CLINICAL STUDIES

本研究的长期目标是开发并应用于 临床设置一个模型的临床和免疫学参数的早期 登革热病毒感染，可预测登革热的进展（D） 严重并发症出血和休克（DHF/DSS）。 这 该项目将涉及一项前瞻性队列研究的儿童疑似 登革热在泰国 研究将分四个阶段进行; I. 试点研究-该阶段，在第1年进行，并持续到第2年 2，将分析潜在的病毒学和免疫学标志物的风险， 血浆显影DHF/DSS。 T细胞和单核细胞活化水平， PBMC的细胞因子和病毒感染将通过临床试验确定。 研究核心和项目2。 临床和实验室观察结果将 与DHF/DSS、D和非登革热发热性疾病患者相比， 确定有希望的预后标志以供进一步研究。 登革病毒 将从DHF/DSS和D患者中获得分离株进行测序 动物实验（3）。 二. 验证研究-该阶段在第2年和第3年进行，将分析 详细研究了选定的早期免疫学、病毒学和 临床标志物，在I期确定，随着DHF/DSS的发展。 这些结果表征了 对登革病毒的免疫应答在开发安全， 有效的疫苗。 三. 干预研究-我们将设计，并计划在第4年启动， 一项研究将使用第二阶段开发的预测模型， DHF/DSS高风险患者。 我们将测试 早期开始治疗，以降低疾病的严重程度， 对照试验 提出的治疗方法将基于以下假设： I期和II期产生的DHF/DSS的发病机制与 项目2和3 四. 长期随访研究-确诊DHF/DSS或D的患者 初步研究将观察6、12和24个月的感染情况。 I类和 将进行claws II HLA分型，以评估是否有特定的HLA 单倍型与DHF/DSS的发生有关。 水平 登革特异性CTL活性，中和和增强抗体将被 在这些时间点测量，以评估初始 呈现（例如DHF/DSS与D）对这些免疫的持久性 应答

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.