medsovetМедицинский СоветMeditsinskiy sovet = Medical Council2079-701X2658-5790REMEDIUM GROUP Ltd.10.21518/2079-701X-2020-11-108-115medsovet-5759Research ArticleПУЛЬМОНОЛОГИЯ, ЛОРBRONCHOPULMONOLOGY, OTORHINOLARYNGOLOGYЭкстрамелкодисперсная комбинация беклометазона дипропионата и формотерола в лечении обструктивных бронхолегочных заболеванийExtrafine combination beclomethasone dipropionate/ formoterol therapy in obstructive lung diseaseshttps://orcid.org/0000-0003-2742-3794ТрофименкоИ. Н.TrofimenkoI. N.

Трофименко Ирина Николаевна, д.м.н., доцент кафедры клинической аллергологии и пульмонологии

664049, Иркутск, м/н Юбилейный, д. 100

Irina N. Trofimenko, Dr. of Sci. (Med), Associate Professor, Department of Clinical Allergology and Pulmonology

100, mkr Yubilejnyy, Irkutsk, 664079

tin11@mail.ruhttps://orcid.org/0000-0002-5902-6198ЧернякБ. А.ChernyakB. A.

Черняк Борис Анатольевич, д.м.н., профессор, заведующий кафедрой клинической аллергологии и пульмонологии

664049, Иркутск, м/н Юбилейный, д. 100

Boris A. Chernyak, Dr. of Sci. (Med), Professor, Head of Department of Clinical Allergology and Pulmonology

100, mkr Yubilejnyy, Irkutsk, 664079

ba.chernyak@gmail.comИркутская государственная медицинская академия последипломного образованияРоссияRussian Medical Academy of Continuing Professional EducationRussian Federation202006082020011108115Copyright © Трофименко И.Н., Черняк Б.А., 20202020Трофименко И.Н., Черняк Б.А.Trofimenko I.N., Chernyak B.A.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.med-sovet.pro/jour/article/view/5759

Бронхиальная астма (БА) и хроническая обструктивная болезнь легких (ХОБЛ) – хронические воспалительные заболевания дыхательных путей (ДП). Основой лечения обоих заболеваний является длительная ингаляционная терапия. Среди возможностей ингаляционной терапии БА и ХОБЛ на протяжении последних десятилетий доступны два класса препаратов: бронходилататоры и ингаляционные глюкокортикостероиды (ИГКС). Очень важным параметром эффективности ингаляционной терапии обструктивных заболеваний легких является степень депонирования лекарственного препарата в дистальных отделах бронхиального дерева, которые представляют собой главную терапевтическую мишень при обоих заболеваниях. Периферические отделы бронхиального дерева активно вовлечены в процесс хронического воспаления и связанных с ним патофизиологических нарушений как при БА, так и при ХОБЛ. Поражение периферических ДП у больных БА ассоциируется с плохим контролем, тяжестью астмы и высоким риском обострений заболевания. Воспаление малых ДП является основным компонентом в патогенезе ХОБЛ, и его выраженность усиливается по мере прогрессирования заболевания. Воздействие на воспаление в дистальных отделах бронхиального дерева с помощью экстрамелкодисперсной фиксированной комбинации беклометазона дипропионата и формотерола (БДП/Ф) обладает клиническим преимуществом в лечении обструктивных бронхолегочных заболеваний при использовании более низких доз ингаляционных глюкокортикостероидов (ИГКС). Применение экстрамелкодисперсной комбинации БДП/Ф способствует улучшению в достижении контроля у больных БА и безопасному снижению риска обострений у пациентов с ХОБЛ. При необходимости продолжения ИГКС в составе двойной или тройной терапии заболевания у пациентов с ХОБЛ на фоне нежелательных явлений этой терапии экстрамелкодисперсную фиксированную комбинацию БДП/Ф можно рассматривать в качестве препарата выбора и оптимальной замены молекулы ИГКС.

