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（调查员提供）：每年在全球范围内，流感和B病毒感染杀死了数十万人，使社会造成数十亿美元的发病率和破坏。季节性流感每年感染5％至20％的人口，导致200,000例住院和约36,000人死亡。我们正处于由包括猪起源病毒DNA的新型H1N1流感菌株引起的流感大流行。 2009年大流行的H1N1流感菌株正在导致儿童和年轻人的发病率过多和死亡率。这项研究由一组既定的儿科重症监护临床试验研究者设计并在流感大流行期间进行的儿童危害生命的流感感染研究，评估宿主先天免疫反应如何与疾病的易感性，严重性和结果有关。我们的初步数据表明，细胞因子风暴和先天免疫抑制与流感感染儿童的死亡率有关。基于此，我们假设感染流感病毒会触发高胞菌血症和先天性免疫抑制，从而在遗传易感宿主中导致严重，有时是致命的感染。我们将在患有流感下呼吸道感染的重症儿童中检验这一假设。通过了解为什么儿童死于流感，我们可以更好地识别流感治疗和预防临床试验的靶标。这项研究具有三个具体目标。目的1是鉴定出与疾病严重程度以及对流感下呼吸道感染儿童死亡或死亡接近死亡有关的临床入院中存在的细胞因子和趋化因子。目的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，我们将在对全体血液中用脂多糖和聚精氨酸的全血刺激后，在患者产生促炎细胞因子的能力下序列地测量：多环酸以允许确定先天免疫反应的功能。目的3是确定患有威胁生命的流感下呼吸道感染的儿童与流感相关的先天免疫基因中的多态性的关联。为了实现这些目标，我们将通过外周血和肺部序列测试重要的炎症和免疫介质，进行敏感的多重病毒PCR测试，以鉴定共同感染并亚型亚型流感菌株，并从患者和亲生父母那里获得DNA。我们的方法将需要在小儿急性肺损伤和败血症研究者（PALISI）网络中参与31个地点，这是北美儿科ICU的一个临床研究人员的财团，具有可靠的生产力记录。包括先前研究的受试者，我们将对400名患有威胁生命或致命的流感及其大多数亲生父母的儿童进行DNA。了解先天免疫和炎症反应在威胁生命和致命的流感感染儿童中的作用，可以为未来的预防性（免疫辅助）和治疗方法提供新的靶标。

项目成果

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。

• DOI: 10.1093/infdis/jiac325
• 发表时间: 2022
• 期刊: The Journal of infectious diseases
• 作者: Britto,Carl;Mohorianu,Irina;Yeung,Tracy;Cheung,Elaine;Novak,Tanya;Hall,MarkW;Mourani,PeterM;Weiss,ScottL;Thomas,NealJ;Markovitz,Barry;Randolph,AdrienneG;Moffitt,KristinL
• 通讯作者: Moffitt,KristinL

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

• DOI: 10.1097/pcc.0b013e318260114e
• 发表时间: 2012-11
• 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: Eriksson CO;Graham DA;Uyeki TM;Randolph AG
• 通讯作者: Randolph AG

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

• DOI: 10.1097/cce.0000000000000175
• 发表时间: 2020-08-01
• 期刊: Critical care explorations
• 作者: Sauthier, Michael S;Jouvet, Philippe A;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.

• DOI: 10.1093/cid/ciy495
• 发表时间: 2019-01-18
• 期刊: Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
• 作者: Randolph AG;Xu R;Novak T;Newhams MM;Bubeck Wardenburg J;Weiss SL;Sanders RC;Thomas NJ;Hall MW;Tarquinio KM;Cvijanovich N;Gedeit RG;Truemper EJ;Markovitz B;Hartman ME;Ackerman KG;Giuliano JS Jr;Shein SL;Moffitt KL;Pediatric Intensive Care Influenza Investigators from the Pediatric Acute Lung Injury and Sepsis Investigator’s Network
• 通讯作者: Pediatric Intensive Care Influenza Investigators from the Pediatric Acute Lung Injury and Sepsis Investigator’s Network