Chronic obstructive pulmonary disease subpopulations and phenotyping
Authors: Leopoldo N. Segal, Fernando J. Martinez
Journal: Journal of Allergy and Clinical Immunology (2018)

Information for Category 1 CME CreditCredit can now be obtained, free for a limited time, by reading the review articles in this issue. Please note the following instructions.Method of Physician Participation in Learning Process: The core material for these activities can be read in this issue of the Journal or online at the JACI Web site: www.jacionline.org. The accompanying tests may only be submitted online at www.jacionline.org. Fax or other copies will not be accepted.Date of Original Release: June 2018. Credit may be obtained for these courses until May 31, 2019.Copyright Statement: Copyright © 2018-2019. All rights reserved.Overall Purpose/Goal: To provide excellent reviews on key aspects of allergic disease to those who research, treat, or manage allergic disease.Target Audience: Physicians and researchers within the field of allergic disease.Accreditation/Provider Statements and Credit Designation: The American Academy of Allergy, Asthma & Immunology (AAAAI) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The AAAAI designates this journal-based CME activity for a maximum of 1.00 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.List of Design Committee Members: Leopoldo N. Segal, MD, MS, and Fernando J. Martinez, MD, MS (authors); Zuhair K. Ballas, MD (editor)Disclosure of Significant Relationships with Relevant CommercialCompanies/Organizations: L. N. Segal has received grants from the National Institutes of Health and personal fees from Advanced Inhalation Therapies. F. J. Martinez has received a grant from the National Heart, Lung, and Blood Institute; has received personal fees from Continuing Education, Forest Laboratories, GlaxoSmithKline, Nycomed/Takeda, AstraZeneca, Boehringer Ingelheim, Bellerophon (formerly Ikaria), Genentech, Novartis, Pearl, Roche, Sunovion, Theravance, CME Incite, the Annenberg Center for Health Sciences at Eisenhower, Integritas, InThought, the National Association for Continuing Education, Paradigm Medical Communications, PeerVoice, UpToDate, Haymarket Communications, the Western Society of Allergy and Immunology, Proterixbio, Unity Biotechnology, ConCert Pharmaceuticals, Lucid, Methodist Hospital, Columbia University, Prime Healthcare, WebMD, the PeerView Network, the California Society of Allergy and Immunology, Chiesi, and the Puerto Rico Thoracic Society and is on the COPD advisory board for Janssen. Z. K. Ballas (editor) disclosed no relevant financial relationships.Activity Objectives:1.To understand the different phenotypes of chronic obstructive pulmonary disease (COPD), including comorbidities, clinical course, and treatment implications.2.To understand the pathogenesis of COPD.3.To understand the characteristics of COPD exacerbations.Recognition of Commercial Support: This CME activity has not received external commercial support.List of CME Exam Authors: Ryan Israelsen, MD, Katherine McCormack, MD, Hannah Duffey, MD, Allison Hicks, MD, Joseph Spahn, MD, and Maureen Egan, MDDisclosure of Significant Relationships with Relevant CommercialCompanies/Organizations: The exam authors disclosed no relevant financial relationships.The diagnosis and treatment of chronic obstructive pulmonary disease (COPD) has been based largely on a one-size-fits-all approach. Diagnosis of COPD is based on meeting the physiologic criteria of fixed obstruction in forced expiratory flows and treatment focus on symptomatic relief, with limited effect on overall prognosis. However, patients with COPD have distinct features that determine very different evolutions of the disease. In this review we highlight distinct subgroups of COPD characterized by unique pathophysiologic derangements, response to treatment, and disease progression. It is likely that identification of subgroups of COPD will lead to discovery of much needed disease-modifying therapeutic approaches. We argue that a precision approach that integrates multiple dimensions (clinical, physiologic, imaging, and endotyping) is needed to move the field forward in the treatment of this