HANTAVIRUS ECOLOGY AND DISEASE IN CHILE AND PANAMA

描述(申请人提供)：汉坦病毒是美国国立卫生研究院A类病原体，包括在北美、中美洲和南美洲引起汉坦病毒心肺综合征(HCPS)的病毒。智利(384例)和阿根廷(595例)报告的猪瘟病例和死亡病例，尽管人口要少得多，但数量超过了美国的报告病例(379例)，北美和南美洲的病例死亡率保持在36-38%。目前还没有已知的有效治疗方法或疫苗。在项目1，安第斯山脉和乔克洛病毒的生态，我们将研究智利和巴拿马的啮齿动物水库的生态，以开发预测模型和快速解释远程监测的结果，以指导公共卫生干预。在项目2，HCPS的治疗和预防中，我们将完成对心肺期疑似HCPS患者静脉注射甲基强的松龙的对照试验，继续通过血浆置换采集Andes病毒感染幸存者的血浆，并使用具有高滴度Andes病毒中和活性(HIP)的免疫血浆进行三项临床试验。HIP的第一个试验将是第一阶段，a)正常成年人和b)HCPS患者的剂量递增安全性和药代动力学试验。第二个试验将是一项针对高危人群的HIP安全性和有效性的公开试验。高危人群是高危人群(高危人群的性伴侣，其高危人群的风险为20%)。第三项试验将是对心肺期疑似HCPS患者进行的髋关节对照试验。在项目3中，我们将改进我们的研究，试图了解哪些因素使性伴侣的感染风险明显高于非性伴侣的家庭接触。我们将a)前瞻性跟踪性伴侣家庭接触者，b)进行问卷调查，以评估共同来源暴露、性行为和深吻等风险，以及c)研究生殖器、口腔和真皮分泌物，包括每天在家收集唾液拭子，以确定是否可以通过聚合酶链式反应识别安第斯病毒RNA，以及是否可以从聚合酶链式反应阳性的样本中培养出病毒。 项目1：安第斯病毒和乔克罗病毒的生态学(Glass，G.) 项目1说明(申请人提供)：由西半球任何一种汉坦病毒引起的汉坦病毒心肺综合征被认为是通过吸入受感染的啮齿动物排泄物而感染的。在智利南部和中部，安第斯病毒感染长尾寡齿啮齿动物，并导致一种罕见但严重的人类感染，死亡率高。在巴拿马西部，乔克罗病毒感染啮齿动物富氏寡妇，并导致一种常见的但通常轻微或不明显的人类感染，死亡率较低。在这两个地区，传播风险似乎受到许多因素的影响，这增加了受感染的啮齿动物与易感人群之间密切接触的机会。我们将重点调查其中三个因素，目的是获得对设计未来环境干预措施以减少汉坦病毒传播至关重要的见解。 首先，最近在智利和巴拿马的调查表明，感染风险与受感染的媒介啮齿动物所青睐的选定植被栖息地有关。在智利，可以通过卫星图像分析对全国三分之二的地区进行遥感来预测暴露风险。在巴拿马，一项微观分析表明，受感染的啮齿动物与农业活动之间存在复杂的关系。我们建议重点研究啮齿动物和栖息地随时间的空间关系，使用标记-重新捕获诱捕和无线电遥测来标记啮齿动物的运动，特别是在齿周环境中。其次，我们将创建一个动态模型，扩展我们目前对风险的静态分析。新模型将应用图论来现场收集啮齿动物栖息地偏好和在景观中的移动数据，以预测受感染的啮齿动物可能的移动。我们将使用来自不同站点的数据来测试模型，这些站点不是用于创建模型的站点。通过量化冬季(低传播期)和春季(高传播期)啮齿动物血液、组织和尿液中的病毒载量，将提高模型的时间精度。最后，巴拿马高危人群的连续血清调查将量化啮齿动物密度和活动的时空变化对人类感染的影响。

DESCRIPTION (provided by applicant): Hantaviruses are NIH category A pathogens, including the viruses that cause hantavirus cardiopulmonary syndrome (HCPS) in North, Central and South America. Reported cases and deaths from HCPS in Chile (384) and Argentina (595), despite much smaller populations, outnumber cases reported in the United States (379), and case fatality rates remain at 36-38% in North and South America. There is no known effective treatment or vaccine. In Project 1, Ecology of Andes and Choclo Viruses, we will study the ecology of the rodent reservoirs in Chile and Panama to develop predictive models and rapid interpretation of results from remote monitoring to guide public health intervention. In Project 2, Treatment and Prevention of HCPS, we will complete a controlled trial of intravenous methylprednisolone in persons with suspected HCPS in the cardiopulmonary phase, continue collection of plasma by plasmapheresis of survivors of Andes virus infection and perform three clinical trials with immune plasma with high titers of Andes virus neutralizing activity (HIP). The first trial with HIP will be a phase I, dose-escalation safety and pharmacokinetics trial in a) normal adults and b) persons with HCPS. The second trial will be an open safety and efficacy trial of HIP in persons at high risk of developing HCPS (sex partners of index patients with HCPS who have a 20% risk of developing HCPS). The third trial will be a controlled trial of HIP in persons with suspected HCPS in the cardiopulmonary phase. In Project 3, we will refine our studies to try to learn what factors put sex partners at significantly higher risk of infection than nonsex partner household contacts. We will a) prospectively follow sex partner household contacts, b) administer questionnaires to assess risks such as common source exposure, sexual practices and deep kissing and c) study genital, oral and dermal secretions, including daily home collection of saliva swabs, to determine whether Andes virus RNA can be identified by PCR and whether virus can be cultured from PCR-positive samples. PROJECT 1: Ecology of Andes & Choclo Viruses (Glass, G.) PROJECT 1 DESCRIPTION (provided by applicant): Hantavirus cardiopulmonary syndrome resulting from any of a number of hantaviruses in the western hemisphere is thought to be contracted through inhalation of infected rodent excreta. In southern and central Chile, the Andes virus infects the sigmodontine rodent Oligoryzomys longicaudatus, and causes a rare but severe human infection with high mortality. In western Panama, the Choclo virus infects the rodent Oligoryzomys fulvescens and causes a common but usually mild or inapparent human infection with a low mortality rate. In both regions the risk of transmission appears to be influenced by many factors increasing the opportunity for close contact between infected rodents and susceptible humans. We will focus our investigations on three of these factors, with the goal of gaining insights critical for the design of future environmental interventions to decrease hantavirus transmission. First, recent investigations in Chile and Panama have associated risk of infection with selected vegetation habitats favored by the infected vector rodents. In Chile exposure risk can be predicted by remote sensing with satellite imagery analysis over 2/3 of the country. In Panama a micro scale analysis has suggested complex relationships between peridomestic infected rodents and agricultural activities. We propose to focus on spatial relationships between rodents and habitats over time, using mark-recapture trapping and radiotelemetry to mark rodent movements, particularly in peridomestic environments. Second we will create a dynamic model that extends our current static analysis of risk. The new model will apply graph theory to field collected data of rodent habitat preferences and movements within the landscape to predict the likely movement of infected rodents. We will test the model using data from sites different from those used to create the model. The temporal precision of the model will be improved by quantitating viral load in rodent blood, tissue, and urine in the winter (low transmission) and spring (high transmission) seasons. Finally, serial serosurveys of at-risk human populations in Panama will quantify the impact on human infection associated with spatial-temporal variations in rodent density and movement.