Inhalation glucocorticosteroids in the treatment of chronic obstructive pulmonary disease

The main objectives of chronic obstructive pulmonary disease (COPD) therapy are to reduce the severity of symptoms and the risk of exacerbations. The article discusses the role of local and systemic inflammation in the pathogenesis of COPD as well as various mechanisms of pharmacological influence on it. Approaches to prescribing basic therapy for patients with COPD, recommended by various national and global guidelines (clinical recommendations of the Russian respiratory society, criteria of the Global Initiative for Chronic Obstructive Lung Disease (GOLD), guidelines of the National Institute for Health and Clinical Excellence (NICE)), as well as recommendations on the therapy frequency review are considered. Currently, so-called triple combinations – fixed combinations of double bronchodilators with inhaled glucocorticosteroids – are being developed and registered in the world, and their place and significance in the treatment of COPD raise many discussions. The paper discusses the role of fixed triple combinations in reducing the incidence of COPD exacerbations, the impact on functional and patient-reported outcomes, and provides recommendations for the use of triple combinations in patients with COPD, taking into account the benefit/risk ratio.

1. Barnes P.J., Burney P.G.J., Silverman E.K et al. Chronic obstructive pulmonary disease. Nat. Rev. Dis. Primers. 2015; 1: 15076. DOI: 10.1038/nrdp.2015.76.

2. Global Initiative for Chronic Obstructive Lung Disease. Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease. 2020 Report. Available at: https://goldcopd.org/wp-content/uploads/2019/12/GOLD-2020-FINAL-ver1.2-03Dec19_WMV.pdf [Accessed: May 11, 2020].

3. McDonough J.E., Yuan R., Suzuki M. et al. Small-airway obstruction and emphysema in chronic obstructive pulmonary disease. N. Engl. J. Med. 2011; 365 (17): 1567–1575. DOI: 10.1056/NEJMoa1106955.

4. Agustí A., Edwards L.D., Rennard S.I. et al. Persistent systemic inflammation is associated with poor clinical outcomes in COPD: A novel phenotype. PLoS One. 2012; 7 (5): e37483. DOI: 10.1371/journal.pone.0037483.

5. Thomsen M., Ingebrigtsen T.S., Marott J.L. et al. Inflammatory biomarkers and exacerbations in chronic obstructive pulmonary disease. JAMA. 2013; 309 (22): 2353–2361. DOI: 10.1001/jama.2013.5732.

6. Brightling C., Greening N. Airway inflammation in COPD: progress to precision medicine. Eur. Respir. J. 2019; 54 (2): 1900651. DOI: 10.1183/13993003.00651-2019.

7. Barnes P.J. Inflammatory endotypes in COPD. Allergy. 2019; 74 (7): 1249–1256. DOI: 10.1111/all.13760.

8. Yousuf A., Brightling C.E. Biologic drugs: a new target therapy in COPD? COPD. 2018; 15 (2): 99–107. DOI: 10.1080/15412555.2018.1437897.

9. Cui Y., Luo L., Li C. et al. Long-term macrolide treatment for the prevention of acute exacerbations in COPD: a systematic review and meta-analysis. Int. J. Chron. Obstruct. Pulmon. Dis. 2018; 13: 3813–3829. DOI: 10.2147/COPD.S181246.

10. Cazzola M., Rogliani P., Calzetta L. et al. Impact of mucolytic agents on COPD exacerbations: a pair-wise and network meta-analysis. COPD. 2017; 14 (5): 552–563. DOI: 10.1080/15412555.2017.1347918.

11. Pavord I.D., Chanez P., Criner G.J. et al. Mepolizumab for eosinophilic chronic obstructive pulmonary disease. N. Engl. J. Med. 2017; 377 (17): 1613–1629. DOI: 10.1056/NEJMoa1708208.

12. Criner G.J., Celli B.R., Brightling C.E. et al. Benralizumab for the prevention of COPD exacerbations. N. Engl. J. Med. 2019; 381 (11): 1023–1034. DOI: 10.1056/NEJMoa1905248.

