Immunobiology of Influenza Virus-related Critical Illness in Young Hosts

年轻宿主流感病毒相关危重疾病的免疫生物学

• 批准号: 10266129
• 负责人: Adrienne G Randolph
• 金额: $ 114.38万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-18 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10266129
• 关键词: 5 year old; Accounting; Acute; Adult; Age; Antibodies; Antiviral Agents; Asthma; Biological; Biological Markers; CD8-Positive T-Lymphocytes; Cessation of life; Child; Childhood; Chronic; Chronic Disease; Clinical; Clinical Trials; Containment; Critical Illness; Custom; DNA; Data Set; Development; Disease; Disease Outcome; Disease susceptibility; Elderly; Enrollment; Exhibits; Failure; Functional disorder; Funding; Future; Genes; Genetic; Genetic Predisposition to Disease; Health; Heart Diseases; Hemagglutination; Hospitalization; Hospitals; Immune; Immune System Diseases; Immune response; Immunity; Immunobiology; Immunologic Markers; Immunosuppression; Impairment; Individual; Infection; Inflammation; Influenza; Influenza A virus; Influenza vaccination; Integral Membrane Protein; Integration Host Factors; Intensive Care; Intensive Care Units; Interferons; Laboratories; Life; Lower Respiratory Tract Infection; Lung; Measures; Minor; Morbidity - disease rate; Mutation; National Institute of Allergy and Infectious Disease; Natural Immunity; Nucleic Acids; Organ; Organ failure; Outcome; Outpatients; Parents; Pathogenicity; Pathway interactions; Patients; Pediatric Intensive Care Units; Phenotype; Predisposition; Prevention; Preventive; Prognostic Marker; Recovery; Recurrence; Research Personnel; Resolution; Respiration Disorders; Risk; Risk Factors; Role; Sampling; School-Age Population; Severities; Severity of illness; Site; Stratification; Survivors; Symptoms; T cell response; TLR4 gene; Testing; Therapeutic; Therapeutic Intervention; Validation; Variant; Viral; Virus; Virus Diseases; Virus Shedding; Whole Blood; acute hypoxemic respiratory failure; adaptive immunity; anti-influenza; antiviral immunity; base; biobank; clinical phenotype; cohort; cytokine; design; druggable target; endophenotype; exome sequencing; genetic variant; genome wide association study; healing; high risk; immunoregulation; improved; influenza infection; influenza virus strain; influenza virus vaccine; influenzavirus; mortality; multidisciplinary; next generation sequencing; novel; pandemic disease; pandemic influenza; personalized care; predictive marker; preventive intervention; proband; prognostic; repaired; risk stratification; seasonal influenza; therapeutic target; ward; young adult

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.

抽象的 流感病毒是一种持续存在的全球威胁，每年估计感染 5-10% 的成年人和 20-30% 全球有超过 500,000 名儿童因流感而死亡。大多数年度流感感染发生在 幼儿、老年人以及患有哮喘等慢性疾病的人。然而， 由高致病性新型甲型流感病毒的出现和传播引起的反复流行的流感大流行 诸如 2009 年发生的菌株，在健康儿童和年龄较小的儿童中引起严重疾病的比例不成比例 成年人。这项针对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 由一个已建立的多学科研究小组设计，旨在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的易感性、严重程度和临床结果相关。 在儿科重症监护流感 (PICFLU1) 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。证实了我们的假设，在 PICFLU1（AI084011，2008-2016 年入学）中，我们 确定了与先天免疫抑制共存的高炎症表型；两者都有关联 与死亡率。我们还确定了 IFITM3 和 MBL2 的功能变异与儿科疾病之间的关联。 流感相关死亡。年轻宿主中流感病毒相关危重疾病的免疫生物学研究 （PICFLU2，2020-2025 年招募），我们测试了以下假设：不同的严重流感 LRTI 表型 – 由宿主免疫生物学定义——可以识别用于有针对性的预防和治疗 干预措施。在本研究中，我们的目标是： 1. 确定患有严重流感 LRTI 的儿童的生物标志物，这些标志物可以 用于未来免疫调节临床试验中的预后分层和预测丰富； 2. 确定现有毒株对流感病毒的特异性免疫力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； 3. 鉴定抗病毒免疫所必需的基因 和/或解释宿主对严重流感感染或其结果的易感性的遏制。达到 为了实现这些目标，我们将另外招募 600 名确诊流感感染的儿童和青少年（300 重症监护病房和 300 个病房或门诊）遍布 35 个 PICFLU 站点。整个 PICFLU 研究（2008-2025） 我们将对约 1,000 名感染流感病毒的年轻宿主进行 DNA 鉴定，以确定重要的内表型 未来临床试验中的风险分层和预测丰富旨在预防和更快 从严重的流感相关疾病中康复。已确定的流感病毒易感性和严重性基因是 免疫调节的潜在“药物靶标”。我们的研究结果可以个性化年轻人的护理 基于不同免疫生物学宿主表型的严重流感感染个体 年龄、流感毒株、临床表现、先天性和适应性免疫生物标志物以及宿主遗传学。