Measurement of small airway function and its clinical significance_West China Medical Journal

Authors：

ZHANG Jinnong ,  CHEN Yuhan

Department of Respiratory, Xiamen Humanity Hospital, Xiamen, Fujian 361016, P. R. China;

Corresponding?author：

CHEN Yuhan, Email: hmmyhyh@163.com

Keywords：

Small airway dysfunction; functional measurement; asthma; chronic obstructive pulmonary disease

DOI：

10.7507/1002-0179.202604137

Video：

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Abstract Full text Figures/Tables Video References Cited by

Small airways play a pivotal role in the early pathological changes of various lung diseases, including asthma, chronic obstructive pulmonary disease, and interstitial lung disease. Owing to the large cross-sectional area of small airways, conventional spirometry may not be sensitive enough, leading to the potential neglect of small airway dysfunction. This article, drawing on the latest findings and academic perspectives in related research fields, briefly introduces the anatomical structure, pathophysiological characteristics, functional measurements, and clinical significance of small airways. The aim is to facilitate early diagnosis, risk prediction, and precision treatment of small airway dysfunction associated with chronic obstructive pulmonary disease and asthma.

Citation： ZHANG Jinnong, CHEN Yuhan. Measurement of small airway function and its clinical significance. West China Medical Journal, 2026, 41(4): 529-534. doi: 10.7507/1002-0179.202604137 Copy

