ENdotypes in Children with Severe Acute Respiratory Distress SyNdrome: ImpAct on REsponse to Treatment (ENSNARE)

总结 急性呼吸窘迫综合征（ARDS）与儿童的高发病率和死亡率相关， 成年人了尽管经过多年的研究，药物治疗已被证明在降低死亡率方面无效， 这可能部分是由于ARDS患者的异质性。数据的潜在类别分析（LCA） 从多个大型资助的成人研究中已经确定了两种ARDS内型（亚表型）， 临床结果和对治疗的反应。没有研究检查是否存在内型， 小儿急性呼吸窘迫综合征（PARDS）。然而，通过检测全血中的全基因组基因表达， 感染性休克是另一种患者异质性很高的疾病， 其涉及炎症/免疫系统的失调。使用此方法鉴定的内型 转录组学方法具有不同的死亡率和免疫炎症基因表达风险。 转录组学尚未用于定义成人或儿童ARDS患者的亚组。 前景试验（UG 3 HL 141736）是一个前所未有的机会，可以使用来自 PARDS患儿回答几个与PARDS异质性相关的高影响力问题。我们的中央 一种假说认为，PARDS患儿存在内在型，其基础病理生理学不同 和对治疗的反应。该提案的目标是a）鉴定和表征 使用LCA（Sp Aim 1）和基因表达谱（Sp Aim 2）方法的PARDS儿童，B） 确定亚组在结果和/或对治疗的反应方面是否存在差异，以及c）确定潜在的 内型结果和治疗反应之间的差异涉及的途径（Sp Aim 3）。这 该提案涉及NHLBI战略愿景中的一个目标，即“确定 病理生物学和治疗反应的个体差异”。我们的具体目标将测试 假设：1）LCA将确定PARDS儿童两种内型及其结果， 对治疗的反应，将在内型之间变化; 2）由内型区分的两种内型， 感染性休克儿童中100个基因的表达也存在于PARDS儿童中， 全基因组表达谱分析将确定PARDS儿童的其他内型， 结果和对治疗的反应将在使用每种方法鉴定的转录组学内型之间变化。 方法; 3）将LCA的结果与用于鉴定的基因表达数据结合， 转录组学内型将允许进一步分层的患者与PARDS，并将揭示 与不同的结果和对治疗的反应相关的基因子集。这项建议会 为PARDS患者的未来精确护理奠定基础，方法是识别： 在PARDS中，PARDS内型的潜在病理生理学差异，无论内型 对治疗的反应不同，以及儿科败血症和PARDS的内源性如何相互关联。

SUMMARY Acute respiratory distress syndrome (ARDS) is associated with high morbidity and mortality in children and adults. Despite years of research, pharmacologic treatment has proven ineffective in decreasing mortality and morbidity which is likely due, in part, to heterogeneity in ARDS patients. Latent class analyses (LCA) of data from multiple large funded adult studies have identified two ARDS endotypes (subphenotypes) with differing clinical outcomes and response to treatment. There are no studies examining whether endotypes exist in pediatric ARDS (PARDS). However, by examining genome-wide gene expression in whole blood, endotypes have been identified in children with septic shock, another condition with a high degree of patient heterogeneity which involves dysregulation of the inflammatory/immune systems. The endotypes identified using this transcriptomic approach have differing risks of mortality and expression of immune inflammatory genes. Transcriptomics have not yet been used to define subgroups of adult or pediatric patients with ARDS. The PROSpect trial (UG3 HL141736) is an unprecedented opportunity to use biological samples from children with PARDS to answer several high impact questions related to PARDS heterogeneity. Our central hypothesis is that there are endotypes in children with PARDS which differ in their underlying pathophysiology and responsiveness to therapies. The goal of this proposal is to a) identify and characterize endotypes in children with PARDS using both LCA (Sp Aim 1) and gene expression profiling (Sp Aim 2) approaches, b) determine whether subgroups differ in outcome and/or response to treatment, and c) identify potential pathways involved in differences between endotype outcomes and response to treatment (Sp Aim 3). This proposal addresses one of the objectives in the strategic vision of the NHLBI, “Identifying factors that account for individual differences in pathobiology and responses to treatment”. Our Specific Aims will test the hypotheses that: 1) LCA will identify two endotypes in children with PARDS, and that outcomes, and response to treatment, will vary between endotypes; 2) The two endotypes distinguished by the expression of 100 genes in children with septic shock also exist in children with PARDS, that de novo genome-wide expression profiling will identify additional endotypes in children with PARDS and, that outcomes and response to treatment will vary between transcriptomic endotypes identified using each approach; 3) Combining the results of the LCA with data on gene expression used for identification of transcriptomic endotypes will allow further stratification of patients with PARDS, and will reveal a subset of genes that are related to differential outcomes and response to treatment. This proposal will lay the fundamental groundwork for future precision care of PARDS patients by identifying: different endotypes within PARDS, differences in the underlying pathophysiology of PARDS endotypes, whether endotypes respond differently to treatment, and how endotypes of pediatric sepsis and PARDS relate to each other.