Genes Associated with MODS in Children with Severe Acute Respiratory Infections

项目摘要 严重急性呼吸道感染（SARI）是儿童死亡和住院的主要原因。在 美国，几乎一半因SARI而进展为急性呼吸衰竭的儿童没有易感因素， 来解释这种严重的疾病。尽管这些孩子中的大多数如果接受 有针对性的抗生素和机械呼吸机支持，许多人将发展严重的多器官功能障碍 多器官功能障碍综合征（MODS）。许多患有MODS的儿童如果心血管和呼吸系统都衰竭，就会死亡。 如果临床医生了解， 如何最佳调节SARI患儿的免疫反应。不幸的是， 这些儿童的免疫反应是产生性的还是病理性的。几乎致命的病例， 致命性SARI的特征是过度炎症和严重的继发性免疫 抑制;在一些儿童中，这两个过程同时发生。本研究的目的是确定 与严重MODS和MODS相关亚型相关的基因和基因生物特征， 重症SARI患儿的预后。我们已经招募了450多名患有SARI的儿童， 儿科重症监护病房（ICU）疑似流感感染（PICFLU），以评估基因， 影响他们的免疫反应。利用丰富的临床知识库和PICFLU研究的生物库，我们 将使用现有血液从600多个免疫相关基因中生成mRNA基因表达数据， 呼吸道样本在目标1中，我们将评估整个识别基因和基因通路，（a）区分 非常严重的肺和心血管器官衰竭的儿童与不太严重的器官功能障碍的儿童 和（B）通过ICU第3天预测哪些患者将存活并在2天内解决心肺器官衰竭 数周与更长时间的失败和/或死亡相比。在目标2中，我们将识别mRNA生物标志物特征 与MODS相关的先天性免疫抑制（免疫麻痹）在SARI儿童使用 全血样本我们假设，通过使用无偏的数据驱动的方法，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 期望鉴定出与MODS和MODS表型相关的多个新的基因通路和基因。这 这项工作将为未来的精准医学铺平道路，在精准医学中，免疫相关治疗将针对那些 患有或发展为最严重的MODS亚型的儿童。新的治疗方法， 这项工作可能对提高SARI生存率和优化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.