disease. Information for Category 1 CME CreditCredit can now be obtained, free for a limited time, by reading the review articles in this issue. Please note the following instructions.Method of Physician Participation in Learning Process: The core material for these activities can be read in this issue of the Journal or online at the JACI Web site: www.jacionline.org. The accompanying tests may only be submitted online at www.jacionline.org. Fax or other copies will not be accepted.Date of Original Release: June 2018. Credit may be obtained for these courses until May 31, 2019.Copyright Statement: Copyright © 2018-2019. All rights reserved.Overall Purpose/Goal: To provide excellent reviews on key aspects of allergic disease to those who research, treat, or manage allergic disease.Target Audience: Physicians and researchers within the field of allergic disease.Accreditation/Provider Statements and Credit Designation: The American Academy of Allergy, Asthma & Immunology (AAAAI) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The AAAAI designates this journal-based CME activity for a maximum of 1.00 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.List of Design Committee Members: Leopoldo N. Segal, MD, MS, and Fernando J. Martinez, MD, MS (authors); Zuhair K. Ballas, MD (editor)Disclosure of Significant Relationships with Relevant CommercialCompanies/Organizations: L. N. Segal has received grants from the National Institutes of Health and personal fees from Advanced Inhalation Therapies. F. J. Martinez has received a grant from the National Heart, Lung, and Blood Institute; has received personal fees from Continuing Education, Forest Laboratories, GlaxoSmithKline, Nycomed/Takeda, AstraZeneca, Boehringer Ingelheim, Bellerophon (formerly Ikaria), Genentech, Novartis, Pearl, Roche, Sunovion, Theravance, CME Incite, the Annenberg Center for Health Sciences at Eisenhower, Integritas, InThought, the National Association for Continuing Education, Paradigm Medical Communications, PeerVoice, UpToDate, Haymarket Communications, the Western Society of Allergy and Immunology, Proterixbio, Unity Biotechnology, ConCert Pharmaceuticals, Lucid, Methodist Hospital, Columbia University, Prime Healthcare, WebMD, the PeerView Network, the California Society of Allergy and Immunology, Chiesi, and the Puerto Rico Thoracic Society and is on the COPD advisory board for Janssen. Z. K. Ballas (editor) disclosed no relevant financial relationships.Activity Objectives:1.To understand the different phenotypes of chronic obstructive pulmonary disease (COPD), including comorbidities, clinical course, and treatment implications.2.To understand the pathogenesis of COPD.3.To understand the characteristics of COPD exacerbations.Recognition of Commercial Support: This CME activity has not received external commercial support.List of CME Exam Authors: Ryan Israelsen, MD, Katherine McCormack, MD, Hannah Duffey, MD, Allison Hicks, MD, Joseph Spahn, MD, and Maureen Egan, MDDisclosure of Significant Relationships with Relevant CommercialCompanies/Organizations: The exam authors disclosed no relevant financial relationships.The diagnosis and treatment of chronic obstructive pulmonary disease (COPD) has been based largely on a one-size-fits-all approach. Diagnosis of COPD is based on meeting the physiologic criteria of fixed obstruction in forced expiratory flows and treatment focus on symptomatic relief, with limited effect on overall prognosis. However, patients with COPD have distinct features that determine very different evolutions of the disease. In this review we highlight distinct subgroups of COPD characterized by unique pathophysiologic derangements, response to treatment, and disease progression. It is likely that identification of subgroups of COPD will lead to discovery of much needed disease-modifying therapeutic approaches. We argue that a precision approach that integrates multiple dimensions (clinical, physiologic, imaging, and endotyping) is needed to move the field forward in the treatment of this disease. Credit can now be obtained, free for a limited time, by reading the review articles in this issue. Please note the following instructions. Method of Physician