Bronchial asthma (BA) and chronic obstructive pulmonary disease (COPD) are chronic inflammatory diseases of the airways. Inhaled bronchodilators and corticosteroids are the cornerstone of pharmacological long-term treatment for asthma and COPD. The efficacy of any topical inhaled medication is dependent upon successful distribution of the drug to the site of disease. Targeting small airways inflammation in severe asthma and COPD are critically important as the combined surface area of small airways far exceeds the surface area that large central airways provide. Small airway dysfunction in BA is associated with increased asthma symptoms, worse asthma control and an increased number of exacerbations. Chronic inflammation in COPD causes structural alterations and narrowing of particularly the small airways. The extrafine combination of beclomethasone dipropionate/formoterol (BDP/F) enables drug delivery to both the large and small airways, and allows the clinical benefits to be achieved with a lower corticosteroid dose. The use of extrafine BDP/F is more effective in achievement asthma control and reduce COPD exacerbations. If it is necessary to continue ICS as part of a double or triple COPD therapy extrafine fixed combination of BDP/F can be considered as the drug of choice and optimal replacement of the ICS molecule.

беклометазона дипропионат/формотеролХОБЛбронхиальная астмамалые дыхательные путивоспаление дыхательных путейbeclomethasone dipropionate/formoterolCOPDbronchial asthmasmall airwaysairway inflammationReferencesBarnes P.J. Cellular and molecular mechanisms of asthma and COPD. Clin Sci (Lond). 2017;131(13):1541–1558. doi: 10.1042/CS20160487.Barnes P.J. Cellular and molecular mechanisms of asthma and COPD. Clin Sci (Lond). 2017;131(13):1541–1558. doi: 10.1042/CS20160487.Чучалин А.Г., Авдеев С.Н., Айсанов З.Р., Белевский А.С., Васильева О.С., Геппе Н.А. и др. Бронхиальная астма. Федеральные клинические рекомендации. М.; 2019. 97 с. Режим доступа: https://www.spulmo.ru/upload/kr_bronhastma_2019.pdf.Chuchalin A.G., Avdeev S.N., Aysanov Z.R., Belevskiy A.S., Vasileva O.S., Geppe N.A. et al. Bronhialnaya astma. Federalnyie klinicheskie rekomendatsii = Bronchial asthma. Federal Clinical Guidelines. Moscow; 2019. 97 р. (In Russ.) Available at: https://www.spulmo.ru/upload/kr_bronhastma_2019.pdf.Price D., Fletcher M., van der Molen T. Asthma control and management in 8,000 European patients: the REcognise Asthma and LInk to Symptoms and Experience (REALISE) survey. NPJ Prim Care Respir Med. 2014;24:14009. doi: 10.1038/npjpcrm.2014.9.Price D., Fletcher M., van der Molen T. Asthma control and management in 8,000 European patients: the REcognise Asthma and LInk to Symptoms and Experience (REALISE) survey. NPJ Prim Care Respir Med. 2014;24:14009. doi: 10.1038/npjpcrm.2014.9.Carr T.F., Altisheh R., Zitt M. Small airways disease and severe asthma. World Allergy Organ J. 2017;10(1):20. doi: 10.1186/s40413-017-0153-4.Carr T.F., Altisheh R., Zitt M. Small airways disease and severe asthma. World Allergy Organ J. 2017;10(1):20. doi: 10.1186/s40413-017-0153-4.Chapman K.R., Boulet L.P., Rea R.M., Franssen E. Suboptimal asthma control: prevalence, detection and consequences in general practice. Eur Respir J. 2008;31(2):320–325. doi: 10.1183/09031936.00039707.Chapman K.R., Boulet L.P., Rea R.M., Franssen E. Suboptimal asthma control: prevalence, detection and consequences in general practice. Eur Respir J. 2008;31(2):320–325. doi: 10.1183/09031936.00039707.Gauthier M., Ray A., Wenzel S.E. Evolving Concepts of Asthma. Am J Respir Crit Care Med. 2015;192(6):660–668. doi: 10.1164/rccm.201504-0763PP.Gauthier M., Ray A., Wenzel S.E. Evolving Concepts of Asthma. Am J Respir Crit Care Med. 2015;192(6):660–668. doi: 10.1164/rccm.201504-0763PP.