Chronic bronchitis and chronic obstructive pulmonary disease

Victor Kim, Gerard J Criner, Victor Kim, Gerard J Criner

Abstract

Chronic bronchitis (CB) is a common but variable phenomenon in chronic obstructive pulmonary disease (COPD). It has numerous clinical consequences, including an accelerated decline in lung function, greater risk of the development of airflow obstruction in smokers, a predisposition to lower respiratory tract infection, higher exacerbation frequency, and worse overall mortality. CB is caused by overproduction and hypersecretion of mucus by goblet cells, which leads to worsening airflow obstruction by luminal obstruction of small airways, epithelial remodeling, and alteration of airway surface tension predisposing to collapse. Despite its clinical sequelae, little is known about the pathophysiology of CB and goblet cell hyperplasia in COPD, and treatment options are limited. In addition, it is becoming increasingly apparent that in the classic COPD spectrum, with emphysema on one end and CB on the other, most patients lie somewhere in the middle. It is known now that many patients with severe emphysema can develop CB, and small airway pathology has been linked to worse clinical outcomes, such as increased mortality and lesser improvement in lung function after lung volume reduction surgery. However, in recent years, a greater understanding of the importance of CB as a phenotype to identify patients with a beneficial response to therapy has been described. Herein we review the epidemiology of CB, the evidence behind its clinical consequences, the current understanding of the pathophysiology of goblet cell hyperplasia in COPD, and current therapies for CB.

Figures

Figure 1.
Figure 1.
Causes of excessive mucus in chronic obstructive pulmonary disease. PEF = peak expiratory flow.
Figure 2.
Figure 2.
Periodic acid fluorescent Schiff stain of a small airway from a patient with advanced emphysema. The entire airway is seen at ×10 magnification in A and a quadrant of the airway at ×40 in B. Mucin granules are shown in red along the apical border of the epithelium. Note the large intraluminal mucin plug (M) in A, also noted in B (white arrow). Reprinted by permission from Reference 120.

References

    1. Mathers CD, Bernard C, Iburg KM, Inoue M, Fat DM, Shibuya K, Stein C, Tomijima N, Xu H. Global Burden of Disease in 2002: data sources, methods and results. Geneva, Switzerland: World Health Organization; 2003. Global Programme on Evidence for Health Policy Discussion Paper No. 54.
    1. National Heart Lung and Blood Institute, National Institutes of Health. Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines, global strategy for the diagnosis, management and prevention of chronic obstructive lung disease: NHLBI/WHO workshop report. Bethesda, MD: NIH; 2001. NIH publication 2701.
    1. Vestbo J, Prescott E, Lange P. Association of chronic mucus hypersecretion with FEV1 decline and chronic obstructive pulmonary disease morbidity. Copenhagen City Heart Study Group. Am J Respir Crit Care Med 1996;153:1530–1535.
    1. Burgel PR, Nesme-Meyer P, Chanez P, Caillaud D, Carre P, Perez T, Roche N, Initiatives Bronchopneumopathie Chronique Obstructive Scientific Committee. Cough and sputum production are associated with frequent exacerbations and hospitalizations in COPD subjects. Chest 2009;135:975–982.
    1. Guerra S, Sherrill DL, Venker C, Ceccato CM, Halonen M, Martinez FD. Chronic bronchitis before age 50 years predicts incident airflow limitation and mortality risk. Thorax 2009;64:894–900.
    1. Kim V, Han MK, Vance GB, Make BJ, Newell JD, Hokanson JE, Hersh CP, Stinson D, Silverman EK, Criner GJ; The COPDGene Investigators. The chronic bronchitic phenotype of COPD: an analysis of the COPDGene study. Chest 2011;140:626–633.
    1. Lange P, Groth S, Nyboe J, Appleyard M, Mortensen J, Jensen G, Schnohr P. Chronic obstructive lung disease in Copenhagen: cross-sectional epidemiological aspects. J Intern Med 1989;226:25–32.
