Tuberculosis and Respiratory Diseases

The Korean Academy of Tuberculosis and Respiratory Diseases (대한결핵및호흡기학회)
권호 표지
DOI QR코드

DOI QR Code

Clinical Characteristics of Chronic Obstructive Pulmonary Disease according to Smoking Status

  • Joo Hun Park (Department of Pulmonary and Critical Care Medicine, Ajou University School of Medicine)
  • Received : 2024.04.18
  • Accepted : 2024.10.28
  • Published : 2025.01.31
Download PDF
⟨ Previous Next ⟩

Abstract

Chronic obstructive pulmonary disease (COPD) can be caused by various factors, including lung infections, asthma, air pollution, childhood growth disorders, and genetic factors, though smoking is the predominant risk factor. The main pathological mechanisms in COPD involve small airway disease, emphysema, mucus hypersecretion, and vascular disorders. COPD in non-smokers is characterized by a normal 1-second forced expiratory volume decline, equal sex distribution, younger age of onset, fewer comorbidities, milder airflow obstruction, preserved diffusing capacity of the lungs for carbon monoxide, and radiological features such as more air-trapping and less severe emphysema compared to COPD in smokers. Nevertheless, non-smokers with COPD still experience a high prevalence of acute exacerbations, nearly equal to that of smokers with COPD. Moreover, COPD itself is an independent risk factor for developing lung cancer, regardless of smoking status. Given that COPD coexists with numerous comorbidities, effectively managing these comorbidities is crucial, requiring multifaceted efforts for comprehensive treatment.

Keywords

References

  1. Agusti A, Hogg JC. Update on the pathogenesis of chronic obstructive pulmonary disease. N Engl J Med 2019;381:1248-56. https://doi.org/10.1056/NEJMra1900475
  2. Mannino DM, Buist AS. Global burden of COPD: risk factors, prevalence, and future trends. Lancet 2007;370:765-73. https://doi.org/10.1016/S0140-6736(07)61380-4
  3. Agusti A, Celli BR, Criner GJ, Halpin D, Anzueto A, Barnes P, et al. Global initiative for chronic obstructive lung disease 2023 report: GOLD executive summary. Am J Respir Crit Care Med 2023;207:819-37. https://doi.org/10.1164/rccm.202301-0106PP
  4. Ananth S, Hurst JR. ERJ advances: state of the art in definitions and diagnosis of COPD. Eur Respir J 2023;61:2202318. https://doi.org/10.1183/13993003.02318-2022
  5. Barnes PJ. Inflammatory endotypes in COPD. Allergy 2019;74:1249-56. https://doi.org/10.1111/all.13760
  6. Sood A, Assad NA, Barnes PJ, Churg A, Gordon SB, Harrod KS, et al. ERS/ATS workshop report on respiratory health effects of household air pollution. Eur Respir J 2018;51:1700698. https://doi.org/10.1183/13993003.00698-2017
  7. Vestbo J. COPD: definition and phenotypes. Clin Chest Med 2014;35:1-6. https://doi.org/10.1016/j.ccm.2013.10.010
  8. Blancol. Tura-Ceide0, Peinado VI, Barbera JA. Updated perspectives on pulmonary hypertension in COPD. Int J Chron Obstruct Pulmon Dis 2020;15:1315-24. https://doi.org/10.2147/COPD.S211841
  9. Yang IA, Jenkins CR, Salvi SS. Chronic obstructive pulmonary disease in never-smokers: risk factors, pathogenesis, and implications for prevention and treatment. Lancet Respir Med 2022;10:497-511. https://doi.org/10.1016/S2213-2600(21)00506-3
  10. Eisner MD, Anthonisen N, Coultas D, Kuenzli N, Perez-Padilla R, Postma D, et al. An official American Thoracic Society public policy statement: novel risk factors and the global burden of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2010;182:693-718. https://doi.org/10.1164/rccm.200811-1757ST
  11. Salvi SS, Barnes PJ. Chronic obstructive pulmonary dis- ease in non-smokers. Lancet 2009;374:733-43. https://doi.org/10.1016/S0140-6736(09)61303-9
  12. Perez-Padilla R, Fernandez R, Lopez Varela MV, Montes de Oca M, Muino A, Talamo C, et al. Airflow obstruction in never smokers in five Latin American cities: the PLATINO study. Arch Med Res 2012;43:159-65. https://doi.org/10.1016/j.arcmed.2012.03.007
  13. Terzikhan N, Verhamme KM, Hofman A, Stricker BH, Brusselle GG, Lahousse L. Prevalence and incidence of COPD in smokers and non-smokers: the Rotterdam study. Eur J Epidemiol 2016;31:785-92. https://doi.org/10.1007/s10654-016-0132-z
  14. Woodruff PG, Barr RG, Bleecker E, Christenson SA, Couper D, Curtis JL, et al. Clinical significance of symptoms in smokers with preserved pulmonary function. N Engl J Med 2016;3741811-21.
