Genes Associated with MODS in Children with Severe Acute Respiratory Infections

严重急性呼吸道感染儿童 MODS 相关基因

• 批准号: 9765361
• 负责人: Adrienne G Randolph
• 金额: $ 16.17万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-17 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9765361
• 关键词: Acute respiratory failure; Acute respiratory infection; Address; Admission activity; Adult Respiratory Distress Syndrome; Anti-inflammatory; Automobile Driving; Biological Markers; Biological Response Modifiers; Blood; Blood specimen; Cardiovascular system; Cause of Death; Cessation of life; Child; Childhood; Clinical; Clinical Trials; Communities; Critically ill children; DNA; Data; Development; Diagnosis; Discrimination; Disease susceptibility; Enrollment; Evaluation; Expression Profiling; Failure; Family; Foundations; Functional disorder; Funding; Future; Gene Expression; Gene Expression Profile; Genes; Health; Hospitalization; Immune; Immune Targeting; Immune response; Immunomodulators; Immunosuppression; Individual; Infection; Inflammation; Inflammatory Response; Influenza; Intensive Care; Intensive Care Units; Investigation; Life; Lipopolysaccharides; Lung; Mechanical Ventilators; Mechanical ventilation; Mediator of activation protein; Messenger RNA; Methods; Multicenter Studies; Multiple Organ Failure; Nosocomial Infections; Organ; Organ failure; Outcome; Pathologic; Pathway interactions; Patients; Pediatric Intensive Care Units; Phenotype; Population; Process; Proteins; Recovery; Resolution; Respiratory System; Risk; Sampling; Septic Shock; Severity of illness; Shock; TNF gene; Testing; Time; United States National Institutes of Health; Variant; Vasoconstrictor Agents; Weaning; Whole Blood; Work; antimicrobial; base; biobank; biosignature; cohort; endotracheal; genetic variant; high risk; immunomodulatory therapies; immunoregulation; improved; innovation; interest; mRNA Expression; mortality; mortality risk; new therapeutic target; novel; precision medicine; recruit; repository; respiratory; response; theranostics; therapeutic target

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.

项目概要 严重急性呼吸道感染（SARI）是儿童死亡和住院的主要原因。在 在美国，几乎一半因 SARI 而发展为急性呼吸衰竭的儿童没有诱发因素 条件来解释如此严重的疾病。尽管这些儿童中的大多数如果接受治疗就能活下来 有针对性的抗菌药物和机械呼吸机支持，许多人会出现严重的多器官功能障碍 综合症（MODS）。如果心血管和呼吸系统同时衰竭，许多患有 MODS 的儿童将会死亡。 如果临床医生理解的话，存在拯救生命和更快逆转器官衰竭的重大机会 如何最佳地调节患有 SARI 的儿童的免疫反应。不幸的是，目前还缺乏 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。近乎致命的案例 致命的 SARI 的特点是过度炎症和严重的二次免疫 抑制;在某些儿童中，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，以及 患有 SARI 的危重儿童的结果。我们已经招募了超过 450 名患有 SARI 的儿童 疑似流感感染 (PICFLU) 的儿科重症监护病房 (ICU) 评估基因 影响他们的免疫反应。利用 PICFLU 研究中丰富的临床存储库和生物库，我们 将使用现有的血液和数据生成 600 多个免疫相关基因的 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，它们 (a) 区分 患有非常严重的肺和心血管器官衰竭的儿童与器官功能障碍较轻的儿童 (b) 在 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 周与更长时间的失败和/或死亡。在目标 2 中，我们将识别 mRNA 生物标志物特征 与 SARI 儿童中 MODS 相关的先天免疫抑制（免疫麻痹）相关 全血样本。我们假设通过使用公正的数据驱动方法来研究基因和基因 SARI 中的通路发现，我们将确定以前被忽视的新治疗靶点。我们 期望识别与 MODS 和 MODS 表型相关的多个新基因途径和基因。这 这项工作将为未来的精准医学铺平道路，其中免疫相关的治疗针对的是那些 患有或正在发展最严重的 MODS 亚型的儿童。新的治疗方法源于 这项工作可能会对提高 SARI 生存率和优化 SARI 相关恢复产生全球影响 器官衰竭。

项目成果

Transcriptomic profiles of multiple organ dysfunction syndrome phenotypes in pediatric critical influenza.

儿科重症流感多器官功能障碍综合征表型的转录组学特征。

• 发表时间: 2023
• 作者: Novak, Tanya;Crawford, Jeremy Chase;Hahn, Georg;Hall, Mark W;Thair, Simone A;Newhams, Margaret M;Chou, Janet;Mourani, Peter M;Tarquinio, Keiko M;Markovitz, Barry;Loftis, Laura L;Weiss, Scott L;Higgerson, Renee;Schwarz, Adam J;Pinto, Neethi P
• 通讯作者: Pinto, Neethi P