    1. Pallasaho P, Lundback B, Laspa SL, Jonsson E, Kotaniemi J, Sovijarvi AR, Laitinen LA. Increasing prevalence of asthma but not of chronic bronchitis in Finland? Report from the FinEsS-Helsinki Study. Respir Med 1999;93:798–809.
    1. Sobradillo V, Miravitlles M, Jimenez CA, Gabriel R, Viejo JL, Masa JF, Fernandez-Fau L, Villasante C. Epidemiological study of chronic obstructive pulmonary disease in Spain (IBERPOC): prevalence of chronic respiratory symptoms and airflow limitation. Arch Bronconeumol 1999;35:159–166.
    1. von Hertzen L, Reunanen A, Impivaara O, Malkia E, Aromaa A. Airway obstruction in relation to symptoms in chronic respiratory disease–a nationally representative population study. Respir Med 2000;94:356–363.
    1. Cerveri I, Accordini S, Verlato G, Corsico A, Zoia MC, Casali L, Burney P, de Marco R; European Community Respiratory Health Survey (ECRHS) Study Group. Variations in the prevalence across countries of chronic bronchitis and smoking habits in young adults. Eur Respir J 2001;18:85–92.
    1. Janson C, Chinn S, Jarvis D, Burney P. Determinants of cough in young adults participating in the European Community Respiratory Health Survey. Eur Respir J 2001;18:647–654.
    1. Huchon GJ, Vergnenegre A, Neukirch F, Brami G, Roche N, Preux PM. Chronic bronchitis among French adults: high prevalence and underdiagnosis. Eur Respir J 2002;20:806–812.
    1. Lundback B, Lindberg A, Lindstrom M, Ronmark E, Jonsson AC, Jonsson E, Larsson LG, Andersson S, Sandstrom T, Larsson K. Obstructive Lung Disease in Northern Sweden Studies. Not 15 but 50% of smokers develop COPD?–Report from the Obstructive Lung Disease in Northern Sweden Studies. Respir Med 2003;97:115–122.
    1. Miravitlles M, de la Roza C, Morera J, Montemayor T, Gobartt E, Martin A, Alvarez-Sala JL. Chronic respiratory symptoms, spirometry and knowledge of COPD among general population. Respir Med 2006;100:1973–1980.
    1. de Marco R, Accordini S, Cerveri I, Corsico A, Anto JM, Kunzli N, Janson C, Sunyer J, Jarvis D, Chinn S, et al. . Incidence of chronic obstructive pulmonary disease in a cohort of young adults according to the presence of chronic cough and phlegm. Am J Respir Crit Care Med 2007;175:32–39.
    1. Miravitlles M, Soriano JB, Garcia-Rio F, Munoz L, Duran-Tauleria E, Sanchez G, Sobradillo V, Ancochea J. Prevalence of COPD in Spain: impact of undiagnosed COPD on quality of life and daily life activities. Thorax 2009;64:863–868.
    1. Harmsen L, Thomsen SF, Ingebrigtsen T, Steffensen IE, Skadhauge LR, Kyvik KO, Backer V. Chronic mucus hypersecretion: prevalence and risk factors in younger individuals. Int J Tuberc Lung Dis 2010;14:1052–1058.
    1. Martinez C, Chen Y, Kazerooni E, Murray S, Criner GJ, Curtis JL, Martinez FJ, Kim V, Han MK. Non-obstructive chronic bronchitis in the COPDGene cohort [abstract]. Am J Respir Crit Care Med 2012;185:A6622.
    1. Agusti A, Calverley PM, Celli B, Coxson HO, Edwards LD, Lomas DA, MacNee W, Miller BE, Rennard S, Silverman EK, et al. , Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) investigators. Characterisation of COPD heterogeneity in the ECLIPSE cohort. Respir Res 2010;11:122.
    1. de Oca MM, Halbert RJ, Lopez MV, Perez-Padilla R, Talamo C, Moreno D, Muino A, Jardim JR, Valdivia G, Pertuze J, et al. . The chronic bronchitis phenotype in subjects with and without COPD: the PLATINO study. Eur Respir J 2012;40:28–36.
