Effects of umeclidinium bromide in the management of small airway disease: a pilot study

Umeclidinium bromide is a long-acting muscarinic antagonist that selectively inhibits muscarinic receptors, preventing bronchoconstriction and promoting sustained bronchodilation. This study aimed to assess the bronchodilatory efficacy of umeclidinium bromide, specifically in terms of its impact on airflow limitation, exertional dyspnea, and indices of lung hyperinflation. We analyzed 50 patients (21 males, 29 females) with a mean age of 67.3±9.59 years, all presenting with a preserved Tiffenau Index [forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC): 74.49±2.58%] but reduced forced mid-expiratory flow [forced mid-expiratory flow (FEF_25-75): 37.85%±7.04%]. Patients exhibited an increased Motley Index ratio (135.24±9.78%), a mean FEV1 of 2.00±0.57 L, an FVC of 2.70±0.57 L, an airway resistance (Raw) of 225.52±56.66%, and a total lung capacity of 98.08±8.26%. Functional exercise capacity was evaluated using the 6-minute walking test (6MWT), with a mean distance of 308.48±31.91 m. Dyspnea severity was assessed using the modified Medical Research Council dyspnea scale (mMRC) (mean score: 1.80±0.73). Post-treatment assessments demonstrated a significant increase in FVC (p=0.04), FEF_25-75 (p<0.001), and a significant decrease in total airway resistance (p<0.001), along with a marked reduction in the Motley Index ratio (p<0.001). Patients exhibited an increase in the distance covered during the 6MWT (p<0.001) and a reduction in dyspnea severity, as reflected by improvements in the mMRC scale (p<0.001). Umeclidinium bromide was effective in mitigating lung hyperinflation, improving exercise capacity, and reducing dyspnea.

Prakash A, Babu KS, Morjaria JB. Novel anti-cholinergics in COPD. Drug Discov Today 2013;18:1117-26. DOI: https://doi.org/10.1016/j.drudis.2013.07.005

Koarai A, Ichinose M. Possible involvement of acetylcholine-mediated inflammation in airway diseases. Allergol Int 2018;67:460-6. DOI: https://doi.org/10.1016/j.alit.2018.02.008

Gosens R, Zaagsma J, Grootte Bromhaar M, et al. Acetylcholine: a novel regulator of airway smooth muscle remodelling?. Eur J Pharmacol 2004;500:193-201. DOI: https://doi.org/10.1016/j.ejphar.2004.07.025

Restrepo RD. Use of inhaled anticholinergic agents in obstructive airway disease. Respir Care 2007;52:833-51. DOI: https://doi.org/10.4187/respcare.07520833

Gosens R, Zaagsma J, Meurs H, Halayko AJ. Muscarinic receptor signaling in the pathophysiology of asthma and COPD. Respir Res 2006;7:73. DOI: https://doi.org/10.1186/1465-9921-7-73

Hogg JC, Paré PD, Hackett TL. The contribution of small airway obstruction to the pathogenesis of chronic obstructive pulmonary disease. Physiol Rev 2017;97:529-52. DOI: https://doi.org/10.1152/physrev.00025.2015

van der Wiel E, ten Hacken NH, Postma DS, van den Berge M. Small-airways dysfunction associates with respiratory symptoms and clinical features of asthma: a systematic review. J Allergy Clin Immunol 2013;131:646-57. DOI: https://doi.org/10.1016/j.jaci.2012.12.1567

Salmon M, Luttmann MA, Foley JJ, et al. Pharmacological characterization of GSK573719 (umeclidinium): a novel, long-acting, inhaled antagonist of the muscarinic cholinergic receptors for treatment of pulmonary diseases. J Pharmacol Exp Ther 2013;345:260-70. DOI: https://doi.org/10.1124/jpet.112.202051

McDonough JE, Yuan R, Suzuki M, et al. Small-airway obstruction and emphysema in chronic obstructive pulmonary disease. N Engl J Med 2011;365:1567-75. DOI: https://doi.org/10.1056/NEJMoa1106955

Crisafulli E, Pisi R, Aiello M, et al. Prevalence of small-airway dysfunction among copd patients with different GOLD stages and its role in the impact of disease. Respiration 2017;93:32-41. DOI: https://doi.org/10.1159/000452479

Frizzelli A, Nicolini G, Chetta A. Small airways: not just air ducts - pathophysiological aspects and clinical implications. Respiration 2022;101:953-8. DOI: https://doi.org/10.1159/000525666

Alfieri V, Aiello M, Pisi R, et al. Small airway dysfunction is associated to excessive bronchoconstriction in asthmatic patients. Respir Res 2014;15:86. DOI: https://doi.org/10.1186/s12931-014-0086-1

Graham BL, Steenbruggen I, Miller MR, et al. Standardization of spirometry 2019 update. An official American Thoracic Society and European Respiratory Society technical statement. Am J Respir Crit Care Med 2019;200:e70-88. DOI: https://doi.org/10.1164/rccm.201908-1590ST

ATS Committee on Proficiency Standards for Clinical Pulmonary Function Laboratories. ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med 2002;166:111-7. DOI: https://doi.org/10.1164/ajrccm.166.1.at1102

