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: 10055872
• 负责人: Adrienne G Randolph
• 金额: $ 126.73万
• 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/10055872
• 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; Preventive Intervention; Prognostic Marker; Recovery; Recurrence; Research Personnel; Resolution; Respiration Disorders; Respiratory Failure; Risk; Risk Factors; Risk stratification; 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; 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 virus strain; influenza virus vaccine; influenzavirus; mortality; multidisciplinary; next generation sequencing; novel; pandemic disease; pandemic influenza; personalized care; predictive marker; proband; prognostic; repaired; respiratory hypoxia; seasonal influenza; therapeutic target; ward; young adult; 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; Preventive Intervention; Prognostic Marker; Recovery; Recurrence; Research Personnel; Resolution; Respiration Disorders; Respiratory Failure; Risk; Risk Factors; Risk stratification; 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; 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 virus strain; influenza virus vaccine; influenzavirus; mortality; multidisciplinary; next generation sequencing; novel; pandemic disease; pandemic influenza; personalized care; predictive marker; proband; prognostic; repaired; respiratory hypoxia; 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的全球威胁，每年都会感染5-10％的成年人和20-30％ 全世界的儿童中造成超过500,000个与影响力有关的死亡。大多数年度影响力感染都在 年轻的，古老的，以及患有慢性健康状况（例如哮喘）的人。然而， 由高度致病的新型影响力的出现和传播引起的复发性影响力大流行 菌株（例如2009年发生的菌株）不成比例地导致健康儿童和年轻人的严重疾病 成年人。这项威胁生命的影响力病毒下呼吸道感染（LRTI）的研究是 由成熟的多学科研究人员设计，以更好地了解主机先天和 影响病毒的适应性免疫学与疾病的敏感性，严重程度和临床结局有关。 在小儿重症监护流感（PICFLU1）研究中，我们假设感染了影响 病毒会触发过度胞菌血症和免疫失调，在易感宿主中，导致严重 威胁生命的感染。在PICFLU1（AI084011，招收2008-2016）中证实我们的假设，我们 确定了与先天免疫抑制并存的高炎性表型。两者都是相关的 死亡。我们还确定了IFITM3和MBL2中功能变体与小儿之间的关联 影响力相关的死亡。在Young Hosts研究中，流感病毒相关疾病的免疫生物学 （Picflu2，招募2020-2025），我们检验了一个假设，即明显的严重影响力LRTI表型 - 由宿主免疫生物学定义 - 可以确定针对靶向预防和治疗 干预措施。在这项研究中，我们的目标是：1。确定患有严重影响力的儿童的生物标志物可以是 用于未来免疫调节临床试验中的预后分层和预测酶； 2。 确定现有的菌株特异性免疫是否影响病毒预防威胁生命的疾病 并影响病毒脱落和疾病的严重程度；和3。确定抗病毒免疫必不可少的基因 和/或遏制，以解释宿主对严重影响感染或其结果的敏感性。实现 这些目的，我们将招募600名具有确认影响的儿童和年轻人（300个 重症监护室和300病房或门诊病人）遍及35个PICFLU站点。在PICFLU研究中（2008-2025） 我们将在约1,000名感染影响力病毒的年轻宿主上有DNA，以识别重要的内型型 对未来的临床试验的风险分层和预测富集，以预防和更快 从严重影响力相关的疾病中恢复。确定的影响力病毒的敏感性和严重性基因是 免疫调节的潜在“可药靶”。我们的发现可以个性化年轻的照顾 基于患者的明显免疫生物学宿主表型，患有严重影响力感染的个体 年龄，影响力菌株，临床表现，先天和适应性免疫生物标志物以及宿主遗传学。