Unraveling the Pathophysiology of the Asthma-COPD Overlap Syndrome
2015; Elsevier BV; Volume: 148; Issue: 2 Linguagem: Inglês
10.1378/chest.14-2483
ISSN1931-3543
AutoresArthur F. Gelb, Alfred Yamamoto, Eric Verbeken, Jay A. Nadel,
Tópico(s)Respiratory and Cough-Related Research
ResumoInvestigators believe most patients with asthma have reversible airflow obstruction with treatment, despite airway remodeling and hyperresponsiveness. There are smokers with chronic expiratory airflow obstruction despite treatment who have features of both asthma and COPD. Some investigators refer to this conundrum as the asthma-COPD overlap syndrome (ACOS). Furthermore, a subset of treated nonsmokers with moderate to severe asthma have persistent expiratory airflow limitation, despite partial reversibility. This residuum has been assumed to be due to large and especially small airway remodeling. Alternatively, we and others have described reversible loss of lung elastic recoil in acute and persistent loss in patients with moderate to severe chronic asthma who never smoked and its adverse effect on maximal expiratory airflow. The mechanism(s) responsible for loss of lung elastic recoil and persistent expiratory airflow limitation in nonsmokers with chronic asthma consistent with ACOS remain unknown in the absence of structure-function studies. Recently we reported a new pathophysiologic observation in 10 treated never smokers with asthma with persistent expiratory airflow obstruction, despite partial reversibility: All 10 patients with asthma had a significant decrease in lung elastic recoil, and unsuspected, microscopic mild centrilobular emphysema was noted in all three autopsies obtained although it was not easily identified on lung CT scan. These sentinel pathophysiologic observations need to be confirmed to further unravel the epiphenomenon of ACOS. The proinflammatory and proteolytic mechanism(s) leading to lung tissue breakdown need to be further investigated. Investigators believe most patients with asthma have reversible airflow obstruction with treatment, despite airway remodeling and hyperresponsiveness. There are smokers with chronic expiratory airflow obstruction despite treatment who have features of both asthma and COPD. Some investigators refer to this conundrum as the asthma-COPD overlap syndrome (ACOS). Furthermore, a subset of treated nonsmokers with moderate to severe asthma have persistent expiratory airflow limitation, despite partial reversibility. This residuum has been assumed to be due to large and especially small airway remodeling. Alternatively, we and others have described reversible loss of lung elastic recoil in acute and persistent loss in patients with moderate to severe chronic asthma who never smoked and its adverse effect on maximal expiratory airflow. The mechanism(s) responsible for loss of lung elastic recoil and persistent expiratory airflow limitation in nonsmokers with chronic asthma consistent with ACOS remain unknown in the absence of structure-function studies. Recently we reported a new pathophysiologic observation in 10 treated never smokers with asthma with persistent expiratory airflow obstruction, despite partial reversibility: All 10 patients with asthma had a significant decrease in lung elastic recoil, and unsuspected, microscopic mild centrilobular emphysema was noted in all three autopsies obtained although it was not easily identified on lung CT scan. These sentinel pathophysiologic observations need to be confirmed to further unravel the epiphenomenon of ACOS. The proinflammatory and proteolytic mechanism(s) leading to lung tissue breakdown need to be further investigated. There are some former or current smoking patients with chronic expiratory airflow obstruction despite therapeutic intervention who have features of both asthma and COPD.1Silva GE Sherrill DL Guerra S et al.Asthma as a risk factor for COPD in a longitudinal study.Chest. 