Biomarkers and subphenotypes predictive of clinical outcomes in patients with COVID-19 related acute respiratory distress syndrome

项目总结/摘要 急性呼吸窘迫综合征（ARDS）是由包括COVID-19在内的各种诱因引起的，是一种 如果没有有效的治疗方法，尽管有许多关于COVID-19相关ARDS的研究， （1），最好的治疗方法只会导致适度或不一致的临床改善。这种匮乏 的发现可能部分是由于宿主对COVID-19的反应的异质性。长期目标是 为ARDS和ARDS患者提供精确治疗。使用血浆蛋白生物标记物和临床数据，博士。 Calfee（申请人的申办者）已确定两种非COVID-19相关或“典型”的生物学亚表型 ARDS。具体来说，具有高炎症亚表型的患者具有更高水平的炎症反应。 生物标志物代谢性酸中毒和休克他们的死亡率也明显更高， 可能受益于某些ICU治疗。相反地，大多数慢性胰腺炎患者表现出低炎症反应， 典型ARDS的亚表型，提出了关于这种不良结局的病理生理学问题。 人口本项目的总体目标是（i）鉴定血浆生物标志物和差异基因， 表达与不良预后相关的研究，以及（ii）寻找存在的肿瘤特异性表达， 具有临床重要性的亚表型。中心假设是，差异基因表达指示 失调的炎症和肺损伤和凝血障碍的高基线血浆生物标志物将 预测预后不良的预后，不同的预后亚表型存在与不同的 结果和治疗反应。这个项目的基本原理是，它将提供机械的见解， 在这一人群中，潜在的不良结果的生物学，导致识别潜在的可药物靶点，并确定 最有可能受益于靶向治疗的患者。中心假设将通过追求这些测试 具体目标：1）确定COPD患者不良临床结局的生物学预测因子; 2） 确定与不良临床结局相关的不同生物学亚表型， 治疗反应。在目标1下，将测量假设驱动的血浆蛋白生物标志物，并且RNA 对ISPY COVID（一项正在进行的自适应 在多个美国机构进行的实验性药物的随机对照试验。在目标2下， 将对蛋白质生物标志物和临床变量的组合进行分析，以确定 与不同结果和对试验研究药物的反应相关的亚表型。的 拟议的研究是创新的，因为在一个大的和有代表性的队列中进行了广泛的生物表型分析， 的患者有一个统一的触发急性呼吸窘迫综合征尚未完成，可能是关键，以确定成功的 治疗最终，这些知识将为进行表型感知试验铺平道路， 治疗的亚表型的患者。

PROJECT SUMMARY/ABSTRACT Acute Respiratory Distress Syndrome (ARDS), caused by a variety of triggers including COVID-19, is a devastating critical illness without effective therapies. Despite numerous studies on COVID-19 related ARDS (CARDS), the best available treatments lead to only modest or inconsistent clinical improvements. This paucity of discoveries is likely in part due to heterogeneity of host response to COVID-19. The long-term goal is to bring precision therapies to patients with ARDS and CARDS. Using plasma protein biomarkers and clinical data, Dr. Calfee (sponsor of the applicant) has identified two biologic subphenotypes of non-COVID-19 related or “typical” ARDS. Specifically, patients with the hyperinflammatory subphenotype had higher levels of inflammatory biomarkers, metabolic acidosis, and shock. They also experienced significantly higher mortality and were more likely to benefit from certain ICU therapies. Conversely, most CARDS patients demonstrate a hypoinflammatory subphenotype of typical ARDS, raising questions about the pathophysiology underlying poor outcomes in this population. The overall objective of this project is to (i) identify plasma biomarkers and differential gene expression associated with poor outcomes in CARDS and (ii) search for the presence of CARDS specific subphenotypes of clinical importance. The central hypothesis is that differential gene expression indicative of dysregulated inflammation and high baseline plasma biomarkers of lung injury and disordered coagulation will predict poor outcomes in CARDS, and that distinct CARDS subphenotypes exist associated with differential outcomes and treatment responses. The rationale for this project is that it will offer mechanistic insights into the biology underlying poor outcomes in this population, lead to identifying potential druggable targets, and identify patients most likely to benefit from targeted therapies. The central hypothesis will be tested by pursuing these specific aims: 1) Identify biological predictors of poor clinical outcomes within patients with CARDS; and 2) Identify distinct biologic subphenotypes of CARDS associated with poor clinical outcomes and differential treatment response. Under aim 1, hypothesis-driven plasma protein biomarkers will be measured, and RNA sequencing performed on blood samples of CARDS patients enrolled in ISPY COVID, an ongoing adaptive randomized controlled trial of experimental drugs across multiple US institutions. Under aim 2, latent class analysis will be performed on a combination of protein biomarkers and clinical variables to identify subphenotypes associated with distinct outcomes and responses to the trial’s investigational agents. The proposed research is innovative, because extensive biological phenotyping in a large and representative cohort of patients with a uniform trigger for ARDS has not been done and may be the key to identifying successful therapies. Ultimately, this knowledge will pave the way for conducting phenotype-aware trials studying targeted therapies in patients with subphenotypes of CARDS.