Precision Medicine in the Acute Respiratory Distress Syndrome

急性呼吸窘迫综合征的精准医学

• 批准号: 10331306
• 负责人: Carolyn Calfee
• 金额: $ 96.73万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-16 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10331306
• 关键词: Acute Respiratory Distress Syndrome; Acute respiratory failure; Biological Markers; Biology; Characteristics; Clinical; Clinical Trials; Clinical Trials Network; Complex; Critical Care; Critical Illness; Data; Data Set; Disease; Environmental Exposure; Environmental Impact; Exhibits; Failure; Goals; Human; Human Biology; Individual; Inflammatory; Lung; Medicine; Modeling; Outcome; Patients; Pharmacotherapy; Precision therapeutics; Prevention strategy; Preventive therapy; Randomized Controlled Trials; Research; Respiratory Failure; Syndrome; Translating; biological heterogeneity; clinical care; clinical heterogeneity; cohort; improved; individual patient; individualized medicine; knowledge base; molecular phenotype; mortality; multidimensional data; novel; novel therapeutics; personalized approach; personalized medicine; precision medicine; programs; tool; treatment response

ABSTRACT The acute respiratory distress syndrome (ARDS) is a common cause of respiratory failure in critically ill patients, with nearly 200,000 cases per year in the US alone and mortality rates of 30-40%. Clinical trials of novel pharmacotherapies in ARDS have met with nearly ubiquitous failure, a dismal track record which has been attributed at least in part to the considerable clinical and biological heterogeneity within this syndrome. With this strong evidence of significant clinical and biological heterogeneity and a major need for new therapies to improve poor clinical outcomes, ARDS is a ripe target for the application of precision medicine, yet little has been done to move from our current one-size-fits-all approach to ARDS clinical care and trials to a more targeted and personalized approach. We recently identified and validated the presence of two distinct subphenotypes (also known as “endotypes”) of ARDS in four large randomized controlled trials. In an independent analysis of all four datasets, there was strong evidence for two different endotypes within ARDS: a hyper-inflammatory endotype and a hypo-inflammatory endotype. These endotypes had strikingly different (1) clinical characteristics, (2) biomarker profiles, (3) clinical outcomes, and (4) treatment responses. Most notably, significant endotype- specific treatment responses were identified within three clinical trials previously thought to be “negative.” While these data are highly promising, we have only a basic understanding of the biology of these endotypes, of the full range of differential treatment responses they exhibit, of the impact of environmental exposures on endotypes, and of how best to translate this growing knowledge base into practical tools for application at the bedside and in clinical trials. In this application, we describe a research program that brings together expertise in molecular phenotyping of critical illness, environmental exposures assessment, advanced statistical approaches to analysis of complex multi-dimensional data, an experimental human lung model of ARDS, and access to clinical trial networks and diverse heterogeneous patient cohorts, in order to determine the optimal approach to applying precision therapeutics in human ARDS. This program has the potential to be paradigm-shifting by developing practical models for personalized medicine for patients with ARDS, targeted to the biology of an individual patient's disease, with a significant impact on both clinical trials and ultimately clinical care. In addition, these studies will have a high impact via identification of endotype-specific therapeutic responses in completed and ongoing ARDS clinical trials and by improving our understanding of the diverse biology of human ARDS, enhancing the likelihood that successful new therapeutics will be identified for each endotype. Finally, this program will develop a framework by which the principles of precision medicine can be applied to the fast-paced, rapidly evolving setting of critical care medicine.

摘要 急性呼吸窘迫综合征（ARDS）是危重病患者呼吸衰竭的常见原因 患者，仅在美国每年就有近20万例，死亡率为30- 40%。临床试验 治疗ARDS的新药物治疗几乎普遍失败，这是一个令人沮丧的记录， 至少部分归因于该综合征中相当大的临床和生物学异质性。 有了这一强有力的证据，显著的临床和生物学异质性和对新疗法的重大需求 为了改善不良的临床结果，ARDS是应用精确医学的成熟目标，但很少有 我们已经做了从我们目前的一刀切的方法，以ARDS临床护理和试验，以更多的 有针对性和个性化的方法。 我们最近发现并验证了两种不同的亚表型（也称为 “内源型”）的ARDS的四个大型随机对照试验。在对这四个人的独立分析中， 数据集，有强有力的证据表明ARDS中存在两种不同的内型： 和低炎性内型。这些内型具有显著不同的（1）临床特征，（2） 生物标志物谱，（3）临床结果和（4）治疗反应。最值得注意的是，重要的内型- 在三个以前被认为是“阴性”的临床试验中确定了特定的治疗反应。 虽然这些数据非常有希望，但我们对这些内型的生物学只有基本的了解， 他们所表现出的各种不同的待遇反应，环境暴露对 内型，以及如何最好地将这一不断增长的知识基础转化为实用工具， 床旁和临床试验。在这个应用程序中，我们描述了一个研究计划， 在危重病的分子表型，环境暴露评估，先进的统计 复杂多维数据的分析方法，ARDS的实验性人肺模型，以及 访问临床试验网络和不同的异质性患者队列，以确定最佳的 在人类ARDS中应用精确疗法的方法。 该计划有可能通过开发个性化的实用模型来实现范式转移 针对ARDS患者的药物，针对个体患者疾病的生物学， 对临床试验和最终的临床护理都有影响。此外，这些研究将产生很大的影响， 在已完成和正在进行的ARDS临床试验中确定内型特异性治疗反应， 提高我们对人类ARDS多样性生物学的理解， 将为每种内型鉴定新的治疗剂。最后，该计划将开发一个框架， 精确医学的原理可以应用于快节奏、快速发展的重症监护环境 药