Ненашева Н.М. Фенотипы бронхиальной астмы и выбор терапии. Практическая пульмонология. 2014;(2):2–11. Режим доступа: http://www.atmosphere-ph.ru/modules/Magazines/articles/pulmo/PP_2_2014_02.pdf.Nenasheva N.M. Bronchial asthma phenotypes and therapy choice. Prakticheskaya pulmonologiya = Practical Pulmonology. 2014;(2):2–11. (In Russ.) Available at: http://www.atmosphere-ph.ru/modules/Magazines/articles/pulmo/PP_2_2014_02.pdf.Marth K., Spinola M., Kisiel J., Woergetter C., Petrovic M., Pohl W. Treatment response according to small airway phenotypes: a real-life observational study. Ther Adv Respir Dis. 2016;10(3):200–210. doi: 10.1177/1753465816642635.Marth K., Spinola M., Kisiel J., Woergetter C., Petrovic M., Pohl W. Treatment response according to small airway phenotypes: a real-life observational study. Ther Adv Respir Dis. 2016;10(3):200–210. doi: 10.1177/1753465816642635.Lipworth B., Manoharan A., Anderson W. Unlocking the quiet zone: the small airway asthma phenotype. Lancet Respir Med. 2014;2(6):497–506. doi: 10.1016/S2213-2600(14)70103-1.Lipworth B., Manoharan A., Anderson W. Unlocking the quiet zone: the small airway asthma phenotype. Lancet Respir Med. 2014;2(6):497–506. doi: 10.1016/S2213-2600(14)70103-1.Barnes P.J., Nicolini G., Bizzi A., Spinola M., Singh D. Do inhaled corticosteroid/long-acting beta2-agonist fixed combinations provide superior clinical benefits compared with separate inhalers? A literature reappraisal. Allergy Asthma Proc. 2012;33(2):140–144. doi: 10.2500/aap.2012.33.3512.Barnes P.J., Nicolini G., Bizzi A., Spinola M., Singh D. Do inhaled corticosteroid/long-acting beta2-agonist fixed combinations provide superior clinical benefits compared with separate inhalers? A literature reappraisal. Allergy Asthma Proc. 2012;33(2):140–144. doi: 10.2500/aap.2012.33.3512.Vos W., De Backer J., Poli G., De Volder A., Ghys L., Van Holsbeke C. et al. Novel functional imaging of changes in small airways of patients treated with extrafine beclomethasone/formoterol. Respiration. 2013;86(5):393–401. doi: 10.1159/000347120.Vos W., De Backer J., Poli G., De Volder A., Ghys L., Van Holsbeke C. et al. Novel functional imaging of changes in small airways of patients treated with extrafine beclomethasone/formoterol. Respiration. 2013;86(5):393–401. doi: 10.1159/000347120.Contoli M., Kraft M., Hamid Q., Bousquet J., Rabe K., Fabbri L. et al. Do small airway abnormalities characterize asthma phenotypes? In search of proof. Clin Exp Allergy. 2012;42(8):1150–1560. doi: 10.1111/j.1365-2222.2012.03963.x.Contoli M., Kraft M., Hamid Q., Bousquet J., Rabe K., Fabbri L. et al. Do small airway abnormalities characterize asthma phenotypes? In search of proof. Clin Exp Allergy. 