    1. Pelkonen M, Notkola IL, Nissinen A, Tukiainen H, Koskela H. Thirty-year cumulative incidence of chronic bronchitis and COPD in relation to 30-year pulmonary function and 40-year mortality: a follow-up in middle-aged rural men. Chest 2006;130:1129–1137.
    1. American Lung Association. Trends in COPD (chronic bronchitis and emphysema): morbidity and mortality. Washington, DC: Research and Program Services Division, Epidemiology and Statistics Unit, Americal Lung Association; 2011.
    1. Speizer FE, Fay ME, Dockery DW, Ferris BG. Chronic obstructive pulmonary disease mortality in six US cities. Am Rev Respir Dis 1989;140:S49–S55.
    1. Lu M, Yao W, Zhong N, Zhou Y, Wang C, Chen P, Kang J, Huang S, Chen B, Wang C, et al. . Chronic obstructive pulmonary disease in the absence of chronic bronchitis in China. Respirology 2010;15:1072–1078.
    1. Han MK, Kim V, Martinez C, Curtis JL, Woodruff PG, Albert RK, Connett J, Criner GJ, Martinez FJ. Significance of chronic bronchitis in the COPD CRN Azithromycin in COPD Study [abstract]. Am J Respir Crit Care Med 2012;185:A3736.
    1. Ehrlich RI, White N, Norman R, Laubscher R, Steyn K, Lombard C, Bradshaw D. Predictors of chronic bronchitis in South African adults. Int J Tuberc Lung Dis 2004;8:369–376.
    1. Watson L, Schouten JP, Lofdahl CG, Pride NB, Laitinen LA, Postma DS; European Respiratory Society Study on Chronic Obstructive Pulmonary Disease. Predictors of COPD symptoms: does the sex of the patient matter? Eur Respir J 2006;28:311–318.
    1. Chapman KR, Tashkin DP, Pye DJ. Gender bias in the diagnosis of COPD. 2001;119:1691–1695.
    1. Trupin L, Earnest G, San Pedro M, Balmes JR, Eisner MD, Yelin E, Katz PP, Blanc PD. The occupational burden of chronic obstructive pulmonary disease. Eur Respir J 2003;22:462–469.
    1. Matheson MC, Benke G, Raven J, Sim MR, Kromhout H, Vermeulen R, Johns DP, Walters EH, Abramson MJ. Biological dust exposure in the workplace is a risk factor for chronic obstructive pulmonary disease. Thorax 2005;60:645–651.
    1. Barish CF, Wu WC, Castell DO. Respiratory complications of gastroesophageal reflux. Arch Intern Med 1985;145:1882–1888.
    1. Smyrnios NA, Irwin RS, Curley FJ. Chronic cough with a history of excessive sputum production. The spectrum and frequency of causes, key components of the diagnostic evaluation, and outcome of specific therapy. Chest 1995;108:991–997.
    1. Ebert RV, Terracio MJ. The bronchiolar epithelium in cigarette smokers. Observations with the scanning electron microscope. Am Rev Respir Dis 1975;111:4–11.
    1. Deshmukh HS, Case LM, Wesselkamper SC, Borchers MT, Martin LD, Shertzer HG, Nadel JA, Leikauf GD. Metalloproteinases mediate mucin 5AC expression by epidermal growth factor receptor activation. Am J Respir Crit Care Med 2005;171:305–314.
    1. Holtzman MJ, Tyner JW, Kim EY, Lo MS, Patel AC, Shornick LP, Agapov E, Zhang Y. Acute and chronic airway responses to viral infection: implications for asthma and chronic obstructive pulmonary disease. Proc Am Thorac Soc 2005;2:132–140.
    1. Burgel PR, Nadel JA. Roles of epidermal growth factor receptor activation in epithelial cell repair and mucin production in airway epithelium. Thorax 2004;59:992–996.