13. Zeiger R.S., Tran T.N., Butler R.K. et al. Relationship of blood eosinophil count to exacerbations in chronic obstructive pulmonary disease. J. Allergy Clin. Immunol. Pract. 2018; 6 (3): 944–954.e5. DOI: 10.1016/j.jaip.2017.10.004.

14. Zysman M., Deslee G., Caillaud D. et al. Relationship between blood eosinophils, clinical characteristics, and mortality in patients with COPD. Int. J. Chron. Obstruct. Pulmon. Dis. 2017; 12: 1819–1824. DOI: 10.2147/COPD.S129787.

15. Avdeev S.N., Trushenko N.V., Merzhoeva Z.M. et al. [Eosinophilic inflammation in chronic obstructive pulmonary disease]. Terapevticheskiy arkhiv. 2019; 91 (10): 135–143. DOI: 10.26442/00403660.2019.10.000426 (in Russian).

16. Criner G.J., Martinez F.J., Aaron S. et al. Current controversies in chronic obstructive pulmonary disease. A report from the Global Initiative for Chronic Obstructive Lung Disease Scientific Committee. Ann. Am. Thorac. Soc. 2019; 16 (1): 29–39. DOI: 10.1513/AnnalsATS.201808-557PS.

17. Noell G., Cosío B.G., Faner R. et al. Multi-level differential network analysis of COPD exacerbations. Eur. Respir. J. 2017; 50 (3): 1700075. DOI: 10.1183/13993003.00075-2017.

18. Bafadhel M., McKenna S., Terry S. et al. Acute exacerbations of chronic obstructive pulmonary disease: identification of biologic clusters and their biomarkers. Am. J. Respir. Crit. Care Med. 2011; 184 (6): 662–671. DOI: 10.1164/rccm.201104-0597OC.

19. Mayhew D., Devos N., Lambert C. et al. Longitudinal profiling of the lung microbiome in the AERIS study demonstrates repeatability of bacterial and eosinophilic COPD exacerbations. Thorax. 2018; 73 (5): 422–430. DOI: 10.1136/thoraxjnl-2017-210408.

20. Lin Y.H. Liao X.N., Fan L.L. et al. Long-term treatment with budesonide/formoterol attenuates circulating CRP levels in chronic obstructive pulmonary disease patients of group D. PLoS One. 2017; 12 (8): e0183300. DOI: 10.1371/journal.pone.0183300.

21. Yamada M., Ichinose M. The Cholinergic Pathways in Inflammation: A Potential Pharmacotherapeutic Target for COPD. Front. Pharmacol. 2018; 9: 1426. DOI: 10.3389/fphar.2018.01426.

22. Jacoby D.B., Yost B.L., Kumaravel B. et al. Glucocorticoid treatment increases inhibitory m(2) muscarinic receptor expression and function in the airways. Am. J. Respir. Cell Mol. Biol. 2001; 24 (4): 485–491. DOI: 10.1165/ajrcmb.24.4.4379.

23. Barnes P.J. Role of HDAC2 in the pathophysiology of COPD. Annu. Rev. Physiol. 2009; 71: 451–464. DOI: 10.1146/annurev.physiol.010908.163257.

24. Anzalone G., Gagliardo R., Bucchieri F. et al. IL-17A induces chromatin remodeling promoting IL-8 release in bronchial epithelial cells: Effect of Tiotropium. Life Sci. 2016; 152: 107–116. DOI: 10.1016/j.lfs.2016.03.031.

25. Singh Sohal S., Soltani A., Reid D. et al. A randomized controlled trial of inhaled corticosteroids (ICS) on markers of epithelial-mesenchymal transition (EMT) in large airway samples in COPD: an exploratory proof of concept study. Int. J. Chron. Obstruct. Pulmon. Dis. 2014; 9 (1): 533–542. DOI: 10.2147/COPD.S63911.

26. Lee Y.M., Kim S.J., Lee J.H., Ha E. Inhaled corticosteroids in COPD and the risk of lung cancer. Int. J. Cancer. 2018; 143 (9): 2311–2318. DOI: 10.1002/ijc.31632.