2012;42(8):1150–1560. doi: 10.1111/j.1365-2222.2012.03963.x.Cottini M., Lombardi C., Micheletto C. Small airway dysfunction and bronchial asthma control: the state of the art. Asthma Res Prac. 2015;1:13. doi: 10.1186/s40733-015-0013-3.Cottini M., Lombardi C., Micheletto C. Small airway dysfunction and bronchial asthma control: the state of the art. Asthma Res Prac. 2015;1:13. doi: 10.1186/s40733-015-0013-3.Kjellberg S., Houltz B.K., Zetterström O., Robinson 3., Gustafsson P.M. Clinical characteristics of adult asthma associated with small airway dysfunction. Respir Med. 2016;117:92–102. doi: 10.1016/j.rmed.2016.05.028.Kjellberg S., Houltz B.K., Zetterström O., Robinson 3., Gustafsson P.M. Clinical characteristics of adult asthma associated with small airway dysfunction. Respir Med. 2016;117:92–102. doi: 10.1016/j.rmed.2016.05.028.Hogg J.C., Macklem P.T., Thurlbeck W.M., Path M.C. Site and Nature of Airway Obstruction in Chronic Obstructive Lung Disease. N Engl J Med. 1968;278(25):1355–1360. doi: 10.1056/NEJM196806202782501.Hogg J.C., Macklem P.T., Thurlbeck W.M., Path M.C. Site and Nature of Airway Obstruction in Chronic Obstructive Lung Disease. N Engl J Med. 1968;278(25):1355–1360. doi: 10.1056/NEJM196806202782501.Yanai M., Sekizawa K., Ohrui T., Sasaki H., Takishima T. Site of airway obstruction in pulmonary disease: direct measuremцent of intrabronchial pressure. J Appl Physiol. 1992;72(3):1016–1023. doi: 10.1152/jappl.1992.72.3.1016.Yanai M., Sekizawa K., Ohrui T., Sasaki H., Takishima T. Site of airway obstruction in pulmonary disease: direct measurement of intrabronchial pressure. J Appl Physiol. 1992;72(3):1016–1023. doi: 10.1152/jappl.1992.72.3.1016.Wagner E.M., Liu M.C., Weinmann G.G., Permutt S., Bleecker E.R. Peripheral lung resistance in normal and asthmatic subjects. Am Rev Respir Dis. 1990;141(3):584–588. doi: 10.1164/ajrccm/141.3.584.Wagner E.M., Liu M.C., Weinmann G.G., Permutt S., Bleecker E.R. Peripheral lung resistance in normal and asthmatic subjects. Am Rev Respir Dis. 1990;141(3):584–588. doi: 10.1164/ajrccm/141.3.584.Pisi R., Tzani P., Aiello M., Martinelli E., Marangio E., Nicolini G. et al. Small airway dysfunction by impulse oscillometry in asthmatic patients with normal forced expiratory volume in the 1st second values. Allergy Asthma Proc. 2013;34(1):e14–20. doi: 10.2500/aap.2013.34.3641.Pisi R., Tzani P., Aiello M., Martinelli E., Marangio E., Nicolini G. et al. Small airway dysfunction by impulse oscillometry in asthmatic patients with normal forced expiratory volume in the 1st second values. Allergy Asthma Proc. 2013;34(1):e14–20. doi: 10.2500/aap.2013.34.3641.Мещерякова Н.Н., Белевский А.С. Возможности применения экстрамелкодисперсной фиксированной комбинации беклометазона и формотерола в едином ингаляторе в качестве поддерживающей и симптоматической терапии. Практическая пульмонология. 2015;(1):88–92. Режим доступа: http://www.atmosphere-ph.ru/modules/Magazines/articles/pulmo/PP_1_2015_88.pdf.Meshcheryakova N.N., Belevskiy A.S. The possibility of using an extra-finely divided fixed combination of beclomethasone and formoterol in a single inhaler as supportive and symptomatic therapy. Prakticheskaya pulmonologiya = Practical Pulmonology. 2015;(1):88–92. (In Russ.) Available at: http://www.atmosphere-ph.ru/modules/Magazines/articles/pulmo/PP_1_2015_88.pdf.Fabbri L.M., Nicolini G., Olivieri D., Papi A. Inhaled beclometasone dipropionate/formoterol extra-fine fixed combination in the treatment of asthma: evidence and future perspectives. Expert Opin Pharmacother. 2008;9(3):479–490. doi: 10.1517/14656566.9.3.479.Fabbri L.M., Nicolini G., Olivieri D., Papi A. Inhaled beclometasone dipropionate/formoterol extra-fine fixed combination in the treatment of asthma: evidence and future perspectives. Expert Opin Pharmacother. 