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

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.

摘要