2004; 126: 59-65Abstract Full Text Full Text PDF PubMed Scopus (275) Google Scholar, 2Carolan BJ Sutherland ER Clinical phenotypes of chronic obstructive pulmonary disease and asthma: recent advances.J Allergy Clin Immunol. 2013; 131: 627-634Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar, 3Belsky DW Sears MR The potential to predict the course of childhood asthma.Expert Rev Respir Med. 2014; 8: 137-141Crossref PubMed Scopus (14) Google Scholar, 4Tai A Tran H Roberts M Clarke N Wilson J Robertson CF The association between childhood asthma and adult chronic obstructive pulmonary disease.Thorax. 2014; 69: 805-810Crossref PubMed Scopus (214) Google Scholar, 5Mattes J Gibson PG The early origins of COPD in severe asthma: the one thing that leads to another or the two things that come together?.Thorax. 2014; 69: 789-790Crossref PubMed Scopus (10) Google Scholar This conundrum has been labeled the asthma-COPD overlap syndrome (ACOS).5Mattes J Gibson PG The early origins of COPD in severe asthma: the one thing that leads to another or the two things that come together?.Thorax. 2014; 69: 789-790Crossref PubMed Scopus (10) Google Scholar, 6Gibson PG McDonald VM Asthma-COPD overlap 2015: now we are six.Thorax. 2015; 70: 683-691Crossref PubMed Scopus (155) Google Scholar, 7Vanfleteren LE Kocks JW Stone IS et al.Moving from the Oslerian paradigm to the post-genomic era: are asthma and COPD outdated terms?.Thorax. 2014; 69: 72-79Crossref PubMed Scopus (55) Google Scholar, 8Christenson SA Steiling K van den Berge M Hijazi K Hiemstra PS Postma DS et al.Asthma-COPD Overlap. Clinical relevance of genomic signatures of type 2 inflammation in chronic obstructive pulmonary disease.Am J Respir Crit Care Med. 2015; 191: 758-766Crossref PubMed Scopus (225) Google Scholar, 9Ghebre MA Bafadhel M Desai D et al.Biological clustering supports both "Dutch" and "British" hypotheses of asthma and chronic obstructive pulmonary disease.J Allergy Clin Immunol. 2015; 135: 63-72Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar In 2014, a document endorsed by both GINA (Global Initiative for Asthma) and GOLD (Global Initiative for Chronic Obstructive Lung Disease) provided in-depth analyses, with diagnostic and therapeutic recommendations for ACOS.10Global Initiative for Asthma and Global Initiative for Chronic Obstructive Lung Disease Joint project of GOLD and GINA 2014. Global strategy for asthma management and prevention 2014. Diagnosis of diseases of chronic airflow limitation: asthma, COPD and asthma-COPD overlap syndrome (ACOS). Global Initiative for Asthma website.http://www.ginasthma.orgGoogle Scholar The clinical course of these patients is often compounded by frequent exacerbations, especially in patients with asthma who continue to smoke. Furthermore, investigators have also identified never smoked asthma phenotypes or subgroups with shared characteristics. This has allowed stratification of patients with moderate to severe asthma using input from multiple sources: clinical data, BAL, large airways pathology, blood inflammatory biomarkers, genetic markers, lung function, demographics, lung CT scan, and medication response.11Wu W Bleecker E Moore W et al.Unsupervised phenotyping of Severe Asthma Research Program participants using expanded lung data.J Allergy Clin Immunol. 2014; 133: 1280-1288Abstract Full Text Full Text PDF PubMed Scopus (201) Google Scholar, 12Haldar P Pavord ID Shaw DE et al.Cluster analysis and clinical asthma phenotypes.Am J Respir Crit Care Med. 2008; 178: 218-224Crossref PubMed Scopus (1531) Google Scholar, 13Sterk PJ Lutter R Asthma phenotyping: TH2-high, TH2-low, and beyond.J Allergy Clin Immunol. 