Cytokine Responses to rhinovirus and development of asthma, allergic sensitization and respiratory infections during childhood
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Abstract Rationale Immunophenotypes of antiviral responses, and their relationship with asthma, allergy, and lower respiratory tract infections, are poorly understood. Objectives 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 after 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 phytohemagglutinin-induced T-helper cell type 2 (Th2)-cytokine responses (PHA-Th2). Measurements and Main 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), proinflammatory (Inflam), Th2-chemokine (Th2-chem), and regulatory (Reg). Clusters differed in their clinical characteristics. Children with an IFNmodInflamhighestTh2-chemhighestReghighest rhinovirus-16–induced pattern had a PHA-Th2low response, and a very low asthma risk (odds ratio [OR], 0.08; 95% confidence interval [CI], 0.01–0.81; P = 0.03). Two clusters had a high risk of asthma and allergic sensitization, but with different trajectories from infancy to adolescence. The IFNlowestInflamhighTh2-chemlowRegmod cluster exhibited a PHA-Th2lowest response and was associated with early-onset asthma and sensitization, and the highest risk of asthma exacerbations (OR, 1.37; 95% CI, 1.07–1.76; P = 0.014) and lower respiratory tract infection hospitalizations (OR, 2.40; 95% CI, 1.26–4.58; P = 0.008) throughout childhood. In contrast, the IFNhighestInflammodTh2-chemmodReghigh cluster with a rhinovirus-16–cytokine pattern was characterized by a PHA-Th2highest response, and a low prevalence of asthma/sensitization in infancy that increased sharply to become the highest among all clusters by adolescence (but with a 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.
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- Authors
- Custovic, A., Belgrave, D., Lin, L., Bakhsoliani, E., Telcian, A. G., Solari, R., Murray, C. S., Walton, R. P., Curtin, J., Edwards, M. R., Simpson, A., Rattray, M., & Johnston, S. L.
- Affiliations
- Section of Paediatrics, Department of Medicine, Imperial College London, London, United Kingdom
- Imperial College London (GB)
- Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom
- Asthma UK (GB)
- Manchester Academic Health Science Centre (GB)
- University of Manchester (GB)
- ORCID
- Venue
- American Journal of Respiratory and Critical Care Medicine
- Publisher
- Oxford University Press (OUP)
- Published
- 2018-05
- Volume
- 197
- Issue
- 10
- Pages
- 1265-1274
- ISSN
- 1073-449X (ISSN-L)
- 1535-4970
- PMC
- PMC5955061
- OpenAlex
- W2793875226
- Cited by
- 95
- References
- 45
- Citations by year
- 2025: 4 · 2024: 4 · 2023: 3 · 2022: 10 · 2021: 36 · 2020: 15 · 2019: 18 · 2018: 5
- FWCI
- 12.68
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- American Journal of Respiratory and Critical Care Medicine (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (publishedVersion, other-oa)
- Spiral (Imperial College London) (submittedVersion)
- Funders
- National Institute for Health and Care Research (NF-SI-0514-10092)
- Asthma and Lung UK (MR/L012693/1, CH11SJ)
- Medical Research Council (MR/K002449/1, MR/K002449/2, MR/L012693/1)
- Topics
- Health Sciences › Medicine › Physiology › Asthma and respiratory diseases
- Health Sciences › Medicine › Epidemiology › Respiratory viral infections research
- Health Sciences › Health Professions › Emergency Medical Services › Pediatric health and respiratory diseases
- Keywords
- rhinovirus 16, cytokine response, asthma, allergen sensitization, lower respiratory tract infection, childhood, interferon, Th2 cytokines, regulatory cytokines, asthma exacerbations, asthma risk, immunophenotype, birth cohort
- MeSH terms
- Adolescent, Antiviral Agents, Asthma, Child, Child, Preschool, Female, Follow-Up Studies, Humans, Infant, Male, Picornaviridae Infections, Respiratory Tract Infections, Rhinovirus, Cytokines
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