2008;9(3):479–490. doi: 10.1517/14656566.9.3.479.Hsieh M.J., Lin Y.C., Lai R.S., Wu C.L., Lai C.L., Wang C.C. et al. Comparative efficacy and tolerability of beclomethasone/formoterol and fluticasone/ salmeterol fixed combination in Taiwanese asthmatic patients. J Formos Med Assoc. 2018;117(12):1078–1085. doi: 10.1016/j.jfma.2017.12.005.Hsieh M.J., Lin Y.C., Lai R.S., Wu C.L., Lai C.L., Wang C.C. et al. Comparative efficacy and tolerability of beclomethasone/formoterol and fluticasone/ salmeterol fixed combination in Taiwanese asthmatic patients. J Formos Med Assoc. 2018;117(12):1078–1085. doi: 10.1016/j.jfma.2017.12.005.Papi A., Paggiaro P.L., Nicolini G., Vignola A.M., Fabbri L.M. Beclomethasone/ formoterol versus budesonide/formoterol combination therapy in asthma. Eur Respir J. 2007;29(4):682–689. doi: 10.1183/09031936.00095906.Papi A., Paggiaro P.L., Nicolini G., Vignola A.M., Fabbri L.M. Beclomethasone/ formoterol versus budesonide/formoterol combination therapy in asthma. Eur Respir J. 2007;29(4):682–689. doi: 10.1183/09031936.00095906.Ненашева Н.М. Безопасность ингаляционных глюкокортикостероидов в терапии бронхиальной астмы. Пульмонология. 2014;(3):113–120. doi: 10.18093/0869-0189-2014-0-3-113-120.Nenasheva N.M. Safety of inhaled corticosteroids in the therapy of bronchial asthma. Pulmonologiya = Pulmonology. 2014;(3):113–120. (In Russ.) doi: 10.18093/0869-0189-2014-0-3-113-120.Huchon G., Magnussen H., Chuchalin A., Dymek L., Gonod F.B., Bousquet J. Lung function and asthma control with beclomethasone and formoterol in a single inhaler. Respir Med. 2009;103(1):41–49. doi: 10.1016/j.rmed.2008.09.002.Huchon G., Magnussen H., Chuchalin A., Dymek L., Gonod F.B., Bousquet J. Lung function and asthma control with beclomethasone and formoterol in a single inhaler. Respir Med. 2009;103(1):41–49. doi: 10.1016/j.rmed.2008.09.002.Papi A., Corradi M., Pigeon-Francisco C., Baronio R., Siergiejko Z., Petruzzelli S. et al. Beclometasone-formoterol as maintenance and reliever treatment in patients with asthma: a double-blind, randomised controlled trial. Lancet Respir Med. 2013;1(1):23–31. doi: 10.1016/S2213-2600(13)70012-2.Papi A., Corradi M., Pigeon-Francisco C., Baronio R., Siergiejko Z., Petruzzelli S. et al. Beclometasone-formoterol as maintenance and reliever treatment in patients with asthma: a double-blind, randomised controlled trial. Lancet Respir Med. 2013;1(1):23–31. doi: 10.1016/S2213-2600(13)70012-2.Allegra L., Cremonesi G., Girbino G., Ingrassia E., Marsico S., Nicolini G., Terzano C. Real-life prospective study on asthma control in Italy: cross-sectional phase results. Respir Med. 2012;106(2):205–214. doi: 10.1016/j.rmed.2011.10.001.Allegra L., Cremonesi G., Girbino G., Ingrassia E., Marsico S., Nicolini G., Terzano C. Real-life prospective study on asthma control in Italy: cross-sectional phase results. Respir Med. 2012;106(2):205–214. doi: 10.1016/j.rmed.2011.10.001.Muller V., Galffy G., Eszes N., Losonczy G., Bizzi A., Nicolini G. et al. Asthma control in patients receiving inhaled corticosteroid and long-acting beta2-agonist fixed combinations. A real-life study comparing dry powder inhalers and a pressurized metered dose inhaler extrafine formulation. BMC Pulm Med. 2011;11:40. doi: 10.1186/1471-2466-11-40.Muller V., Galffy G., Eszes N., Losonczy G., Bizzi A., Nicolini G. et al. Asthma control in patients receiving inhaled corticosteroid and long-acting beta2-agonist fixed combinations. A real-life study comparing