1.	GBD 2023 Asia Chronic Respiratory Disease Collaborators. Burden of chronic respiratory disease in Asia, 1990-2023: a systematic analysis for the Global Burden of Disease Study 2023. Lancet Respir Med, 2026, 14(3): 233-255.
2.	Celli BR, Christenson SA, Rabe KF, et al. Current smoker: a clinical chronic obstructive pulmonary disease phenotype affecting disease progression and response to therapy. Am J Respir Crit Care Med, 2025, 211(5): 729-736.
3.	Li N, Xu Y, Xiao X, et al. Long-term trends in the burden of asthma in China: a joinpoint regression and age-period-cohort analysis based on the GBD 2021. Respir Res, 2025, 26(1): 56.
4.	Gao F, Lei J, Zhu H, et al. Small airway dysfunction links asthma exacerbations with asthma control and health-related quality of life. Respir Res, 2024, 25(1): 306.
5.	Galant SP, Kuks PJM, Kole TM, et al. Assessment of the role of small airway dysfunction in relation to exacerbation risk in patients with well controlled asthma (ATLANTIS): an observational study. Lancet Respir Med, 2025, 13(11): 990-1000.
6.	McDonough JE, 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.
7.	Zhou R, Wang H, Zhang Y, et al. Small airway disease as a key factor in COPD: new perspectives and insights. Front Med (Lausanne), 2025, 12: 1648612.
8.	Okajima Y, Lenburg ME, Diaz AA. When asthmatic distal airways lose their identity: a new mechanism of mucus plugs pathogenesis. Am J Respir Crit Care Med, 2026, 23: aamaf100.
9.	Liegeois MA, Hsieh A, Al-Fouadi M, et al. Cellular and molecular features of asthma mucus plugs provide clues about their formation and persistence. J Clin Invest, 2025, 135(6): e186889.
10.	Schworer SA, Murano H, Dang H, et al. Airway epithelial heterogeneity and mucus plugging in asthmatic bronchioles. Am J Respir Crit Care Med, 2025, 23: 10.
11.	Blackburn JB, Li NF, Bartlett NW, et al. An update in club cell biology and its potential relevance to chronic obstructive pulmonary disease. Am J Physiol Lung Cell Mol Physiol, 2023, 324(5): L652-L665.
12.	Hogg JC, Macklem PT, Thurlbeck WM. Site and nature of airway obstruction in chronic obstructive lung disease. N Engl J Med, 1968, 278(25): 1355-1360.
13.	van den Bosch WB, James AL, Tiddens HAWM. Structure and function of small airways in asthma patients revisited. Eur Respir Rev, 2021, 30(159): 200186.
14.	Park H, Lee HJ, Lee HW, et al. Diagnosis and evaluation of small airway disease and COPD using impulse oscillometry. Sci Rep, 2024, 14(1): 28030.
15.	Woodward IR, Fromen CA. Recent developments in aerosol pulmonary drug delivery: new technologies, new cargos, and new targets. Annu Rev Biomed Eng, 2024, 26(1): 307-330.
16.	Siora A, Vontetsianos A, Chynkiamis N, et al. Small airways in asthma: from inflammation and pathophysiology to treatment response. Respir Med, 2024, 222: 107532.
17.	King GG, Chung LP, Usmani OS, et al. Improving asthma outcomes: clinicians’ perspectives on peripheral airways. J Allergy Clin Immunol Glob, 2024, 3(2): 100228.
18.	Stanojevic S, Kaminsky DA, Miller MR, et al. ERS/ATS technical standard on interpretive strategies for routine lung function tests. Eur Respir J, 2022, 60(1): 2101499.
19.	Toumpanakis D, Kim Y, Usmani OS. Small airways disease in patients with COPD: a question-and-answer approach for everyday clinical practice. Chest, 2026, 169(3): 641-651.
20.	Yee N, Markovic D, Buhr RG, et al. Significance of FEV₃/FEV₆ in recognition of early airway disease in smokers at risk of development of COPD: analysis of the SPIROMICS cohort. Chest, 2022, 161(4): 949-959.