  15. Rennard SI, Vestbo J. COPD: the dangerous underesti-mate of 15%. Lancet 2006;367:1216-9. https://doi.org/10.1016/S0140-6736(06)68516-4
  16. Sargent JD, Halenar M, Steinberg AW, Ozga J, Tang 2, Stanton CA, et al. Childhood cigarette smoking and risk of chronic obstructive pulmonary disease in older U.S. adults. Am J Respir Crit Care Med 2023;208:428-34. https://doi.org/10.1164/rccm.202303-0476OC
  17. Chen P, Li Y, Wu D, Liu F, Cao C. Secondhand smoke exposure and the risk of chronic obstructive pulmonary disease: a systematic review and meta-analysis. Int J Chron Obstruct Pulmon Dis 2023;18:1067-76. https://doi.org/10.2147/COPD.S403158
  18. Brakema EA, van Gemert FA, van der Kleij RM, Salvi S, Puhan M, Chavannes NH, et al. COPD's early origins in low-and-middle income countries: what are the implications of a false start? NPJ Prim Care Respir Med 2019;29:6.
  19. Bush A. Impact of early life exposures on respiratory disease. Paediatr Respir Rev 2021;40:24-32. https://doi.org/10.1016/j.prrv.2021.05.006
  20. Baraldi E, Filippone M. Chronic lung disease after premature birth. N Engl J Med 2007;3571946-55. https://doi.org/10.1056/NEJMra067279
  21. de Marco R, Accordini S, Marcon A, Cerveri I, Anto JM, Gislason T, et al. Risk factors for chronic obstructive pulmonary disease in a European cohort of young adults. Am J Respir Crit Care Med 2011;183:891-7. https://doi.org/10.1164/rccm.201007-1125OC
  22. Silva GE, Sherrill DL, Guerra S, Barbee RA. Asthma as a risk factor for COPD in a longitudinal study. Chest 2004;126:59-65. https://doi.org/10.1378/chest.126.1.59
  23. Bardsen T, Roksund OD, Benestad MR, Hufthammer KO, Clemm HH, Mikalsen IB, et al. Tracking of lung function from 10 to 35 years after being born extremely preterm or with extremely low birth weight. Thorax 2022;77:790-8. https://doi.org/10.1136/thoraxjnl-2021-218400
  24. Choi H, Lee H, Ra SW, Kim HK, Lee JS, Um SJ, et al. Clinical characteristics of patients with post-tuberculosis bronchiectasis: findings from the KMBARC registry. J Clin Med 2021;10:4542. https://doi.org/10.3390/jcm10194542
  25. Martinez FD. Early-life origins of chronic obstructive pulmonary disease. N Engl J Med 2016;375:871-8. https://doi.org/10.1056/NEJMra1603287
  26. Perez MF, Atuegwu NC, Mead EL, Oncken C, Mortensen EM. Adult E-cigarettes use associated with a self-report-ed diagnosis of COPD. Int J Environ Res Public Health 2019;16:3938. https://doi.org/10.3390/ijerph16203938
  27. Zhou JJ, Cho MH, Castaldi PJ, Hersh CP, Silverman EK, Laird NM. Heritability of chronic obstructive pulmonary disease and related phenotypes in smokers. Am J Respir Crit Care Med 2013;188:941-7. https://doi.org/10.1164/rccm.201302-0263OC
  28. Cho MH, Hobbs BD, Silverman EK. Genetics of chronic obstructive pulmonary disease: understanding the pathobiology and heterogeneity of a complex disorder. Lancet Respir Med 2022;10:485-96. https://doi.org/10.1016/S2213-2600(21)00510-5
  29. Strange C. Alpha-1 antitrypsin deficiency associated COPD. Clin Chest Med 2020;41:339-45. https://doi.org/10.1016/j.ccm.2020.05.003
