Clinical Sequelae and Urogenital Viral Dynamics in Survivors of Ebola Virus Disease

项目总结 肆虐西非的埃博拉疫情在几个月内从一个地区性的 人道主义危机演变为全球公共卫生紧急状态。超过27,000例感染和11,000多例感染 世界卫生组织(WHO)报告的死亡人数--已经低估了 令之前所有埃博拉疫情的感染和死亡人数相形见绌 震级。虽然埃博拉疫情已经消退，甚至可能已经结束，但埃博拉的临床并发症 数千名幸存者中的大多数人都患有病毒病(EVD)。我们的工作和他人的工作 表明肌肉骨骼、神经和眼部并发症即使在两年后也会持续存在 从急性埃博拉病毒病中恢复。此外，有证据表明，可以持续地减少 在幸存者的精液和阴道液中至少有病毒RNA，这可能是传染性疾病存在的信号 病毒和/或用于刺激可能产生某些埃博拉后症状的免疫反应。这个 以前的疫情规模较小，缺乏足够的基础设施来收集、处理和 在现场分析样本限制了我们对埃博拉幸存者自然历史的理解。 这项建议的主要目标是更好地了解EVD的临床后遗症。具体地说，就是： 在目标I中，我们将描述和分类埃博拉幸存者的临床症状和 调查这些疾病的宿主和疾病相关因素。 在AIM II中，我们探讨了埃博拉病毒后状况的可能致病机制，包括持续 免疫激活、肠道完整性改变和病毒抗原在泌尿生殖系统中的持久性 车厢。 我们将在与卫生保健密切和牢固的工作关系的背景下开展这项工作 西非的领导人和埃博拉幸存者代表，以及完善的基础设施 我们在利比里亚和塞拉利昂建立了临床研究，我们在那里招募、招募、 并对400多名埃博拉幸存者进行了纵向跟踪和抽样。建立这些队列 允许我们的团队确定我们方法的可行性，并开发、试验和改进 维持高质量数据收集所需的程序。这项工作还允许我们构建和支持 容量。两国的工作人员都接受了研究方法方面的培训，并被鼓励 制定自己的建议。我们已经建立了经过验证的埃博拉RNA检测平台 血液，精液和阴道液，在利比里亚的一个国家参考实验室，并在这个网站上进行了质量培训 控制力。总的来说，拟议的工作将提供亟需的对 埃博拉病毒的康复及其潜在机制，以及更好地描述 生殖器分泌液中的埃博拉RNA检测。在过去的40年里有25起疫情，而且有显著的增加 在埃博拉病毒病暴发的频率上，问题不是是否会再次爆发，而是何时发生。这 研究将确保世界更好地为下一次流行病做好准备 了解埃博拉病毒病的临床并发症，并通过实施 在可能出现EVD复发的领域建立临床研究平台。

PROJECT SUMMARY The Ebola epidemic that has devastated West Africa evolved within months from a regional humanitarian crisis to a global public health emergency. Over 27,000 infections and more than 11,000 deaths were reported by the World Health Organization (WHO) – an underestimate that already eclipses the numbers of infections and deaths in all previous Ebola outbreaks combined by orders of magnitude. While this epidemic has ebbed, and may even be over, the clinical complications of Ebola virus disease (EVD) endure for the majority of the thousands of survivors. Our work and that of others indicate that musculoskeletal, neurologic, and ocular complications can persist even two years after recovery from acute Ebola disease. Further, there is evidence that there can be sustained shedding of at least viral RNA in semen and vaginal fluid of survivors, which could signal presence of infectious virus and/or serve to stimulate immune responses that may produce certain post-Ebola symptoms. The small size of previous outbreaks and the absence of adequate infrastructure to collect, process and analyze samples in the field have limited our understanding of the natural history of Ebola survivorship. The primary goal of this proposal is a better understanding of the clinical sequelae of EVD. Specifically:  In AIM I we will describe and categorize the clinical symptomatology of Ebola survivors and investigate host- and disease-related factors for these conditions.  In AIM II we probe putative pathogenic mechanisms for post-Ebola conditions including sustained immune activation, altered gut integrity, and persistence of viral antigens in the uro-genital compartment. We will conduct this work in the context of close and strong working relationships with health care leaders and Ebola survivor representatives in West Africa, and a well-developed infrastructure for clinical research we have established in Liberia and Sierra Leone where we have recruited, enrolled, and longitudinally followed and sampled over 400 Ebola survivors. Establishment of these cohorts allowed our team to determine the feasibility of our approach and develop, pilot, and refine the procedures needed to sustain high-quality data collection. This work also allows us to build and support capacity. Staff in both nations have been trained in research methodology and are being encouraged to develop their own proposals. We have established a validated platform for Ebola RNA detection in blood, semen, and vaginal fluid at a national reference lab in Liberia and have trained this site in quality control. Collectively, the proposed work will provide a much-needed characterization of the convalescence from Ebola and its potential mechanisms, as well as better characterize the patterns of Ebola RNA detection in genital fluids. With 25 outbreaks over the past 40 years and a notable increase in the frequency of EVD outbreaks, the question is not if another outbreak will occur but when. This study will ensure that the world is better prepared for the next epidemic through the improved understanding of the clinical complications of Ebola virus disease, and through the implementation of clinical research platforms in areas that are likely to see a recurrence of EVD.