2014; 133: 395-396Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar, 14Bourdin A Molinari N Vachier I et al.Prognostic value of cluster analysis of severe asthma phenotypes.J Allergy Clin Immunol. 2014; 134: 1043-1050Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar A recent study demonstrated the potential therapeutic limitation using cluster analysis and variable response in Cluster 5, which is best aligned with ACOS.14Bourdin A Molinari N Vachier I et al.Prognostic value of cluster analysis of severe asthma phenotypes.J Allergy Clin Immunol. 2014; 134: 1043-1050Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar And, genetic studies have suggested less than a firm overlap between asthma and COPD.8Christenson SA Steiling K van den Berge M Hijazi K Hiemstra PS Postma DS et al.Asthma-COPD Overlap. Clinical relevance of genomic signatures of type 2 inflammation in chronic obstructive pulmonary disease.Am J Respir Crit Care Med. 2015; 191: 758-766Crossref PubMed Scopus (225) Google Scholar, 9Ghebre MA Bafadhel M Desai D et al.Biological clustering supports both "Dutch" and "British" hypotheses of asthma and chronic obstructive pulmonary disease.J Allergy Clin Immunol. 2015; 135: 63-72Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar, 15Smolonska J Koppelman GH Wijmenga C et al.Common genes underlying asthma and COPD? Genome-wide analysis on the Dutch hypothesis.Eur Respir J. 2014; 44: 860-872Crossref PubMed Scopus (46) Google Scholar However, these asthma cluster studies have not specifically addressed ACOS and the pathophysiologic mechanism(s) responsible for persistent expiratory airflow limitation. In patients with asthma who are nonsmokers, we16Gold WM Kaufman HS Nadel JA Elastic recoil of the lungs in chronic asthmatic patients before and after therapy.J Appl Physiol. 1967; 23: 433-438Crossref PubMed Scopus (86) Google Scholar and several other investigators17Woolcock AJ Read J The static elastic properties of the lungs in asthma.Am Rev Respir Dis. 1968; 98: 788-794PubMed Google Scholar, 18McFadden Jr, ER Lyons HA Serial studies of factors influencing airway dynamics during recovery from acute asthma attacks.J Appl Physiol. 1969; 27: 452-459PubMed Google Scholar, 19Blackie SP al-Majed S Staples CA Hilliam C Paré PD Changes in total lung capacity during acute spontaneous asthma.Am Rev Respir Dis. 1990; 142: 79-83Crossref PubMed Scopus (26) Google Scholar, 20Colebatch HJH Finucane KE Smith MM Pulmonary conductance and elastic recoil relationships in asthma and emphysema.J Appl Physiol. 1973; 34: 143-153PubMed Google Scholar, 21Peress L Sybrecht G Macklem PT The mechanism of increase in total lung capacity during acute asthma.Am J Med. 1976; 61: 165-169Abstract Full Text PDF PubMed Scopus (58) Google Scholar, 22Freedman S Tattersfield AE Pride NB Changes in lung mechanics during asthma induced by exercise..J Appl Physiol. 1975; 38: 974-982PubMed Google Scholar, 23Mansell A Dubrawsky C Levison H et al.Lung mechanics in antigen-induced asthma.J Appl Physiol. 1974; 37: 297-301Crossref PubMed Scopus (44) Google Scholar, 24Müller N Bryan AC Zamel N Tonic inspiratory muscle activity as a cause of hyperinflation in histamine-induced asthma.J Appl Physiol. 1980; 49: 869-874PubMed Google Scholar have previously reported reversible loss of lung elastic recoil and hyperinflation at total lung capacity during acute attacks of asthma that were either spontaneous16Gold WM Kaufman HS Nadel JA Elastic recoil of the lungs in chronic asthmatic patients before and after therapy.J Appl Physiol. 