TY - JOUR
T1 - Cytokine responses to rhinovirus and development of asthma, allergic sensitization and respiratory infections during childhood
AU - Custovic, Adnan
AU - Belgrave, Danielle
AU - Lin, Lijing
AU - Bakhsoliani, Eteri
AU - Telcian, Aurica G.
AU - Solari, Roberto
AU - Murray, Clare
AU - Walton, Ross P.
AU - Curtin, John
AU - Edwards, Michael R
AU - Simpson, Angela
AU - Rattray, Magnus
AU - Johnston, Sebastian L.
PY - 2018/5/15
Y1 - 2018/5/15
N2 - 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.
AB - 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.
KW - Asthma
KW - Rhinovirus
KW - Cytokines
KW - machine learning
U2 - 10.1164/rccm.201708-1762OC
DO - 10.1164/rccm.201708-1762OC
M3 - Article
SN - 1073-449X
VL - 197
JO - American Journal of Respiratory and Critical Care Medicine
JF - American Journal of Respiratory and Critical Care Medicine
IS - 10
ER -