  30. Stolz D, Mkorombindo T. Schumann DM, Agusti A, Ash SY, Bafadhel M, et al. Towards the elimination of chronic obstructive pulmonary disease: a lancet commission. Lancet 2022;400:921-72. https://doi.org/10.1016/S0140-6736(22)01273-9
  31. Ortega VE, Li X, O'Neal WK, Lackey L, Ampleford E, Hawkins GA, et al. The effects of rare SERPINA1 variants on lung function and emphysema in SPIROMICS. Am J Respir Crit Care Med 2020;201:540-54. https://doi.org/10.1164/rccm.201904-0769OC
  32. Alder JK, Guo N, Kembou F, Parry EM, Anderson CJ, Gorgy AI, et al. Telomere length is a determinant of emphysema susceptibility. Am J Respir Crit Care Med 2011;184:904-12. https://doi.org/10.1164/rccm.201103-0520OC
  33. Stanley SE, Chen JJ, Podlevsky JD, Alder JK, Hansel NN, Mathias RA, et al. Telomerase mutations in smokers with severe emphysema. J Clin Invest 2015;125:563-70. https://doi.org/10.1172/JCI78554
  34. Pillai SG, Ge D, Zhu G, Kong X, Shianna KV, Need AC, et al. A genome-wide association study in chronic obstructive pulmonary disease (COPD): identification of two major susceptibility loci. PLoS Genet 2009;5.e1000421. https://doi.org/10.1371/journal.pgen.1000421
  35. Wilk JB, Chen TH, Gottlieb DJ, Walter RE, Nagle MW, Brandler BJ, et al. A genome-wide association study of pulmonary function measures in the Framingham heart study. PLoS Genet 2009;5.e1000429. https://doi.org/10.1371/journal.pgen.1000429
  36. Hancock DB, Eijgelsheim M, Wilk JB, Gharib SA, Loehr LR, Marciante KD, et al. Meta-analyses of genome-wide association studies identify multiple loci associated with pulmonary function. Nat Genet 2010;42:45-52. https://doi.org/10.1038/ng.500
  37. Cho MH, Boutaoui N, Klanderman BJ, Sylvia JS, Ziniti JP, Hersh CP, et al. Variants in FAM13A are associated with chronic obstructive pulmonary disease. Nat Genet 2010;42:200-2. https://doi.org/10.1038/ng.535
  38. Cho MH, Castaldi PJ, Wan ES, Siedlinski M, Hersh CP, Demeo DL, et al. A genome-wide association study of COPD identifies a susceptibility locus on chromosome 19q13. Hum Mol Genet 2012;21:947-57 https://doi.org/10.1093/hmg/ddr524
  39. Agusti A, Melen E, DeMeo DL, Breyer-Kohansal R, Fan-er R. Pathogenesis of chronic obstructive pulmonary disease: understanding the contributions of gene-environment interactions across the lifespan. Lancet Respir Med 2022;10:512-24. https://doi.org/10.1016/S2213-2600(21)00555-5
  40. Murgia N, Gambelunghe A. Occupational COPD - The most under-recognized occupational lung disease? Respirology 2022;27:399-410. https://doi.org/10.1111/resp.14272
  41. Coggon D, Newman Taylor A. Coal mining and chronic obstructive pulmonary disease: a review of the evidence. Thorax 1998;53:398-407. https://doi.org/10.1136/thx.53.5.398
  42. Oxman AD, Muir DC, Shannon HS, Stock SR, Hnizdo E, Lange HJ. Occupational dust exposure and chronic obstructive pulmonary disease: a systematic overview of the evidence. Am Rev Respir Dis 1993;148:38-48. https://doi.org/10.1164/ajrccm/148.1.38
  43. Hessel PA, Melenka LS, Michaelchuk D, Herbert FA, Cowie RL. Lung health among plumbers and pipe fitters in Edmonton, Alberta. Occup Environ Med 1998;55:678-83. https://doi.org/10.1136/oem.55.10.678
