Linking Endotypes and Outcomes in Pediatric Acute Respiratory Distress Syndrome

项目总结/摘要 急性呼吸窘迫综合征（ARDS）是以急性发作的弥漫性、双侧肺动脉高压为特征的一种呼吸系统疾病。 水肿和严重低氧血症不能完全由心力衰竭解释。该综合症影响了45，000名儿童， 在美国，每年有10%的儿童在儿科重症监护室接受机械通气。 单位（PICU），相关死亡率高达20%。没有特定的药物治疗 尽管进行了几次试验，但支持性护理仍然是治疗的主要手段。在儿童中，缺乏 治疗的不确定性进一步加剧了管理的不确定性，因为指南通常是从 成人ARDS，适用性不确定。然而，小儿ARDS具有独特的流行病学特征， 结果概况，需要针对该人群进行研究。考虑到ARDS的异质性， 已经提出了生物标志物来帮助诊断，改善风险分层，并识别内源性亚细胞。 表型（内型）与共同的病理生理，生物标志物，或转录谱。危险分层 和内型鉴定对于改进靶向治疗试验的患者选择是必不可少的， 特别是对于支持性治疗以外的靶向治疗。然而，缺乏具有良好功效的队列， 生物标志物数据留下了关于内型的存在和临床相关性的知识空白， 小儿ARDS。这个建议建立在Yehya博士在血浆生物标志物和全血方面的经验基础上 在他的K23奖期间获得的儿科ARDS的转录组学，以进行前瞻性风险分层， 来自美国12个PICU的500名患有ARDS的儿童的内型鉴定。具体目标是 1）验证PARDSEVERE，一种基于多种生物标志物的儿科ARDS风险分层工具; 2）测试 已知的100基因分类器是否鉴定儿科ARDS中的转录组内型;以及3）使用 聚类方法来鉴定新的基于血浆生物标志物和mRNA的内型。这些研究 预后富集（选择预后较差的受试者进行试验）和预测的第一步 富集（选择可能对试验干预有反应的受试者）用于未来的儿科ARDS试验。的 拟议的研究将验证儿科ARDS的风险分层工具，并确定与成人呼吸窘迫综合征（ARDS）共有的内型。 生物学，以便在未来的试验中更适当地靶向治疗。该提案利用现有的 费城儿童医院、宾夕法尼亚大学、 和辛辛那提儿童医院医疗中心。总的来说，这些研究是该领域的重大进展 儿童ARDS，代表了未来研究的巨大资源，并为下一个研究奠定了基础。 使用富集策略生成干预性试验，以减轻异质性。

PROJECT SUMMARY/ABSTRACT Acute respiratory distress syndrome (ARDS) is characterized by acute onset of diffuse, bilateral pulmonary edema and severe hypoxemia not fully explained by cardiac failure. The syndrome affects 45,000 children in the United States annually, representing 10% of mechanically ventilated children in pediatric intensive care units (PICUs), with an associated mortality rate of up to 20%. There are no specific pharmacological therapies for ARDS despite several trials, and supportive care remains the mainstay of treatment. In children, a lack of therapies is further compounded by uncertainty in management, as guidelines are typically extrapolated from adult ARDS, with uncertain applicability. However, pediatric ARDS possesses a distinct epidemiologic and outcome profile, necessitating studies specific to this population. Given the heterogeneity of ARDS, biomarkers have been proposed to aid in diagnosis, improve risk stratification, and identify endogenous sub- phenotypes (endotypes) with shared pathophysiologic, biomarker, or transcriptomic profiles. Risk stratification and endotype identification are essential for improved patient selection for trials of targeted therapies, particularly for targeted therapies beyond supportive care. However, the absence of well-powered cohorts with biomarker data leaves a knowledge gap regarding the existence and clinical relevance of endotypes in pediatric ARDS. This proposal builds off of Dr. Yehya’s experience with plasma biomarkers and whole blood transcriptomics in pediatric ARDS obtained during his K23 award to perform prospective risk stratification and endotype identification in 500 children with ARDS from 12 PICUs in the United States. The specific goals are to 1) validate PARDSEVERE, a multiple biomarker-based risk stratification tool in pediatric ARDS; 2) test whether a known 100-gene classifier identifies transcriptomic endotypes in pediatric ARDS; and 3) use clustering methodology to identify novel plasma biomarker- and mRNA-based endotypes. These studies are the first steps towards prognostic enrichment (selecting subjects with worse prognosis for trials) and predictive enrichment (selecting subjects likely to respond to a trial intervention) for future pediatric ARDS trials. The proposed studies will validate a risk stratification tool for pediatric ARDS and identify endotypes with shared biology in order to more appropriately target therapies in future trials. The proposal leverages the existing infrastructure and extensive expertise at the Children’s Hospital of Philadelphia, the University of Pennsylvania, and Cincinnati Children’s Hospital Medical Center. Overall, these studies are a significant advance for the field of pediatric ARDS, represent a tremendous resource for future studies, and form the basis for the next generation of interventional trials using enrichment strategies to mitigate heterogeneity.