    1. Hogg JC, Chu F, Utokaparch S, Woods R, Elliott WM, Buzatu L, Cherniack RM, Rogers RM, Sciurba FC, Coxson HO, et al. . The nature of small-airway obstruction in chronic obstructive pulmonary disease. N Engl J Med 2004;350:2645–2653.
    1. Verra F, Escudier E, Lebargy F, Bernaudin JF, De Cremoux H, Bignon J. Ciliary abnormalities in bronchial epithelium of smokers, ex-smokers, and nonsmokers. Am J Respir Crit Care Med 1995;151:630–634.
    1. Innes AL, Woodruff PG, Ferrando RE, Donnelly S, Dolganov GM, Lazarus SC, Fahy JV. Epithelial mucin stores are increased in the large airways of smokers with airflow obstruction. Chest 2006;130:1102–1108.
    1. Saetta M, Turato G, Baraldo S, Zanin A, Braccioni F, Mapp CE, Maestrelli P, Cavallesco G, Papi A, Fabbri LM. Goblet cell hyperplasia and epithelial inflammation in peripheral airways of smokers with both symptoms of chronic bronchitis and chronic airflow limitation. Am J Respir Crit Care Med 2000;161:1016–1021.
    1. Kim V, Kelemen SE, Abuel-Haija M, Gaughan J, Sharafkhaneh A, Evans CM, Dickey BF, Solomides CC, Rogers TJ, Criner GJ. Small airway mucous metaplasia and inflammation in chronic obstructive pulmonary disease. COPD 2008;5:329–338.
    1. James AL, Wenzel S. Clinical relevance of airway remodelling in airway diseases. Eur Respir J 2007;30:134–155.
    1. Macklem PT, Proctor DF, Hogg JC. The stability of peripheral airways. Respir Physiol 1970;8:191–203.
    1. Kim V, Criner GJ, Abdallah HY, Gaughan JP, Furukawa S, Solomides CC. Small airway morphometry and improvement in pulmonary function after lung volume reduction surgery. Am J Respir Crit Care Med 2005;171:40–47.
    1. Sciurba F, Martinez FJ, Rogers RM, Make B, Criner GJ, Cherniak RM, Patel SA, Chu F, Coxson HO, Sharafkhaneh A, et al. . The effect of small airway pathology on survival following lung volume reduction surgery (LVRS) [abstract]. Proc Am Thorac Soc 2006;3:A712.
    1. O'Donnell RA, Richter A, Ward J, Angco G, Mehta A, Rousseau K, Swallow DM, Holgate ST, Djukanovic R, Davies DE, et al. . Expression of ErbB receptors and mucins in the airways of long term current smokers. Thorax 2004;59:1032–1040.
    1. Reid LM. Pathology of chronic bronchitis. Lancet 1954;266:274–278.
    1. Mullen JB, Wright JL, Wiggs BR, Pare PD, Hogg JC. Reassessment of inflammation of airways in chronic bronchitis. Br Med J (Clin Res Ed) 1985;291:1235–1239.
    1. Kim WD, Ling SH, Coxson HO, English JC, Yee J, Levy RD, Pare PD, Hogg JC. The association between small airway obstruction and emphysema phenotypes in COPD. Chest 2007;131:1372–1378.
    1. Zhu Z, Homer RJ, Wang Z, Chen Q, Geba GP, Wang J, Zhang Y, Elias JA. Pulmonary expression of interleukin-13 causes inflammation, mucus hypersecretion, subepithelial fibrosis, physiologic abnormalities, and eotaxin production. J Clin Invest 1999;103:779–788.
    1. Romagnani S. T-cell subsets (Th1 versus Th2). Ann Allergy Asthma Immunol 2000;85:9–18; quiz 18, 21.
    1. Kikly K, Liu L, Na S, Sedgwick JD. The IL-23/Th(17) axis: therapeutic targets for autoimmune inflammation. Curr Opin Immunol 2006;18:670–675.