  44. Saric M, Kalacic I, Holetic A. Follow-up of ventilatory lung function in a group of cement workers. Br J Ind Med 1976;33:18-24. https://doi.org/10.1136/oem.33.1.18
  45. Soumagne T, Degano B, Guillien A, Annesi-Maesano I, Andujar P, Hue S, et al. Characterization of chronic obstructive pulmonary disease in dairy farmers. Environ Res 2020;188:109847. https://doi.org/10.1016/j.envres.2020.109847
  46. Andersson E, Sallsten G, Lohman S, Neitzel R, Toren K. Lung function and paper dust exposure among workers in a soft tissue paper mill. Int Arch Occup Environ Health 2020;93:105-10. https://doi.org/10.1007/s00420-019-01469-6
  47. Cui L, Gallagher LG, Ray RM, Li W, Gao D, Zhang Y, et al. Unexpected excessive chronic obstructive pulmonary disease mortality among female silk textile workers in Shanghai, China. Occup Environ Med 2011;68:883-7. https://doi.org/10.1136/oem.2010.062034
  48. Oh CM, Oh IH, Lee JK, Park YH, Choe BK, Yoon TY, et al. Blood cadmium levels are associated with a decline in lung function in males. Environ Res 2014;132:119-25. https://doi.org/10.1016/j.envres.2014.04.008
  49. Becklake MR, Goldman HI, Bosman AR, Freed CC. The long-term effects of exposure to nitrous fumes. Am Rev Tuberc 1957;76:398-409.
  50. Henneberger PK, Lax MB, Ferris BG. Decrements in spirometry values associated with chlorine gassing events and pulp millwork. Am J Respir Crit Care Med 1996;153:225-31. https://doi.org/10.1164/ajrccm.153.1.8542120
  51. Dumas 0, Varraso R, Boggs KM, Quinot C, Zock JP, Hen-neberger PK, et al. Association of occupational expo-sure to disinfectants with incidence of chronic obstructive pulmonary disease among US female nurses. JAMA Netw Open 2019;2:e1913563 https://doi.org/10.1001/jamanetworkopen.2019.13563
  52. Thomsen M, Nordestgaaro BG, Vestbo J, Lange P. Char-acteristics and outcomes of chronic obstructive pulmonary disease in never smokers in Denmark: a prospective population study. Lancet Respir Med 2013;1:543-50. https://doi.org/10.1016/S2213-2600(13)70137-1
  53. Tan WC, Sin DD, Bourbeau J, Hernandez P, Chapman KR, Cowie R, et al. Characteristics of COPD in never-smokers and ever-smokers in the general population: results from the CanCOLD study. Thorax 2015;70:822-9 https://doi.org/10.1136/thoraxjnl-2015-206938
  54. Ahn SV, Lee E, Park B, Jung JH, Park JE, Sheen SS, et al. Cancer development in patients with COPD: a retrospective analysis of the National Health Insurance Service-national sample cohort in Korea. BMC Pulm Med 2020;20:170. https://doi.org/10.1186/s12890-020-01194-8
  55. Choi JY, Kim JW, Kim YH, Yoo KH, Jung KS, Lee JH, et al. Clinical characteristics of non-smoking chronic obstructive pulmonary disease patients: findings from the KOCOSS cohort. COPD 2022;19:174-81. https://doi.org/10.1080/15412555.2022.2053088
  56. Salvi SS, Brashier BB, Londhe J, Pyasi K, Vincent V, Ka-jale SS, et al. Phenotypic comparison between smoking and non-smoking chronic obstructive pulmonary disease. Respir Res 2020;21:50. https://doi.org/10.1186/s12931-020-1310-9
  57. Tan L, Li Y, Wang Z, Wang Z, Liu S, Lin J, et al. Comprehensive appraisal of lung function in young COPD patients: a single center observational study. BMC Pulm Med 2024;24:358. https://doi.org/10.1186/s12890-024-03165-9
