Genetic Epidemiology of Life-Threatening Influenza in Children

儿童危及生命的流感的遗传流行病学

• 批准号: 8508174
• 负责人: Adrienne G Randolph
• 金额: $ 76.79万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-11 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8508174
• 关键词: Acute; Acute Lung Injury; Admission activity; American; Asthma; Biological; Biological Markers; Biological Response Modifiers; CCL2 gene; CCL7 gene; CXC chemokine IP-10; Candidate Disease Gene; Cessation of life; Child; Childhood; Clinical; Clinical Investigator; Clinical Trials; Critical Care; Critically ill children; DNA; Data; Disease susceptibility; Endotoxins; Equilibrium; Family suidae; Future; Gene Expression; Genes; Genetic Polymorphism; Granulocyte Colony-Stimulating Factor; Health; Hospitalization; IL10 gene; Immune; Immune response; Immune system; Immunologic Adjuvants; Immunosuppression; Infection; Inflammation; Inflammation Mediators; Inflammatory Response; Influenza; Influenza A Virus, H1N1 Subtype; Interleukin-10; Interleukin-6; Interleukin-8; Life; Lipopolysaccharides; Lower Respiratory Tract Infection; Lung; Measures; Mediating; Messenger RNA; Monocyte Chemoattractant Protein-1; Morbidity - disease rate; Natural Immunity; Outcome; Parents; Patients; Pediatric Intensive Care Units; Physiology; Poly I-C; Population; Predisposition; Prevention; Preventive; Productivity; Proteins; RNA; Receptor Gene; Research Personnel; Risk; Risk Factors; Role; Sampling; Sepsis; Serum; Severities; Severity of illness; Site; Small Inducible Cytokine A3; Societies; Stratification; Testing; Therapeutic; Toll-like receptors; Viral; Virus Diseases; Whole Blood; antimicrobial; base; chemokine; cost; cytokine; design; genetic epidemiology; high risk; influenzavirus; killings; monocyte; mortality; novel; pandemic disease; pandemic influenza; peripheral blood; public health relevance; seasonal influenza; treatment strategy; viral DNA; young adult

DESCRIPTION (provided by investigator): Influenza A and B viral infections kill hundreds of thousands of people worldwide each year, costing society billions of dollars in morbidity and disruption. Seasonal influenza annually infects 5 to 20 percent of the population, leading to 200,000 hospitalizations and approximately 36,000 deaths. We are in the midst of an influenza pandemic caused by a novel H1N1 influenza strain that includes swine origin viral DNA. The 2009 Pandemic H1N1 influenza strain is causing excess morbidity and mortality in children and young adults. This study of life-threatening influenza infection in children, designed by an established group of pediatric critical care clinical trial investigators and being conducted during an influenza pandemic, evaluates how the host innate immune response is associated with disease susceptibility, severity and outcome. Our preliminary data revealed that both cytokine storm and innate immunosuppression are associated with mortality in children with influenza infection. Based on this, we hypothesize that infection with the influenza virus triggers hypercytokinemia and innate immunosuppression in a genetically susceptible host leading to severe and sometimes fatal infection. We will test this hypothesis in critically ill children with influenza lower respiratory tract infection. By understanding why children die from influenza, we can better identify targets for clinical trials in influenza treatment and prevention. This study has three specific aims. Aim 1 is to identify cytokines and chemokines present on clinical admission that are associated with illness severity and predictive of death or near death in children with influenza lower respiratory tract infection. Aim 2 is to assess the role of innate immunosuppression in influenza lower respiratory tract infection severity and mortality. To do this, we will serially measure the patient's ability to produce proinflammatory cytokines upon ex vivo stimulation of whole blood with lipopolysaccharide and polyinosinic:polycytidylic acid to allow functional determination of innate immune responsiveness. Aim 3 is to identify associations between children with life-threatening influenza lower respiratory tract infection and polymorphisms in influenza-related innate immunity genes. To achieve these aims, we will serially test important inflammatory and immune mediators from peripheral blood and lung, performing sensitive multiplex viral PCR testing to identify coinfection and subtype the influenza strain, and obtain DNA from patients and biological parents. Our approach will entail engagement of 31 sites across the Pediatric Acute Lung Injury and Sepsis Investigator's (PALISI) Network, a consortium of clinical investigators across North American pediatric ICUs with a proven track record of productivity. Including subjects from prior studies, we will have DNA on 400 children admitted to the ICU with life-threatening or fatal influenza and most of their biological parents. Understanding of the role of the innate immune and inflammatory response in children with life-threatening and fatal influenza infection could provide new targets for future preventive (immune adjuvant) and therapeutic approaches.

