Neurodevelopmental outcomes in children with severe malaria

严重疟疾儿童的神经发育结果

• 批准号: 9196386
• 负责人: CHANDY C. JOHN
• 金额: $ 55.35万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-26 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9196386
• 关键词: Affect; Africa South of the Sahara; African; Age; Anemia; Animals; Area; Attention; Behavioral; Biometry; Brain Injuries; Carboxyhemoglobin; Cerebral Malaria; Cerebrospinal Fluid; Child; Clinical; Cognitive; Coma; Country; Data; Development; Dose; Enrollment; Goals; Hospitals; Hypoglycemia; Immunologics; Impaired cognition; Impairment; Inflammation; Injury; Intervention; Iron; Knowledge; Lactic Acidosis; Lead; Longitudinal Studies; Malaria; Memory; Metabolic; Micronutrients; N,N-dimethylarginine; Neuraxis; Neurodevelopmental Impairment; Neurologic; Neurology; Neuropsychology; Nitric Oxide; Nutritional; Outcome; Oxidative Stress; Parasites; Pathogenesis; Pathogenicity; Pathway interactions; Production; Quinine; Research; Research Infrastructure; Resolution; Respiratory distress; Retrospective Studies; Risk; Risk Factors; Seizures; Survivors; Testing; Uganda; Vitamin A; Vitamin E; artesunate; behavioral impairment; cognitive function; cytokine; inhibitor/antagonist; mortality; neurodevelopment; neurotoxicity; prevent; prostration; public health relevance

DESCRIPTION (provided by applicant): Results from our studies in Ugandan children with severe malaria suggest children with severe malaria other than cerebral malaria may have cognitive sequelae and that the functional areas, degree, and pathogenesis of cognitive impairment may differ by type of severe malaria. African countries plan to switch from quinine to artesunate for treatment of severe malaria because lower mortality has been documented with artesunate treatment. However, the effects of artesunate on neurodevelopment in children with severe malaria are unknown, as quinine has been used in all studies of neurodevelopment in severe malaria to date. Artesunate has effects that may be neuroprotective (e.g., more rapid parasite clearance, fewer seizures, less hypoglycemia than quinine), but high-dose artesunate has been associated with neurotoxicity in some animal studies. We propose to study the pathogenesis of developmental sequelae in the five most common types of severe malaria, in children treated with artesunate. The study's central hypothesis is that different types of severe malaria affect distinct pathogenic pathways leading to specific functional areas and levels of impairment. Our study has two primary aims. Aim 1 is to establish the areas and level of neurodevelopmental function affected by the five major types of severe malaria in children treated with artesunate. To accomplish this aim, we will compare areas and age-adjusted level of neurologic, developmental, and behavioral impairment in children with severe malaria (cerebral malaria [CM], severe malarial anemia [SMA], repeated seizures, respiratory distress, prostration) treated with artesunate versus healthy children, 12 months after enrollment. Level of impairment in children with CM or SMA will be compared between children in the present (artesunate) and in past (quinine) studies. Aim 2 is to identify immunologic, metabolic, and nutritional risk factors associated with neurodevelopmental impairment in children with severe malaria who are treated with artesunate. To accomplish this aim, we will compare the presence/level of risk factors in children with severe malaria to the level of neurologic, developmental, and behavioral deficits 12 months after enrollment. We will assess markers of endovascular and central nervous system inflammation, metabolic changes, and micronutrients that are affected by inflammation and associated with developmental impairment. We predict neurodevelopmental impairment will be present in all forms of severe malaria that level of impairment after artesunate treatment will be lower than after quinine treatment, and that specific immunologic, metabolic, and nutritional factors will be associated with risk of impairment. We expect this study will constitute a significant advance in the understanding of malaria-associated developmental impairment, and will provide a basis for interventions to prevent neurodevelopmental impairment in the millions of children who develop severe malaria every year.

描述（由申请人提供）：我们对乌干达严重疟疾患儿的研究结果表明，除脑型疟疾外，严重疟疾患儿可能有认知后遗症，认知障碍的功能区域、程度和发病机制可能因严重疟疾类型而异。非洲国家计划从奎宁转向青蒿琥酯治疗严重疟疾，因为有记录表明，青蒿琥酯治疗的死亡率较低。然而，青蒿琥酯对严重疟疾患儿神经发育的影响尚不清楚，因为迄今为止，所有关于严重疟疾患者神经发育的研究都使用了奎宁。青蒿琥酯可能具有神经保护作用（例如，与奎宁相比，更快速地清除寄生虫，更少癫痫发作，更少低血糖），但在一些动物研究中，高剂量青蒿琥酯与神经毒性有关。我们建议研究五种最常见类型的严重疟疾的发病机制，在儿童用青蒿琥酯治疗。该研究的中心假设是，不同类型的严重疟疾影响不同的致病途径，导致特定的功能区域和损伤程度。我们的研究有两个主要目的。目标1是确定在接受青蒿琥酯治疗的儿童中，受五种主要类型的严重疟疾影响的神经发育功能的领域和水平。为了实现这一目标，我们将在入组12个月后比较重症疟疾患儿（脑型疟疾[CM]、重度疟疾贫血[SMA]、反复发作、呼吸窘迫、虚弱）与健康儿童的神经、发育和行为障碍的区域和年龄调整水平。将比较目前（青蒿琥酯）和过去（奎宁）研究中患有CM或SMA的儿童的损伤水平。目的2是确定接受青蒿琥酯治疗的严重疟疾患儿中与神经发育障碍相关的免疫、代谢和营养危险因素。为了实现这一目标，我们将在入组12个月后比较患有严重疟疾的儿童中危险因素的存在/水平与神经、发育和行为缺陷的水平。我们将评估血管内和中枢神经系统炎症、代谢变化和受炎症影响并与发育障碍相关的微量营养素的标志物。我们预测所有形式的严重疟疾都会出现神经发育障碍，青蒿琥酯治疗后的损伤水平将低于奎宁治疗后的损伤水平，并且特定的免疫、代谢和营养因素将与损伤风险相关。我们期望这项研究将在理解疟疾相关发育障碍方面取得重大进展，并将为干预措施提供基础，以预防每年数百万患有严重疟疾的儿童的神经发育障碍。