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• W2999691230 abstract "Inhaled corticosteroids (ICSs) are frequently prescribed medications for patients with the inflammatory airway diseases asthma and chronic obstructive pulmonary disease (COPD). The broad anti-inflammatory effects of these medications provide a range of beneficial effects on symptoms, exacerbation frequency, and lung function. In asthma, current Global Initiative for Asthma guidance states that all patients (regardless of severity) should be prescribed ICSs, with “as required” combined ICS/β2-agonist therapy recommended for those with mild intermittent disease (avoiding β2-agonist therapy alone) and maintenance ICSs at appropriately increasing doses advocated for greater disease severities. For COPD, current Global Initiative for Chronic Obstructive Lung Disease guidance advocates more selective ICS use than in asthma, with ICSs to be considered for patients with blood eosinophils greater than or equal to 300 cells/μL or greater than or equal to 100 cells/μL if there is a history of 2 or more moderate severity or 1 or more hospitalized exacerbation episodes (thresholds where the beneficial effects of ICSs on exacerbation reduction are believed to outweigh the increased risk of pneumonia). For patients with asthma/COPD overlap syndrome, Global Initiative for Chronic Obstructive Lung Disease suggests that ICSs should always be used, at either low or moderate dose, depending on the level of symptoms, with avoidance of long-acting β2-agonist monotherapy if there are features of asthma. There is increasing recognition that, particularly in COPD, these commonly used inhalers may impair critical components of the immune system that are essential for effective host-defense against respiratory pathogens. This has driven a shifting paradigm with increasing recognition that potential detrimental effects of ICSs on antimicrobial immunity should now be carefully weighed up against any potentially beneficial anti-inflammatory and clinical effects. Viruses are the major triggers of acute exacerbations of asthma and COPD, with experimental challenge studies confirming a causal relationship.1Ritchie A.I. Farne H.A. Singanayagam A. Jackson D.J. Mallia P. Johnston S.L. Pathogenesis of viral infection in exacerbations of airway disease.Ann Am Thorac Soc. 2015; 12: S115-S132PubMed Google Scholar There is evidence from many studies that induction of the innate mediators type I and III IFNs by viruses is impaired in both asthma and COPD, although this has not been shown universally.1Ritchie A.I. Farne H.A. Singanayagam A. Jackson D.J. Mallia P. Johnston S.L. Pathogenesis of viral infection in exacerbations of airway disease.Ann Am Thorac Soc. 2015; 12: S115-S132PubMed Google Scholar Additional impairment of antiviral responses could be caused by immune suppression secondary to chronic ICS use in these patients. It has long been recognized that corticosteroids can impair production of IFN, an effect first reported in 1961 by a study in which cortisone administration increased virus replication in chick embryos.2Kilbourne E.D. Smart K.M. Pokorny B.A. Inhibition by cortisone of the synthesis and action of interferon.Nature. 1961; 190: 650-651Crossref PubMed Scopus (33) Google Scholar We have shown that the ICS fluticasone propionate (FP) can inhibit epithelial type I and III IFN production using in vitro and in vivo models of rhinovirus infection alone, as well as rhinovirus infection in COPD.3Singanayagam A. Glanville N. Girkin J.L. Ching Y.M. Marcellini A. Porter J.D. et al.Corticosteroid suppression of antiviral immunity increases bacterial loads and mucus production in COPD exacerbations.Nat Commun. 2018; 9: 2229Crossref PubMed Scopus (67) Google Scholar Suppression of IFN was causally related to increased virus replication and subsequent increased secretion of the mucin glycoprotein MUC5AC, a major component of airway mucus. Therefore, the use of ICSs during a virus-induced exacerbation of inflammatory airway disease could potentially impair protective innate responses and drive increased exacerbation severity through greater virus loads and increased mucus hypersecretion. Similar effects were observed in a cohort of patients with COPD presenting with virus-associated exacerbation where ICS users had suppressed IFN expression and mucus hypersecretion associated with a greater acute fall in lung function compared with ICS nonusers, thus confirming that these effects are likely to be clinically important. Notably, these effects could be reversed by administration of recombinant IFN-β in a mouse rhinovirus infection model,3Singanayagam A. Glanville N. Girkin J.L. Ching Y.M. Marcellini A. Porter J.D. et al.Corticosteroid suppression of antiviral immunity increases bacterial loads and mucus production in COPD exacerbations.Nat Commun. 