dry powder inhalers and a pressurized metered dose inhaler extrafine formulation. BMC Pulm Med. 2011;11:40. doi: 10.1186/1471-2466-11-40.Terzano C., Cremonesi G., Girbino G., Ingrassia E., Marsico S., Nicolini G., Allegra L. 1-year prospective real life monitoring of asthma control and quality of life in Italy. Respir Res. 2012;13(1):112. doi: 10.1186/1465-9921-13-112.Terzano C., Cremonesi G., Girbino G., Ingrassia E., Marsico S., Nicolini G., Allegra L. 1-year prospective real life monitoring of asthma control and quality of life in Italy. Respir Res. 2012;13(1):112. doi: 10.1186/1465-9921-13-112.Jaakkola J.J.K., Hernberg S., Lajunen T.K., Sripaijboonkij P., Malmberg L.P., Jaakkola M.S. Smoking and lung function among adults with newly onset asthma. BMJ Open Respir Res. 2019;6(1):e000377.10.1136/bmjresp-2018-000377.Jaakkola J.J.K., Hernberg S., Lajunen T.K., Sripaijboonkij P., Malmberg L.P., Jaakkola M.S. Smoking and lung function among adults with newly onset asthma. BMJ Open Respir Res. 2019;6(1):e000377. 10.1136/bmjresp-2018-000377.Ненашева Н.М. Бронхиальная астма и курение. Эффективная фармакотерапия. Пульмонология и оториноларингология. 2013;(1):16–26. Режим доступа: https://umedp.ru/articles/bronkhialnaya_astma_i_kurenie.html.Nenasheva N.M. Asthma and smoking. Effektivnaya farmakoterapiya. Pulmonologiya i otorinolaringologiya. = Effective Pharmacotherapy. Pulmonology & Otorhinolaryngology. 2013;(1):16–26. (In Russ.) Availabel at: https://umedp.ru/articles/bronkhialnaya_astma_i_kurenie.html.Thomson N.C., Chaudhuri R. Asthma in smokers: challenges and opportunities. Curr Opin Pulm Med. 2009;15(1):39–45. doi: 10.1097/MCP.0b013e32831da894.Thomson N.C., Chaudhuri R. Asthma in smokers: challenges and opportunities. Curr Opin Pulm Med. 2009;15(1):39–45. doi: 10.1097/MCP.0b013e32831da894.Contoli M., Bellini F., Morandi L., Forini G., Bianchi S., Gnesini G. et al. Assessing small airway impairment in mild-to-moderate smoking asthmatic patients. Eur Respir J. 2016;47(4):1264–1267. doi: 10.1183/13993003.01708-2015.Contoli M., Bellini F., Morandi L., Forini G., Bianchi S., Gnesini G. et al. Assessing small airway impairment in mild-to-moderate smoking asthmatic patients. Eur Respir J. 2016;47(4):1264–1267. doi: 10.1183/13993003.01708-2015.Han M.K., Dransfield M.T., Martinez F.J. Chronic obstructive pulmonary disease: Definition, clinical manifestations, diagnosis, and staging. 2020. Available at: https://www.uptodate.com/contents/chronic-obstructive-pulmonary-disease-definition-clinical-manifestations-diagnosis-and-staging.Han M.K., Dransfield M.T., Martinez F.J. Chronic obstructive pulmonary disease: Definition, clinical manifestations, diagnosis, and staging. 2020. Available at: https://www.uptodate.com/contents/chronic-obstructive-pulmonary-disease-definition-clinical-manifestations-diagnosis-and-staging.Tanabe N., Vasilescu D.M., Kirby M., Coxson H.O., Verleden S.E., Vanaudenaerde B.M. et al. Analysis of airway pathology in COPD using a combination of computed tomography, micro-computed tomography and histology. Eur Respir J. 2018;51(2):1701245. doi: 10.1183/13993003.01245-2017.Tanabe N., Vasilescu D.M., Kirby M., Coxson H.O., Verleden S.E., Vanaudenaerde B.M. et al. Analysis of airway pathology in COPD using a combination of computed tomography, micro-computed tomography and histology. Eur Respir J. 2018;51(2):1701245. doi: 10.1183/13993003.01245-2017.Koo H.K., Vasilescu D.M., Booth S., Hsieh