The long-term objective of this study is to develop and apply to the clinical setting a model of clinical and immunologic parameters of early dengue virus infection which predict the progression from dengue fever (D) to the serious complications of hemorrhage and shock (DHF/DSS). This project will involve a prospective cohort study of children with suspected dengue in Thailand. The study will be conducted in four phases; I. Pilot Study - The phase, conducted in year 1 and continuing into year 2, will analyze potential virologic and immunologic markers of risk for plasma developing DHF/DSS. The levels of T cell and monocyte activation, cytokines, and virus infection of PBMC will be determined by the clinical research core and Project 2. Clinical and laboratory observations will be compared in patients with DHF/DSS, D, and nondengue febrile illness to identify promising prognostic markes for further study. Dengue virus isolates from patients with DHF/DSS and D will be obtained for sequencing and animal studies (Projects 3). II. Validation Study - This phase, conducted in years 2 & 3, will analyze in detail the association of selected early immunologic, virologic, and clinical markers, determined in phase I, with the development of DHF/DSS. These results characterizing beneficial and immunopathological aspects of immune responses to dengue virus will be important in developing safe, effective vaccines. III. Intervention Study - We will design, and plan to initiate in year 4, a study that will use the predictive model developed in phase II to select patients who are at high risk for DHF/DSS. We will test the efficacy of early initiation of therapy in reducing the severity of illness in a controlled trial. The therapy proposed will be based on the hypotheses of pathogenesis of DHF/DSS generated in phases I and II in conjunction with projects 2 and 3 IV. Long-term Follow-up Study - Patients with confirmed DHF/DSS or D in the pilot study will be seen 6, 12, and 24 months infection. Class I and claws II HLA typing will be performed to assess whether specific HLA haplotypes are associated with the development of DHF/DSS. The levels of dengue-specific CTL activity, neutralizing and enhancing antibodies will be measured at these time points to assess the influence of initial presentation (e.g. DHF/DSS vs D) on the persistence of these immune responses.
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