Genetic Epidemiology of Life-Threatening Influenza in Children

描述（由研究者提供）：甲型和乙型流感病毒感染每年在全球造成数十万人死亡，在发病率和破坏方面给社会造成数十亿美元的损失。季节性流感每年感染5%至20%的人口，导致20万人住院，约3.6万人死亡。我们正处于由新型H1N1流感毒株引起的流感大流行之中，该毒株含有猪源病毒DNA。2009年H1N1流感大流行毒株在儿童和青年中造成过高的发病率和死亡率。在流感大流行期间，一组儿科重症临床试验研究人员设计了一项针对危及生命的儿童流感感染的研究，评估了宿主先天免疫反应与疾病易感性、严重程度和结局之间的关系。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有关。基于此，我们假设感染流感病毒会在遗传易感宿主中引发高细胞分裂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的。目的1是确定临床入院时存在的与流感下呼吸道感染儿童的疾病严重程度和预测死亡或接近死亡相关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，我们将在体外用脂多糖和多肌苷：多胞酸刺激全血时，连续测量患者产生促炎细胞因子的能力，以确定先天免疫反应的功能。目的3是确定危及生命的流感下呼吸道感染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，我们将从外周血和肺中连续检测重要的炎症和免疫介质，进行敏感的多重病毒PCR检测以识别合并感染和流感毒株亚型，并从患者和亲生父母那里获得DNA。我们的方法将需要在儿科急性肺损伤和败血症研究者（PALISI）网络中的31个站点参与，PALISI是北美儿科icu临床研究人员的联盟，具有良好的生产力记录。包括先前研究的对象，我们将获得400名重症监护室收治的患有危及生命或致命流感的儿童及其大多数亲生父母的DNA。了解先天性免疫和炎症反应在危及生命和致命的流感感染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靶点。

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. PUBLIC HEALTH RELEVANCE: 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 project provides a more sophisticated understanding of the role of the innate immune response in life-threatening influenza infection in children, providing new targets for preventive and therapeutic approaches to decrease influenza-related morbidity and mortality.