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The aim of this study was to determine the innate immune mechanisms that underlie susceptibility to frequent exacerbations in COPD. We measured sputum expression of immune mediators and bacterial loads in samples from patients with COPD at stable state and during virus-associated exacerbations. In vitro immune responses to rhinovirus infection in differentiated primary bronchial epithelial cells (BECs) sampled from patients with COPD were additionally evaluated. Patients were stratified as frequent exacerbators (\u22652 exacerbations in the preceding year) or infrequent exacerbators (&lt;2 exacerbations in the preceding year) with comparisons made between these groups. Frequent exacerbators had reduced sputum cell mRNA expression of the antiviral immune mediators type I and III interferons and reduced interferon-stimulated gene (ISG) expression when clinically stable and during virus-associated exacerbation. A role for epithelial cell-intrinsic innate immune dysregulation was identified: induction of interferons and ISGs during in vitro rhinovirus (RV) infection was also impaired in differentiated BECs from frequent exacerbators. Frequent exacerbators additionally had increased sputum bacterial loads at 2 wk following virus-associated exacerbation onset. These data implicate deficient airway innate immunity involving epithelial cells in the increased propensity to exacerbations observed in some patients with COPD. Therapeutic approaches to boost innate antimicrobial immunity in the lung could be a viable strategy for prevention and treatment of frequent exacerbations. <\/jats:p>","DOI":"10.1152\/ajplung.00253.2019","type":"journal-article","created":{"date-parts":[[2019,9,12]],"date-time":"2019-09-12T15:36:27Z","timestamp":1568302587000},"page":"L893-L903","source":"Crossref","is-referenced-by-count":76,"title":["Antiviral immunity is impaired in COPD patients with frequent exacerbations"],"prefix":"10.1152","volume":"317","author":[{"given":"Aran","family":"Singanayagam","sequence":"first","affiliation":[{"name":"National Heart and Lung Institute, Imperial College London, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Su-Ling","family":"Loo","sequence":"additional","affiliation":[{"name":"Faculty of Health and Medicine and Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and University of Newcastle, Newcastle, New South Wales, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Calderazzo","sequence":"additional","affiliation":[{"name":"National Heart and Lung Institute, Imperial College London, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lydia J.","family":"Finney","sequence":"additional","affiliation":[{"name":"National Heart and Lung Institute, Imperial College London, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria-Belen","family":"Trujillo Torralbo","sequence":"additional","affiliation":[{"name":"National Heart and Lung Institute, Imperial College London, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eteri","family":"Bakhsoliani","sequence":"additional","affiliation":[{"name":"National Heart and Lung Institute, Imperial College London, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason","family":"Girkin","sequence":"additional","affiliation":[{"name":"Faculty of Health and Medicine and Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and University of Newcastle, Newcastle, New South Wales, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Punnam","family":"Veerati","sequence":"additional","affiliation":[{"name":"Faculty of Health and Medicine and Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and University of Newcastle, Newcastle, New South Wales, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prabuddha S.","family":"Pathinayake","sequence":"additional","affiliation":[{"name":"Faculty of Health and Medicine and Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and University of Newcastle, Newcastle, New South Wales, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristy S.","family":"Nichol","sequence":"additional","affiliation":[{"name":"Faculty of Health and Medicine and Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and University of Newcastle, Newcastle, New South Wales, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5751-7025","authenticated-orcid":false,"given":"Andrew","family":"Reid","sequence":"additional","affiliation":[{"name":"Faculty of Health and Medicine and Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and University of Newcastle, Newcastle, New South Wales, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph","family":"Footitt","sequence":"additional","affiliation":[{"name":"National Heart and Lung Institute, Imperial College London, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter A. 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