27. Barnes N.C., Qiu Y.S., Pavord I.D. et al. Antiinflammatory effects of salmeterol/fluticasone propionate in chronic obstructive lung disease. Am. J. Respir. Crit. Care Med. 2006; 173 (7): 736–743. DOI: 10.1164/rccm.200508-1321OC.

28. Ozol D., Aysan T., Solak Z.A. et al. The effect of inhaled corticosteroids on bronchoalveolar lavage cells and IL-8 levels in stable COPD patients. Respir. Med. 2005; 99 (12): 1494–1500. DOI: 10.1016/j.rmed.2005.04.025.

29. Calverley P.M., Anderson J.A., Celli B. et al. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N. Engl. J. Med. 2007; 356 (8): 775–789. DOI: 10.1056/NEJMoa063070.

30. Kunz L.I.Z., Postma D.S., Klooster K. et al. Relapse in FEV1 decline after steroid withdrawal in COPD. Chest. 2015; 148 (2): 389–396. DOI: 10.1378/chest.14-3091.

31. Worth H., Peterson S., Nihlen U., Magnussen H. Improved exercise tolerance with budesonide/formoterol vs placebo and formoterol in COPD patients. Am. J. Respir. Crit. Care Med. 2009; 179: A6193. DOI: 10.1164/ajrccm-conference.2009.179.1_MeetingAbstracts.A6193.

32. Calverley P.M., Boonsawat W., Cseke Z. et al. Maintenance therapy with budesonide and formoterol in chronic obstructive pulmonary disease. Eur. Respir. J. 2003; 22 (6): 912–919. DOI: 10.1183/09031936.03.00027003.

33. Szafranski W., Cukier A., Ramirez A. et al. Efficacy and safety of budesonide/formoterol in the management of chronic obstructive pulmonary disease. Eur. Respir. J. 2003; 21 (1): 74–81. DOI: 10.1183/09031936.03.00031402.

34. Sharafkhaneh A., Southard J.G., Goldman M. et al. Effect of budesonide/formoterol pMDI on COPD exacerbations: a double-blind, randomized study. Respir. Med. 2012; 106 (2): 257–268. DOI: 10.1016/j.rmed.2011.07.020.

35. Agusti A., Corradi M., Cohuet G. et al. FORWARD: A study of extrafine beclomethasone/formoterol compared with formoterol alone in patients with severe COPD and a history of exacerbations. Eur. Respir. J. 2013; 42 (Suppl. 57): 762.

36. Oba Y., Lone N.A. Comparative efficacy of inhaled corticosteroid and long-acting beta agonist combinations in preventing COPD exacerbations: a Bayesian network meta-analysis. Int. J. Chron. Obstruct. Pulmon. Dis. 2014; 9 (1): 469–479. DOI: 10.2147/COPD.S48492.

37. Bafadhel M., Peterson S., De Blas M.A. et al. Predictors of exacerbation risk and response to budesonide in patients with chronic obstructive pulmonary disease: a post-hoc analysis of three randomised trials. Lancet. Respir. Med. 2018; 6 (2): 117–126. DOI: 10.1016/S2213-2600(18)30006-7.

38. Vestbo J., Anderson J.A., Brook R.D. et al. Fluticasone furoate and vilanterol and survival in chronic obstructive pulmonary disease with heightened cardiovascular risk (SUMMIT): a double-blind randomised controlled trial. Lancet. 2016; 387 (10030): 1817–1826. DOI: 10.1016/S0140-6736(16)30069-1.

39. Nannini L.J., Lasserson T.J., Poole P. Combined corticosteroid and long-acting beta2-agonist in one inhaler versus long-acting beta2-agonists for chronic obstructive pulmonary disease. Cochrane Database Syst. Rev. 2012; (9): CD006829. DOI: 10.1002/14651858.CD006829.pub2.

40. Suissa S., Ernst P. Precision medicine urgency: The case of inhaled corticosteroids in COPD. Chest. 2017; 152 (2): 227–231. DOI: 10.1016/j.chest.2017.05.020.

41. Avdeev S.N. Aisanov Z.R., Belevskiy A.S. et al. [Perspectives of pharmacological therapy of chronic obstructive pulmonary disease: opportunities of dual bronchodilation and a role of inhaled steroids. Expert Council Consensus]. Pul'monologiya. 2016; 26 (1): 65–72. DOI: 10.18093/0869-0189-2016-26-1-65-72 (In Russian).

