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Principal Investigator: Adrienne G Randolph
Organization: BOSTON CHILDREN'S HOSPITAL
Fiscal Year: 2024
Award: $1,126,202
Funding agency: National Institute of Allergy and Infectious Diseases
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.
Terms: <0-11 years old><21+ years old><5 year old><5 years of age><Accounting><Acute><Adult><Adult Human><Age><Antibodies><Asthma><Biological><Biological Markers><Bronchial Asthma><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><Cardiac Diseases><Cardiac Disorders><Cessation of life><Child><Child Youth><Childhood><Children (0-21)><Chronic><Chronic Disease><Chronic Illness><Clinical><Clinical Trials><Containment><Critical Illness><Critically Ill><Custom><DNA><Data Set><Death><Deoxyribonucleic Acid><Development><Diathesis><Disease><Disease Outcome><Disease susceptibility><Disorder><Dysfunction><Elderly><Enrollment><Exclusion><Exhibits><Flu vaccination><Functional disorder><Funding><Future><GWA study><GWAS><Gene variant><Genes><Genetic><Genetic Predisposition><Genetic Predisposition to Disease><Genetic Susceptibility><Genetic propensity><Grippe><Health><Heart Diseases><Hemagglutination><Heterozygote><Homolog of Drosophila TOLL><Hospital Admission><Hospitalization><Hospitals><Host Factor><Host Factor Protein><IFN><Immune><Immune Diseases><Immune Disorders><Immune Dysfunction><Immune Markers><Immune System Diseases><Immune System Disorder><Immune System Dysfunction><Immune System and Related Disorders><Immune response><Immunes><Immunity><Immunobiology><Immunodeficiency and Immunosuppression Disorders><Immunologic Diseases><Immunologic Markers><Immunological Diseases><Immunological Dysfunction><Immunological System Dysfunction><Immunological response><Immunomodulation><Immunophysiology><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><Impairment><Individual><Infection><Inflammation><Inflammatory><Influenza><Influenza A><Influenza A virus><Influenza Vaccines><Influenza Virus><Influenza Viruses Type A><Influenza immunization><Influenza vaccination><Influenzavirus A><Inherited Predisposition><Inherited Susceptibility><Innate Immunity><Integral Membrane Protein><Integration Host Factors><Intensive Care><Intensive Care Units><Interferons><Intrinsic Membrane Protein><Investigators><Laboratories><Life><Lower Respiratory Tract Infection><Lower respiratory infection><Lung><Lung Respiratory System><Measures><Minor><Morbidity><Morbidity - disease rate><NGS Method><NGS system><NIAID><National Institute of Allergy and Infectious Disease><Native Immunity><Natural Immunity><Non-Specific Immunity><Nonspecific Immunity><Nucleic Acids><Organ><Organ failure><Orthomyxovirus Type A><Out-patients><Outcome><Outpatients><Parents><Pathogenicity><Pathway interactions><Patients><Pediatric Intensive Care Units><Persons><Phenotype><Physiopathology><Precision care><Predicting Risk><Predisposition><Preventative intervention><Prevention><Preventive><Prognostic Marker><Prophylactic vaccination against influenza><Recovery><Recurrence><Recurrent><Research Personnel><Researchers><Resolution><Respiration Disorders><Respiratory Disorder><Risk><Risk Factors><Role><Sampling><School-Age Population><Severities><Severity of illness><Site><Stratification><Survivors><Susceptibility><Symptoms><T cell response><T8 Cells><T8 Lymphocytes><TLR4><TLR4 gene><Testing><Therapeutic><Therapeutic Intervention><Toll Homologue><Transmembrane Protein><Transmembrane Protein Gene><Type A Influenza><Validation><Variant><Variation><Viral><Viral Diseases><Viral Shedding><Virus><Virus Diseases><Virus Shedding><Whole Blood><acute hypoxemic respiratory failure><acute hypoxic respiratory failure><acute onset hypoxemic respiratory failure><adaptive immunity><adult youth><adulthood><advanced age><age 5 years><ages><allele variant><allelic variant><anti-flu><anti-influenza><anti-viral immunity><antiflu><antiviral immunity><bio-markers><biobank><biologic><biologic marker><biomarker><biomarker identification><biorepository><breathing disorder><chronic disorder><clinical phenotype><cohort><customs><cytokine><design><designing><developmental><disease severity><druggable target><endophenotype><enroll><exome sequencing><exome-seq><five year old><five years of age><flu immunisation><flu infection><flu serotype><flu strain><flu subtype><flu vaccine><flu viral strain><flu virus infection><flu virus pandemic><flu virus strain><flu virus vaccine><forecasting risk><genetic etiology><genetic mechanism of disease><genetic variant><genetic vulnerability><genetically predisposed><genome wide association><genome wide association scan><genome wide association studies><genome wide association study><genomewide association scan><genomewide association studies><genomewide association study><genomic variant><geriatric><healing><heart disorder><heterozygosity><high risk><host response><identification of biomarkers><identification of new biomarkers><immune modulation><immune regulation><immune suppression><immune suppressive activity><immune suppressive function><immune system response><immune-based biomarkers><immunologic reactivity control><immunological biomarkers><immunological markers><immunomodulatory><immunoregulation><immunoregulatory><immunoresponse><immunosuppressive activity><immunosuppressive function><immunosuppressive response><improved><individualized care><individualized patient care><infected with flu><infected with flu virus><infected with influenza><infected with influenza virus><influenza infection><influenza serotype><influenza strain><influenza subtype><influenza viral strain><influenza virus infection><influenza virus pandemic><influenza virus strain><influenza virus vaccination><influenza virus vaccine><influenzavirus><inhibiting antibody><intervention for prevention><intervention therapy><kids><liability to disease><marker identification><mortality><multidisciplinary><next gen sequencing><next generation sequencing><nextgen sequencing><novel><pandemic><pandemic concern><pandemic disease><pandemic flu><pandemic influenza><pandemic potential><pandemic risk><pandemic strain of influenza><pandemic threat><parent><pathophysiology><pathway><pediatric><personalized care><personalized patient care><predict risk><predict risks><predicted risk><predicted risks><predicting risks><predictive biomarkers><predictive marker><predictive molecular biomarker><predictive risk><predicts risk><prevention intervention><preventional intervention strategy><preventive intervention><proband><prognostic><prognostic biomarker><pulmonary><rare allele><rare mutation><rare variant><repair><repaired><resolutions><respiratory dysfunction><risk prediction><risk predictions><risk stratification><school age><seasonal flu><seasonal influenza><senior citizen><social role><stratify risk><therapeutic target><toll-like receptor 4><vaccination against influenza><vaccine against flu><vaccine against influenza><vaccine failure><validations><viral infection><virus infection><virus-induced disease><ward><whole genome association analysis><whole genome association studies><whole genome association study><young adult><young adulthood><youngster>