Gennimata SA, Palamidas A, Karakontaki F, et al. Pathophysiology of evolution of small airways disease to overt COPD. COPD 2010;7:269-75. DOI: https://doi.org/10.3109/15412555.2010.497515

Eltayara L, Becklake MR, Volta CA, Milic-Emili J. Relationship between chronic dyspnea and expiratory flow limitation in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1996;154:1726-34. DOI: https://doi.org/10.1164/ajrccm.154.6.8970362

Calverley PM, Koulouris NG. Flow limitation and dynamic hyperinflation: key concepts in modern respiratory physiology. Eur Respir J 2005;25:186-99. DOI: https://doi.org/10.1183/09031936.04.00113204

Deesomchok A, Webb KA, Forkert L, et al. Lung hyperinflation and its reversibility in patients with airway obstruction of varying severity. COPD 2010;7:428-37. DOI: https://doi.org/10.3109/15412555.2010.528087

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;132:1275-82. DOI: https://doi.org/10.1378/chest.07-0913

Manco A, Pisi R, Aiello M, et al. Small airway dysfunction predicts excess ventilation and dynamic hyperination during exercise in patients with COPD. Respir Med X 2020;100020. DOI: https://doi.org/10.1016/j.yrmex.2020.100020

Takeda T, Oga T, Niimi A, et al. Relationship between small airway function and health status, dyspnea and disease control in asthma. Respiration 2010;80:120-6. DOI: https://doi.org/10.1159/000242113

Babu KS, Morjaria JB. Umeclidinium in chronic obstructive pulmonary disease: latest evidence and place in therapy. Ther Adv Chronic Dis 2017;8:81-91. DOI: https://doi.org/10.1177/2040622317700822

Eglen RM, Hegde SS, Watson N. Muscarinic receptor subtypes and smooth muscle function. Pharmacol Rev 1996;48:531-65. DOI: https://doi.org/10.1016/S0031-6997(25)06957-1

Milic-Emili J. Does mechanical injury of the peripheral airways play a role in the genesis of COPD in smokers? COPD 2004;1:85-92. DOI: https://doi.org/10.1081/COPD-120028700

Petrone A, Fimognari FL, Mormile F, et al. The respiratory "overlap syndrome": efficacy and usefulness of the combined double bronchodilation. Respiration 2018;95:15-8. DOI: https://doi.org/10.1159/000487179

Corbin RP, Loveland M, Martin RR, Macklem PT. A four-year follow-up study of lung mechanics in smokers. Am Rev Respir Dis 1979;120:293-304.

Hernández Vázquez J, Ali García I, Jiménez-García R, et al. COPD phenotypes: differences in survival. Int J Chron Obstruct Pulmon Dis 2018;13:2245-51. DOI: https://doi.org/10.2147/COPD.S166163

Friedlander AL, Lynch D, Dyar LA, Bowler RP. Phenotypes of chronic obstructive pulmonary disease. COPD 2007;4:355-84. DOI: https://doi.org/10.1080/15412550701629663

Xiao D, Chen Z, Wu S, et al. Prevalence and risk factors of small airway dysfunction, and association with smoking, in China: findings from a national cross-sectional study. Lancet Respir Med 2020;8:1081-93. DOI: https://doi.org/10.1016/S2213-2600(20)30155-7

Wessler IK, Kirkpatrick CJ. The Non-neuronal cholinergic system: an emerging drug target in the airways. Pulm Pharmacol Ther 2001;14:423-34. DOI: https://doi.org/10.1006/pupt.2001.0313

Gwilt CR, Donnelly LE, Rogers DF. The non-neuronal cholinergic system in the airways: an unappreciated regulatory role in pulmonary inflammation? Pharmacol Ther 2007;115:208-22. DOI: https://doi.org/10.1016/j.pharmthera.2007.05.007

Wessler I, Kilbinger H, Bittinger F, et al. The non-neuronal cholinergic system in humans: expression, function and pathophysiology. Life Sci 2003;72:2055-61. DOI: https://doi.org/10.1016/S0024-3205(03)00083-3

Agusti A, Bel E, Thomas M, et al. Treatable traits: toward precision medicine of chronic airway diseases. Eur Respir J 2016;47:410-9. DOI: https://doi.org/10.1183/13993003.01359-2015

Petrone A, Pelaia C, Quartieri M, et al. Effectiveness of glycopyrronium bromide in the treatment of small airway dysfunction: a retrospective study. SAGE Open Med 2022;10:20503121221145605. DOI: https://doi.org/10.1177/20503121221145605

Postma DS, Brightling C, Baldi S, et al. Exploring the relevance and extent of small airways dysfunction in asthma (ATLANTIS): baseline data from a prospective cohort study. Lancet Respir Med 2019;7:402-16. DOI: https://doi.org/10.1016/S2213-2600(19)30049-9

Cooper CB, Dransfield M. Primary care of the patient with chronic obstructive pulmonary disease-part 4: understanding the clinical manifestations of a progressive disease. Am J Med 2008;121:S33-45. DOI: https://doi.org/10.1016/j.amjmed.2008.04.005