Linking Endotypes and Outcomes in Pediatric Acute Respiratory Distress Syndrome

项目摘要/摘要 急性呼吸窘迫综合征(ARDS)的特征是急性发作的弥漫性双侧肺 心力衰竭不能完全解释水肿和严重低氧血症。该综合症影响了印度的4.5万名儿童 美国每年，占儿科重症监护机械通气儿童的10% (PICU)，相关死亡率高达20%。目前还没有特定的药物疗法。 对于ARDS，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 治疗因管理上的不确定性而进一步复杂化，因为指南通常是从 成人急性呼吸窘迫综合征，适用性不确定。然而，儿童ARDS具有明显的流行病学和 结果简介，有必要进行针对这一人群的研究。鉴于ARDS的异质性， 生物标记物已被提出用于辅助诊断，改善风险分层，并识别内源性亚细胞 具有共同的病理生理、生物标记物或转录图谱的表型(内型)。风险分层 和内型鉴定对于改善靶向治疗试验的患者选择至关重要， 特别是针对支持性护理以外的靶向治疗。然而，由于缺乏实力雄厚的团队， 生物标记物数据留下了关于内型的存在和临床相关性的知识空白 儿科ARDS。这一建议基于耶亚博士在血浆生物标记物和全血方面的经验 在他的K23奖期间获得的儿科ARDS的转录本进行了前瞻性风险分层和 来自美国12个PICU的500名ARDS儿童的内型鉴定。具体目标是 1)验证PARDSEVERE，一种基于多个生物标记物的儿童ARDS风险分层工具；2)测试 已知的100基因分类器是否识别儿童ARDS的转录切分内型；以及3)使用 识别新的基于血浆生物标记物和信使核糖核酸的内型的聚类方法。这些研究是 走向预后丰富的第一步(选择预后较差的受试者进行试验)和预测性 浓缩(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。这个 拟议的研究将验证儿科ARDS的风险分层工具，并确定共享的内型 生物学，以便在未来的试验中更恰当地针对治疗。该提案利用了现有的 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。总体而言，这些研究是该领域的重大进步 为未来的研究提供了巨大的资源，并为下一步的研究奠定了基础 使用浓缩策略生成干预试验以减轻异质性。

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.