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 流感和B病毒感染每年杀死数十万人 数十亿美元的发病率和破坏。这项对威胁生命的影响力的多中心研究较低 急性呼吸衰竭儿童的呼吸道感染（LRTI），由已建立的组设计 开发了儿科重症监护临床试验研究者，以评估宿主先天免疫 反应与疾病的敏感性和临床结果有关。我们假设这种先天免疫 介导对影响力的识别的组件，包括收费受体（TLRS 2、3、7、8和9）， 视黄酸诱导蛋白（RIG-I），collectin蛋白表面活性剂蛋白A和D（SP-A，SP-D）和甘露糖 结合讲座（MBL），维生素D相关基因（VDR）和基因影响下游细胞因子，例如 干扰素-Alpha（IFN-€），在宿主对严重影响力感染的敏感性中起重要作用。另外，我们 假设这些儿童在向ICU介绍中先天免疫反应的特定特征 将预测疾病的严重程度和恢复持续时间。我们将通过招募 240名患有威胁生命的影响力LRTI的重症儿童的代表性样本，串行测试很重要 外周血和肺部的炎症和免疫介质，进行敏感测试以识别 共同感染并获得DNA，以实现3个具体目标：1。）比较炎症和先天 从影响力感染到7个对照组的危及生命的LRTI儿童的免疫反应 包括健康肺部的儿童，呼吸综合病毒的严重LRTI和rANTARKZA的LRTI 与重要病毒和细菌亚组（例如金黄色葡萄球菌）共同感染。2。）评估先天性如何 免疫反应与疾病的严重程度和疾病恢复的持续时间有关 免疫反应性（免疫分析），白介素8（败血症和急性肺预后的预测指标 损伤），维生素D和SP-A和SP-D（对于肺功能和病毒免疫很重要），3。）确定 在11个重要的先天 与影响力的免疫激素有关的免疫学基因（TLRS 2、3、7、8和9，VDR，SFTPA1，SFTPA2，SFTPA2， SFTPD，RIG-1，MBL），并对与I型有关的69多个基因进行探索性分析 干扰素反应。我们的方法将需要在小儿急性肺损伤中参与31个地点 和败血症调查员（Palisi）网络，这是一个完善的临床研究人员的财团 美国和加拿大的儿科ICU具有可靠的生产力记录。最终，这个项目将 对先天免疫基因和免疫分析在 流感感染，为未来的预防范围（免疫调整和/或疫苗）提供了新的目标 治疗方法可降低影响力相关的发病率和死亡率。

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

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

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