Viral Co-Infections in Cerebral Malaria: Preparing for Clinical Trials

脑型疟疾的病毒合并感染：为临床试验做准备

• 批准号: 8617351
• 负责人: Douglas Postels
• 金额: $ 14.31万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-20 至 2016-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8617351
• 关键词: Address; Africa; Antiviral Agents; Antiviral Therapy; Area; Autopsy; Caring; Central Nervous System Viral Diseases; Cerebral Malaria; Cerebrovascular Circulation; Characteristics; Child; Clinical; Clinical Trials; Clinical Trials Design; Coma; Country; Data; Databases; Development; Diagnosis; Drug Formulations; Eastern Africa; Enzyme-Linked Immunosorbent Assay; Erythrocytes; Future; Geographic Locations; Ghana; Goals; Human Resources; Infection; Intervention; Knowledge; Laboratories; Lead; Life; Malaria; Malawi; Medical Research; Methods; Morbidity - disease rate; Neuraxis; Neurologic; Outcome; Parasites; Patients; Performance; Phase II Clinical Trials; Regimen; Research; Research Infrastructure; Resources; Retinal Diseases; Seizures; Site; Southern Africa; Subgroup; Syndrome; Testing; Uganda; Viral; Virus; Virus Diseases; Western Africa; White Blood Cell Count procedure; Work; base; design; high risk; innovation; mortality; pathogen; public health relevance; skills; therapy design

DESCRIPTION (provided by applicant): Autopsy studies reveal that one third of children dying of clinically defined cerebral malaria have a non- malarial cause of coma. During life these children can be identified as they lack a malaria-specific retinopathy. Preliminary data show that viral co-infection is common in children with retinopathy negative cerebral malaria. Antiviral agents have never been tested as adjunctive therapy in this condition. To proceed with rational design of a clinical trial of adjunctive antiviral therapy in retinopathy negative cerebral malaria several fundamental knowledge gaps must first be filled. The long-term goal is to decrease rates of morbidity or mortality in children with retinopathy negative cerebral malaria. The objectives here, which are the next step in pursuit of that goal, are: to determine if children with retinopaty negative CM with a viral co-infection can be differentiated from those without co-infection using readily available clinical or laboratory parameters; to determine if the presence of viral co-infection changes rates of morbidity or mortality; and to identify viral co- infecting pathogens in children with retinopathy negative cerebral malaria from Ghana, Uganda, and Malawi. The central hypotheses are that: readily available clinical and laboratory parameters can differentiate children at higher risk of viral co-infection, that viral co-infection increases rates of morbidityand mortality, and that the identities of viral co-infecting pathogens are similar in western, eastern, and southern Africa. The rationale for the proposed research is that formulation of a clinical tria of adjunctive antiviral therapy for children with retinopathy negative cerebral malaria may be strengthened by identification of a patient subgroup that may most benefit from the intervention. Rational design of a clinical trial with wide external generalizability requires identifying viruse from multiple geographic areas. This project will build infrastructure and personnel capacity in Kumasi, Ghana, to allow them to be a full partner with Blantyre, Malawi, in this and anticipated future studies. This project is innovative in that it combines advanced microbiological methods (quantitative PCR and ELISA) and a comprehensive database of patient demographic, laboratory, and outcome data to determine if there are patient characteristics that increase the likelihood of a detectable central nervous system viral infection in a child with retinopathy negative for cerebral malaria. It lays the groundwork for the performance of a Phase II clinical trial of adjunctive antiviral therapy in retinopathy negative cerebral malaria in Ghana and Malawi, sites of differing levels of care. The proposed study is significant because it is the firs step in a continuum of research that is expected to lead to development of effective adjunctive antiviral therapies for children with the retinopathy negative cerebral malaria syndrome. If such therapies are successful, there is the promise that rates of mortality and neurologic morbidity in children with this condition may be decreased. This study is an important step in the path toward continued efforts to decrease rates of morbidity and mortality from this devastating common condition.

描述（由申请人提供）：尸检研究表明，死于临床定义的脑疟疾的儿童中有三分之一具有昏迷的非疟疾原因。在生命中，这些孩子可以被确定，因为他们缺乏特异性的视网膜病。初步数据表明，病毒共同感染在视网膜病阴性脑疟疾的儿童中很常见。在这种情况下，从未将抗病毒药作为辅助治疗进行测试。为了进行视网膜病阴性脑疟疾辅助性抗病毒疗法的临床试验的合理设计，必须首先填补一些基本知识差距。长期目标是降低视网膜病阴性脑疟疾儿童的发病率或死亡率。这里的目标是追求该目标的下一步，是：确定具有病毒共同感染的视网膜阴性CM儿童是否可以使用随时可用的临床或实验室参数来区分没有共同感染的孩子；确定病毒共感染的存在是否会改变发病率或死亡率的发生率；并确定病毒感染病原体 来自加纳，乌干达和马拉维的视网膜病变阴性脑疟疾的儿童。中心假设是：随时可用的临床和实验室参数可以区分 病毒共同感染风险较高的儿童，病毒共同感染会增加发病率和死亡率，并且在西部，东部，东方，病毒共同感染的病原体的身份相似 和南部非洲。拟议研究的理由是，可以通过鉴定可能从干预措施中受益最大的患者亚组来加强视网膜病阴性脑疟疾儿童的辅助抗病毒疗法的临床三亚疗法。具有广泛外部概括性的临床试验的合理设计需要从多个地理区域识别病毒。该项目将在加纳的库马西建立基础设施和人员能力，以使他们能够与马拉维的布兰蒂尔（Blantyre）成为完整的合作伙伴，并在这一预期的未来研究中。该项目具有创新性，因为它结合了先进的微生物方法（定量PCR和ELISA）以及患者人口统计学，实验室和结果数据的全面数据库，以确定患者特征是否会增加患有脑因脑性脑疟疾的视网膜疾病的儿童感染的可检测到的中枢性中枢神经系统病毒感染的可能性。它为在加纳和马拉维的视网膜病阴性脑疟疾阴性的辅助性抗病毒疗法进行II期临床试验的基础上奠定了基础。拟议的研究很重要，因为这是一项连续研究的FIR步骤，预计会导致为患有视网膜病阴性大脑疟疾综合征的儿童的有效辅助抗病毒药疗法发展。如果这种疗法是成功的，则有望降低患有这种疾病儿童的死亡率和神经系统发病率。这项研究是努力从这种毁灭性的共同条件中降低发病率和死亡率的持续努力的重要步骤。