    1. Molet S, Hamid Q, Davoine F, Nutku E, Taha R, Page N, Olivenstein R, Elias J, Chakir J. IL-17 is increased in asthmatic airways and induces human bronchial fibroblasts to produce cytokines. J Allergy Clin Immunol 2001;108:430–438.
    1. Chen Y, Thai P, Zhao YH, Ho YS, DeSouza MM, Wu R. Stimulation of airway mucin gene expression by interleukin (IL)-17 through IL-6 paracrine/autocrine loop. J Biol Chem 2003;278:17036–17043.
    1. Bhowmik A, Seemungal TA, Sapsford RJ, Wedzicha JA. Relation of sputum inflammatory markers to symptoms and lung function changes in COPD exacerbations. Thorax 2000;55:114–120.
    1. Sherman CB, Xu X, Speizer FE, Ferris BG, Weiss ST, Dockery DW. Longitudinal lung function decline in subjects with respiratory symptoms. Am Rev Respir Dis 1992;146:855–859.
    1. Lange P, Nyboe J, Appleyard M, Jensen G, Schnohr P. Relation of ventilatory impairment and of chronic mucus hypersecretion to mortality from obstructive lung disease and from all causes. Thorax 1990;45:579–585.
    1. Vestbo J. Epidemiological studies in mucus hypersecretion. Novartis Found Symp 2002;248:3–12; discussion 12–9, 277–282.
    1. Di Stefano A, Caramori G, Gnemmi I, Contoli M, Vicari C, Capelli A, Magno F, D’Anna SE, Zanini A, Brun P, et al. . T helper type 17-related cytokine expression is increased in the bronchial mucosa of stable chronic obstructive pulmonary disease patients. Clin Exp Immunol 2009;157:316–324.
    1. Lindberg A, Eriksson B, Larsson LG, Ronmark E, Sandstrom T, Lundback B. Seven-year cumulative incidence of COPD in an age-stratified general population sample. Chest 2006;129:879–885.
    1. Kohansal R, Martinez-Camblor P, Agusti A, Buist AS, Mannino DM, Soriano JB. The natural history of chronic airflow obstruction revisited: an analysis of the Framingham offspring cohort. Am J Respir Crit Care Med 2009;180:3–10.
    1. Prescott E, Lange P, Vestbo J. Chronic mucus hypersecretion in COPD and death from pulmonary infection. Eur Respir J 1995;8:1333–1338.
    1. Kim V, Gaughan JP, Desai P, Washko GR, Make BJ, Han MK, Martinez FJ, Criner GJ. Chronic bronchitis is associated with worse survival in advanced emphysema [abstract]. Am J Respir Crit Care Med 2012;185:A1529.
    1. Mannino DM, Buist AS, Petty TL, Enright PL, Redd SC. Lung function and mortality in the United States: data from the First National Health and Nutrition Examination Survey follow up study. Thorax 2003;58:388–393.
    1. Tockman MS, Comstock GW. Respiratory risk factors and mortality: longitudinal studies in Washington County, Maryland. Am Rev Respir Dis 1989;140:S56–S63.
    1. Seemungal TA, Donaldson GC, Bhowmik A, Jeffries DJ, Wedzicha JA. Time course and recovery of exacerbations in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2000;161:1608–1613.
    1. Kim V, Make BJ, Reagan EA, Han MK, Martinez FJ, Bowler R, Silverman EK, Crapo JD, Rogers TJ, Criner GJ, et al. . Chronic bronchitis predicts greater frequency and severity of COPD exacerbations in moderate to severe COPD [abstract]. Am J Respir Crit Care Med 2012;185:A3735.
    1. Kim V, Garfield JL, Grabianowski CL, Krahnke JS, Gaughan JP, Jacobs MR, Criner GJ. The effect of chronic sputum production on respiratory symptoms in severe COPD. COPD 2011;8:114–120.
    1. Mullen JB, Wright JL, Wiggs BR, Pare PD, Hogg JC. Structure of central airways in current smokers and ex-smokers with and without mucus hypersecretion: relationship to lung function. Thorax 1987;42:843–848.
