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，死于临床定义的脑型疟疾的儿童中有三分之一是由非疟疾原因引起的昏迷。这些儿童在一生中可以被识别，因为他们没有疟疾特异性视网膜病变。初步数据显示，病毒合并感染在视网膜病变阴性脑型疟疾儿童中很常见。抗病毒药物从未在这种情况下作为辅助治疗进行过测试。为了合理设计视网膜病阴性脑型疟疾辅助抗病毒治疗的临床试验，必须首先填补几个基本知识空白。长期目标是降低视网膜病变阴性脑型疟疾儿童的发病率或死亡率。这里的目标，也是实现这一目标的下一步，是：使用现成的临床或实验室参数，确定是否可以将病毒合并感染的视网膜病阴性 CM 儿童与未合并感染的儿童区分开来；确定病毒合并感染的存在是否会改变发病率或死亡率；并识别病毒共感染病原体 来自加纳、乌干达和马拉维的患有视网膜病变阴性脑型疟疾的儿童。中心假设是：现成的临床和实验室参数可以区分 病毒合并感染的风险较高的儿童，病毒合并感染会增加发病率和死亡率，并且病毒合并感染的病原体的特性在西方、东方、 和南部非洲。拟议研究的基本原理是，通过确定最能从干预中受益的患者亚组，可以加强针对视网膜病变阴性脑型疟疾儿童辅助抗病毒治疗的临床试验的制定。具有广泛外部普遍性的临床试验的合理设计需要从多个地理区域识别病毒。该项目将在加纳库马西建设基础设施和人员能力，使他们能够在本项研究和预期的未来研究中成为马拉维布兰太尔的全面合作伙伴。该项目的创新之处在于，它结合了先进的微生物学方法（定量 PCR 和 ELISA）以及患者人口统计、实验室和结果数据的综合数据库，以确定患者特征是否增加了可检测到的中枢神经系统病毒感染的可能性。患有脑疟疾阴性视网膜病变的儿童。它为在加纳和马拉维这两个不同护理水平的地点进行视网膜病阴性脑型疟疾辅助抗病毒治疗的 II 期临床试验奠定了基础。这项拟议的研究意义重大，因为它是连续研究的第一步，预计将为患有视网膜病变阴性脑型疟疾综合征的儿童开发有效的辅助抗病毒疗法。如果此类疗法成功，则有望降低患有这种疾病的儿童的死亡率和神经系统发病率。这项研究是继续努力降低这种破坏性常见疾病的发病率和死亡率的重要一步。