描述（由研究者提供）：甲型和乙型流感病毒感染每年导致全世界数十万人死亡，给社会带来数十亿美元的发病率和破坏性损失。季节性流感每年感染 5% 至 20% 的人口，导致 200,000 人住院治疗，约 36,000 人死亡。我们正处于由一种新型 H1N1 流感病毒株引起的流感大流行之中，该流感病毒株含有猪源病毒 DNA。 2009 年大流行的 H1N1 流感病毒株导致儿童和年轻人发病率和死亡率过高。这项针对危及生命的儿童流感感染的研究由一组儿科重症监护临床试验研究人员设计，并在流感大流行期间进行，评估了宿主先天免疫反应与疾病易感性、严重程度和结果之间的关系。我们的初步数据显示，细胞因子风暴和先天免疫抑制都与流感感染儿童的死亡率相关。基于此，我们假设流感病毒感染会在遗传易感宿主中引发高细胞因子血症和先天免疫抑制，从而导致严重甚至有时致命的感染。我们将在患有流感下呼吸道感染的危重儿童中检验这一假设。通过了解儿童死于流感的原因，我们可以更好地确定流感治疗和预防临床试验的目标。这项研究有三个具体目标。目标 1 是确定临床入院时存在的细胞因子和趋化因子，这些细胞因子和趋化因子与流感下呼吸道感染儿童的疾病严重程度相关，并可预测死亡或濒临死亡。目标 2 是评估先天免疫抑制在流感下呼吸道感染严重程度和死亡率中的作用。为此，我们将连续测量患者在用脂多糖和聚肌苷：聚胞苷酸离体刺激全血时产生促炎细胞因子的能力，以允许先天免疫反应的功能测定。目标 3 是确定患有危及生命的流感下呼吸道感染的儿童与流感相关先天免疫基因多态性之间的关联。为了实现这些目标，我们将连续检测来自外周血和肺部的重要炎症和免疫介质，进行敏感的多重病毒PCR检测，以识别共感染和流感毒株亚型，并从患者和亲生父母那里获取DNA。我们的方法将涉及儿科急性肺损伤和脓毒症调查员 (PALISI) 网络的 31 个站点的参与，该网络是一个由北美儿科 ICU 的临床研究人员组成的联盟，具有良好的生产力记录。包括之前研究的对象在内，我们将对 400 名因危及生命或致命流感而入住 ICU 的儿童及其大多数亲生父母进行 DNA 检测。了解先天免疫和炎症反应在危及生命和致命流感感染的儿童中的作用可以为未来的预防（免疫佐剂）和治疗方法提供新的目标。

项目成果

Machine Learning Predicts Prolonged Acute Hypoxemic Respiratory Failure in Pediatric Severe Influenza.

机器学习预测儿童严重流感的长期急性低氧性呼吸衰竭。

• 发表时间: 2020-08
• 作者: Sauthier, Michaël S;Jouvet, Philippe A;Newhams, Margaret M;Randolph, Adrienne G
• 通讯作者: Randolph, Adrienne G

Vancomycin Monotherapy May Be Insufficient to Treat Methicillin-resistant Staphylococcus aureus Coinfection in Children With Influenza-related Critical Illness.

万古霉素单一疗法可能不足以治疗患有流感相关危重疾病的儿童的耐甲氧西林金黄色葡萄球菌合并感染。

• 发表时间: 2019
• 作者: Randolph, Adrienne G;Xu, Ruifei;Novak, Tanya;Newhams, Margaret M;Bubeck Wardenburg, Juliane;Weiss, Scott L;Sanders, Ronald C;Thomas, Neal J;Hall, Mark W;Tarquinio, Keiko M;Cvijanovich, Natalie;Gedeit, Rainer G;Truemper, Edward J;Markovitz, Ba
• 通讯作者: Markovitz, Ba

Estimated Pao2: A Continuous and Noninvasive Method to Estimate Pao2 and Oxygenation Index.

估计 Pao2：一种连续、无创的估计 Pao2 和氧合指数的方法。

• 发表时间: 2021-10
• 作者: Sauthier, Michaël;Tuli, Gaurav;Jouvet, Philippe A;Brownstein, John S;Randolph, Adrienne G
• 通讯作者: Randolph, Adrienne G

Risk factors for mechanical ventilation in U.S. children hospitalized with seasonal influenza and 2009 pandemic influenza A*.

因季节性流感和 2009 年大流行甲型流感住院的美国儿童机械通气的危险因素。

• 发表时间: 2012-11
• 作者: Eriksson, Carl O;Graham, Dionne A;Uyeki, Timothy M;Randolph, Adrienne G
• 通讯作者: Randolph, Adrienne G

Host Respiratory Transcriptome Signature Associated with Poor Outcome in Children with Influenza-Staphylococcus aureus Pneumonia.

宿主呼吸转录组特征与流感金黄色葡萄球菌肺炎儿童的不良结局相关。

• 发表时间: 2022-09-28
• 作者: Britto, Carl;Mohorianu, Irina;Yeung, Tracy;Cheung, Elaine;Novak, Tanya;Hall, Mark W;Mourani, Peter M;Weiss, Scott L;Thomas, Neal J;Markovitz, Barry;Randolph, Adrienne G;Moffitt, Kristin L
• 通讯作者: Moffitt, Kristin L