42. Short P.M., Williamson P.A., Elder D.H.J. et al. The impact of tiotropium on mortality and exacerbations when added to inhaled corticosteroids and long-acting β-agonist therapy in COPD. Chest. 2012; 141 (1): 81–86. DOI: 10.1378/chest.11-0038.

43. Lipson D.A., Barnhart F., Brealey N. et al. Once-daily single-inhaler triple versus dual therapy in patients with COPD. N. Engl. J. Med. 2018; 378 (18): 1671–1680. DOI: 10.1056/NEJMoa1713901.

44. Lipson D.A., Barnacle H., Birk R. et al. FULFIL Trial: Once-daily triple therapy for patients with chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 2017; 196 (4): 438–446. DOI: 10.1164/rccm.201703-0449OC.

45. Papi A., Vestbo J., Fabbri L. et al. Extrafine inhaled triple therapy versus dual bronchodilator therapy in chronic obstructive pulmonary disease (TRIBUTE): a double-blind, parallel group, randomised controlled trial. Lancet. 2018; 391 (10125): 1076–1084. DOI: 10.1016/S0140-6736(18)30206-X.

46. Singh D., Papi A., Corradi M. et al. Single inhaler triple therapy versus inhaled corticosteroid plus long-acting β2-agonist therapy for chronic obstructive pulmonary disease (TRILOGY): a double-blind, parallel group, randomised controlled trial. Lancet. 2016; 388 (10048): 963–973. DOI: 10.1016/S0140-6736(16)31354-X.

47. Vestbo J., Papi A., Corradi M. et al. Single inhaler extrafine triple therapy versus long-acting muscarinic antagonist therapy for chronic obstructive pulmonary disease (TRINITY): a double-blind, parallel group, randomised controlled trial. Lancet. 2017; 389 (10082):1919–1929. DOI: 10.1016/S0140-6736(17)30188-5.

48. Ferguson G.T., Rabe K.F., Martinez F.J. et al. Triple therapy with budesonide/glycopyrrolate/formoterol fumarate with co-suspension delivery technology versus dual therapies in chronic obstructive pulmonary disease (KRONOS): a double-blind, parallel-group, multicentre, phase 3 randomised controlled trial. Lancet. Respir. Med. 2018; 6 (10): 747–758. DOI: 10.1016/S2213-2600(18)30327-8.

49. Pascoe S., Barnes N., Brusselle G. et al. Blood eosinophils and treatment response with triple and dual combination therapy in chronic obstructive pulmonary disease: analysis of the IMPACT trial. Lancet Respir. Med. 2019; 7 (9): 745–756. DOI: 10.1016/S2213-2600(19)30190-0.

50. Singh D., Fabbri L.M., Vezzoli S. et al. Extrafine triple therapy delays COPD clinically important deterioration vs ICS/LABA, LAMA, or LABA/LAMA. Int. J. Chron. Obstruct. Pulmon. Dis. 2019; 14: 531–546. DOI: 10.2147/COPD.S196383.

51. Williams N.P., Coombs N.A., Johnson M.J. et al. Seasonality, risk factors and burden of community-acquired pneumonia in COPD patients: a population database study using linked health care records. Int. J. Chron. Obstruct. Pulmon. Dis. 2017; 12: 313–322. DOI: 10.2147/COPD.S121389.

52. Lee H.W., Park J., Jo J. et al. Comparisons of exacerbations and mortality among regular inhaled therapies for patients with stable chronic obstructive pulmonary disease: Systematic review and Bayesian network meta-analysis. PLoS Med. 2019; 16 (11): e1002958. DOI: 10.1371/journal.pmed.1002958.

53. Brassard P., Suissa S., Kezouh A., Ernst P. Inhaled corticosteroids and risk of tuberculosis in patients with respiratory diseases. Am. J. Respir. Crit. Care Med. 2011; 183 (5): 675–678. DOI: 10.1164/rccm.201007-1099OC.