Participation in Learning Process: The core material for these activities can be read in this issue of the Journal or online at the JACI Web site: www.jacionline.org. The accompanying tests may only be submitted online at www.jacionline.org. Fax or other copies will not be accepted. Date of Original Release: June 2018. Credit may be obtained for these courses until May 31, 2019. Copyright Statement: Copyright © 2018-2019. All rights reserved. Overall Purpose/Goal: To provide excellent reviews on key aspects of allergic disease to those who research, treat, or manage allergic disease. Target Audience: Physicians and researchers within the field of allergic disease. Accreditation/Provider Statements and Credit Designation: The American Academy of Allergy, Asthma & Immunology (AAAAI) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The AAAAI designates this journal-based CME activity for a maximum of 1.00 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. List of Design Committee Members: Leopoldo N. Segal, MD, MS, and Fernando J. Martinez, MD, MS (authors); Zuhair K. Ballas, MD (editor) Disclosure of Significant Relationships with Relevant Commercial Companies/Organizations: L. N. Segal has received grants from the National Institutes of Health and personal fees from Advanced Inhalation Therapies. F. J. Martinez has received a grant from the National Heart, Lung, and Blood Institute; has received personal fees from Continuing Education, Forest Laboratories, GlaxoSmithKline, Nycomed/Takeda, AstraZeneca, Boehringer Ingelheim, Bellerophon (formerly Ikaria), Genentech, Novartis, Pearl, Roche, Sunovion, Theravance, CME Incite, the Annenberg Center for Health Sciences at Eisenhower, Integritas, InThought, the National Association for Continuing Education, Paradigm Medical Communications, PeerVoice, UpToDate, Haymarket Communications, the Western Society of Allergy and Immunology, Proterixbio, Unity Biotechnology, ConCert Pharmaceuticals, Lucid, Methodist Hospital, Columbia University, Prime Healthcare, WebMD, the PeerView Network, the California Society of Allergy and Immunology, Chiesi, and the Puerto Rico Thoracic Society and is on the COPD advisory board for Janssen. Z. K. Ballas (editor) disclosed no relevant financial relationships. Activity Objectives:1.To understand the different phenotypes of chronic obstructive pulmonary disease (COPD), including comorbidities, clinical course, and treatment implications.2.To understand the pathogenesis of COPD.3.To understand the characteristics of COPD exacerbations. Recognition of Commercial Support: This CME activity has not received external commercial support. List of CME Exam Authors: Ryan Israelsen, MD, Katherine McCormack, MD, Hannah Duffey, MD, Allison Hicks, MD, Joseph Spahn, MD, and Maureen Egan, MD Disclosure of Significant Relationships with Relevant Commercial Companies/Organizations: The exam authors disclosed no relevant financial relationships. Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease. Although this statement is currently widely accepted, the beginning of the debate about how to categorize different subtypes of COPD goes back to more than 50 years ago when the so-called Dutch hypothesis was introduced. This hypothesis argued that bronchodilator responsiveness was an overlapping feature shared by various forms of obstructive lung diseases, including asthma. In contrast, the British hypothesis argued that bronchodilator responsiveness in patients with COPD was due to concomitant asthma.1Barnes P.J. Against the Dutch hypothesis: asthma and chronic obstructive pulmonary disease are distinct diseases.Am J Respir Crit Care Med. 2006; 174: 240-244Google Scholar, 2Kraft M. Asthma and chronic obstructive pulmonary disease exhibit common origins in any country.Am J Respir Crit Care Med. 2006; 174 (discussion 43-4): 238-240Google Scholar In 1959, during the Ciba Guest Symposium, the scientific community began to recognize the problems of poor phenotyping and published an article in Thorax under the title of "Terminology, definitions, and classification of chronic pulmonary emphysema and related conditions."3Terminology, definitions, and classification of chronic pulmonary emphysema and related conditions. A report of the conclusions of a Ciba guest symposium.Thorax. 