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.

PUBLIC HEALTH RELEVANCE: One third of children with clinically defined cerebral malaria have a non-malarial cause of coma and can be identified during life as they lack a malarial retinopathy. Preliminary data reveal that one third of these children with retinopathy negative cerebral malaria have a viral co-infection. In children with retinopathy negative cerebral malaria, we will identify viral co-infecting pathogens, determine if the presence of a viral co-infecting pathogen changes rates of morbidity or mortality, and investigate whether children with viral co-infection can be identified using routine laboratory or clinical parameters.