Blantyre Malaria Project, Queen Elizabeth Central Hospital, Blantyre, Malawi.
Department of Biostatistics and Computational Biology, University of Rochester, Rochester, New York, United States of America.
PLoS One. 2022 Oct 7;17(10):e0268414. doi: 10.1371/journal.pone.0268414. eCollection 2022.
Malaria remains a major public health challenge in Africa where annually, ~250,000 children with malaria experience a neurologic injury with subsequent neuro-disability. Evidence indicates that a higher temperature during the acute illness is a risk factor for post-infectious neurologic sequelae. As such, aggressive antipyretic therapy may be warranted among children with complicated malaria at substantial risk of brain injury. Previous clinical trials conducted primarily 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 using dual therapies. In this clinical trial of aggressive antipyretic therapy, children hospitalized with central nervous system (CNS) malaria will be randomized to usual care (acetaminophen every 6 hours for a temperature ≥ 38.5°C) vs. prophylactic acetaminophen and ibuprofen every 6 hours for 72 hours.
In this double-blinded, placebo controlled, two-armed clinical trial, we will enroll 284 participants from three settings at Queen Elizabeth Central Hospital in Blantyre, Malawi; at the University Teaching Hospitals Children's Hospital in Lusaka, Zambia and at Chipata Central Hospital, Chipata, Zambia. Parents or guardians must provide written informed consent. Eligible participants are 2-11 years with evidence of P. falciparum malaria infection by peripheral blood smear or rapid diagnostic test with CNS symptoms associated with malaria. Eligible children will receive treatment allocation randomization either to standard of care for fever management or to prophylactic, scheduled treatment every 6 hours for 72 hours with dual antipyretic therapies using acetaminophen and ibuprofen. Assignment to treatment groups will be with 1:1 allocation using blocked randomization. The primary outcome will be maximum temperature in the 72 hours after enrolment. Secondary outcomes include parasite clearance as determined by quantitative Histidine Rich Protein II and seizures through 72 hours after enrolment.
This clinical trial seeks to challenge the practice paradigm of limited fever treatment based upon hyperpyrexia by evaluating the fever-reduction efficacy of more aggressive antipyretic using two antipyretics and prophylactic administration and will elucidate the impact of antipyretics on parasite clearance and acute symptomatic seizures. If aggressive antipyretic therapy is shown to safely reduce the maximum temperature, a clinical trial evaluating the neuroprotective effects of temperature reduction in CNS malaria is warranted.
疟疾仍然是非洲的一个主要公共卫生挑战，每年约有 25 万名患有疟疾的儿童出现神经损伤，随后出现神经残疾。有证据表明，急性疾病期间体温较高是发生感染后神经后遗症的一个危险因素。因此，对于存在严重脑损伤风险的合并疟疾儿童，可能需要积极的退热治疗。之前的临床试验主要在没有并发症的疟疾儿童中进行，且仅使用单一的退热药物，结果表明在降低体温方面获益有限；然而，迄今为止尚无研究使用双药疗法来管理疟疾发热。在这项积极退热治疗的临床试验中，患有中枢神经系统（CNS）疟疾的住院儿童将被随机分配至常规治疗组（体温≥38.5°C 时每 6 小时给予对乙酰氨基酚）与预防性每 6 小时给予对乙酰氨基酚和布洛芬 72 小时组。
在这项双盲、安慰剂对照、双臂临床试验中，我们将从马拉维布兰太尔伊丽莎白女王中央医院、赞比亚卢萨卡大学教学医院儿童医院和赞比亚奇帕塔中央医院招募 284 名参与者。父母或监护人必须提供书面知情同意书。符合条件的参与者为 2-11 岁，外周血涂片或快速诊断检测显示有恶性疟原虫感染，且有与疟疾相关的中枢神经系统症状。符合条件的儿童将接受治疗分配随机分组，要么接受常规发热管理，要么接受 72 小时内每 6 小时给予两次退热药物（对乙酰氨基酚和布洛芬）的预防性、计划治疗。采用区组随机化进行治疗组分配，1:1 分配。主要结局是入组后 72 小时内的最高体温。次要结局包括通过定量富组氨酸蛋白 II 确定的寄生虫清除率和入组后 72 小时内的癫痫发作。
这项临床试验旨在通过评估更积极的退热治疗（使用两种退热药物和预防性给药）的退热效果，挑战基于高热而有限退热治疗的实践模式，并阐明退热对寄生虫清除和急性症状性癫痫发作的影响。如果积极的退热治疗能安全地降低最高体温，则有必要进行评估 CNS 疟疾中降低体温的神经保护作用的临床试验。