  58. Cosio BG, Pascual-Guardia S, Borras-Santos A, Pec-es-Barba G, Santos S, Vigil L, et al. Phenotypic charac- terisation of early COPD: a prospective case-control study. ERJ Open Res 2020;6:00047-2020. https://doi.org/10.1183/23120541.00047-2020
  59. Fletcher C, Peto R. The natural history of chronic airflow obstruction. Br Med J 1977;1:1645-8. https://doi.org/10.1136/bmj.1.6077.1645
  60. Lange P, Celli B, Agusti A, Boje Jensen G, Divo M, Faner R, et al. Lung-function trajectories leading to chronic obstructive pulmonary disease. N Engl J Med 2015;373:111-22. https://doi.org/10.1056/NEJMoa1411532
  61. Decramer M, Celli B, Kesten S, Lystig T, Mehra S, Tashkin DP, et al. Effect of tiotropium on outcomes in patients with moderate chronic obstructive pulmonary disease (UPLIFT): a prespecified subgroup analysis of a randomised controlled trial. Lancet 2009, 374:1171-8. https://doi.org/10.1016/S0140-6736(09)61298-8
  62. Jenkins CR, Jones PW, Calverley PM, Celli B, Anderson JA, Ferguson GT, et al. Efficacy of salmeterol/fluticasone propionate by GOLD stage of chronic obstructive pulmonary disease: analysis from the randomised, placebo-controlled TORCH study. Respir Res 2009;10:59. https://doi.org/10.1186/1465-9921-10-59
  63. Dawkins PA, Dawkins CL, Wood AM, Nightingale PG, Stockley JA, Stockley RA. Rate of progression of lung function impairment in alpha1-antitrypsin deficiency. Eur Respir J 2009;33:1338-44. https://doi.org/10.1183/09031936.00061208
  64. Donaldson GC, Seemungal TA, Bhowmik A, Wedzicha JA. Relationship between exacerbation frequency and lung function decline in chronic obstructive pulmonary disease. Thorax 2002;57:847-52 https://doi.org/10.1136/thorax.57.10.847
  65. Vestbo J, Edwards LD, Scanlon PD, Yates JC, Agusti A, Bakke P, et al. Changes in forced expiratory volume in 1 second over time in COPD. N Engl J Med 2011;365:1184-92. https://doi.org/10.1056/NEJMoa1105482
  66. Nishimura M, Makita H, Nagai K, Konno S, Nasuhara Y, Hasegawa M, et al. Annual change in pulmonary function and clinical phenotype in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2012;185:44-52. https://doi.org/10.1164/rccm.201106-0992OC
  67. Drummond MB, Hansel NN, Connett JE, Scanlon PD, Tashkin DP, Wise RA. Spirometric predictors of lung function decline and mortality in early chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2012;185:1301-6. https://doi.org/10.1164/rccm.201202-0223OC
  68. Wang M, Aaron CP, Madrigano J, Hoffman EA, Angelini E, Yang J, et al. Association between long-term expo-sure to ambient air pollution and change in quantitatively assessed emphysema and lung function. JAMA 2019;322:546-56. https://doi.org/10.1001/jama.2019.10255
  69. Ruan S, Wang W, Qiu L, Yan X, Peng Z, Zhu H, et al. Preparation of 3D flexible SERS substrates by mixing gold nanorods in hydrogels for the detection of malachite green and crystal violet. Mikrochim Acta 2024;191:205. https://doi.org/10.1007/s00604-024-06284-6