54. Lipworth B.J. Systemic adverse effects of inhaled corticosteroid therapy: A systematic review and meta-analysis. Arch. Intern. Med. 1999; 159 (9): 941–955. DOI: 10.1001/archinte.159.9.941.

55. Loke Y.K., Cavallazzi R., Singh S. Risk of fractures with inhaled corticosteroids in COPD: systematic review and meta-analysis of randomised controlled trials and observational studies. Thorax. 2011; 66 (8): 699–708. DOI: 10.1136/thx.2011.160028.

56. Suissa S., Kezouh A., Ernst P. Inhaled corticosteroids and the risks of diabetes onset and progression. Am. J. Med. 2010; 123 (11): 1001–1006. DOI: 10.1016/j.amjmed.2010.06.019.

57. Izquierdo J.L., Cosio B.G. The dose of inhaled corticosteroids in patients with COPD: when less is better. Int. J. Chron. Obstruct. Pulmon. Dis. 2018; 13: 3539–3547. DOI: 10.2147/COPD.S175047.

58. Rodrigo G.J., Castro-Rodriguez J.A., Plaza V. Safety and efficacy of combined long-acting beta-agonists and inhaled corticosteroids vs long-acting beta-agonists monotherapy for stable COPD: a systematic review. Chest. 2009; 136 (4): 1029–1038. DOI: 10.1378/chest.09-0821.

59. Sabroe I., Postma D., Heijink I., Dockrell D.H. The yin and the yang of immunosuppression with inhaled corticosteroids. Thorax. 2013; 68 (12): 1085–1087. DOI: 10.1136/thoraxjnl-2013-203773.

60. Yawn B.P., Li Y., Tian H. et al. Inhaled corticosteroid use in patients with chronic obstructive pulmonary disease and the risk of pneumonia: a retrospective claims data analysis. Int. J. Chron. Obstruct. Pulmon. Dis. 2013; 8: 295–304. DOI: 10.2147/COPD.S42366.

61. Avdeev S.N., Trushenko N.V. [Triple therapy in chronic obstructive pulmonary disease]. Pul'monologiya. 2019; 29 (2): 199–206. DOI: 10.18093/0869-0189-2019-29-2-199-206 (In Russian).

62. Avdeev S.N., Nevzorova V.A., Kudelya L.M. et al. [Issues of triple therapy of chronic obstructive pulmonary disease. Comments to the algorithm. A resolution of expert panel, June 13, 2018, Vladivostok]. Pul'monologiya. 2019; 29 (3): 365–374. DOI: 10.18093/0869-0189-2019-29-3-365-374 (In Russian).

63. Agusti A., Fabbri L.M., Singh D. et al. Inhaled corticosteroids in COPD: friend or foe? Eur. Respir. J. 2018; 52 (6): 1801219. DOI: 10.1183/13993003.01219-2018.

64. Avdeev S., Aisanov Z., Arkhipov V. et al. Withdrawal of inhaled corticosteroids in COPD patients: rationale and algorithms. Int. J. Chron. Obstruct. Pulmon. Dis. 2019; 14: 1267–1280. DOI: 10.2147/COPD.S207775.

65. NICE 2019 guideline. Chronic obstructive pulmonary disease in over 16s: diagnosis and management. Available at: https://www.guidelines.co.uk/respiratory/nice-copd-guideline/454912.article [Accessed: May 11, 2020].

66. Vukoja M., Kopitovic I., Lazic Z. et al. Diagnosis and management of chronic obstructive pulmonary disease in Serbia: an expert group position statement. Int. J. Chron. Obstruct. Pulmon. Dis. 2019; 14: 1993–2002. DOI: 10.2147/COPD.S214690.

67. Russian Respiratory Society. Federal clinical recommendations. Chronic obstructive pulmonary disease. Available at: http://spulmo.ru/obrazovatelnye-resursy/federalnye-klinicheskie-rekomendatsii/ [Accessed: December 21, 2019] (in Russian).

68. Vanfleteren L.E.G.W., Ullman A., Nordenson A. et al. Triple therapy (ICS/LABA/LAMA) in COPD: thinking out of the box. ERJ Open Res. 2019; 5 (1): 00185-2018. DOI: 10.1183/23120541.00185-2018.