Genetic Epidemiology of Life-Threatening Influenza Infection in Children

儿童危及生命的流感感染的遗传流行病学

• 批准号: 7912663
• 负责人: Adrienne G Randolph
• 金额: $ 71.22万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-17 至 2010-06-10
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7912663
• 关键词: Acute; Acute Lung Injury; Acute respiratory failure; Adult Respiratory Distress Syndrome; Affect; Age; Asthma; Biological Response Modifiers; Blood; Bronchiolitis; Canada; Cells; Centers for Disease Control and Prevention (U.S.); Cessation of life; Child; Childhood; Clinical; Clinical Investigator; Clinical Trials; Collectins; Complement component C1s; Control Groups; Critical Care; Critical Illness; Critically ill children; DNA; Data; Disease susceptibility; Family; Flow Cytometry; Future; Genes; Genetic Polymorphism; Goals; Health; Hospitalization; Human; Immune; Immune response; Immunity; Immunologic Adjuvants; Infection; Inflammatory; Influenza; Intensive Care Units; Interferon Type I; Interferon-alpha; Interleukin-8; Life; Lipopolysaccharides; Lower Respiratory Tract Infection; Lung; Mannose; Mannose Binding Lectin; Mannose-Binding Lectins; Measures; Mediating; Mediator of activation protein; Morbidity - disease rate; Multicenter Studies; Natural Immunity; Outcome; Parents; Pathway interactions; Patients; Play; Population; Predisposition; Prevention strategy; Preventive; Productivity; Proteins; Public Health; Publishing; Pulmonary Surfactant-Associated Protein A; Pulmonary Surfactant-Associated Protein D; RNA; Recovery; Recruitment Activity; Reporting; Research Design; Research Personnel; Respiratory physiology; Respiratory syncytial virus; Role; Saliva; Sampling; Sepsis; Serum; Severity of illness; Site; Societies; Staphylococcus aureus; Stream; Streptococcus pneumoniae; Subgroup; Testing; Therapeutic; Toll-like receptors; Tretinoin; Viral; Virus; Virus Diseases; Vitamin D; Whole Blood; Work; abstracting; base; case control; cost; cytokine; design; experience; genetic epidemiology; high risk; illness length; killings; mortality; pandemic disease; peripheral blood; response; therapeutic vaccine

ABSTRACT Influenza A and B viral infections kill hundreds of thousands of people worldwide each year, costing society many billions of dollars in morbidity and disruption. This multicenter study of life-threatening influenza lower respiratory tract infection (LRTI) in children with acute respiratory failure, designed by an established group of pediatric critical care clinical trial investigators, was developed to evaluate how the host innate immune response is associated with disease susceptibility and clinical outcome. We hypothesize that innate immune components that mediate recognition of influenza, including Toll-like receptors (TLRs 2, 3, 7, 8, and 9), retinoic-acid inducible protein (RIG-I), the collectins surfactant proteins A and D (SP-A, SP-D) and mannose binding lectin (MBL), Vitamin D related genes (VDR), and genes influencing down-stream cytokines such as interferon-alpha (IFN-¿), play important roles in host susceptibility to severe influenza infection. In addition, we hypothesize that specific features of the innate immune response of these children on presentation to the ICU will predict disease severity and duration of recovery. We will test these hypotheses by recruiting a representative sample of 240 critically ill children with life-threatening influenza LRTI, serially testing important inflammatory and immune mediators from peripheral blood and lung, performing sensitive tests to identify coinfection, and obtaining DNA, to achieve 3 Specific Aims: 1.) To compare the inflammatory and innate immune response of children with life-threatening LRTI from influenza infection alone to 7 control groups including children with healthy lungs, severe LRTI from respiratory syncytial virus, and LRTI from influenza coinfected with important viral and bacterial subgroups such as S. aureus, 2.) To assess how the innate immune response is associated with disease severity and duration of disease recovery focusing on innate immune responsiveness (immunoparalysis), Interleukin 8 (a predictor of outcome for sepsis and acute lung injury), Vitamin D, and SP-A and SP-D (important for lung function and viral immunity), and 3.) To identify associations between life-threatening influenza LRI susceptibility and polymorphisms in 11 important innate immunity genes related to the immune response to influenza (TLRs 2, 3, 7, 8, and 9, VDR, SFTPA1, SFTPA2, SFTPD, RIG-1, MBL) and to perform an exploratory analysis of over 69 additional genes related to the type I interferon response. Our approach will entail engagement of 31 sites across the Pediatric Acute Lung Injury and Sepsis Investigator's (PALISI) Network, a well-established consortium of clinical investigators across pediatric ICUs in the US and Canada with a proven track record of productivity. Ultimately, this project will provide a more sophisticated understanding of the role of innate immune genes and immunoparalysis in influenza infection, providing new targets for future preventive (immune adjuvant and/or vaccine) and therapeutic approaches to decrease influenza-related morbidity and mortality.