    1. Swan GE, Hodgkin JE, Roby T, Mittman C, Jacobo N, Peters J. Reversibility of airways injury over a 12-month period following smoking cessation. Chest 1992;101:607–612.
    1. van der Schans CP. Conventional chest physical therapy for obstructive lung disease. Respir Care 2007;52:1198–1206, discussion 1206–1209.
    1. Rubin BK. Mucolytics, expectorants, and mucokinetic medications. Respir Care 2007;52:859–865.
    1. Thomson ML, Pavia D, McNicol MW. A preliminary study of the effect of guaiphenesin on mucociliary clearance from the human lung. Thorax 1973;28:742–747.
    1. Levin MH, Sullivan S, Nielson D, Yang B, Finkbeiner WE, Verkman AS. Hypertonic saline therapy in cystic fibrosis: evidence against the proposed mechanism involving aquaporins. J Biol Chem 2006;281:25803–25812.
    1. Boucher RC. Cystic fibrosis: a disease of vulnerability to airway surface dehydration. Trends Mol Med 2007;13:231–240.
    1. Valderramas SR, Atallah AN. Effectiveness and safety of hypertonic saline inhalation combined with exercise training in patients with chronic obstructive pulmonary disease: a randomized trial. Respir Care 2009;54:327–333.
    1. Fahy JV, Steiger DJ, Liu J, Basbaum CB, Finkbeiner WE, Boushey HA. Markers of mucus secretion and DNA levels in induced sputum from asthmatic and from healthy subjects. Am Rev Respir Dis 1993;147:1132–1137.
    1. O’Donnell AE, Barker AF, Ilowite JS, Fick RB. Treatment of idiopathic bronchiectasis with aerosolized recombinant human DNase I. rhDNase Study Group. Chest 1998;113:1329–1334.
    1. Tamaoki J, Kondo M, Takizawa T. Effect of cAMP on ciliary function in rabbit tracheal epithelial cells. J Appl Physiol 1989;66:1035–1039.
    1. Devalia JL, Sapsford RJ, Rusznak C, Toumbis MJ, Davies RJ. The effects of salmeterol and salbutamol on ciliary beat frequency of cultured human bronchial epithelial cells, in vitro. Pulm Pharmacol 1992;5:257–263.
    1. Salathe M. Effects of beta-agonists on airway epithelial cells. J Allergy Clin Immunol 2002;110:S275–S281.
    1. Nguyen LP, Omoluabi O, Parra S, Frieske JM, Clement C, Ammar-Aouchiche Z, Ho SB, Ehre C, Kesimer M, Knoll BJ, et al. . Chronic exposure to beta-blockers attenuates inflammation and mucin content in a murine asthma model. Am J Respir Cell Mol Biol 2008;38:256–262.
    1. Nguyen LP, Lin R, Parra S, Omoluabi O, Hanania NA, Tuvim MJ, Knoll BJ, Dickey BF, Bond RA. Beta2-adrenoceptor signaling is required for the development of an asthma phenotype in a murine model. Proc Natl Acad Sci USA 2009;106:2435–2440.
    1. Wanner A. Effects of methylxanthines on airway mucociliary function. Am J Med 1985;79:16–21.
    1. Anderson G, Peel ET, Pardoe T, Jones R. Sustained-release theophylline in chronic bronchitis. Br J Dis Chest 1982;76:261–265.
    1. Taylor DR, Buick B, Kinney C, Lowry RC, McDevitt DG. The efficacy of orally administered theophylline, inhaled salbutamol, and a combination of the two as chronic therapy in the management of chronic bronchitis with reversible air-flow obstruction. Am Rev Respir Dis 1985;131:747–751.
    1. Foster WM, Langenback EG, Bergofsky EH. Lung mucociliary function in man: interdependence of bronchial and tracheal mucus transport velocities with lung clearance in bronchial asthma and healthy subjects. Ann Occup Hyg 1982;26:227–244.