A., Katsamenis O.L., Fishbane N. et al. Small airways disease in mild and moderate chronic obstructive pulmonary disease: a cross-sectional study. Lancet Respir Med. 2018;6(8):591–602. doi: 10.1016/S2213-2600(18)30196-6.Koo H.K., Vasilescu D.M., Booth S., Hsieh A., Katsamenis O.L., Fishbane N. et al. Small airways disease in mild and moderate chronic obstructive pulmonary disease: a cross-sectional study. Lancet Respir Med. 2018;6(8):591–602. doi: 10.1016/S2213-2600(18)30196-6.McDonough J.E., Yuan R., Suzuki M., Seyednejad N., Elliott W.M., Sanchez P.G. 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.McDonough J.E., Yuan R., Suzuki M., Seyednejad N., Elliott W.M., Sanchez P.G. 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.Han M.K., Quibrera P.M., Carretta E.E., Barr R.G., Bleecker E.R., Bowler R.P. et al. Frequency of exacerbations in patients with chronic obstructive pulmonary disease: an analysis of the SPIROMICS cohort. Lancet Respir Med. 2017;5(8):619–626. doi: 10.1016/S2213-2600(17)30207-2.Han M.K., Quibrera P.M., Carretta E.E., Barr R.G., Bleecker E.R., Bowler R.P. et al. Frequency of exacerbations in patients with chronic obstructive pulmonary disease: an analysis of the SPIROMICS cohort. Lancet Respir Med. 2017;5(8):619–626. doi: 10.1016/S2213-2600(17)30207-2.Higham A., Quinn A.M., Cançado J.E.D., Singh D. The pathology of small airways disease in COPD: historical aspects and future directions. Respir Res. 2019;20(1):49. doi: 10.1186/s12931-019-1017-y.Higham A., Quinn A.M., Cançado J.E.D., Singh D. The pathology of small airways disease in COPD: historical aspects and future directions. Respir Res. 2019;20(1):49. doi: 10.1186/s12931-019-1017-y.Contoli M., Baraldo S., Conti V., Gnesini G., Marku B., Casolari P. et al. Airway inflammatory profile is correlated with symptoms in stable COPD: A longitudinal proof-of-concept cohort study. Respirology. 2020;25(1):80–88. doi: 10.1111/resp.13607.Contoli M., Baraldo S., Conti V., Gnesini G., Marku B., Casolari P. et al. Airway inflammatory profile is correlated with symptoms in stable COPD: A longitudinal proof-of-concept cohort study. Respirology. 2020;25(1):80–88. doi: 10.1111/resp.13607.Garudadri S., Woodruff P.G., Han M.K., Curtis J.L., Barr R.G., Bleecker E.R. et al. Systemic Markers of Inflammation in Smokers With Symptoms Despite Preserved Spirometry in SPIROMICS. Chest. 2019;155(5):908–917. doi: 10.1016/j.chest.2018.12.022.Garudadri S., Woodruff P.G., Han M.K., Curtis J.L., Barr R.G., Bleecker E.R. et al. Systemic Markers of Inflammation in Smokers With Symptoms Despite Preserved Spirometry in SPIROMICS. Chest. 2019;155(5):908–917. doi: 10.1016/j.chest.2018.12.022.Barnes N.C., Sharma R., Lettis S., Calverley P.M. Blood eosinophils as a marker of response to inhaled corticosteroids in COPD. Eur Respir J. 2016;47(5):1374–1382. doi: 10.1183/13993003.01370-2015.Barnes N.C., Sharma R., Lettis S., Calverley P.M. Blood eosinophils as a marker of response to inhaled corticosteroids in COPD. Eur Respir J. 2016;47(5):1374–1382. doi: 10.1183/13993003.01370-2015.Hospers J.J., Schouten J.P., Weiss S.T., Rijcken B., Postma D.S. Asthma attacks with eosinophilia predict mortality from chronic obstructive pulmonary disease in a general population sample. Am J Respir Crit Care Med. 1999;160(6):1869–1874. doi: 10.1164/ajrccm.160.6.9811041.Hospers J.J., Schouten J.P., Weiss S.T., Rijcken B., Postma D.S. Asthma attacks with eosinophilia predict