1959; 14: 286-299Google Scholar That report stated the following: "At present, the diagnosis of 'chronic bronchitis,' 'asthma,' and 'emphysema' are used without any general agreement about the clinical conditions to which they refer. Any one (or more) of these words may be used by different clinicians to describe the condition of the same patient. It appears that chronic bronchitis is often used in Great Britain to describe cases that would be called asthma or emphysema in the Unites States." Importantly, this remains an ongoing controversy in clinical practice. This blurred vision of disease was represented as a nonproportional Venn diagram of COPD, one of the most famous diagrams in pulmonary medicine.4Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease. American Thoracic Society.Am J Respir Crit Care Med. 1995; 152: S77-S121Google Scholar For many years, a unifying view of COPD influenced physicians to take a one-size-fits-all approach to patients with COPD. This was applied to diagnostic approaches in which physicians rely on spirometry with bronchodilator responsiveness, as well as therapeutic management. In these approaches, first-line medications have been applied consistently once COPD is diagnosed without much consideration of possible distinct phenotypes of COPD. However, several lines of investigation have demonstrated that subgroups of COPD can have distinct pathophysiologic derangements, response to treatment, and disease progression.5Han M.K. Agusti A. Calverley P.M. Celli B.R. Criner G. Curtis J.L. et al.Chronic obstructive pulmonary disease phenotypes: the future of COPD.Am J Respir Crit Care Med. 2010; 182: 598-604Google Scholar Thus a precision approach to this disease is needed to overcome the many years of stagnant therapeutic advances by identifying novel treatable traits and treating them at a stage at which disease-modifying approaches are more likely to succeed.6Woodruff P.G. Agusti A. Roche N. Singh D. Martinez F.J. Current concepts in targeting chronic obstructive pulmonary disease pharmacotherapy: making progress towards personalised management.Lancet. 2015; 385: 1789-1798Google Scholar This review will focus on the state of the art and knowledge gaps of COPD subpopulations and phenotyping. COPD is defined by airflow obstruction (postbronchodilator FEV1/forced vital capacity [FVC] ratio <0.7) that is not fully reversible after bronchodilator administration.7Vogelmeier C.F. Criner G.J. Martinez F.J. Anzueto A. Barnes P.J. Bourbeau J. et al.Global strategy for the diagnosis, management, and prevention of chronic obstructive lung disease 2017 report: GOLD executive summary.Am J Respir Crit Care Med. 2017; 195: 557-582Google Scholar FEV1 has been used to quantify and grade obstruction severity. This criterion does not consider the multiplicity of pathophysiologic derangements and heterogeneous histopathologic conditions that lead to airway obstruction. Both decrease in elastic recoil and decrease in cross-sectional airway diameter (independent of [and frequently concomitant with] each other) will lead to an increase in airway resistance during expiration, leading to airflow limitation.8Hogg J.C. Pare P.D. Hackett T.L. The contribution of small airway obstruction to the pathogenesis of chronic obstructive pulmonary disease.Physiol Rev. 2017; 97: 529-552Google Scholar This ramification increases further if one considers the multiple molecular derangements that lead to loss of elastic recoil and airway damage. This definition also leaves a large proportion of subjects with physiologic abnormalities, respiratory symptoms, or both that do not reach COPD diagnostic criteria. For example, use of 0.7 as a cut point for FEV1/FVC ratio excludes a significant portion of subjects (many of them with ratios of less than the predictive lower limit of normal values) that have significant symptoms.9Woodruff P.G. Barr R.G. Bleecker E. Christenson S.A. Couper D. Curtis J.L. et al.Clinical significance of symptoms in smokers with preserved pulmonary function.N Engl J Med. 2016; 374: 1811-1821Google Scholar In addition, the lower limit of normal for FEV1/FVC ratio decreases with age. Thus the accuracy of these diagnostic criteria also changes with age, affecting the establishment of early diagnosis in this disease among younger patients.10Cerveri I. Corsico A.G. Accordini S. Niniano R. Ansaldo E. Anto J.M. et al.Underestimation of airflow obstruction among young adults using FEV1/FVC <70% as a fixed cut-off: a longitudinal evaluation of clinical and functional outcomes.Thorax. 