    1. Jones PW, Bosh TK. Quality of life changes in COPD patients treated with salmeterol. Am J Respir Crit Care Med 1997;155:1283–1289.
    1. Mahler DA, Donohue JF, Barbee RA, Goldman MD, Gross NJ, Wisniewski ME, Yancey SW, Zakes BA, Rickard KA, Anderson WH. Efficacy of salmeterol xinafoate in the treatment of COPD. Chest 1999;115:957–965.
    1. van Noord JA, Aumann JL, Janssens E, Verhaert J, Smeets JJ, Mueller A, Cornelissen PJ. Effects of tiotropium with and without formoterol on airflow obstruction and resting hyperinflation in patients with COPD. Chest 2006;129:509–517.
    1. Melloni B, Germouty J. The influence of a new beta agonist: formoterol on mucociliary function. Rev Mal Respir 1992;9:503–507.
    1. Wine JJ, Joo NS. Submucosal glands and airway defense. Proc Am Thorac Soc 2004;1:47–53.
    1. Kummer W, Lips KS, Pfeil U. The epithelial cholinergic system of the airways. Histochem Cell Biol 2008;130:219–234.
    1. Bateman ED, Rennard S, Barnes PJ, Dicpinigaitis PV, Gosens R, Gross NJ, Nadel JA, Pfeifer M, Racke K, Rabe KF, et al. . Alternative mechanisms for tiotropium. Pulm Pharmacol Ther 2009;22:533–542.
    1. Ghafouri MA, Patil KD, Kass I. Sputum changes associated with the use of ipratropium bromide. Chest 1984;86:387–393.
    1. Bennett WD, Chapman WF, Mascarella JM. The acute effect of ipratropium bromide bronchodilator therapy on cough clearance in COPD. Chest 1993;103:488–495.
    1. Casaburi R, Briggs DD, Donohue JF, Serby CW, Menjoge SS, Witek TJ. The spirometric efficacy of once-daily dosing with tiotropium in stable COPD: a 13-week multicenter trial. The US Tiotropium Study Group. Chest 2000;118:1294–1302.
    1. Hasani A, Toms N, Agnew JE, Sarno M, Harrison AJ, Dilworth P. The effect of inhaled tiotropium bromide on lung mucociliary clearance in patients with COPD. Chest 2004;125:1726–1734.
    1. Hattotuwa KL, Gizycki MJ, Ansari TW, Jeffery PK, Barnes NC. The effects of inhaled fluticasone on airway inflammation in chronic obstructive pulmonary disease: a double-blind, placebo-controlled biopsy study. Am J Respir Crit Care Med 2002;165:1592–1596.
    1. Innes AL, Carrington SD, Thornton DJ, Kirkham S, Rousseau K, Dougherty RH, Raymond WW, Caughey GH, Muller SJ, Fahy JV. Ex vivo sputum analysis reveals impairment of protease-dependent mucus degradation by plasma proteins in acute asthma. Am J Respir Crit Care Med 2009;180:203–210.
    1. Leung SY, Eynott P, Nath P, Chung KF. Effects of ciclesonide and fluticasone propionate on allergen-induced airway inflammation and remodeling features. J Allergy Clin Immunol 2005;115:989–996.
    1. Chen Y, Nickola TJ, DiFronzo NL, Colberg-Poley AM, Rose MC. Dexamethasone-mediated repression of MUC5AC gene expression in human lung epithelial cells. Am J Respir Cell Mol Biol 2006;34:338–347.
    1. O’Riordan TG, Mao Y, Otero R, Lopez J, Sabater JR, Abraham WM. Budesonide affects allergic mucociliary dysfunction. J Appl Physiol 1998;85:1086–1091.
    1. Burge PS, Calverley PM, Jones PW, Spencer S, Anderson JA, Maslen TK. Randomised, double blind, placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial. BMJ 2000;320:1297–1303.