21.	Wang Z, Lin J, Liang L, et al. Combining small airway parameters with conventional parameters obtained during spirometry to diagnose airflow obstruction: a cross-sectional study. Respirology, 2024, 29(7): 605-613.
22.	Wang Z, Gao Y, Jian W, et al. Establishment and application of reference equations for FEF50 and FEF75 in the Chinese population. J Thorac Dis, 2024, 16(1): 379-390.
23.	Kaminsky DA, Simpson SJ, Berger KI, et al. Clinical significance and applications of oscillometry. Eur Respir Rev, 2022, 31(163): 210208.
24.	Yao S, Huang L, Chen B, et al. Impulse oscillometry and traditional pulmonary function testing: correlation, advances and clinical implications. BMJ Open Respir Res, 2026, 13(1): e003881.
25.	Chan R, Gochicoa-Rangel L, Cottini M, et al. Ascertainment of small airways dysfunction using oscillometry to better define asthma control and future risk: are we ready to implement it in clinical practice?. Chest, 2025, 167(5): 1287-1296.
26.	Gong X, Sang L, Huang Y, et al. Impulse oscillometry for the detection of small airway dysfunction in patients with chronic respiratory symptoms, preserved ratio impaired spirometry and COPD. BMC Pulm Med, 2025, 25(1): 458.
27.	Olin AC. Inclusion of small airway dysfunction in asthma assessment and management: a place for impulse oscillometry?. Lancet Respir Med. 2025 Nov;13(11): 955-956.
28.	Lu L, Wu F, Tang G, et al. Associations of small airway dysfunction assessed by impulse oscillometry with lung function decline and exacerbations in participants with chronic obstructive pulmonary disease: a prospective cohort study in China. Respir Med, 2025, 241: 108075.
29.	Athavale T, Athavale A. Comparison of forced oscillation technique, lung volumes by body plethysmography, and spirometry in moderate persistent adult asthma. J Assoc Physicians India, 2024, 72(5): 29-35.
30.	Vasi ?, Karaduman ?, Alacao?lu ?, et al. Assessment of interstitial lung disease in systemic sclerosis using oscillometric methods: a novel approach to respiratory assessment. Rheumatology (Oxford), 2026, 65(1): keaf572.
31.	Siebeneichler AS, Schumann DM, Karakioulaki M, et al. Single and multiple breath nitrogen washout compared with the methacholine test in patients with suspected asthma and normal spirometry. BMJ Open Respir Res, 2024, 11(1): e001919.
32.	Verbanck S, Hanon S, Vandemeulebroucke J, et al. Structure-function in smokers: when a small airways test really reflects the small airways. J Appl Physiol (1985), 2024, 137(2): 343-348.
33.	Kraft M, Richardson M, Hallmark B, et al. The role of small airway dysfunction in asthma control and exacerbations: a longitudinal, observational analysis using data from the ATLANTIS study. Lancet Respir Med, 2022, 10(7): 661-668.
34.	Woodruff PG, Barr RG, Bleecker E, et al. Clinical significance of symptoms in smokers with preserved pulmonary function. N Engl J Med, 2016, 374(19): 1811-1821.
35.	COPDGene 2025 Diagnosis Working Group and CanCOLD Investigators, Bhatt SP, Abadi E, et al. A multidimensional diagnostic approach for chronic obstructive pulmonary disease. JAMA, 2025, 333(24): 2164-2175.
36.	Verleden SE, Hendriks JMH, Snoeckx A, et al. Small airway disease in pre-chronic obstructive pulmonary disease with emphysema: a cross-sectional study. Am J Respir Crit Care Med, 2024, 209(6): 683-692.
37.	Lee BY, Han MK. Understanding early COPD. Respir Care, 2023, 68(7): 881-888.
38.	Stanojevic S, Yung MH, Sahin B, et al. Association between e-cigarette exposure and ventilation homogeneity in young adults: a cross-sectional study. Eur Respir J, 2025, 65(3): 2401675.