2018; 9: 2229Crossref PubMed Scopus (67) Google Scholar raising speculation that inhaled IFN could represent an effective treatment of virus-induced exacerbations of airway disease. In a previous study of subjects with asthma who developed a cold, inhaled IFN-β administration conferred clinical benefit only in a subgroup with moderate to severe disease.4Djukanovic R. Harrison T. Johnston S.L. Gabbay F. Wark P. Thomson N.C. et al.The effect of inhaled IFN-beta on worsening of asthma symptoms caused by viral infections: a randomized trial.Am J Respir Crit Care Med. 2014; 190: 145-154Crossref PubMed Scopus (176) Google Scholar This therapy is also currently in clinical trials for COPD, and future studies should more accurately define groups that are most likely to derive benefit, perhaps focusing on people with asthma or COPD of greater severity or asthma that is less well controlled, where IFN supplementation may have greatest effects. Consideration of prophylactic therapy is also being discussed, because acute intervention, at least in asthma, appears to require very early intervention after reporting of illness. What are the implications of these findings for the use of ICSs in patients with inflammatory airway conditions? In COPD, ICS use has limited benefit, with only modest effects on reducing exacerbation frequency (although a recent, as yet unproven hypothesis is that effectiveness may be greater in subjects with raised blood eosinophils) and no significant effect on mortality, with a clear increase in pneumonia risk. In contrast, in asthma, the effect of ICSs on exacerbations and mortality is clearer. Asthma is much more commonly associated with enhanced type 2 airway inflammation and this suppresses IFN induction by virus.5Contoli M. Ito K. Padovani A. Poletti D. Marku B. Edwards M.R. et al.Th2 cytokines impair innate immune responses to rhinovirus in respiratory epithelial cells.Allergy. 2015; 70: 910-920Crossref PubMed Scopus (88) Google Scholar Because ICSs have clear beneficial effects on suppression of type 2 inflammation, this will help to restore deficient antiviral immunity in asthma. This restoration clearly outweighs the direct effects of ICSs on suppression of antiviral immunity described above, and, thus, the net effect of ICSs in asthma is very clearly one of protection against exacerbations and mortality. Both asthma and COPD are inherently associated with a significantly increased risk of bacterial infection with a range of impairments in antibacterial immunity widely reported in the literature. The link between ICS use and pneumonia is most clearly established for COPD, with less data to support a role in asthma, although severe asthma is associated with a 12-fold increased risk of invasive pneumococcal disease,6Klemets P. Lyytikainen O. Ruutu P. Ollgren J. Kaijalainen T. Leinonen M. et al.Risk of invasive pneumococcal infections among working age adults with asthma.Thorax. 2010; 65: 698-702Crossref PubMed Scopus (79) Google Scholar which may, in part, be related to ICS use in these patients. A secondary analysis of the Investigating New Standards for Prophylaxis in Reducing Exacerbations study indicated that approximately 50% of ICS-induced pneumonias in COPD occur after a preceding coryzal illness (likely consistent with virus-induced secondary bacterial pneumonia) and approximately 50% occur as de novo pneumonia episodes.7Calverley P.M. Stockley R.A. Seemungal T.A. Hagan G. Willits L.R. Riley J.H. et al.Reported pneumonia in patients with COPD: findings from the INSPIRE study.Chest. 2011; 139: 505-512Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar We thus hypothesized that distinct mechanisms may be driving these 2 syndromes. For virus-induced secondary bacterial infection, we identified, in human and animal studies, that suppression of IFN by FP is associated with increased pulmonary bacterial loads after rhinovirus infection.3Singanayagam A. Glanville N. Girkin J.L. Ching Y.M. Marcellini A. Porter J.D. et al.Corticosteroid suppression of antiviral immunity increases bacterial loads and mucus production in COPD exacerbations.Nat Commun. 