Project 2. Expansion of Clinical Research Capacity at Kenema Government Hospital

项目2.扩大凯内马政府医院的临床研究能力 拉沙病毒（LASV）是沙粒病毒科的成员，是拉沙热（LF）的病原体， 并且常常是致命的出血性疾病。据报道，从西非的几内亚到 东部的尼日利亚。人类主要通过直接或间接接触啮齿类动物的体液感染LASV， Mastomys属，天然水库。医院内传播可导致大规模医院暴发。的 气溶胶传播的可能性和缺乏疫苗导致其被归类为BSL-4， A类选择代理。在20世纪80年代进行的先前研究估计多达300，000人LASV 每年有5,000人死亡。然而，疾病的自然史和死亡率 仍然定义不清。自从这些具有里程碑意义的研究进行以来， LF临床诊断以及流行地区的实验室能力。使用新开发的Ag、IgG和 IgM重组酶联免疫吸附试验（rELISA）和提高能力的网站，我们现在能够准确地研究 病毒血症和免疫反应。这项提议将检验这一假设：IgM的发展，但不是一个 细胞炎症反应，并在症状性LF疾病的早期阶段减少病毒血症 降低死亡率。 目的1是在一个有症状的拉沙热队列中确定拉沙热结局的临床和病毒学决定因素。 拉沙热病人到凯内马政府医院就诊。以前的研究已经确定了几个 预测预后不良的临床特征和临床实验室参数。然而，没有任何研究 确定病毒血症程度是否与临床特征或实验室检查异常相关。我们将测试 假设：长期病毒血症与疾病进展和死亡率增加相关。我们将确定 LF的临床和实验室诊断和预后危险因素，并将其与病毒血症和 mortality.这一目标将建立LF疾病的自然史，并确定时间进程是否可以 如前所述分为不同的阶段。目的2是确定感染和死亡率的生物标志物。 rLASV IgM和IgG ELISA的最新发展以及KGH拉沙热的能力增加 实验室提供了一个独特的机会，以确定特定的免疫与疾病的严重程度和风险， mortality.我们将检验这一假设：体液发育延迟和TH 1增加 炎性免疫应答与死亡率增加相关。我们将把特定的体液和 细胞因子谱与疾病进展和结果。这些研究对未来的设计至关重要 介入性试验和LF和其他病毒性出血热治疗的开发。目标3将 启动临床试验能力培训。在过去的十年里，人们对 LF的发病机制和人体免疫反应。现在需要试验来测试现有的和新的 治疗这种疾病。这一目标的目的是加强该地点以前供资的能力， 培训关键团队成员进行临床试验所需的基本要素。这种培训至关重要， KGH网站将继续为我们的VHF知识和管理策略做出贡献。

Project 2. Expansion of clinical research capacity at Kenema Government Hospital Lassa virus (LASV), a member of the family Arenaviridae, is the etiologic agent of Lassa fever (LF), a severe and often fatal hemorrhagic illness. It has been reported throughout West Africa from Guinea in the west to Nigeria in the east. Humans contract LASV primarily via direct or indirect contact with body fluids of rodents of the genus Mastomys, the natural reservoir. Nosocomial transmission can lead to large hospital outbreaks. The possibility of aerosol transmission and the lack of a vaccine have led to its classification as a BSL-4 and Category A Select Agent. Previous studies performed in the 1980's estimated up to 300,000 human LASV infections per year with 5,000 deaths per year. However, the natural history and mortality rate of disease remain poorly defined. Since these landmark studies were performed, significant advances have been made in LF clinical diagnostics as well as the laboratory capacity in endemic areas. Using newly developed Ag, IgG and IgM recombinant ELISAs (rELISA) and improved capacity at the site, we are now able to accurately study viremia and the immune response. This proposal will test the hypothesis: Development of IgM, but not a cellular inflammatory response, and decline in viremia during the early stages of symptomatic LF disease decreases mortality. Aim 1 is too identify clinical and virological determinants of Lassa fever outcome in a cohort of symptomatic Lassa fever patients presenting to Kenema Government Hospital. Previous studies have identified several clinical features and clinical laboratory parameters that predict a poor prognosis. However, no study has determined if degree of viremia correlates with clinical features or laboratory test abnormalities. We will test the hypothesis: Prolonged viremia correlates with disease progression and increased mortality. We will identify clinical and laboratory diagnostic and prognostic risk factors for LF and correlate them with viremia and risk of mortality. This aim will establish the natural history of LF disease and determine if the time course can be divided into distinct stages as previously suggested. Aim 2 is to identify biomarkers of infection and mortality. Recent development of rLASV IgM and IgG ELISAs as well as increased capacity at the KGH Lassa Fever Laboratory provide a unique opportunity to identify specific immune correlates with disease severity and risk of mortality. We will test the hypothesis: Delayed development of the humoral and an increased TH1 inflammatory immune response correlates with increased mortality. We will correlate specific humoral and cytokine profiles with disease progression and outcome. These studies are critical for the design of future interventional trials and the development of therapies for LF and other viral hemorrhagic fevers. Aim 3 will initiate Clinical trial capacity training. Over the past decade, a significant amount has been learned about the pathogenesis of LF and the human immune response. Trials are now needed to test existing and novel therapies for this disease. The objective of this aim is to build on previously funded capacity at the site and train critical team members in the essential elements needed to conduct clinical trials. This training is critical if the KGH site is to continue to contribute to our knowledge of and management strategies for VHFs.