39.	Oppenheimer BW, Goldring RM, Herberg ME, et al. Distal airway function in symptomatic subjects with normal spirometry following World Trade Center dust exposure. Chest, 2007, 132(4): 1275-1282.
40.	Wang Z, Ge J, Wang Y, et al. Assessing the impact of World Trade Center (WTC) exposures on post-bronchodilator lung function: insights from WTC survivor population. PLoS One, 2026, 21(3): e0344458.
41.	Schneider C, Koenig C, ?arkovi? M, et al. Nitrogen single and multiple breath washout test and lung imaging to detect treatment-related pulmonary toxicity in paediatric cancer patients and survivors: a systematic review. Eur Respir Rev, 2025, 34(175): 240178.
42.	中國醫學裝備協會呼吸病學專委會吸入治療與呼吸康復學組. 穩定期慢性氣道疾病吸入裝置規范應用中國專家共識(2023 版). 中華結核和呼吸雜志, 2023, 46(11): 1055-1067.
43.	Rigby D. Inhaler device selection for people with asthma or chronic obstructive pulmonary disease. Aust Prescr, 2024, 47(5): 140-147.
44.	Usmani OS, Toumpanakis D, Meah S, et al. Whole lung directed anti-muscarinic therapy improves small airway dysfunction in COPD patients. Eur Respir J, 2026, 67(2): 2501326.
45.	Carpagnano GE, Portacci A, Dragonieri S, et al. Managing small airway disease in patients with severe asthma: transitioning from the “silent zone” to achieving “quiet asthma”. J Clin Med, 2024, 13(8): 2320.
46.	Afreen S, Waters M, Eapen MS, et al. Advances in biologic therapies for COPD: precision medicine approaches and implications for small-airway disease. Expert Rev Respir Med, 2026, 12: 1-18.
47.	Usmani OS, Dhand R, Lavorini F, et al. Why we should target small airways disease in our management of chronic obstructive pulmonary disease. Mayo Clin Proc, 2021, 96(9): 2448-2463.
48.	Gogali A, Kostikas K, Kyriakopoulos C, et al. Managing small airways dysfunction in COPD patients in real life under fixed triple combination of beclomethasone/formoterol/glycopyrronium: the MASCOT real world evidence study. Int J Chron Obstruct Pulmon Dis, 2025, 20: 1651-1663.
49.	Usmani OS, Scichilone N, Mignot B, et al. Airway deposition of extrafine inhaled triple therapy in patients with COPD: a model approach based on functional respiratory imaging computer simulations. Int J Chron Obstruct Pulmon Dis, 2020, 15: 2433-2440.
50.	Agache I, Adcock IM, Baraldi F, et al. Personalized therapeutic approaches for asthma. J Allergy Clin Immunol, 2025, 156(3): 503-522.
51.	Kotsiou OS, Kirgou P, Siachpazidou D, et al. Early benefit of mepolizumab on small airways in severe asthma: insights from the IMPOSE study. ERJ Open Res, 2025, 11(3): 00939-2024.
52.	Bonini M, Boccabella C, Cefaloni F, et al. Small airways disease as a novel target for mepolizumab in asthma-the SASAM prospective real-life study. J Clin Med, 2025, 14(9): 2928.
53.	Hill DB, Button B, Rubinstein M, et al. Physiology and pathophysiology of human airway mucus. Physiol Rev, 2022, 102(4): 1757-1836.
54.	Bradley JM, O’Neill B, McAuley DF, et al. Hypertonic saline or carbocisteine in bronchiectasis. N Engl J Med, 2025, 393(16): 1565-1577.
55.	Nguyen N, Zawam Y, Tran NB, et al. Hypertonic saline in non-cystic fibrosis bronchiectasis (hyper-BRONCHI): an updated systematic review and meta-analysis. BMC Pulm Med, 2026, 26(1): 122.
56.	Zhou Y, Wu F, Shi Z, et al. Effect of high-dose N-acetylcysteine on exacerbations and lung function in patients with mild-to-moderate COPD: a double-blind, parallel group, multicentre randomised clinical trial. Nat Commun, 2024, 15(1): 8468.