1967; 23: 433-438Crossref PubMed Scopus (86) Google Scholar, 17Woolcock AJ Read J The static elastic properties of the lungs in asthma.Am Rev Respir Dis. 1968; 98: 788-794PubMed Google Scholar, 18McFadden Jr, ER Lyons HA Serial studies of factors influencing airway dynamics during recovery from acute asthma attacks.J Appl Physiol. 1969; 27: 452-459PubMed Google Scholar, 19Blackie SP al-Majed S Staples CA Hilliam C Paré PD Changes in total lung capacity during acute spontaneous asthma.Am Rev Respir Dis. 1990; 142: 79-83Crossref PubMed Scopus (26) Google Scholar, 20Colebatch HJH Finucane KE Smith MM Pulmonary conductance and elastic recoil relationships in asthma and emphysema.J Appl Physiol. 1973; 34: 143-153PubMed Google Scholar or induced by exercise21Peress L Sybrecht G Macklem PT The mechanism of increase in total lung capacity during acute asthma.Am J Med. 1976; 61: 165-169Abstract Full Text PDF PubMed Scopus (58) Google Scholar, 22Freedman S Tattersfield AE Pride NB Changes in lung mechanics during asthma induced by exercise..J Appl Physiol. 1975; 38: 974-982PubMed Google Scholar or by antigen challenge.23Mansell A Dubrawsky C Levison H et al.Lung mechanics in antigen-induced asthma.J Appl Physiol. 1974; 37: 297-301Crossref PubMed Scopus (44) Google Scholar, 24Müller N Bryan AC Zamel N Tonic inspiratory muscle activity as a cause of hyperinflation in histamine-induced asthma.J Appl Physiol. 1980; 49: 869-874PubMed Google Scholar Furthermore, loss of lung elastic recoil has been reported in chronic asthma with only partially reversible airway obstruction despite treatment17Woolcock AJ Read J The static elastic properties of the lungs in asthma.Am Rev Respir Dis. 1968; 98: 788-794PubMed Google Scholar, 18McFadden Jr, ER Lyons HA Serial studies of factors influencing airway dynamics during recovery from acute asthma attacks.J Appl Physiol. 1969; 27: 452-459PubMed Google Scholar, 20Colebatch HJH Finucane KE Smith MM Pulmonary conductance and elastic recoil relationships in asthma and emphysema.J Appl Physiol. 1973; 34: 143-153PubMed Google Scholar, 25Gelb AF Zamel N Unsuspected pseudophysiologic emphysema in chronic persistent asthma.Am J Respir Crit Care Med. 2000; 162: 1778-1782Crossref PubMed Scopus (113) Google Scholar, 26Gelb AF Licuanan J Shinar CM Zamel N Unsuspected loss of lung elastic recoil in chronic persistent asthma.Chest. 2002; 121: 715-721Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar, 27Gelb AF Schein A Nussbaum E et al.Risk factors for near-fatal asthma.Chest. 2004; 126: 1138-1146Abstract Full Text Full Text PDF PubMed Google Scholar, 28McCarthy DS Sigurdson M Lung elastic recoil and reduced airflow in clinically stable asthma.Thorax. 1980; 35: 298-302Crossref PubMed Scopus (53) Google Scholar and also in mild asthma.29Kraft M Cairns CB Ellison MC Pak J Irvin C Wenzel S Improvements in distal lung function correlate with asthma symptoms after treatment with oral montelukast..Chest. 2006; 130: 1726-1732Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar The sentinel study by Gold et al16Gold WM Kaufman HS Nadel JA Elastic recoil of the lungs in chronic asthmatic patients before and after therapy.J Appl Physiol. 1967; 23: 433-438Crossref PubMed Scopus (86) Google Scholar in 1967 reported the reversible loss of lung elastic recoil in acute asthma. And, the sentinel study by Woolcock and Read17Woolcock AJ Read J The static elastic properties of the lungs in asthma.Am Rev Respir Dis. 1968; 98: 788-794PubMed Google Scholar in 1968 demonstrated the unexpected chronic loss of lung elastic recoil in patients with stable asthma with expiratory airflow limitation and partially reversible, nearly parallel left shift in the pressure-volume curve with exacerbation. This unexpected loss of lung elastic recoil contributes greatly to exaggerate airflow limitation due to intrinsic peripheral airway bronchoconstriction.30Mead J Turner JM Macklem PT Little JB Significance of the relationship between lung recoil and maximum expiratory flow.J Appl Physiol. 