抽象的 甲型和乙型流感病毒感染每年导致全世界数十万人死亡，给社会造成损失 发病率和破坏造成数十亿美元的损失。这项针对危及生命的流感的多中心研究降低了 急性呼吸衰竭儿童呼吸道感染（LRTI），由一组已建立的团队设计 儿科重症监护临床试验研究者，旨在评估宿主先天免疫的情况 反应与疾病易感性和临床结果相关。我们假设先天免疫 介导流感识别的成分，包括 Toll 样受体（TLR 2、3、7、8 和 9）， 视黄酸诱导蛋白 (RIG-I)、集合素表面活性蛋白 A 和 D (SP-A、SP-D) 和甘露糖 结合凝集素 (MBL)、维生素 D 相关基因 (VDR) 以及影响下游细胞因子的基因，例如 干扰素-α (IFN-¿) 在宿主对严重流感感染的易感性中发挥重要作用。此外，我们 假设这些儿童在进入 ICU 时先天免疫反应的具体特征 将预测疾病的严重程度和恢复时间。我们将通过招募一名 240 名患有危及生命的流感 LRTI 的危重儿童的代表性样本，连续检测很重要 来自外周血和肺部的炎症和免疫介质，进行敏感测试来识别 共感染，并获取 DNA，以实现 3 个具体目标： 1.) 比较炎症和先天性感染 仅因流感感染而危及生命的 LRTI 儿童与 7 个对照组的免疫反应 包括肺部健康的儿童、呼吸道合胞病毒引起的严重 LRTI 以及流感引起的 LRTI 与重要的病毒和细菌亚群（例如金黄色葡萄球菌）同时感染，2.) 评估先天性如何 免疫反应与疾病严重程度和疾病恢复持续时间相关，重点关注先天性 免疫反应性（免疫麻痹）、白细胞介素 8（脓毒症和急性肺损伤结果的预测因子） 损伤）、维生素 D、SP-A 和 SP-D（对肺功能和病毒免疫很重要），以及 3.) 识别 危及生命的流感 LRI 易感性与 11 种重要先天基因多态性之间的关联 与流感免疫反应相关的免疫基因（TLR 2、3、7、8 和 9、VDR、SFTPA1、SFTPA2、 SFTPD、RIG-1、MBL）并对超过 69 个与 I 型相关的其他基因进行探索性分析 干扰素反应。我们的方法将涉及儿科急性肺损伤的 31 个站点的参与 脓毒症研究者 (PALISI) 网络，这是一个由跨领域临床研究者组成的完善联盟 美国和加拿大的儿科 ICU 具有良好的生产力记录。最终，该项目将 提供对先天免疫基因和免疫麻痹的作用的更深入的理解 流感感染，为未来的预防（免疫佐剂和/或疫苗）提供新的目标 降低流感相关发病率和死亡率的治疗方法。

项目成果

Surfactant protein D is a biomarker of influenza-related pediatric lung injury.

• DOI: 10.1002/ppul.25776
• 发表时间: 2022-03
• 期刊: Pediatric pulmonology
• 影响因子: 3.1
• 作者: Chakrabarti A;Nguyen A;Newhams MM;Ohlson MB;Yang X;Ulufatu S;Liu S;Park S;Xu M;Jiang J;Halpern WG;Anania VG;McBride JM;Rosenberger CM;Randolph AG;Pediatric Intensive Care Influenza (PICFLU) Investigators
• 通讯作者: Pediatric Intensive Care Influenza (PICFLU) Investigators

Enterovirus D68 Reemerges Globally as a Severe Pathogen Targeting Children.

肠道病毒 D68 在全球重新出现，成为针对儿童的严重病原体。

• DOI: 10.1097/pcc.0000000000000961
• 发表时间: 2016
• 期刊: Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies
• 作者: Randolph,AdrienneG

Innate immune function and mortality in critically ill children with influenza: a multicenter study.

• DOI: 10.1097/ccm.0b013e318267633c
• 发表时间: 2013-01
• 期刊: Critical care medicine
• 影响因子: 8.8
• 作者: Hall MW;Geyer SM;Guo CY;Panoskaltsis-Mortari A;Jouvet P;Ferdinands J;Shay DK;Nateri J;Greathouse K;Sullivan R;Tran T;Keisling S;Randolph AG;Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network PICFlu Study Investigators
• 通讯作者: Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network PICFlu Study Investigators

A Biosignature Predicting Complicated Course in Children Presenting with Septic Shock. Why PERSEVERE?

预测感染性休克儿童复杂病程的生物特征。

• DOI: 10.1164/rccm.201704-0759ed
• 发表时间: 2017
• 期刊: American journal of respiratory and critical care medicine
• 影响因子: 24.7
• 作者: Randolph,AdrienneG

The Modified Clinical Progression Scale for Pediatric Patients: Evaluation as a Severity Metric and Outcome Measure in Severe Acute Viral Respiratory Illness.

• DOI: 10.1097/pcc.0000000000003331
• 发表时间: 2023-12-01
• 期刊: Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies