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

描述（由申请人提供）：尸检研究显示，三分之一死于临床定义的脑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患儿中很常见。在这种情况下，抗病毒药物从未作为辅助治疗进行过测试。为了合理设计视网膜病变阴性脑疟疾辅助抗病毒治疗的临床试验，必须首先填补几个基本的知识空白。长期目标是降低视网膜病变阴性脑疟疾患儿的发病率或死亡率。这里的目标是追求这一目标的下一步，目的是：确定是否可以使用现成的临床或实验室参数将视网膜阴性CM合并病毒感染的儿童与未合并感染的儿童区分开来；确定病毒合并感染是否会改变发病率或死亡率；并鉴定病毒共感染病原体

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.