2018; 9: 2229Crossref PubMed Scopus (67) Google Scholar This effect was mechanistically driven by reduced production of the antimicrobial peptide secretory leucocyte protease inhibitor. Using gain- and loss-of-function experiments in mouse models, we confirmed that type I IFN directly induces production of secretory leucocyte protease inhibitor, thereby confirming that ICS-mediated suppression of type I IFN is causally related to impaired antibacterial immunity and secondary bacterial infection.3Singanayagam A. Glanville N. Girkin J.L. Ching Y.M. Marcellini A. Porter J.D. et al.Corticosteroid suppression of antiviral immunity increases bacterial loads and mucus production in COPD exacerbations.Nat Commun. 2018; 9: 2229Crossref PubMed Scopus (67) Google Scholar Recent data have indicated that the lower respiratory tract is colonized by complex bacterial communities (microbiota) with alterations (“dysbiosis”) characteristic of both asthma and COPD. ICSs could theoretically promote de novo pneumonic episodes either by inducing expansion of bacteria within the existing lung microbiota or by contributing to acquisition of new bacteria from the environment. Existing evidence supports the former of these 2 mechanisms as evaluation of the in vivo effects of ICSs in animal models and patients with COPD has indicated disruption of the endogenous microbiota with increased relative abundance of the genus Streptococcus.8Singanayagam A. Glanville N. Cuthbertson L. Bartlett N.W. Finney L.J. Turek E. et al.Inhaled corticosteroid suppression of cathelicidin drives dysbiosis and bacterial infection in chronic obstructive pulmonary disease.Sci Transl Med. 2019; 11Crossref PubMed Scopus (20) Google Scholar Using mouse models to understand cause and effect, we identified that impairment of lung bacterial control by ICSs occurs mechanistically through suppression of epithelial production of the antimicrobial peptide cathelicidin.8Singanayagam A. Glanville N. Cuthbertson L. Bartlett N.W. Finney L.J. Turek E. et al.Inhaled corticosteroid suppression of cathelicidin drives dysbiosis and bacterial infection in chronic obstructive pulmonary disease.Sci Transl Med. 2019; 11Crossref PubMed Scopus (20) Google Scholar In contrast to wild-type mice, FP had no effect on bacterial loads in Streptococcus pneumoniae–infected cathelicidin-deficient (Camp−/−) mice, whereas recombinant cathelicidin protein could reverse FP-mediated increases in Streptococci within the microbiota, indicating that cathelicidin is necessary and sufficient for FP to impart its adverse effects on host defense. Intriguingly, the suppressive effect of FP on cathelicidin did not occur through inhibition of gene transcription but by FP augmentation of the protease cathepsin D, a steroid-inducible gene that can cleave and inactivate cathelicidin. Airway cathepsin D expression is increased in COPD8Singanayagam A. Glanville N. Cuthbertson L. Bartlett N.W. Finney L.J. Turek E. et al.Inhaled corticosteroid suppression of cathelicidin drives dysbiosis and bacterial infection in chronic obstructive pulmonary disease.Sci Transl Med. 2019; 11Crossref PubMed Scopus (20) Google Scholar but unchanged in asthma9Faiz A. Tjin G. Harkness L. Weckmann M. Bao S. Black J.L. et al.The expression and activity of cathepsins D, H and K in asthmatic airways.PLoS One. 2013; 8: e57245Crossref PubMed Scopus (22) Google Scholar compared with healthy control subjects. This mechanism may thus explain why the risk of pneumonia associated with ICS use in clinical studies has been more clearly observed for COPD than for asthma. An additional contributory factor could be relative immunosenesence because COPD tends to affect an older patient population compared with asthma. Notably, in animal models, cathelicidin expression has been shown to diminish with aging, an effect that permits more prolonged S pneumoniae colonization in the respiratory tract.10Krone C.L. Trzcinski K. Zborowski T. Sanders E.A. Bogaert D. Impaired innate mucosal immunity in aged mice permits prolonged Streptococcus pneumoniae colonization.Infect Immun. 2013; 81: 4615-4625Crossref PubMed Scopus (46) Google Scholar In summary, ICS use is associated with a number of benefits, particularly in asthma, whereas their use in COPD may induce disruption of antimicrobial responses via a range of mechanisms (see Fig 1). These effects may promote more severe virus infections and pneumonia in these patients. Whether immune phenotyping to guide more targeted ICS use or replacement of suppressed mediators such as IFNs and cathelicidin could offer a more effective approach to therapy requires future consideration." @default.
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• W2999691230 title "Long-term impact of inhaled corticosteroid use in asthma and chronic obstructive pulmonary disease (COPD): Review of mechanisms that underlie risks" @default.
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