mortality from chronic obstructive pulmonary disease in a general population sample. Am J Respir Crit Care Med. 1999;160(6):1869–1874. doi: 10.1164/ajrccm.160.6.9811041.Siddiqui S.H., Guasconi A., Vestbo J., Jones P., Agusti A., Paggiaro P., Wedzicha J.A. et al. Blood Eosinophils: A Biomarker of Response to Extrafine Beclomethasone/Formoterol in Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med. 2015;192(4):523–525. doi: 10.1164/rccm.201502-0235LE.Siddiqui S.H., Guasconi A., Vestbo J., Jones P., Agusti A., Paggiaro P., Wedzicha J.A. et al. Blood Eosinophils: A Biomarker of Response to Extrafine Beclomethasone/Formoterol in Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med. 2015;192(4):523–525. doi: 10.1164/rccm.201502-0235LE.Singh D., Nicolini G., Bindi E., Corradi M., Guastalla D., Kampschulte J. et al. Extrafine beclomethasone/formoterol compared to fluticasone/salmeterol combination therapy in COPD. BMC Pulm Med. 2014;14:43. doi: 10.1186/1471-2466-14-43.Singh D., Nicolini G., Bindi E., Corradi M., Guastalla D., Kampschulte J. et al. Extrafine beclomethasone/formoterol compared to fluticasone/salmeterol combination therapy in COPD. BMC Pulm Med. 2014;14:43. doi: 10.1186/1471-2466-14-43.Овчаренко С.И. Ингаляционные глюкокортикостероиды в терапии больных хронической обструктивной болезнью легких: быть или не быть?! Практическая пульмонология. 2016;(1):16–22. Режим доступа: http://www.atmosphere-ph.ru/modules/Magazines/articles/pulmo/PP_1_2016_16.pdf.Ovcharenko S.I. Inhaled glucocorticosteroids in the treatment of patients with chronic obstructive pulmonary disease: to be or not to be?! Prakticheskaya pulmonologiya = Practical Pulmonology. 2016;(1):16–22. (In Russ.) Availabel at: http://www.atmosphere-ph.ru/modules/Magazines/articles/pulmo/PP_1_2016_16.pdf.Kew K.M., Seniukovich A. Inhaled steroids and risk of pneumonia for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2014;(3):CD010115. doi: 10.1002/14651858.CD010115.pub2.Kew K.M., Seniukovich A. Inhaled steroids and risk of pneumonia for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2014;(3):CD010115. doi: 10.1002/14651858.CD010115.pub2.Papi A., Vestbo J., Fabbri L., Corradi M., Prunier H., Cohuet G. 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.Papi A., Vestbo J., Fabbri L., Corradi M., Prunier H., Cohuet G. 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.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.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.Sonnappa S., Martin R., Israel E., Postma D., van Aalderen W., Burden A. et al. Risk of pneumonia in obstructive lung disease: A real-life study comparing extra-fine and fine-particle inhaled corticosteroids. PLoS One. 2017;12(6):e0178112. doi: 10.1371/journal.pone.0178112.Sonnappa S., Martin R., Israel E., Postma D., van Aalderen W., Burden A. et al. Risk of pneumonia in obstructive lung disease: A real-life study comparing extra-fine and fine-particle inhaled corticosteroids. PLoS One. 2017;12(6):e0178112. doi: 10.1371/journal.pone.0178112.Lipworth B., Kuo C.R., Jabbal S. Current appraisal of single inhaler triple therapy in COPD. Int J Chron Obstruct Pulmon Dis. 2018;13:3003–3009. doi: 10.2147/COPD.S177333.Lipworth B., Kuo C.R., Jabbal S. Current appraisal of single inhaler triple therapy in COPD. Int J Chron Obstruct Pulmon Dis. 2018;13:3003–3009. doi: 10.2147/COPD.S177333.

The authors declare that there are no conflicts of interest present.