2008; 63: 1040-1045Google Scholar Furthermore, the use of a fixed cut point might misclassify some older patients as having COPD. Although using the lower limit of normal would be a more desirable parameter, this value is dependent on the reference population and is unlikely to accurately reflect the normality of many different ethnic groups. In addition, FEV1 normally decreases with age, and the rate of decrease is an important spirometric indicator of disease progression in patients with COPD. However, the rate of lung function decrease is not considered for diagnosing or staging the disease. The current approach to diagnosis and staging of COPD is based on spirometric values, even though disease is believed generally to begin in the small airways,8Hogg J.C. Pare P.D. Hackett T.L. The contribution of small airway obstruction to the pathogenesis of chronic obstructive pulmonary disease.Physiol Rev. 2017; 97: 529-552Google Scholar an area classically labelled as the "quiet zone" because it cannot be easily assessed by means of spirometry alone.11Macklem P.T. Mead J. Resistance of central and peripheral airways measured by a retrograde catheter.J Appl Physiol. 1967; 22: 395-401Google Scholar A large proportion of patients at risk for COPD have significant respiratory symptoms but without the spirometric abnormalities required to meet COPD criteria. Accordingly, there are several forms of smoke-related lung diseases, even with an FEV1/FVC ratio of greater than 0.7,12Thomson N.C. Asthma and smoking-induced airway disease without spirometric COPD.Eur Respir J. 2017; 49Google Scholar including chronic bronchitis (based on frequency of cough and sputum production), emphysema (based on computed tomography [CT]), small-airway disease (based on specialized lung function or imaging), or asthma (based on symptom characteristics, bronchodilator response, or both). In addition, some patients present with overlap within these broad entities, whereas others do not fit any of the available definitions. The lack of clear agreement on how to define the above entities has delayed pathophysiologic understanding of these disease states. Several multicenter cohorts have been developed that allow study of these smoke-related lung diseases. Examples include the COPDGene,13Pillai S.G. Ge D. Zhu G. Kong X. Shianna K.V. Need A.C. et al.A genome-wide association study in chronic obstructive pulmonary disease (COPD): identification of two major susceptibility loci.PLoS Genet. 2009; 5: e1000421Google Scholar Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS),14Couper D. LaVange L.M. Han M. Barr R.G. Bleecker E. Hoffman E.A. et al.Design of the Subpopulations and Intermediate Outcomes in COPD Study (SPIROMICS).Thorax. 2014; 69: 491-494Google Scholar Canadian Cohort Obstructive Lung Diseases (canCOLD) study,15Bourbeau J. Tan W.C. Benedetti A. Aaron S.D. Chapman K.R. Coxson H.O. et al.Canadian Cohort Obstructive Lung Disease (CanCOLD): fulfilling the need for longitudinal observational studies in COPD.COPD. 2014; 11: 125-132Google Scholar and the Copenhagen City Heart Study16Lange P. Parner J. Vestbo J. Schnohr P. Jensen G. A 15-year follow-up study of ventilatory function in adults with asthma.N Engl J Med. 1998; 339: 1194-1200Google Scholar cohorts. Overall, these smoke-related lung diseases are very common, with significant morbidity and possible risk for progression to COPD, as defined by using spirometric criteria. For example, in the COPDGene cohort, smokers without spirometric criteria for COPD have worse health status when assessed by using the St George Respiratory Questionnaire.17Regan E.A. Lynch D.A. Curran-Everett D. Curtis J.L. Austin J.H. Grenier P.A. et al.Clinical and radiologic disease in smokers with normal spirometry.JAMA Intern Med. 2015; 