  70. Guo C, Zhang Z, Lau AK, Lin CQ, Chuang YC, Chan J, et al. Effect of long-term exposure to fine particulate matter on lung function decline and risk of chronic obstructive pulmonary disease in Taiwan: a longitudinal, cohort study. Lancet Planet Health 2018;2:e114-25. https://doi.org/10.1016/S2542-5196(18)30028-7
  71. Muttoo S, Jeena PM, Roosli M, de Hoogh K, Meliefste K, Tularam H, et al. Effect of short-term exposure to ambient nitrogen dioxide and particulate matter on repeated lung function measures in infancy: a South African birth cohort. Environ Res 2022;213:113645. https://doi.org/10.1016/j.envres.2022.113645
  72. Redlich CA, Tarlo SM. Longitudinal assessment of lung function decline in the occupational setting. Curr Opin Allergy Clin Immunol 2015;15:145-9. https://doi.org/10.1097/ACI.0000000000000153
  73. Rabbani G, Nimmi N, Benke GP, Dharmage SC, Bui D, Sim MR, et al. Ever and cumulative occupational expo-sure and lung function decline in longitudinal population-based studies: a systematic review and meta-analysis. Occup Environ Med 2023;80:51-60 https://doi.org/10.1136/oemed-2022-108237
  74. Lytras T, Beckmeyer-Borowko A, Kogevinas M, Krom-hout H, Carsin AE, Anto JM, et al. Cumulative occupational exposures and lung-function decline in two large general-population cohorts. Ann Am Thorac Soc 2021;18:238-46. https://doi.org/10.1513/AnnalsATS.202002-113OC
  75. Alif SM, Dharmage S, Benke G, Dennekamp M, Burgess J, Perret JL, et al. Occupational exposure to solvents and lung function decline: a population based study. Thorax 2019;74:650-8. https://doi.org/10.1136/thoraxjnl-2018-212267
  76. Szram J, Schofield SJ, Cosgrove MP, Cullinan P. Welding, longitudinal lung function decline and chronic respiratory symptoms: a systematic review of cohort studies. Eur Respir J 2013;42:1186-93. https://doi.org/10.1183/09031936.00206011
  77. Hong YS, Park HY, Ryu S, Shin SH, Zhao D, Singh D, et al. The association of blood eosinophil counts and FEV1 decline: a cohort study. Eur Respir J 2024, 63:2301037. https://doi.org/10.1183/13993003.01037-2023
  78. Tan WC, Bourbeau J, Nadeau G, Wang W, Barnes N, Landis SH, et al. High eosinophil counts predict decline in FEV1: results from the CanCOLD study. Eur Respir J 2021;57:2000838. https://doi.org/10.1183/13993003.00838-2020
  79. Celli BR, Anderson JA, Cowans NJ, Crim C, Hartley BF, Martinez FJ, et al. Pharmacotherapy and lung function decline in patients with chronic obstructive pulmonary disease: a systematic review. Am J Respir Crit Care Med 2021;203:689-98. https://doi.org/10.1164/rccm.202005-1854OC
  80. Rabe KF, Watz H. Chronic obstructive pulmonary dis- ease. Lancet 2017;389:1931-40. https://doi.org/10.1016/S0140-6736(17)31222-9
  81. Chan SM, Selemidis S, Bozinovski S, Vlahos R. Pathobi-ological mechanisms underlying metabolic syndrome (MetS) in chronic obstructive pulmonary disease (COPD): clinical significance and therapeutic strategies. Pharmacol Ther 2019;1993160-88. https://doi.org/10.1016/j.pharmthera.2019.02.013
  82. Barnes PJ, Celli BR. Systemic manifestations and comorbidities of COPD. Eur Respir J 2009;33:1165-85. https://doi.org/10.1183/09031936.00128008
