Pediatric Sepsis Biorepository and Clinical Database

项目总结 脓毒症的广泛定义是由感染引起的危及生命的器官功能障碍。然而，经历了 败血症在个体之间和个体内差异很大。这种个体间和个体内的异质性 反映了由宿主-病原体相互作用引起的复杂的、不断演变的病理生物学，并由预先存在的 患者特征和正在进行的医疗治疗。这是非常不可能的一单-甚至是小的 一组生物标志物将以足够的准确性表征个人的病理生物学，以解锁精确度 脓毒症的药物治疗方法。因此，挑战是识别和准确地描述相关的 脓毒症的表型，并开发丰富战略，以设计和测试新的靶向治疗。为了这个 项目中，我们建议测试收集、处理和分析生物数据的新方法的可行性 代表败血症病程早期对感染的免疫-炎症-代谢反应，并与此联系 从电子健康记录(EHR)获得基于器官功能障碍的相关表型数据的信息。 我们已经组建了一个由翻译免疫学专家组成的多学科团队，儿科 急诊医学、重症监护和数据科学。我们将测试收集和处理的可行性 在复苏前阶段，不同数量的血液样本用于深度表型分析，这是一个关键 时间点以及48小时后，以捕获复苏后的动态变化。我们将使用这些样品 高维流式细胞术用于功能免疫-炎症-代谢生物学的研究 追踪淋巴细胞增殖、凋亡、耗竭和细胞因子的表面和细胞内标志物 制作。此外，我们将扩展流式细胞仪技术来进行生物能量评估，并将 使用O-link对血浆免疫-炎症-代谢反应进行蛋白质组学评估。 该项目将利用三个研究地点广泛的临床研究基础设施。在……里面 此外，调查人员将在CHOP获得创新的生物分析，这将使我们的 从危重和复杂患者中收集关键生物表型的协作团队。在R21阶段， 我们将完成一项单中心试点研究，以测试收集、处理和分析 脓毒症早期用于深度表型的最佳血液样本，将它们与EHR登记联系起来 数据，并开发和测试一个数据管道来表征患者基于器官功能障碍的临床特征 表型。在R33阶段，我们将把样本收集扩展到三个站点，并执行 概念分析以确定在免疫-炎症-代谢模式中是否存在差异 患有任何一种高危器官功能障碍的脓毒症表型的儿童。确定相关 R33阶段的生物模式然后可以导致未来的假说驱动的机制研究和 开发靶向治疗。

PROJECT SUMMARY Sepsis is broadly defined as life-threatening organ dysfunction caused by infection. However, the experience of sepsis varies widely between individuals and within individuals. Such inter- and intra-individual heterogeneity reflects complex, evolving pathobiology induced by host-pathogen interactions and modified by pre-existing patient characteristics and ongoing medical treatments. It is highly unlikely that a single—or even a small panel—of biomarkers will characterize an individual’s pathobiology with enough accuracy to unlock precision medicine approaches in sepsis. The challenge, therefore, is to identify and accurately characterize relevant phenotypes of sepsis and develop enrichment strategies to design and test novel targeted therapies. For this project, we propose testing the feasibility of novel approaches to collect, process, and analyze biologic data representing the immuno-inflammatory-metabolic response to infection early in the sepsis course and link this information to relevant organ dysfunction-based phenotype data from the electronic health record (EHR). We have assembled a multi-disciplinary team composed of experts in translational immunology, pediatric emergency medicine, critical care, and data science. We will test the feasibility of collecting and processing blood samples of different volumes for deep phenotyping at the pre-resuscitation phase, which is a critical timepoint, as well as 48 hours later to capture dynamic changes post-resuscitation. We will use these samples to characterize the functional immuno-inflammatory-metabolic biology using high dimensional flow cytometry to track surface and intracellular markers of lymphocyte proliferation, apoptosis, exhaustion, and cytokine production. In addition, we will extend flow cytometric techniques to perform bioenergetic evaluation, and will perform proteomic evaluation of the plasma immuno-inflammatory-metabolomic response using O-link. This project will take advantage of extensive clinical research infrastructure at the three study sites. In addition, the investigators will have access to innovative biologic assays at CHOP which will allow our collaborative team to glean key biologic phenotypes from critically ill and complex patients. In the R21 phase, we will complete a single-center pilot study to test the feasibility of collecting, processing, and analyzing the optimal blood specimens for deep phenotyping in the early phase of sepsis, linking them to the EHR registry data, and developing and testing a data pipeline to characterize the patients’ organ dysfunction-based clinical phenotypes. In the R33 phase, we will expand the sample collection to three sites and perform a proof-of- concept analysis to determine if there are differences in the immuno-inflammatory-metabolomic patterns of the children who develop either of the high-risk organ dysfunction-based sepsis phenotypes. Identifying relevant biological patterns in the R33 phase can then lead to future hypothesis-driven mechanistic studies and the development of targeted therapies.