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

项目 2. 凯内马政府医院临床研究能力扩展

• 批准号: 9223661
• 负责人: John Scribner Schieffelin
• 金额: $ 28.66万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9223661
• 关键词: APACHE II; Abnormal Laboratory Test Result; Aerosols; Africa; Anti-Inflammatory Agents; Anti-inflammatory; Area; Arenaviridae; Arenavirus; Biological Markers; Body Fluids; Categories; Cessation of life; Characteristics; Classification; Clinical; Clinical Research; Clinical Trials; Clinical Virology; Collaborations; Conduct Clinical Trials; Contracts; Development; Diagnostic; Diagnostic Trial; Disease; Disease Outbreaks; Disease Outcome; Disease Progression; Elements; Enrollment; Enzyme-Linked Immunosorbent Assay; Etiology; Extravasation; Family member; Funding; Future; Goals; Government; Guinea; Hemorrhage; Hospital Mortality; Hospitalization; Hospitals; Human; Immune; Immune response; Immunoglobulin G; Immunoglobulin M; Infection; Infectious Diseases Research; Inflammatory; Inflammatory Response; Information Resources Management; Institutional Review Boards; International; Intervention; Intervention Trial; Laboratories; Lassa Fever; Lassa virus; Lead; Length of Stay; Liquid substance; Mastomys; Metabolic; Natural History; Nigeria; Outcome; Pathogenesis; Patients; Pilot Projects; Recombinants; Reporting; Risk; Risk Factors; Rodent; Role; SCAP2 gene; Scheme; Severity of illness; Sierra Leone; Site; Staging; Testing; Therapeutic Trials; Time; Training; Ultrasonography; Universities; Vaccines; Viral Hemorrhagic Fevers; Viremia; Virus Diseases; Work; base; clinical diagnostics; cohort; cytokine; design; disorder risk; improved; member; mortality; novel therapeutics; outcome forecast; prognostic; therapy development; tool; transmission process

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.

项目2.扩大凯内马政府医院的临床研究能力 拉萨病毒(Lassa Virus，LASV)是沙蚕病毒科(Arenaviridae)的成员，是一种严重的传染性疾病--拉沙热(Lassa First，LF)的病原。 而且常常是致命的出血性疾病。据报道，从西非的几内亚到西非， 东部的尼日利亚。人类感染LASV主要是通过直接或间接接触鼠类的体液。 马斯提斯属，天然的储水池。医院内传播可导致大规模医院暴发。这个 气雾剂传播的可能性和缺乏疫苗导致它被归类为BSL-4和 A类选择代理。之前的研究是在20世纪80年代进行的，S估计有300,000人LASV 每年有5,000人死于感染。然而，疾病的自然病史和死亡率 仍然没有明确的定义。自从进行这些里程碑式的研究以来，在以下方面取得了重大进展 如临床诊断以及疫区的实验室能力。使用新开发的Ag、Ig G和 免疫球蛋白重组ELISA(REL ISA)和改进的能力，我们现在能够准确地研究 病毒血症和免疫反应。这一提议将检验假设：IgM的发展，但不是 症状性LF病早期的细胞炎症反应和病毒血症的下降 降低死亡率。 目标1是在一组症状队列中确定拉沙热结果的临床和病毒学决定因素 到凯内马政府医院就诊的拉沙热患者。之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，没有研究表明 确定病毒血症的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：长期的病毒血症与疾病进展和死亡率增加相关。我们将确定 肝功能衰竭的临床和实验室诊断及预后危险因素，并与病毒血症和 死亡率。这一目标将建立LF疾病的自然病史，并确定时间进程是否可以 按照前面的建议分为不同的阶段。目标2是确定感染和死亡的生物标志物。 重组LASV Ig M和Ig G EISA的最新进展以及KGH Lassa热病能力的提高 实验室提供了一个独特的机会来确定特定的免疫与疾病严重程度和风险的相关性 死亡率。我们将检验这一假设：体液发育延迟和TH1增加 炎性免疫反应与死亡率的增加相关。我们将把特定的幽默和 细胞因子与疾病进展和结局的关系。这些研究对未来的设计至关重要。 LF和其他病毒性出血热的介入性试验和治疗方法的发展。目标3将 开展临床试验能力培训。在过去的十年里，人们已经了解了大量关于 肝功能衰竭的发病机制与人体免疫反应。现在需要试验来测试现有的和新的 这种疾病的治疗方法。这一目标的目的是在该地点以前资助的能力的基础上进行建设，并 在进行临床试验所需的基本要素方面培训关键团队成员。在以下情况下，此培训至关重要 KGH网站将继续促进我们对VHF的了解和管理策略。