1967; 22: 95-108Crossref PubMed Scopus (641) Google Scholar These nonsmokers with asthma with loss of lung elastic recoil and persistent limitation of maximal expiratory airflow have normal diffusing capacity corrected for alveolar volume. They have normal or only mild parenchymal attenuation of lung density using voxel quantification on high-resolution thin-section (1 mm) lung CT scan at full inspiration,25Gelb AF Zamel N Unsuspected pseudophysiologic emphysema in chronic persistent asthma.Am J Respir Crit Care Med. 2000; 162: 1778-1782Crossref PubMed Scopus (113) Google Scholar, 26Gelb AF Licuanan J Shinar CM Zamel N Unsuspected loss of lung elastic recoil in chronic persistent asthma.Chest. 2002; 121: 715-721Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar, 27Gelb AF Schein A Nussbaum E et al.Risk factors for near-fatal asthma.Chest. 2004; 126: 1138-1146Abstract Full Text Full Text PDF PubMed Google Scholar with trivial Thurlbeck "emphysema scores" ≤ 15.31Gelb AF Hogg JC Müller NL et al.Contribution of emphysema and small airways in COPD.Chest. 1996; 109: 353-359Abstract Full Text Full Text PDF PubMed Scopus (166) Google Scholar, 32Thurlbeck WM Dunnill MS Hartung W Heard BE Heppleston AG Ryder RC A comparison of three methods of measuring emphysema.Hum Pathol. 1970; 1: 215-226Abstract Full Text PDF PubMed Scopus (100) Google Scholar However, the limited resolution of lung CT scan may not be capable of discriminating between mild emphysema and hyperinflation.33Busacker A Newell Jr, JD Keefe T et al.A multivariate analysis of risk factors for the air-trapping asthmatic phenotype as measured by quantitative CT analysis.Chest. 2009; 135: 48-56Abstract Full Text Full Text PDF PubMed Scopus (226) Google Scholar, 34Biernacki W Redpath AT Best JJK MacNee W Measurement of CT lung density in patients with chronic asthma.Eur Respir J. 1997; 10: 2455-2459Crossref PubMed Scopus (62) Google Scholar, 35Madani A De Maertelaer V Zanen J Gevenois PA Pulmonary emphysema: radiation dose and section thickness at multidetector CT quantification—comparison with macroscopic and microscopic morphometry.Radiology. 2007; 243: 250-257Crossref PubMed Scopus (171) Google Scholar Because wellperformed structure-function studies of the lungs in asthma are rarely published, the pathophysiologic mechanism(s) responsible for the loss of lung elastic recoil in acute16Gold WM Kaufman HS Nadel JA Elastic recoil of the lungs in chronic asthmatic patients before and after therapy.J Appl Physiol. 1967; 23: 433-438Crossref PubMed Scopus (86) Google Scholar, 17Woolcock AJ Read J The static elastic properties of the lungs in asthma.Am Rev Respir Dis. 1968; 98: 788-794PubMed Google Scholar, 18McFadden Jr, ER Lyons HA Serial studies of factors influencing airway dynamics during recovery from acute asthma attacks.J Appl Physiol. 1969; 27: 452-459PubMed Google Scholar, 19Blackie SP al-Majed S Staples CA Hilliam C Paré PD Changes in total lung capacity during acute spontaneous asthma.Am Rev Respir Dis. 1990; 142: 79-83Crossref PubMed Scopus (26) Google Scholar, 20Colebatch HJH Finucane KE Smith MM Pulmonary conductance and elastic recoil relationships in asthma and emphysema.J Appl Physiol. 1973; 34: 143-153PubMed Google Scholar, 21Peress L Sybrecht G Macklem PT The mechanism of increase in total lung capacity during acute asthma.Am J Med. 1976; 61: 165-169Abstract Full Text PDF PubMed Scopus (58) Google Scholar, 22Freedman S Tattersfield AE Pride NB Changes in lung mechanics during asthma induced by exercise..J Appl Physiol. 