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）：我们对乌干达患有严重疟疾儿童的研究的结果表明，除脑疟疾以外的其他严重疟疾儿童可能具有认知后遗症，并且认知障碍的功能区域，程度和发病机理可能因严重的疟疾类型而有所不同。非洲国家计划从奎宁转到敏捷的治疗严重的疟疾，因为暂停死亡率较低。但是，尚不清楚疟疾严重疟疾儿童神经发育的影响，因为奎宁已用于迄今为止严重疟疾的所有神经发育研究。嘌呤酸盐的作用可能是神经保护作用（例如，寄生虫清除率更快，癫痫发作少，低血糖少于奎宁），但是在某些动物研究中，高剂量的砷酸盐与神经毒性有关。我们建议研究五种最常见的严重疟疾类型的发育后遗症的发病机理，即用秋千治疗的儿童。该研究的中心假设是，不同类型的严重疟疾会影响导致特定功能区域和损害水平的不同致病途径。我们的研究有两个主要目标。目的1是建立受青霉素治疗的儿童受到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，我们将比较患有严重疟疾的儿童的神经，发育和行为障碍的区域和年龄调整水平（脑疟疾[CM] [CM]，严重的疟疾贫血[SMA] [SMA] [SMA]，反复癫痫发作，呼吸困难，呼吸困扰，俯卧）在健康的儿童中治疗12个月，在招生12个月后接受。在目前（奎宁）研究中，将比较患有CM或SMA儿童的儿童的损害水平。目的2是确定与疟疾严重疟疾儿童的神经发育障碍有关的免疫，代谢和营养危险因素。为了实现这一目标，我们将将严重疟疾儿童的危险因素的存在/水平与入学后12个月后的神经系统，发育和行为缺陷水平进行比较。我们将评估血管内和中枢神经系统炎症，代谢变化以及受炎症影响并与发育障碍相关的微量营养素的标志。我们预测，神经发育障碍将以各种形式的严重疟疾存在存在，暂停治疗后的损害水平将低于奎宁治疗后的损害，并且特定的免疫学，代谢和营养因素将与损害的风险相关。我们预计，这项研究将在理解与疟疾相关的发育障碍方面构成重大进步，并将为防止每年出现严重疟疾的数百万儿童的神经发育障碍提供干预措施的基础。