  83. Divo M, Cote C, de Torres JP, Casanova C, Marin JM, Pinto-Plata V, et al. Comorbidities and risk of mortality in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2012;186:155-61. https://doi.org/10.1164/rccm.201201-0034OC
  84. Lee SH, Hwang ED, Lim JE, Moon S, Kang YA, Jung JY, et al. The risk factors and characteristics of COPD among nonsmokers in Korea: an analysis of KNHANES IV and V. Lung 2016;194:353-61. https://doi.org/10.1007/s00408-016-9871-6
  85. Takiguchi Y, Sekine I, Iwasawa S, Kurimoto R, Tatsumi K. Chronic obstructive pulmonary disease as a risk factor for lung cancer. World J Clin Oncol 2014;5:660-6. https://doi.org/10.5306/wjco.v5.i4.660
  86. Maldonado F, Bartholmai BJ, Swensen SJ, Midthun DE, Decker PA, Jett JR. Are airflow obstruction and radiographic evidence of emphysema risk factors for lung cancer? A nested case-control study using quantitative emphysema analysis. Chest 2010;138:1295-302. https://doi.org/10.1378/chest.09-2567
  87. Mannino DM, Aguayo SM, Petty TL, Redd SC. Low lung function and incident lung cancer in the United States: data from the First National Health and Nutrition Examination Survey follow-up. Arch Intern Med 2003;163:1475-80. https://doi.org/10.1001/archinte.163.12.1475
  88. Fry JS, Hamling JS, Lee PN. Systematic review with meta-analysis of the epidemiological evidence relating FEV1 decline to lung cancer risk. BMC Cancer 2012;12:498. https://doi.org/10.1186/1471-2407-12-498
  89. Gauderman WJ, Urman R, Avol E, Berhane K, McConnell R, Rappaport E, et al. Association of improved air quality with lung development in children. N Engl J Med 2015;372:905-13. https://doi.org/10.1056/NEJMoa1414123
  90. Khomenko S, Cirach M, Pereira-Barboza E, Mueller N, Barrera-Gomez J, Rojas-Rueda D, et al. Premature mortality due to air pollution in European cities: a health impact assessment. Lancet Planet Health 2021;5:e121-34. https://doi.org/10.1016/S2542-5196(20)30272-2
  91. Hogg JC, Chu F, Utokaparch S, Woods R, Elliott WM, Buzatu L, et al. The nature of small-airway obstruction in chronic obstructive pulmonary disease. N Engl J Med 2004;350:2645-53. https://doi.org/10.1056/NEJMoa032158
  92. Zhou Y, Zhong NS, Li X, Chen S, Zheng J, Zhao D, et al. Tiotropium in early-stage chronic obstructive pulmonary disease. N Engl J Med 2017;377:923-35. https://doi.org/10.1056/NEJMoa1700228
  93. Hansel NN, Woo H, Koehler K, Gassett A, Paulin LM, Alexis NE, et al. Indoor pollution and lung function decline in current and former smokers: SPIROMICS AIR. Am J Respir Crit Care Med 2023;208:1042-51. https://doi.org/10.1164/rccm.202302-0207OC
  94. Lee PN, Fry JS. Systematic review of the evidence relating FEV1 decline to giving up smoking. BMC Med 2010;8:84. https://doi.org/10.1186/1741-7015-8-84
  95. Calzetta L, Rogliani P, Matera MG, Cazzola M. A systematic review with meta-analysis of dual bronchodilation with LAMA/LABA for the treatment of stable COPD. Chest 2016;149:1181-96. https://doi.org/10.1016/j.chest.2016.02.646
  96. Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: 2024 report [Internet]. Fontana: GOLD; 2024 [cited 2024 Nov 12]. https://goIdcopd.org/wp-content/up-loads/2024/01/GOLD-2024_v1.2-11Jan24_WMV-1.pdf.
