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

描述（由申请人提供）：尸检研究表明，三分之一死于临床定义的脑型疟疾的儿童有非疟疾原因的昏迷。在生活中，这些儿童可以被确定为他们缺乏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的脑型疟疾儿童中很常见。抗病毒药物从未被测试为这种情况下的连续治疗。为了进行视网膜病变阴性脑型疟疾连续抗病毒治疗临床试验的合理设计，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。这里的目标是追求该目标的下一步，是：确定是否可以使用容易获得的临床或实验室参数将患有视网膜病变阴性CM的儿童与病毒合并感染的儿童与没有合并感染的儿童区分开;确定病毒合并感染的存在是否改变发病率或死亡率;以及确定是否存在病毒合并感染的病原体。 来自加纳、乌干达和马拉维的视网膜病变阴性脑型疟疾儿童。中心假设是：现有的临床和实验室参数可以区分 儿童病毒合并感染的风险较高，病毒合并感染增加了发病率和死亡率，病毒合并感染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，通过确定可能从干预中获益最多的患者亚组，可以加强视网膜病变阴性脑型疟疾儿童连续抗病毒治疗的临床试验。具有广泛外部推广性的临床试验的合理设计需要确定来自多个地理区域的风险。该项目将在加纳的库马西建设基础设施和人员能力，使他们能够在本研究和预期的未来研究中成为马拉维布兰太尔的正式合作伙伴。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）和患者人口统计学，实验室和结果数据的综合数据库，以确定是否有患者特征增加了脑型疟疾视网膜病变阴性儿童可检测到中枢神经系统病毒感染的可能性。它为在加纳和马拉维进行视网膜病变阴性脑型疟疾的连续性抗病毒治疗的第二阶段临床试验奠定了基础，这两个国家的护理水平不同。这项研究意义重大，因为它是一系列研究的第一步，有望为视网膜病变阴性脑型疟疾综合征儿童开发有效的抗病毒治疗。如果这种治疗是成功的，有希望的死亡率和神经系统的发病率在儿童与这种情况可能会减少。这项研究是朝着继续努力降低这种破坏性常见疾病的发病率和死亡率的道路上迈出的重要一步。

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.