Genes Associated with MODS in Children with Severe Acute Respiratory Infections

项目总结 严重急性呼吸道感染是导致儿童死亡和住院的主要原因。在 在美国，几乎一半因纱丽而进展为急性呼吸衰竭的儿童没有任何诱因 条件来解释如此严重的疾病。尽管这些孩子中的大多数会活下来，如果他们得到 靶向抗菌药和机械呼吸机支持，许多人会出现严重的多器官功能障碍 综合征(MODS)。许多患有MODS的儿童如果心血管系统和呼吸系统都失效，就会死亡。 如果临床医生理解，存在拯救生命和更快扭转器官衰竭的重大机会 如何以最佳方式调节纱丽儿童的免疫反应。不幸的是，有很少的 区分这些儿童的生产性免疫反应和病理性免疫反应的数据。险些致死的病例和 致命的sari的特征是过度的炎症和深度的二次免疫。 压抑；在某些儿童中，这两个过程同时发生。这项研究的目的是确定 与严重MODS和MODS相关亚型相关的基因和基因生物特征 患有纱利病的危重儿童的结局。我们已经招募了450多名患有沙利病的儿童 疑似流感感染的儿科重症监护病房(ICU)评估 影响它们的免疫反应。使用来自PICFLU研究的丰富的临床知识库和生物库，我们 将利用现有的血液和免疫相关基因产生超过600个免疫相关基因的基因表达数据 呼吸道样本。在目标1中，我们将评估(A)区分的识别基因和基因路径 严重肺和心血管器官衰竭的儿童来自那些不太严重的器官功能障碍者 和(B)在ICU第3天预测哪些患者将在2天内存活并解决心肺器官衰竭 几周，而不是有更长的失败和/或死亡。在目标2中，我们将确定mrna生物标记物的特征。 SARI儿童中与MODS相关的先天免疫抑制(免疫麻痹) 全血样本。我们假设，通过使用一种无偏见的数据驱动的方法来研究基因和基因 在SARI中，我们将发现以前被忽视的新的治疗靶点。我们 期望发现多条新的基因通路和与MODS和MODS表型相关的基因。这 这项工作将为未来的精确医学铺平道路，在那里免疫相关的治疗将针对那些 出现或发展为最严重的MODS亚型的儿童。新的治疗方法产生于 这项工作可能会对提高sari存活率和优化sari相关疾病的恢复产生全球影响。 器官衰竭。

PROJECT SUMMARY Severe acute respiratory infections (SARI) are a leading cause of death and hospitalization in children. In the U.S., almost half of the children who will progress to acute respiratory failure from SARI have no predisposing conditions to explain such severe illness. Although the majority of these children will survive if they receive targeted antimicrobials and mechanical ventilator support, many will develop severe multiple organ dysfunction syndrome (MODS). Many children with MODS will die if both their cardiovascular and respiratory systems fail. Major opportunity exists to save lives and more rapidly reverse organ failure if clinicians understood how to optimally modulate the immune response of a child with SARI. Unfortunately, there is a paucity of data differentiating a productive from a pathologic immune response in these children. Cases of near-fatal and fatal SARI have been characterized by excessive inflammation and by profound secondary immune suppression; in some children both processes occur at the same time. The objective of this study is to identify genes and gene biosignatures associated with severe MODS and MODS-related subtypes and outcomes in critically ill children with SARI. We already recruited over 450 children with SARI admitted to the pediatric intensive care unit (ICU) with suspected influenza infection (PICFLU) to evaluate genes that influence their immune response. Using the rich clinical repository and biobank from the PICFLU study, we will generate mRNA gene expression data from over 600 immune-related genes using existing blood and respiratory samples. In Aim 1 we will evaluate whole identify genes and gene pathways that (a) distinguish children with very severe lung and cardiovascular organ failure from those with less severe organ dysfunction and (b) predict by ICU day 3 which patients will survive and resolve cardiorespiratory organ failure within 2 weeks versus have more prolonged failure and/or die. In Aim 2 we will identify the mRNA biomarker signature associated with MODS-related innate immune suppression (immunoparalysis) in children with SARI using whole blood samples. We hypothesize that by using an unbiased data driven approach to gene and gene pathway discovery in SARI, we will identify new therapeutic targets that have previously been overlooked. We expect to identify multiple new gene pathways and genes associated with MODS and MODS-phenotypes. This work will pave the way for future precision medicine where immune-related treatments are targeted at those children presenting with or developing the most severe subtypes of MODS. Novel treatments resulting from this work could have a global impact on improving SARI survival and in optimizing recovery from SARI-related organ failure.