1. GBD 2023 Asia Chronic Respiratory Disease Collaborators. Burden of chronic respiratory disease in Asia, 1990-2023: a systematic analysis for the Global Burden of Disease Study 2023. Lancet Respir Med, 2026, 14(3): 233-255.
2. Celli BR, Christenson SA, Rabe KF, et al. Current smoker: a clinical chronic obstructive pulmonary disease phenotype affecting disease progression and response to therapy. Am J Respir Crit Care Med, 2025, 211(5): 729-736.
3. Li N, Xu Y, Xiao X, et al. Long-term trends in the burden of asthma in China: a joinpoint regression and age-period-cohort analysis based on the GBD 2021. Respir Res, 2025, 26(1): 56.
4. Gao F, Lei J, Zhu H, et al. Small airway dysfunction links asthma exacerbations with asthma control and health-related quality of life. Respir Res, 2024, 25(1): 306.
5. Galant SP, Kuks PJM, Kole TM, et al. Assessment of the role of small airway dysfunction in relation to exacerbation risk in patients with well controlled asthma (ATLANTIS): an observational study. Lancet Respir Med, 2025, 13(11): 990-1000.
6. McDonough JE, 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.
7. Zhou R, Wang H, Zhang Y, et al. Small airway disease as a key factor in COPD: new perspectives and insights. Front Med (Lausanne), 2025, 12: 1648612.
8. Okajima Y, Lenburg ME, Diaz AA. When asthmatic distal airways lose their identity: a new mechanism of mucus plugs pathogenesis. Am J Respir Crit Care Med, 2026, 23: aamaf100.
9. Liegeois MA, Hsieh A, Al-Fouadi M, et al. Cellular and molecular features of asthma mucus plugs provide clues about their formation and persistence. J Clin Invest, 2025, 135(6): e186889.
10. Schworer SA, Murano H, Dang H, et al. Airway epithelial heterogeneity and mucus plugging in asthmatic bronchioles. Am J Respir Crit Care Med, 2025, 23: 10.
11. Blackburn JB, Li NF, Bartlett NW, et al. An update in club cell biology and its potential relevance to chronic obstructive pulmonary disease. Am J Physiol Lung Cell Mol Physiol, 2023, 324(5): L652-L665.
12. Hogg JC, Macklem PT, Thurlbeck WM. Site and nature of airway obstruction in chronic obstructive lung disease. N Engl J Med, 1968, 278(25): 1355-1360.
13. van den Bosch WB, James AL, Tiddens HAWM. Structure and function of small airways in asthma patients revisited. Eur Respir Rev, 2021, 30(159): 200186.
14. Park H, Lee HJ, Lee HW, et al. Diagnosis and evaluation of small airway disease and COPD using impulse oscillometry. Sci Rep, 2024, 14(1): 28030.
15. Woodward IR, Fromen CA. Recent developments in aerosol pulmonary drug delivery: new technologies, new cargos, and new targets. Annu Rev Biomed Eng, 2024, 26(1): 307-330.
16. Siora A, Vontetsianos A, Chynkiamis N, et al. Small airways in asthma: from inflammation and pathophysiology to treatment response. Respir Med, 2024, 222: 107532.
17. King GG, Chung LP, Usmani OS, et al. Improving asthma outcomes: clinicians’ perspectives on peripheral airways. J Allergy Clin Immunol Glob, 2024, 3(2): 100228.
18. Stanojevic S, Kaminsky DA, Miller MR, et al. ERS/ATS technical standard on interpretive strategies for routine lung function tests. Eur Respir J, 2022, 60(1): 2101499.
19. Toumpanakis D, Kim Y, Usmani OS. Small airways disease in patients with COPD: a question-and-answer approach for everyday clinical practice. Chest, 2026, 169(3): 641-651.
20. Yee N, Markovic D, Buhr RG, et al. Significance of FEV₃/FEV₆ in recognition of early airway disease in smokers at risk of development of COPD: analysis of the SPIROMICS cohort. Chest, 2022, 161(4): 949-959.
21. Wang Z, Lin J, Liang L, et al. Combining small airway parameters with conventional parameters obtained during spirometry to diagnose airflow obstruction: a cross-sectional study. Respirology, 2024, 29(7): 605-613.
22. Wang Z, Gao Y, Jian W, et al. Establishment and application of reference equations for FEF50 and FEF75 in the Chinese population. J Thorac Dis, 2024, 16(1): 379-390.
23. Kaminsky DA, Simpson SJ, Berger KI, et al. Clinical significance and applications of oscillometry. Eur Respir Rev, 2022, 31(163): 210208.
24. Yao S, Huang L, Chen B, et al. Impulse oscillometry and traditional pulmonary function testing: correlation, advances and clinical implications. BMJ Open Respir Res, 2026, 13(1): e003881.
25. Chan R, Gochicoa-Rangel L, Cottini M, et al. Ascertainment of small airways dysfunction using oscillometry to better define asthma control and future risk: are we ready to implement it in clinical practice?. Chest, 2025, 167(5): 1287-1296.
26. Gong X, Sang L, Huang Y, et al. Impulse oscillometry for the detection of small airway dysfunction in patients with chronic respiratory symptoms, preserved ratio impaired spirometry and COPD. BMC Pulm Med, 2025, 25(1): 458.
27. Olin AC. Inclusion of small airway dysfunction in asthma assessment and management: a place for impulse oscillometry?. Lancet Respir Med. 2025 Nov;13(11): 955-956.
28. Lu L, Wu F, Tang G, et al. Associations of small airway dysfunction assessed by impulse oscillometry with lung function decline and exacerbations in participants with chronic obstructive pulmonary disease: a prospective cohort study in China. Respir Med, 2025, 241: 108075.
29. Athavale T, Athavale A. Comparison of forced oscillation technique, lung volumes by body plethysmography, and spirometry in moderate persistent adult asthma. J Assoc Physicians India, 2024, 72(5): 29-35.
