºC）与预防性对乙酰氨基酚和布洛芬 每6小时一次持续72小时这项概念验证研究将确定积极的退热治疗是否 导致平均最高温度相对于常规护理较低。HRP 2的系列定量水平， ciparum特异性蛋白，有助于估计全身寄生虫负荷和CNS寄生虫隔离， 也将收集，以澄清解热药的使用和体内寄生虫行为之间的关系。找到- 这项研究的结果将决定是否进行一项针对神经保护的侵袭性解热药的III期临床试验 在小儿中枢神经系统疟疾应进行。这项研究将在赞比亚和马拉维进行， NIH资助的合作帮助开发了开展临床试验所需的大量基础设施， 这种性质的审判。

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.