title: Susceptibility to Lower Respiratory Infections in Childhood is Associated with Perturbation of the Cytokine Response to Pathogenic Airway Bacteria.
abstract: BACKGROUND
  Neonatal colonization of the airways with respiratory pathogens is associated with increased risk of lower respiratory infections (LRI) in early childhood. Therefore, we hypothesized that children developing LRI have an aberrant immune response to pathogenic bacteria in infancy. The objective was to characterize in vitro the early life systemic immune response to pathogenic bacteria and study the possible association with incidence of LRI during the first 3 years of life.
  
  
  METHODS
  The Copenhagen Prospective Studies on Asthma in Childhood2000 (COPSAC2000) is a clinical birth cohort study of 411 children born of mothers with asthma. LRI incidence was prospectively captured from 6-monthly planned visits and visits at acute respiratory episodes. The in vitro systemic immune response to Haemophilus influenzae, Moraxella catarrhalis and Streptococcus pneumoniae was characterized by the production of TNF-α, IFN-γ, IL-2, IL-5, IL-10, IL-13 and IL-17 in peripheral blood mononuclear cells isolated at age 6 months from 291 infants. Data were analyzed by Poisson regression against incidence of LRI in infancy.
  
  
  RESULTS
  A multivariable model including all cytokine responses from the 3 different bacterial stimulations significantly identified children at risk of LRI (P = 0.006). The immune response pattern associated with LRI was characterized by perturbed production of several cytokines rather than production of one specific cytokine, and was independent of concurrent asthma. TNF-α and IL-5 were key drivers but did not explain the entire variation in LRI susceptibility.
  
  
  CONCLUSIONS
  Children at risk of future LRI present a perturbed systemic immune response upon exposure to common airway pathogens in early life.
authors.affiliation: From the *Copenhagen Prospective Studies on Asthma in Childhood, Faculty of Health and Medical Sciences, University of Copenhagen & Danish Pediatric Asthma Center, Copenhagen University Hospital, Gentofte, Denmark; and †Department of Systems Biology, Center for Biological Sequence Analysis, Technical University of Denmark, Lyngby, Denmark.
authors.forename: Nadja Hawwa
authors.initials: NH
authors.lastname: Vissing
authors.forename: Jeppe Madura
authors.initials: JM
authors.lastname: Larsen
authors.forename: Morten Arendt
authors.initials: MA
authors.lastname: Rasmussen
authors.forename: Bo Lund Krogsgaard
authors.initials: BL
authors.lastname: Chawes
authors.forename: Anna Hammerich
authors.initials: AH
authors.lastname: Thysen
authors.forename: Klaus
authors.initials: K
authors.lastname: Bønnelykke
authors.forename: Susanne
authors.initials: S
authors.lastname: Brix
authors.forename: Hans
authors.initials: H
authors.lastname: Bisgaard
mesh_terms: D001419:Bacteria / Q000276:immunology* / Q000472:pathogenicity; D001424:Bacterial Infections / Q000453:epidemiology / Q000276:immunology* / Q000382:microbiology; D002675:Child, Preschool; D015331:Cohort Studies; D016207:Cytokines / Q000378:metabolism*; D004198:Disease Susceptibility; D005260:Female; D054884:Host-Pathogen Interactions; D006801:Humans; D015994:Incidence; D007223:Infant; D007231:Infant, Newborn; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008297:Male; D011247:Pregnancy; D012141:Respiratory Tract Infections / Q000453:epidemiology / Q000276:immunology* / Q000382:microbiology
chemical_list: D016207:Cytokines