Neurodevelopmental outcomes in children with severe malaria

严重疟疾儿童的神经发育结果

• 批准号: 9040687
• 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/9040687
• 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; Health; Hospitals; Hypoglycemia; Immunologics; Impaired cognition; Impairment; Inflammation; Injury; Intervention; Iron; Knowledge; Lactic Acidosis; Lead; Longitudinal Studies; Malaria; Memory; Metabolic; Micronutrients; Neuraxis; Neurodevelopmental Impairment; Neurologic; Neurology; Neuropsychology; Nitric Oxide; Nutritional; Outcome; Oxidative Stress; Parasites; Pathogenesis; Pathway interactions; Production; Quinine; Research; Research Infrastructure; Resolution; Respiratory distress; Retrospective Studies; Risk; Risk Factors; Seizures; Survivors; Testing; Uganda; Vitamin A; Vitamin E; Work; artesunate; base; behavioral impairment; cognitive function; cytokine; dimethylarginine; inhibitor/antagonist; mortality; neurodevelopment; neurotoxicity; prevent; prostration

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）：我们在乌干达重度疟疾儿童中进行的研究结果表明，除脑型疟疾外，重度疟疾儿童可能有认知后遗症，并且认知障碍的功能区、程度和发病机制可能因重度疟疾类型而异。非洲国家计划在治疗严重疟疾时从奎宁改为青蒿琥酯，因为青蒿琥酯治疗的死亡率较低。然而，青蒿琥酯对重症疟疾儿童神经发育的影响尚不清楚，因为迄今为止，所有重症疟疾神经发育研究都使用了奎宁。青蒿琥酯具有神经保护作用（例如，与奎宁相比，青蒿琥酯清除寄生虫更快，癫痫发作更少，低血糖症更少），但在一些动物研究中，高剂量青蒿琥酯与神经毒性有关。我们建议研究青蒿琥酯治疗的儿童中五种最常见的严重疟疾类型的发育后遗症的发病机制。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。目的1是确定青蒿琥酯治疗的儿童中受五种主要类型的重症疟疾影响的神经发育功能的区域和水平。为了实现这一目标，我们将在入组后12个月，对接受青蒿琥酯治疗的重度疟疾（脑型疟疾[CM]、重度疟疾性贫血[SMA]、反复癫痫发作、呼吸窘迫、虚脱）儿童与健康儿童的神经功能、发育和行为障碍的区域和年龄调整水平进行比较。将比较本研究（青蒿琥酯）和既往研究（奎宁）中CM或SMA儿童的损伤程度。目的2是确定免疫，代谢和营养的危险因素与神经发育障碍的儿童严重疟疾谁是青蒿琥酯治疗。为了实现这一目标，我们将比较严重疟疾儿童的危险因素的存在/水平与入组后12个月的神经、发育和行为缺陷水平。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。我们预测神经发育障碍将存在于所有形式的严重疟疾中，青蒿琥酯治疗后的障碍水平将低于奎宁治疗后，特定的免疫，代谢和营养因素将与障碍的风险相关。我们预计这项研究将在了解疟疾相关的发育障碍方面取得重大进展，并将为预防每年数百万患有严重疟疾的儿童的神经发育障碍的干预措施提供基础。