175: 1539-1549Google Scholar In the SPIROMICS cohort, respiratory symptoms are present in half of smokers with preserved pulmonary function; when compared with asymptomatic smokers, these symptomatic subjects had greater limitation of physical activity, impaired pulmonary function (although still within the limits considered as normal), and evidence of airway wall thickening on CT imaging of the chest.9Woodruff P.G. Barr R.G. Bleecker E. Christenson S.A. Couper D. Curtis J.L. et al.Clinical significance of symptoms in smokers with preserved pulmonary function.N Engl J Med. 2016; 374: 1811-1821Google Scholar Importantly, smokers with preserved lung function and respiratory symptoms had higher rates of exacerbations than asymptomatic smokers (COPD Assessment Test [CAT] score <10). In addition, the coexistence of asthma with other smoke-related lung diseases in subjects that do not fit the spirometric criteria for COPD has significant health implications. For example, coexistence of asthma with chronic bronchitis is associated with poor symptom control and a greater decrease in FEV1.16Lange P. Parner J. Vestbo J. Schnohr P. Jensen G. A 15-year follow-up study of ventilatory function in adults with asthma.N Engl J Med. 1998; 339: 1194-1200Google Scholar, 18Thomson N.C. Chaudhuri R. Messow C.M. Spears M. MacNee W. Connell M. et al.Chronic cough and sputum production are associated with worse clinical outcomes in stable asthma.Respir Med. 2013; 107: 1501-1508Google Scholar The inflammatory changes observed in the airways of smokers with asthma are distinct from hose in never-smokers with asthma. In smokers with asthma, there are fewer eosinophils, increased numbers of cytotoxic T lymphocytes, and goblet cell hyperplasia.19Broekema M. ten Hacken N.H. Volbeda F. Lodewijk M.E. Hylkema M.N. Postma D.S. et al.Airway epithelial changes in smokers but not in ex-smokers with asthma.Am J Respir Crit Care Med. 2009; 180: 1170-1178Google Scholar, 20Ravensberg A.J. Slats A.M. van Wetering S. Janssen K. van Wijngaarden S. de Jeu R. et al.CD8(+) T cells characterize early smoking-related airway pathology in patients with asthma.Respir Med. 2013; 107: 959-966Google Scholar Of note, there are no clear treatment guidelines for this group of symptomatic smokers who have no spirometric criteria for COPD. However, a large proportion (between 20% and 42%) receive respiratory treatment with inhaled medications,9Woodruff P.G. Barr R.G. Bleecker E. Christenson S.A. Couper D. Curtis J.L. et al.Clinical significance of symptoms in smokers with preserved pulmonary function.N Engl J Med. 2016; 374: 1811-1821Google Scholar, 17Regan E.A. Lynch D.A. Curran-Everett D. Curtis J.L. Austin J.H. Grenier P.A. et al.Clinical and radiologic disease in smokers with normal spirometry.JAMA Intern Med. 2015; 175: 1539-1549Google Scholar despite data that smokers with asthma might be poorly responsive to corticosteroid therapy.21Chalmers G.W. Macleod K.J. Little S.A. Thomson L.J. McSharry C.P. Thomson N.C. Influence of cigarette smoking on inhaled corticosteroid treatment in mild asthma.Thorax. 2002; 57: 226-230Google Scholar The above considerations indicate that more research is needed to define the phenotypic changes and pathophysiologic derangements of smoke-related lung disease before meeting the spirometric definition for COPD. In patients with COPD, early pathologic derangements occur in bronchioles less than 2 mm in diameter, followed by parenchymal remodeling,22Cosio M.G. Cosio Piqueras M.G. Pathology of emphysema in chronic obstructive pulmonary disease.Monaldi Arch Chest Dis. 2000; 55: 124-129Google Scholar, 23McDonough J.E. Yuan R. Suzuki M. Seyednejad N. Elliott W.M. Sanchez P.G. et al.Small-airway obstruction and emphysema in chronic obstructive pulmonary disease.N Engl J Med. 2011; 365: 1567-1575Google Scholar leading to a minimal increase in total lung resistance. The 2-mm cutoff used to define small airways is based on experiments using retrograde catheters inserted into open lungs of dogs performed by Macklem and Mead11Macklem P.T. Mead J. Resistance of central and peripheral airways measured by a retrograde catheter.J Appl Physiol. 