1975; 38: 974-982PubMed Google Scholar, 23Mansell A Dubrawsky C Levison H et al.Lung mechanics in antigen-induced asthma.J Appl Physiol. 1974; 37: 297-301Crossref PubMed Scopus (44) Google Scholar, 24Müller N Bryan AC Zamel N Tonic inspiratory muscle activity as a cause of hyperinflation in histamine-induced asthma.J Appl Physiol. 1980; 49: 869-874PubMed Google Scholar and chronic asthma17Woolcock AJ Read J The static elastic properties of the lungs in asthma.Am Rev Respir Dis. 1968; 98: 788-794PubMed Google Scholar, 18McFadden Jr, ER Lyons HA Serial studies of factors influencing airway dynamics during recovery from acute asthma attacks.J Appl Physiol. 1969; 27: 452-459PubMed Google Scholar, 20Colebatch HJH Finucane KE Smith MM Pulmonary conductance and elastic recoil relationships in asthma and emphysema.J Appl Physiol. 1973; 34: 143-153PubMed Google Scholar, 25Gelb AF Zamel N Unsuspected pseudophysiologic emphysema in chronic persistent asthma.Am J Respir Crit Care Med. 2000; 162: 1778-1782Crossref PubMed Scopus (113) Google Scholar, 26Gelb AF Licuanan J Shinar CM Zamel N Unsuspected loss of lung elastic recoil in chronic persistent asthma.Chest. 2002; 121: 715-721Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar, 27Gelb AF Schein A Nussbaum E et al.Risk factors for near-fatal asthma.Chest. 2004; 126: 1138-1146Abstract Full Text Full Text PDF PubMed Google Scholar, 28McCarthy DS Sigurdson M Lung elastic recoil and reduced airflow in clinically stable asthma.Thorax. 1980; 35: 298-302Crossref PubMed Scopus (53) Google Scholar, 29Kraft M Cairns CB Ellison MC Pak J Irvin C Wenzel S Improvements in distal lung function correlate with asthma symptoms after treatment with oral montelukast..Chest. 2006; 130: 1726-1732Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar remain an enigma. Here, we review our pathologic and physiologic data36Gelb AF Yamamoto A Mauad T Kollin J Schein MJ Nadel JA Unsuspected mild emphysema in nonsmoking patients with chronic asthma with persistent airway obstruction.J Allergy Clin Immunol. 2014; 133: 263-265Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar in never smokers with asthma with persistent expiratory airflow limitation consistent with asthma guidelines,37Chung KF Wenzel SE Brozek JL et al.International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma [published correction appears in Eur Respir J. 2014;43(4):1216].Eur Respir J. 2014; 43: 343-373Crossref PubMed Scopus (2433) Google Scholar which we hope will begin to unravel the paradigm of ACOS.5Mattes J Gibson PG The early origins of COPD in severe asthma: the one thing that leads to another or the two things that come together?.Thorax. 2014; 69: 789-790Crossref PubMed Scopus (10) Google Scholar, 6Gibson PG McDonald VM Asthma-COPD overlap 2015: now we are six.Thorax. 2015; 70: 683-691Crossref PubMed Scopus (155) Google Scholar, 7Vanfleteren LE Kocks JW Stone IS et al.Moving from the Oslerian paradigm to the post-genomic era: are asthma and COPD outdated terms?.Thorax. 2014; 69: 72-79Crossref PubMed Scopus (55) Google Scholar, 8Christenson SA Steiling K van den Berge M Hijazi K Hiemstra PS Postma DS et al.Asthma-COPD Overlap. Clinical relevance of genomic signatures of type 2 inflammation in chronic obstructive pulmonary disease.Am J Respir Crit Care Med. 2015; 191: 758-766Crossref PubMed Scopus (225) Google Scholar, 9Ghebre MA Bafadhel M Desai D et al.Biological clustering supports both "Dutch" and "British" hypotheses of asthma and chronic obstructive pulmonary disease.J Allergy Clin Immunol. 