    1. Calverley P, Pauwels R, Vestbo J, Jones P, Pride N, Gulsvik A, Anderson J, Maden C. TRial of Inhaled STeroids ANd long-acting beta2 agonists study group. Combined salmeterol and fluticasone in the treatment of chronic obstructive pulmonary disease: a randomised controlled trial. Lancet 2003;361:449–456.
    1. Szafranski W, Cukier A, Ramirez A, Menga G, Sansores R, Nahabedian S, Peterson S, Olsson H. Efficacy and safety of budesonide/formoterol in the management of chronic obstructive pulmonary disease. Eur Respir J 2003;21:74–81.
    1. Chong J, Poole P, Leung B, Black PN. Phosphodiesterase 4 inhibitors for chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2011; (5):CD002309.
    1. Calverley PM, Rabe KF, Goehring UM, Kristiansen S, Fabbri LM, Martinez FJ. M2–124 and M2–125 study groups. Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials. Lancet 2009;374:685–694.
    1. Fabbri LM, Calverley PM, Izquierdo-Alonso JL, Bundschuh DS, Brose M, Martinez FJ, Rabe KF. M2–127 and M2–128 study groups. Roflumilast in moderate-to-severe chronic obstructive pulmonary disease treated with longacting bronchodilators: two randomised clinical trials. Lancet 2009;374:695–703.
    1. MacNee W. Oxidants/antioxidants and COPD. Chest 2000;117:303S–317S.
    1. Ishibashi Y, Takayama G, Inouye Y, Taniguchi A. Carbocisteine normalizes the viscous property of mucus through regulation of fucosylated and sialylated sugar chain on airway mucins. Eur J Pharmacol 2010;641:226–228.
    1. Decramer M, Rutten-van Molken M, Dekhuijzen PN, Troosters T, van Herwaarden C, Pellegrino R, van Schayck CP, Olivieri D, Del Donno M, De Backer W, et al. . Effects of N-acetylcysteine on outcomes in chronic obstructive pulmonary disease (Bronchitis Randomized on NAC Cost-Utility Study, BRONCUS): a randomised placebo-controlled trial. Lancet 2005;365:1552–1560.
    1. Zheng JP, Kang J, Huang SG, Chen P, Yao WZ, Yang L, Bai CX, Wang CZ, Wang C, Chen BY, et al. . Effect of carbocisteine on acute exacerbation of chronic obstructive pulmonary disease (PEACE Study): a randomised placebo-controlled study. Lancet 2008;371:2013–2018.
    1. Poole P, Black PN. Mucolytic agents for chronic bronchitis or chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2010; (2):CD001287.
    1. Gotfried MH. Macrolides for the treatment of chronic sinusitis, asthma, and COPD. Chest 2004;125:52S–60S; quiz 60S–61S.
    1. Seemungal TA, Wilkinson TM, Hurst JR, Perera WR, Sapsford RJ, Wedzicha JA. Long-term erythromycin therapy is associated with decreased chronic obstructive pulmonary disease exacerbations. Am J Respir Crit Care Med 2008;178:1139–1147.
    1. Albert RK, Connett J, Bailey WC, Casaburi R, Cooper JA, Criner GJ, Curtis JL, Dransfield MT, Han MK, Lazarus SC, et al. , COPD Clinical Research Network. Azithromycin for prevention of exacerbations of COPD. N Engl J Med 2011;365:689–698.
    1. Miravitlles M. Cough and sputum production as risk factors for poor outcomes in patients with COPD. Respir Med 2011;105:1118–1128.
    1. Kim V, Rogers TJ, Criner GJ. New concepts in the pathobiology of chronic obstructive pulmonary disease. Proc Am Thor Soc 2008;5:478–485.
    1. Annesi I, Kauffmann F. Is respiratory mucus hypersecretion really an innocent disorder? A 22-year mortality survey of 1,061 working men. Am Rev Respir Dis 1986;134:688–693.
    1. Burgel PR. Chronic cough and sputum production: a clinical COPD phenotype? Eur Respir J 2012;40:4–6.

Source: PubMed

3
Abonnere