Immunobiology of Influenza Virus-related Critical Illness in Young Hosts

摘要 流感病毒是一种持续的全球性威胁，每年估计感染5-10%的成年人和20-30%的 全球儿童流感导致超过50万人死亡。大多数年度流感感染发生在 幼儿、老年人和患有慢性健康状况如哮喘的个体。然而，在这方面， 高致病性新型甲型流感的出现和传播导致的反复流感大流行 2009年发生的菌株，不成比例地导致健康儿童和年幼儿童患上严重疾病， 成年人了本项关于年轻宿主中危及生命的流感病毒下呼吸道感染（LRTI）的研究是 由一个既定的多学科研究小组设计，以更好地了解宿主的先天和 对流感病毒的适应性免疫与疾病易感性、严重性和临床结果相关。 在儿科重症监护流感（PICFLU 1）研究中，我们假设流感感染 病毒在遗传易感宿主中引发高细胞因子血症和免疫失调，导致严重的 危及生命的感染为了证实我们的假设，在PICFLU 1（AI 084011，招募2008-2016）中，我们 确定了与先天性免疫抑制共存的高炎症表型;两者均与 死亡率。我们还确定了IFITM 3和MBL 2中的功能变体与儿科疾病之间的关联。 流感相关死亡免疫生物学在流感病毒相关危重病中的应用研究 （PICFLU 2，招募2020-2025），我们检验了不同的严重流感LRTI表型的假设- 由宿主免疫生物学定义-可被确定用于靶向预防和治疗 干预措施。在这项研究中，我们的目标是：1。确定严重流感LRTI儿童的生物标志物， 用于未来免疫调节临床试验中的预后分层和预测富集; 2. 确定对流感病毒的既存毒株特异性免疫力是否可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/或遏制，解释宿主对严重流感感染的易感性或其结果。实现 为了达到这些目标，我们将再招募600名确诊感染流感的儿童和年轻人（300名 重症监护室和300个病房或门诊）。在PICFLU研究中（2008-2025） 我们将在大约1,000名感染流感病毒的年轻宿主身上采集DNA，以确定重要的内表型， 在未来的临床试验中进行风险分层和预测富集，以预防和更快速地 从严重流感相关疾病中恢复。已鉴定的流感病毒易感性和严重性基因是 免疫调节的潜在“药物靶点”。我们的发现可以个性化地照顾年轻人， 基于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、先天性和适应性免疫生物标志物和宿主遗传学。

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.