2015; 135: 63-72Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar, 10Global Initiative for Asthma and Global Initiative for Chronic Obstructive Lung Disease Joint project of GOLD and GINA 2014. Global strategy for asthma management and prevention 2014. Diagnosis of diseases of chronic airflow limitation: asthma, COPD and asthma-COPD overlap syndrome (ACOS). Global Initiative for Asthma website.http://www.ginasthma.orgGoogle Scholar We have studied many adult nonsmokers with asthma followed in a tertiary referral asthma clinic for moderate to severe cases37Chung KF Wenzel SE Brozek JL et al.International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma [published correction appears in Eur Respir J. 2014;43(4):1216].Eur Respir J. 2014; 43: 343-373Crossref PubMed Scopus (2433) Google Scholar with persistent maximal expiratory airflow limitation despite treatment and partial reversibilty.25Gelb AF Zamel N Unsuspected pseudophysiologic emphysema in chronic persistent asthma.Am J Respir Crit Care Med. 2000; 162: 1778-1782Crossref PubMed Scopus (113) Google Scholar, 26Gelb AF Licuanan J Shinar CM Zamel N Unsuspected loss of lung elastic recoil in chronic persistent asthma.Chest. 2002; 121: 715-721Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar, 27Gelb AF Schein A Nussbaum E et al.Risk factors for near-fatal asthma.Chest. 2004; 126: 1138-1146Abstract Full Text Full Text PDF PubMed Google Scholar, 36Gelb AF Yamamoto A Mauad T Kollin J Schein MJ Nadel JA Unsuspected mild emphysema in nonsmoking patients with chronic asthma with persistent airway obstruction.J Allergy Clin Immunol. 2014; 133: 263-265Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar All patients with asthma were clinically stable at the time of lung function studies and had tapered off oral corticosteroid for ≥ 6 weeks. Most of the patients with asthma studied had nearly lifelong history of asthma and had never smoked. None had chronic bronchitis or history of exposure to potential agents that might cause lung injury, including exposure to secondhand smoke. In our sentinel pilot pathophysiologic study initiated nearly 10 years ago, only two of 10 patients with asthma had recurrent chronic rhinosinusitis.36Gelb AF Yamamoto A Mauad T Kollin J Schein MJ Nadel JA Unsuspected mild emphysema in nonsmoking patients with chronic asthma with persistent airway obstruction.J Allergy Clin Immunol. 2014; 133: 263-265Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar All had normal serum values for α1-antitrypsin. Two of the 10 patients with asthma had experienced acute exacerbations in the past that required hospitalization including endotracheal intubation and short-term mechanical ventilation. Within the previous 2 years of study, all patients with asthma satisfied the spirometric criteria for at least partial reversibility, with an increase in FEV1 > 200 mL and 12% following 270 μg aerosolized albuterol sulfate via spacer chamber when not using any long-acting and short-acting ß2-agonist and muscarinic antagonist metered dose inhalers for 24 and 6 h, respectively. Results in the 10 patients in our pilot study36Gelb AF Yamamoto A Mauad T Kollin J Schein MJ Nadel JA Unsuspected mild emphysema in nonsmoking patients with chronic asthma with persistent airway obstruction.J Allergy Clin Immunol. 2014; 133: 263-265Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar have not been included in our previous studies.25Gelb AF Zamel N Unsuspected pseudophysiologic emphysema in chronic persistent asthma.Am J Respir Crit Care Med. 2000; 162: 1778-1782Crossref PubMed Scopus (113) Google Scholar, 26Gelb AF Licuanan J Shinar CM Zamel N Unsuspected loss of lung elastic recoil in chronic persistent asthma.Chest. 2002; 121: 715-721Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar, 27Gelb AF Schein A Nussbaum E et al.Risk factors for near-fatal asthma.Chest. 