30. Vasi ?, Karaduman ?, Alacao?lu ?, et al. Assessment of interstitial lung disease in systemic sclerosis using oscillometric methods: a novel approach to respiratory assessment. Rheumatology (Oxford), 2026, 65(1): keaf572.
31. Siebeneichler AS, Schumann DM, Karakioulaki M, et al. Single and multiple breath nitrogen washout compared with the methacholine test in patients with suspected asthma and normal spirometry. BMJ Open Respir Res, 2024, 11(1): e001919.
32. Verbanck S, Hanon S, Vandemeulebroucke J, et al. Structure-function in smokers: when a small airways test really reflects the small airways. J Appl Physiol (1985), 2024, 137(2): 343-348.
33. Kraft M, Richardson M, Hallmark B, et al. The role of small airway dysfunction in asthma control and exacerbations: a longitudinal, observational analysis using data from the ATLANTIS study. Lancet Respir Med, 2022, 10(7): 661-668.
34. Woodruff PG, Barr RG, Bleecker E, et al. Clinical significance of symptoms in smokers with preserved pulmonary function. N Engl J Med, 2016, 374(19): 1811-1821.
35. COPDGene 2025 Diagnosis Working Group and CanCOLD Investigators, Bhatt SP, Abadi E, et al. A multidimensional diagnostic approach for chronic obstructive pulmonary disease. JAMA, 2025, 333(24): 2164-2175.
36. Verleden SE, Hendriks JMH, Snoeckx A, et al. Small airway disease in pre-chronic obstructive pulmonary disease with emphysema: a cross-sectional study. Am J Respir Crit Care Med, 2024, 209(6): 683-692.
37. Lee BY, Han MK. Understanding early COPD. Respir Care, 2023, 68(7): 881-888.
38. Stanojevic S, Yung MH, Sahin B, et al. Association between e-cigarette exposure and ventilation homogeneity in young adults: a cross-sectional study. Eur Respir J, 2025, 65(3): 2401675.
39. Oppenheimer BW, Goldring RM, Herberg ME, et al. Distal airway function in symptomatic subjects with normal spirometry following World Trade Center dust exposure. Chest, 2007, 132(4): 1275-1282.
40. Wang Z, Ge J, Wang Y, et al. Assessing the impact of World Trade Center (WTC) exposures on post-bronchodilator lung function: insights from WTC survivor population. PLoS One, 2026, 21(3): e0344458.
41. Schneider C, Koenig C, ?arkovi? M, et al. Nitrogen single and multiple breath washout test and lung imaging to detect treatment-related pulmonary toxicity in paediatric cancer patients and survivors: a systematic review. Eur Respir Rev, 2025, 34(175): 240178.
42. 中國醫學裝備協會呼吸病學專委會吸入治療與呼吸康復學組. 穩定期慢性氣道疾病吸入裝置規范應用中國專家共識(2023 版). 中華結核和呼吸雜志, 2023, 46(11): 1055-1067.
43. Rigby D. Inhaler device selection for people with asthma or chronic obstructive pulmonary disease. Aust Prescr, 2024, 47(5): 140-147.
44. Usmani OS, Toumpanakis D, Meah S, et al. Whole lung directed anti-muscarinic therapy improves small airway dysfunction in COPD patients. Eur Respir J, 2026, 67(2): 2501326.
45. Carpagnano GE, Portacci A, Dragonieri S, et al. Managing small airway disease in patients with severe asthma: transitioning from the “silent zone” to achieving “quiet asthma”. J Clin Med, 2024, 13(8): 2320.
46. Afreen S, Waters M, Eapen MS, et al. Advances in biologic therapies for COPD: precision medicine approaches and implications for small-airway disease. Expert Rev Respir Med, 2026, 12: 1-18.
47. Usmani OS, Dhand R, Lavorini F, et al. Why we should target small airways disease in our management of chronic obstructive pulmonary disease. Mayo Clin Proc, 2021, 96(9): 2448-2463.
48. Gogali A, Kostikas K, Kyriakopoulos C, et al. Managing small airways dysfunction in COPD patients in real life under fixed triple combination of beclomethasone/formoterol/glycopyrronium: the MASCOT real world evidence study. Int J Chron Obstruct Pulmon Dis, 2025, 20: 1651-1663.
49. Usmani OS, Scichilone N, Mignot B, et al. Airway deposition of extrafine inhaled triple therapy in patients with COPD: a model approach based on functional respiratory imaging computer simulations. Int J Chron Obstruct Pulmon Dis, 2020, 15: 2433-2440.
50. Agache I, Adcock IM, Baraldi F, et al. Personalized therapeutic approaches for asthma. J Allergy Clin Immunol, 2025, 156(3): 503-522.
51. Kotsiou OS, Kirgou P, Siachpazidou D, et al. Early benefit of mepolizumab on small airways in severe asthma: insights from the IMPOSE study. ERJ Open Res, 2025, 11(3): 00939-2024.
52. Bonini M, Boccabella C, Cefaloni F, et al. Small airways disease as a novel target for mepolizumab in asthma-the SASAM prospective real-life study. J Clin Med, 2025, 14(9): 2928.
53. Hill DB, Button B, Rubinstein M, et al. Physiology and pathophysiology of human airway mucus. Physiol Rev, 2022, 102(4): 1757-1836.
54. Bradley JM, O’Neill B, McAuley DF, et al. Hypertonic saline or carbocisteine in bronchiectasis. N Engl J Med, 2025, 393(16): 1565-1577.
55. Nguyen N, Zawam Y, Tran NB, et al. Hypertonic saline in non-cystic fibrosis bronchiectasis (hyper-BRONCHI): an updated systematic review and meta-analysis. BMC Pulm Med, 2026, 26(1): 122.
56. Zhou Y, Wu F, Shi Z, et al. Effect of high-dose N-acetylcysteine on exacerbations and lung function in patients with mild-to-moderate COPD: a double-blind, parallel group, multicentre randomised clinical trial. Nat Commun, 2024, 15(1): 8468.

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