  97. Tashkin DP, Goodin T, Bowling A, Price B, Ozol-Godfrey A, Sharma S, et al. Effect of smoking status on lung function, patient-reported outcomes, and safety among COPD patients treated with glycopyrrolate inhalation powder: pooled analysis of GEM1 and GEM2 studies. Respir Res 2019;20:135. https://doi.org/10.1186/s12931-019-1112-0
  98. Jabbal S, Kuo CR, Lipworth B. Randomized controlled trial of triple versus dual inhaler therapy on small airways in smoking asthmatics. Clin Exp Allergy 2020;50:1140-7. https://doi.org/10.1111/cea.13702
  99. Han MK, Ye W, Wang D, White E, Arjomandi M, Barjak-tarevic IZ, et al. Bronch' dilatin tobacco-exposed persons with symptoms and preserved lung function. N Engl j Med 2022;387:1173-84. https://doi.org/10.1056/NEJMoa2204752
  100. Lipson DA, Barnhart F, Brealey N, Brooks J, Criner GJ, Day NC, et al. Once-daily single-inhaler triple versus dual therapy in patients with COPD. N Engl J Med 2018;378:1671-80. https://doi.org/10.1056/NEJMoa1713901
  101. Wedzicha JA, Banerji D, Chapman KR, Vestbo J, Roche N, Ayers RT, et al. Indacatelol-glycopyrronium versus salmeterol-fluticasone for COPD. N Engl J Med 2016;374:2222-34. https://doi.org/10.1056/NEJMoa1516385
  102. Magnussen H, Disse B, Rodriguez-Roisin R, Kirsten A, Watz H, Tetzlaff K, et al. Withdrawal of inhaled glucocorticoids and exacerbations of COPD. N Engl J Med 2014;371:1285-94. https://doi.org/10.1056/NEJMoa1407154
  103. Rabe KF, Martinez FJ, Ferguson GT, Wang C, Singh D, Wedzicha JA, et al. Triple inhaled therapy at two glucocorticoid doses in moderate-to-very-severe COPD. N Engl Med 2020;383:35-48. https://doi.org/10.1056/NEJMoa1916046
  104. Calverley PM, Anderson JA, Celli B, Ferguson GT, Jen- kins C, Jones PW, et al. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med 2007;356:775-89. https://doi.org/10.1056/NEJMoa063070
  105. Dekhuijzen PN, Batsiou M, Bjermer L, Bosnic-Anticevich S, Chrystyn H, Papi A, et al. Incidence of oral thrush in patients with COPD prescribed inhaled corticosteroids: effect of drug, dose, and device. Respir Med 2016;120:54-63. https://doi.org/10.1016/j.rmed.2016.09.015
  106. Lee CH, Kim K, Hyun MK, Jang EJ, Lee NR, Yim JJ. Use of inhaled corticosteroids and the risk of tuberculosis. Thorax 2013;68:1105-13. https://doi.org/10.1136/thoraxjnl-2012-203175
  107. Kim JH, Park JS, Kim KH, Jeong HC, Kim EK, Lee JH. Inhaled corticosteroid is associated with an increased risk of TB in patients with COPD. Chest 2013;143:1018-24. https://doi.org/10.1378/chest.12-1225
  108. Brode SK, Campitelli MA, Kwong JC, Lu H, March-and-Austin A, Gershon AS, et al. The risk of mycobacterial infections associated with inhaled corticosteroid use. Eur Respir J 2017;50:1700037. https://doi.org/10.1183/13993003.00037-2017
  109. Barnes PJ, Adcock IM, Ito K. Histone acetylation and deacetylation: importance in inflammatory lung diseases. Eur Respir J 2005;25:552-63. https://doi.org/10.1183/09031936.05.00117504
  110. Calverley PM, Rabe KF, Goehring UM, Kristiansen S, Fabbri LM, Martinez FJ, et al. Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials. Lancet 2009;374:685-94. https://doi.org/10.1016/S0140-6736(09)61255-1
  111. Schmid A, Baumlin N, Ivonnet P, Dennis JS, Campos M, Krick S, et al. Roflumilast partially reverses smoke-induced mucociliary dysfunction. Respir Res 2015;16:135. https://doi.org/10.1186/s12931-015-0294-3
  112. Albert RK, Connett J, Bailey WC, Casaburi R, Cooper JA, Criner GJ, et al. Azithromycin for prevention of exacerbations of COPD. N Engl J Med 2011;365:689-98. https://doi.org/10.1056/NEJMoa1104623
  113. Han MK, Tayob N, Murray S, Dransfield MT, Washko G, Scanlon PD, et al. Predictors of chronic obstructive pulmonary disease exacerbation reduction in response to daily azithromycin therapy. Am J Respir Crit Care Med 2014;189:1503-8. https://doi.org/10.1164/rccm.201402-0207OC