2004; 126: 1138-1146Abstract Full Text Full Text PDF PubMed Google Scholar In 10 adult treated patients with asthma (five women) aged 52 ± 14 years (mean ± SD), the BMI was 27 ± 6, total blood eosinophil values were 206 (131-260) cells/μL (median, 1-3 interquartile range), and IgE level was 280 (31-500) kμ/L.36Gelb AF Yamamoto A Mauad T Kollin J Schein MJ Nadel JA Unsuspected mild emphysema in nonsmoking patients with chronic asthma with persistent airway obstruction.J Allergy Clin Immunol. 2014; 133: 263-265Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar The Asthma Control Test38Nathan RA Sorkness CA Kosinski M et al.Development of the asthma control test: a survey for assessing asthma control.J Allergy Clin Immunol. 2004; 113: 59-65Abstract Full Text Full Text PDF PubMed Scopus (2022) Google Scholar score was 16 to 19 when both clinical status and spirometry were optimally improved by maximizing therapeutic intervention. This included both short- and long-acting β2 agonist, muscarinic receptor antagonist, inhaled beclomethasone equivalent ≤ 0.4 mg/d, and tapering oral corticosteroid as needed. Thurlbeck lung CT scan emphysema score32Thurlbeck WM Dunnill MS Hartung W Heard BE Heppleston AG Ryder RC A comparison of three methods of measuring emphysema.Hum Pathol. 1970; 1: 215-226Abstract Full Text PDF PubMed Scopus (100) Google Scholar was ≤ 10, consistent with trivial or no emphysema in seven patients with asthma. In the three patients with asthma with loss of lung elastic recoil and persistent expiratory airflow limitation who died, all had mild, diffuse centrilobular emphysema at autopsy, The Thurlbeck lung CT scan emphysema score (0 = none to 100 = very extensive lung tissue breakdown)32Thurlbeck WM Dunnill MS Hartung W Heard BE Heppleston AG Ryder RC A comparison of three methods of measuring emphysema.Hum Pathol. 1970; 1: 215-226Abstract Full Text PDF PubMed Scopus (100) Google Scholar was between 10 and 20, consistent with trivial to mild emphysema as per radiologist Mark J. Schein, MD, by this criterion.36Gelb AF Yamamoto A Mauad T Kollin J Schein MJ Nadel JA Unsuspected mild emphysema in nonsmoking patients with chronic asthma with persistent airway obstruction.J Allergy Clin Immunol. 2014; 133: 263-265Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar In one patient with asthma with a Thurlbeck emphysema score32Thurlbeck WM Dunnill MS Hartung W Heard BE Heppleston AG Ryder RC A comparison of three methods of measuring emphysema.Hum Pathol. 1970; 1: 215-226Abstract Full Text PDF PubMed Scopus (100) Google Scholar of 10 who was autopsied, the lung CT scan voxel quantification score for ≤ −950 Hounsfield units (HU) was 6.5% for right lung and 0.9% for left lung. This is consistent with hyperinflation and air trapping but not diagnostic for emphysema (≥ 10% lung voxel ≤ −950 HU).33Busacker A Newell Jr, JD Keefe T et al.A multivariate analysis of risk factors for the air-trapping asthmatic phenotype as measured by quantitative CT analysis.Chest. 2009; 135: 48-56Abstract Full Text Full Text PDF PubMed Scopus (226) Google Scholar, 34Biernacki W Redpath AT Best JJK MacNee W Measurement of CT lung density in patients with chronic asthma.Eur Respir J. 1997; 10: 2455-2459Crossref PubMed Scopus (62) Google Scholar, 35Madani A De Maertelaer V Zanen J Gevenois PA Pulmonary emphysema: radiation dose and section thickness at multidetector CT quantification—comparison with macroscopic and microscopic morphometry.Radiology. 2007; 243: 250-257Crossref PubMed Scopus (171) Google Scholar In 10 patients with asthma, the postbronchodilator (270 μg albuterol sulfate metered dose inhaler with spacer) vital capacity was 4.2 ± 1.1 L (90% ± 14% p
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