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: 10553660
• 负责人: Carolyn Calfee
• 金额: $ 96.82万
• 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/10553660
• 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.

抽象的 急性呼吸窘迫综合征（ARDS）是重症患者呼吸衰竭的常见原因 仅在美国每年就有近 20 万例病例，死亡率为 30-40%。临床试验 ARDS 的新型药物疗法几乎无处不在，失败的记录令人沮丧。 至少部分归因于该综合征内相当大的临床和生物学异质性。 强有力的证据表明显着的临床和生物学异质性以及对新疗法的主要需求 为了改善不良的临床结果，ARDS 是精准医学应用的成熟目标，但很少有 我们已经完成了从目前一刀切的 ARDS 临床护理和试验方法转向更全面的方法 有针对性和个性化的方法。 我们最近鉴定并验证了两种不同亚表型（也称为 四项大型随机对照试验中 ARDS 的“内型”）。在对所有四个的独立分析中 数据集中，有强有力的证据表明 ARDS 中有两种不同的内型：高炎症内型 和低炎症内型。这些内型具有显着不同的 (1) 临床特征，(2) 生物标志物概况，(3) 临床结果，以及 (4) 治疗反应。最值得注意的是，显着的内型- 在之前被认为是“阴性”的三项临床试验中确定了具体的治疗反应。 虽然这些数据很有希望，但我们对这些内型的生物学只有基本的了解， 它们表现出的各种不同的处理反应，环境暴露对 内型，以及如何最好地将这一不断增长的知识库转化为实用工具以供应用 床边和临床试验中。在此应用程序中，我们描述了一个汇集专业知识的研究计划 危重疾病的分子表型分析、环境暴露评估、高级统计 复杂多维数据分析方法、ARDS 实验人肺模型，以及 访问临床试验网络和不同的异质患者队列，以确定最佳方案 在人类 ARDS 中应用精准治疗的方法。 该计划有可能通过开发个性化的实用模型来实现范式转变。 针对 ARDS 患者的药物，针对个体患者疾病的生物学，具有显着的效果 对临床试验和最终临床护理的影响。此外，这些研究将通过以下方式产生重大影响： 在已完成和正在进行的 ARDS 临床试验中鉴定内型特异性治疗反应，并通过 提高我们对人类 ARDS 多样化生物学的理解，提高成功的可能性 将为每种内型确定新的治疗方法。最后，该计划将开发一个框架，通过该框架 精准医学的原理可以应用于快节奏、快速发展的重症监护环境 药品。