1967; 22: 395-401Google Scholar more than 50 years ago. As such, the physiologic abnormalities occur in a large silent region, and spirometric abnormalities become significant only later in disease development. Direct measurement of the distribution of resistance in the lower respiratory tract has confirmed that the small airways (ie, <2 mm in internal diameter) are the major sites in which obstruction starts in patients with emphysema.24Hogg J.C. Macklem P.T. Thurlbeck W.M. Site and nature of airway obstruction in chronic obstructive lung disease.N Engl J Med. 1968; 278: 1355-1360Google Scholar, 25Yanai M. Sekizawa K. Ohrui T. Sasaki H. Takishima T. Site of airway obstruction in pulmonary disease: direct measurement of intrabronchial pressure.J Appl Physiol. 1992; 72: 1016-1023Google Scholar Micro-CT of surgical specimens from patients with Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage I COPD further demonstrated airway narrowing and loss of the small conducting airways.23McDonough J.E. Yuan R. Suzuki M. Seyednejad N. Elliott W.M. Sanchez P.G. et al.Small-airway obstruction and emphysema in chronic obstructive pulmonary disease.N Engl J Med. 2011; 365: 1567-1575Google Scholar Therefore it is not surprising that respiratory symptoms and structural changes in the lung are frequently discordant with spirometric results. There is an increasing need to consider novel approaches using earlier indicators that would uncover underlying parenchymal and airway injury before meeting spirometric COPD criteria. Examples of such approaches include imaging methods, such as specialized CT methods,26Labaki W.W. Martinez C.H. Martinez F.J. Galban C.J. Ross B.D. Washko G.R. et al.The role of chest computed tomography in the evaluation and management of the patient with chronic obstructive pulmonary disease.Am J Respir Crit Care Med. 2017; 196: 1372-1379Google Scholar and measurements of small-airway physiology, such as the forced oscillation technique.8Hogg J.C. Pare P.D. Hackett T.L. The contribution of small airway obstruction to the pathogenesis of chronic obstructive pulmonary disease.Physiol Rev. 2017; 97: 529-552Google Scholar Newer CT techniques can evaluate changes in lung density between inspiration and expiration to perform parametric response mapping, which suggests differentiation between small-airways disease and emphysema.27Galban C.J. Han M.K. Boes J.L. Chughtai K.A. Meyer C.R. Johnson T.D. et al.Computed tomography-based biomarker provides unique signature for diagnosis of COPD phenotypes and disease progression.Nat Med. 2012; 18: 1711-1715Google Scholar This methodology demonstrated the widespread presence of functional small-airway disease, even within smokers with GOLD 0 and those with early GOLD 1 COPD, suggesting a role for assessment of small-airway disease in COPD phenotyping. Moreover, additional data have strongly suggested that functional small-airways abnormalities identified by using this technique are associated with rate of FEV1 decrease.28Bhatt S.P. Soler X. Wang X. Murray S. Anzueto A.R. Beaty T.H. et al.Association between functional small airway disease and FEV1 decline in chronic obstructive pulmonary disease.Am J Respir Crit Care Med. 2016; 194: 178-184Google Scholar In addition, CT can provide a measure of airway count, a parameter shown recently to be an earlier marker of COPD and associated independently with rapid lung function decrease.29Kirby M. Tanabe N. Tan W.C. Zhou G. Obeidat M. Hague C.J. et al.Total airway count on computed tomography and the risk of COPD progression: findings from a population-based study.Am J Respir Crit Care Med. 2018; 197: 56-65Google Scholar Expiratory central airway collapse can be identified by bronchoscopic visualization or expiratory CT and has been suggested to be associated with significant respiratory morbidity.30Murgu S. Colt H. Tracheobronchomalacia and excessive dynamic airway collapse.Clin Chest Med. 2013; 34: 527-555Google Scholar, 31Ochs R.A. Petkovska I. Kim H.J. Abtin F. Brown M. Goldin J. Prevalence of tracheal collapse in an emphysema cohort as measured with end-expiration CT.Acad Radiol. 2009; 16: 46-53Google Scholar, 32Bhatt S.P. Terry N.L. Nath H. Zach J.A. Tschirren J. Bolding M.S. et al.Association between expi