Immunobiology of Influenza Virus-related Critical Illness in Young Hosts

摘要 流感病毒是一种持久的全球威胁，估计每年有5%-10%的成年人和20%-30%的人感染流感病毒 全世界有500,000多名儿童死于流感。每年大多数流感感染病例都在 幼儿、老年人和患有慢性疾病(如哮喘)的个人。然而， 高致病性新型甲型流感病毒的出现和传播导致的反复流感大流行 菌株，如2009年发生的，不成比例地导致健康儿童和更小的儿童患上严重疾病 成年人。这项关于年轻宿主中危及生命的流感病毒下呼吸道感染(LRTI)的研究 由一个成熟的多学科研究小组设计，以更好地了解宿主天生和 对流感病毒的获得性免疫与疾病的易感性、严重性和临床结果有关。 在儿科重症监护病房流感(PICFLU1)研究中，我们假设感染了流感 病毒在遗传易感宿主中触发高细胞分裂素血症和免疫失调，导致严重的 危及生命的感染。证实了我们的假设，在PICFLU1(AI084011,2008-2016入学)中，我们 发现一种与先天免疫抑制共存的高炎性表型；两者均相关 伴随着死亡。我们还确定了IFITM3和MBL2的功能变异与儿科疾病的关联 与流感相关的死亡。青年宿主中流感病毒相关危重疾病的免疫生物学研究 (PICFLU2，招募2020-2025)，我们检验了以下假设：不同的严重流感LRTI表型- 由宿主免疫生物学定义-可被确定为有针对性的预防和治疗 干预措施。在这项研究中，我们的目标是：1.确定严重流感LRTI儿童中可能存在的生物标记物 用于未来免疫调节临床试验的预后分层和预测性浓缩； 确定先前存在的针对流感病毒的毒株特异性免疫是否可以预防危及生命的疾病 并影响病毒脱落和疾病严重程度；以及3.识别抗病毒免疫所必需的基因 和/或解释宿主对严重流感感染的易感性或其后果的遏制措施。要实现 为了实现这些目标，我们将再招收600名确诊感染流感的儿童和年轻人(300人 重症监护病房和300名病房或门诊患者)，分布在35个PICFLU站点。跨PICFLU研究(2008-2025) 我们将对感染流感病毒的约1,000名年轻宿主进行DNA检测，以确定重要的内表型 未来临床试验中的风险分层和预测性丰富，旨在更快地预防 从与严重流感相关的疾病中康复。已确定的流感病毒易感性和严重程度基因为 免疫调节的潜在“可用药靶点”。我们的发现可以个性化地照顾年轻的 基于患者不同免疫生物学宿主表型的严重流感感染个体 年龄、流感病毒株、临床表现、先天和获得性免疫生物标志物以及宿主遗传学。

ABSTRACT Influenza virus is a persistent global menace that every year infects an estimated 5-10% of adults and 20-30% of children worldwide causing over 500,000 influenza-related deaths. Most annual influenza infections are in the very young, the elderly, and in individuals with chronic health conditions such as asthma. However, recurrent influenza pandemics caused by the emergence and spread of highly pathogenic novel influenza A strains, such as occurred in 2009, disproportionately causes severe illness in healthy children and younger adults. This study of life-threatening influenza virus lower respiratory tract infection (LRTI) in young hosts is designed by an established multidisciplinary group of investigators to better understand how host innate and adaptive immunity to influenza virus is associated with disease susceptibility, severity and clinical outcomes. In the Pediatric Intensive Care Influenza (PICFLU1) study, we hypothesized that infection with the influenza virus triggers hypercytokinemia and immune dysregulation in a genetically susceptible host resulting in severe life-threatening infection. Confirming our hypothesis, in PICFLU1 (AI084011, enrolling 2008-2016), we identified a hyperinflammatory phenotype coexisting with innate immunosuppression; both were associated with mortality. We also identified associations between functional variants in IFITM3 and MBL2 with pediatric influenza-related death. In the Immunobiology of Influenza Virus-Related Critical Illness in Young Hosts study (PICFLU2, enrolling 2020-2025), we test the hypothesis that distinct severe influenza LRTI phenotypes – defined by host immunobiology – can be identified for targeted preventive and therapeutic interventions. In this study we aim to: 1. Identify biomarkers in children with severe influenza LRTI that can be used for prognostic stratification and predictive enrichment in future immunomodulatory clinical trials; 2. Determine if pre-existing strain specific immunity to influenza virus protects against life-threatening disease and influences viral shedding and disease severity; and 3. Identify genes essential for anti-viral immunity and/or containment that explain host susceptibility to severe influenza infection or its outcome. To achieve these aims, we will enroll 600 additional children and young adults with confirmed influenza infection (300 intensive care unit and 300 ward or outpatient) across 35 PICFLU sites. Across PICFLU studies (2008-2025) we will have DNA on ~1,000 young hosts infected with influenza virus to identify important endophenotypes for risk stratification and predictive enrichment in future clinical trials targeting prevention of and more rapid recovery from severe influenza-related disease. Identified influenza virus susceptibility and severity genes are potential “druggable targets” for immune modulation. Our findings could personalize the care of young individuals with severe influenza infection based on distinct immunobiologic host phenotypes based on patient age, influenza strain, clinical presentation, innate and adaptive immune biomarkers and host genetics.