Precision Medicine in the Acute Respiratory Distress Syndrome

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。 仅在美国，每年就有近20万例患者，死亡率为30%-40%。临床试验 ARDS的新药物疗法几乎无处不在的失败，一个令人沮丧的记录，已经 至少部分归因于这种综合征相当大的临床和生物学异质性。 有了显著的临床和生物异质性的有力证据，以及对新疗法的主要需求 为了改善糟糕的临床结果，ARDS是应用精确医学的成熟目标，但很少有 我们已经完成了从目前的一刀切的ARDS临床护理和试验方法转向更多 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的亚表型(也称为 四个大型随机对照试验中的ARDS的“内型”)。在对这四个国家的独立分析中 数据集，有强有力的证据表明ARDS中存在两种不同的内型：一种高炎性内型 和一种低炎性内型。这些内型有明显不同的(1)临床特征，(2) 生物标记物概况，(3)临床结果，(4)治疗反应。最值得注意的是，重要的内型- 在之前被认为是“阴性”的三项临床试验中，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一个基本的了解， 他们表现出的各种不同的处理反应，环境暴露对 内部类型，以及如何最好地将这个不断增长的知识库转化为实用工具，以便在 在床边和临床试验中。在本申请中，我们描述了一个汇集专业知识的研究计划 在危重疾病的分子表型、环境暴露评估、高级统计学 分析复杂多维数据的方法，ARDS的实验性人类肺模型，以及 访问临床试验网络和各种不同的患者队列，以确定最佳 精准疗法在人类ARDS中的应用探讨。 该计划有可能通过开发个性化的实用模型来实现范式转换 针对ARDS患者的药物，针对单个患者的疾病的生物学，具有显著的 对临床试验和最终的临床护理都有影响。此外，这些研究将通过以下方式产生很大影响 已完成和正在进行的ARDS临床试验中内型特异性治疗反应的鉴定 提高我们对人类ARDS的多样化生物学的理解，增加成功的可能性 将针对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 医药。

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.