title: Mucosal immune responses predict clinical outcomes during influenza infection independently of age and viral load.
abstract: BACKGROUND
  Children are an at-risk population for developing complications following influenza infection, but immunologic correlates of disease severity are not understood. We hypothesized that innate cellular immune responses at the site of infection would correlate with disease outcome.
  
  
  OBJECTIVE
  To test the immunologic basis of severe illness during natural influenza virus infection of children and adults at the site of infection.
  
  
  METHODS
  An observational cohort study with longitudinal sampling of peripheral and mucosal sites in 84 naturally influenza-infected individuals, including infants. Cellular responses, viral loads, and cytokines were quantified from nasal lavages and blood, and correlated to clinical severity.
  
  
  RESULTS
  We show for the first time that although viral loads in children and adults were similar, innate responses in the airways were stronger in children and varied considerably between plasma and site of infection. Adjusting for age and viral load, an innate immune profile characterized by increased nasal lavage monocyte chemotactic protein-3, IFN-α2, and plasma IL-10 levels at enrollment predicted progression to severe disease. Increased plasma IL-10, monocyte chemotactic protein-3, and IL-6 levels predicted hospitalization. This inflammatory cytokine production correlated significantly with monocyte localization from the blood to the site of infection, with conventional monocytes positively correlating with inflammation. Increased frequencies of CD14(lo) monocytes were in the airways of participants with lower inflammatory cytokine levels.
  
  
  CONCLUSIONS
  An innate profile was identified that correlated with disease progression independent of viral dynamics and age. The airways and blood displayed dramatically different immune profiles emphasizing the importance of cellular migration and localized immune phenotypes.
authors.affiliation: 1 Department of Immunology, and.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Oshansky
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Gartland
authors.forename: Sook-San
authors.initials: SS
authors.lastname: Wong
authors.forename: Trushar
authors.initials: T
authors.lastname: Jeevan
authors.forename: David
authors.initials: D
authors.lastname: Wang
authors.forename: Philippa L
authors.initials: PL
authors.lastname: Roddam
authors.forename: Miguela A
authors.initials: MA
authors.lastname: Caniza
authors.forename: Tomer
authors.initials: T
authors.lastname: Hertz
authors.forename: John P
authors.initials: JP
authors.lastname: Devincenzo
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Webby
authors.forename: Paul G
authors.initials: PG
authors.lastname: Thomas
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D015415:Biomarkers / Q000378:metabolism; D002634:Chemotaxis, Leukocyte; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D016207:Cytokines / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D006760:Hospitalization; D006801:Humans; D007113:Immunity, Innate; D007223:Infant; D007251:Influenza, Human / Q000175:diagnosis / Q000276:immunology* / Q000628:therapy / Q000821:virology; D008137:Longitudinal Studies; D008297:Male; D009000:Monocytes / Q000378:metabolism; D017817:Nasal Lavage Fluid / Q000276:immunology; D011379:Prognosis; D020545:Respiratory Mucosa / Q000276:immunology* / Q000821:virology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012720:Severity of Illness Index; D019562:Viral Load; D055815:Young Adult
chemical_list: D015415:Biomarkers; D016207:Cytokines