Genetic Epidemiology of Life-Threatening Influenza in Children

描述（由研究者提供）：甲型流感和B型流感病毒感染每年在全世界造成数十万人死亡，导致社会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20万人住院治疗，约36，000人死亡。我们正处于一场由一种新型H1N1流感毒株引起的流感大流行之中，这种毒株包括猪源病毒DNA。2009年H1N1大流行流感毒株导致儿童和青少年发病率和死亡率过高。本研究由儿科重症监护临床试验研究人员设计，在流感大流行期间进行，旨在评估宿主先天免疫应答与疾病易感性、严重程度和结局的相关性。我们的初步数据显示，细胞因子风暴和先天性免疫抑制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在遗传易感宿主中引发高细胞因子血症和先天性免疫抑制，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。目的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，并预测死亡或濒临死亡。目的2是评估先天性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胞苷酸离体刺激全血后产生促炎细胞因子的能力，以允许先天免疫应答的功能测定。目的3是确定威胁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，我们将连续检测外周血和肺中重要的炎症和免疫介质，进行敏感的多重病毒PCR检测，以确定合并感染和流感毒株亚型，并从患者和生物学父母中获得DNA。我们的方法将涉及儿科急性肺损伤和脓毒症研究者网络（PALISI）中的31个研究中心，PALISI是北美儿科ICU临床研究者联盟，具有良好的生产力记录。包括先前研究的受试者，我们将对400名患有危及生命或致命流感的ICU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儿童致命性流感感染中的作用，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B型流感病毒感染每年在全世界造成数十万人死亡，使社会在发病率和破坏方面损失数十亿美元。该项目提供了对先天免疫反应在威胁生命的儿童流感感染中的作用的更深入的理解，为预防和治疗方法提供了新的目标，以减少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.