Cytokine responses to rhinovirus and development of asthma, allergic sensitization and respiratory infections during childhood

Adnan Custovic, Danielle Belgrave, Lijing Lin, Eteri Bakhsoliani, Aurica G. Telcian, Roberto Solari, Clare Murray, Ross P. Walton, John Curtin, Michael R Edwards, Angela Simpson, Magnus Rattray, Sebastian L. Johnston

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Abstract

Background: Immunophenotypes of anti-viral responses, and their relationship with asthma, allergy and lower respiratory tract infections (LRTIs) are poorly understood. We characterized multiple cytokine responses of peripheral-blood mononuclear cells to rhinovirus stimulation, and their relationship with clinical outcomes. Methods: In a population-based birth cohort, we measured 28 cytokines post-stimulation with rhinovirus-16 in 307 children aged 11 years. We used machine learning to identify patterns of cytokine responses, and related these patterns to clinical outcomes using longitudinal models. We also ascertained phytohaemagglutinin-induced TH2-cytokine responses [PHA-TH2]. Results: We identified six clusters of children based on their rhinovirus-16 responses, which were differentiated by the expression of four cytokine/chemokine groups: interferon-related-(IFN); pro-inflammatory-(Inflam); TH2-chemokine-(TH2-chem); regulatory-(Reg). Clusters differed in their clinical characteristics. Children with IFNmodInflamhighestTH2-chemhighestReghighest rhinovirus-16-induced pattern had PHA-TH2low response, and a very low asthma risk (OR:0.08 [95%CI 0.01–0.81], P=0.03). Two clusters had high risk of asthma and allergic sensitization, but with different trajectories from infancy to adolescence. The IFNlowestInflamhighTH2-chemlowRegmod cluster exhibited PHA-TH2lowest response, and was associated with early-onset asthma and sensitization, and the highest risk of asthma exacerbations (1.37 [1.07–1.76], P=0.014) and LRTI hospitalizations (2.40 [1.26–4.58], P=0.008) throughout childhood. In contrast, cluster with IFNhighestInflammodTH2-chemmodReghigh rhinovirus-16-cytokine pattern was characterized by PHA-TH2highest response, and a low prevalence of asthma/sensitization in infancy which increased sharply to become the highest among all clusters by adolescence (but with low risk of asthma exacerbations). Conclusions: Early-onset troublesome asthma with early-life sensitization, later-onset milder allergic asthma, and disease protection are each associated with different patterns of rhinovirus-induced immune responses.
Original languageEnglish
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume197
Issue number10
Early online date21 Feb 2018
DOIs
Publication statusPublished - 15 May 2018

Keywords

  • Asthma
  • Rhinovirus
  • Cytokines
  • machine learning

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