CLINICAL STUDIES

这项研究的长期目标是开发和应用于 早期临床和免疫学参数模型的建立 预测登革热(D)进展的登革病毒感染 严重的出血和休克并发症(DHF/DSS)。这 该项目将涉及一项针对疑似儿童的前瞻性队列研究。 泰国的登革热。研究将分四个阶段进行； 一.试点研究--这一阶段在第一年进行，一直持续到第一年 2，将分析潜在的病毒学和免疫学风险标记物 等离子体显影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由临床决定 研究核心和项目2。临床和实验室观察将 与患有DHF/DSS、D和非登革热疾病的患者相比 为进一步研究找出有前景的预后指标。登革热病毒 将获得DHF/DSS和D患者的分离株进行测序 和动物研究(项目3)。 二、验证研究--这一阶段在第二年和第三年进行，将分析 详细介绍了选定的早期免疫学、病毒学和 随着DHF/DSS的发展，临床标记物在I期确定。 这些结果表征了有益的和免疫病理方面的 对登革热病毒的免疫反应将对发展安全、 有效的疫苗。 干预研究-我们将设计并计划在第四年启动， 一项研究，将使用第二阶段开发的预测模型来选择 DHF/DSS高危人群。我们要测试一下它的疗效 早期开始治疗以降低患者的病情严重程度 对照试验。建议的治疗方法将基于以下假设 I、II期合并DHF/DSS的发病机制 项目2和项目3 IV.长期随访研究--确诊为DHF/DSS或DIN的患者 初步研究将在6个月、12个月和24个月内感染。第I类及 将进行爪状II人类白细胞抗原分型，以评估特定的人类白细胞抗原 单倍型与DHF/DSS的发生有关。的水平 登革热特异性CTL活性、中和和增强抗体将 在这些时间点测量以评估初始 介绍(例如DHF/DSS与D)这些免疫的持久性 回应。

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.