Genetic Epidemiology of Life-Threatening Influenza in Children

描述(由调查人员提供)：甲型和乙型流感病毒感染每年导致全球数十万人死亡，给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20万人住院，约3.6万人死亡。我们正处于一场由一种新型H1N1流感病毒株引起的流感大流行中，这种病毒株包括猪源病毒DNA。2009年甲型H1N1流感大流行毒株在儿童和年轻人中造成过高的发病率和死亡率。这项关于儿童中危及生命的流感感染的研究由一组公认的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，评估宿主的先天免疫反应与疾病易感性、严重性和预后的关系。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一个遗传易感的宿主中触发高细胞分裂素血症和先天免疫抑制，从而导致严重的、有时是致命的感染。我们将在患有流感下呼吸道感染的危重儿童身上测试这一假设。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。目的1是确定临床入院时存在的细胞因子和趋化因子，它们与流感下呼吸道感染儿童的病情严重程度和死亡或濒临死亡的预测有关。目的2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脂多糖和多肌苷：多胞苷酸体外刺激全血时产生促炎细胞因子的能力，以实现天然免疫反应性的功能测定。目的3是确定儿童患危及生命的流感下呼吸道感染与流感相关先天免疫基因多态性之间的关系。为了实现这些目标，我们将对来自外周血和肺部的重要炎症和免疫介质进行一系列检测，进行敏感的多重病毒聚合酶链式反应检测以确定流感病毒株的混合感染和亚型，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网络(Palisi)的31个地点，该网络是一个由北美儿科ICU的临床调查人员组成的联盟，具有经过证明的生产力记录。包括以前研究的对象，我们将对400名住进ICU的患有危及生命或致命流感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威胁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靶点。 公共卫生相关性：甲型和乙型流感病毒感染每年导致全球数十万人死亡，给社会造成数十亿美元的发病率和破坏性损失。该项目提供了对先天免疫反应在威胁儿童生命的流感感染中的作用的更深入的了解，为预防和治疗方法提供了新的目标，以减少与流感相关的发病率和死亡率。

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.