Abstract - University of Manchester
At the root: defining and halting progression of early chronic obstructive pulmonary diseaseFernando J. Martinez, MD, MS*MeiLan K. Han, MD, MS*James P. Allinson, MB, BS, BScR. Graham Barr, MD, DrPHRichard C. Boucher, MDPeter M. A. Calverley, MDBartolome R. Celli, MDStephanie Christenson, MDRonald G. Crystal, MDMalin Fager?s, PhDChristine Freeman, PhDLars Gr?enke, MDEric A. Hoffman, PhDMehmet Kesimer, PhDKostantinos Kostikas, MD, PhDRobert Paine III, MDShahin Rafii, MDStephen I. Rennard, MDLeopoldo N. Segal, MDRenat Shaykhiev, MD, PhDChristopher Stevenson, PhDRuth Tal-Singer, PhDJ?rgen Vestbo, MDPrescott G. Woodruff, MD, MPHJeffrey L. Curtis, MD?Jadwiga A. Wedzicha, MD?*Co-first authors?Co-senior authorsCurrent word length: 4683Current References: 120Figures: 3Tables: 1 Key Words: Early COPD, cigarette smoking, airway disease, emphysemaAbstractChronic obstructive pulmonary disease is a heterogeneous disorder with varying presentation and progression, but with limited disease-modifying therapies. It is increasingly evident that lung function trajectories in COPD differ significantly and that differences are detectable in young adulthood. It is important to distinguish “early disease” from “late mild disease”. We propose an operational definition of early COPD as occurring in a person younger than 55; and either: (1) FEV1/FVC less than lower limit of normal; or (2) respiratory symptoms and CT abnormalities (airway abnormality and/or emphysema), (3) evidence of accelerated FEV1 decline; or (4) any combination of categories (1) through (3).? The biological underpinnings of early COPD are quite complex. Recent evidence implies that cigarette smoke-exposure induces sequential, stereotypical changes in distal airways, in the absence of inflammatory cell infiltration. Epithelial reprogramming is associated with mucus that is less readily cleared. Focal airway injury has also been associated with polymeric immunoglobulin receptor down-regulation. Resulting differences in the lung microbial community structures might prove to be mechanistically important. Global gene analysis suggests that tissue degradation around small airways predominates over repair. Emphysema might also develop in early COPD due to loss of pulmonary endothelial cell-derived factors. To reduce COPD’s long-term societal impact, the goal of interventions must change, from a sole focus on reducing symptoms and exacerbations in advanced disease, to halting pathological progression in early disease. IntroductionChronic obstructive pulmonary disease (COPD) is a prevalent heterogeneous disorder with varying presentation and progression, but with limited number of disease-modifying therapies PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Wb2dlbG1laWVyPC9BdXRob3I+PFllYXI+MjAxNzwvWWVh
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ADDIN EN.CITE.DATA (1). This marked heterogeneity impedes identification of subpopulations at risk for accelerated progression, thwarting therapeutic advances. Most COPD studies have included a population of COPD individuals with mean ages older than 60 years. However, it is increasingly evident that lung function trajectories in COPD differ significantly, and that differences are detectable in young adulthood PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MYW5nZTwvQXV0aG9yPjxZZWFyPjIwMTU8L1llYXI+PFJl
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ADDIN EN.CITE.DATA (2-4). In this Perspective, we highlight the need to distinguish “early disease” from “late mild disease”; propose an operational definition of early COPD; and attempt to unify current views on potential disease mechanisms. We focus on smoking, the chief etiologic factor for COPD in the industrialized world. Whether pathogenic mechanisms and effective treatments are shared with the sizable fraction of COPD in never-smokers or resulting from biomass fuel, electronic nicotine delivery systems and other exposures are separate, significant research questions. We argue that refocusing investigation on early COPD could revolutionize understanding and therapies of this leading cause of worldwide death. Limitations of previous concepts of COPD developmentDefining the early stages of COPD is crucial to design individualized interventions to arrest progression before irreversible damage. Although the degree of obstruction has been used to distinguish mild disease, no currently accepted definition exists for ‘early disease’ – due to lack of consensus on what constitutes ‘early’ and ‘disease’ in this context. Concepts of COPD have generally been derived from analysis of older individuals with established disease, emphasized incompletely reversible airflow obstruction, and postulated accelerated decline from normal lung function in early adulthood ADDIN EN.CITE <EndNote><Cite><Author>Fletcher</Author><Year>1977</Year><RecNum>1250</RecNum><DisplayText>(5)</DisplayText><record><rec-number>1250</rec-number><foreign-keys><key app="EN" db-id="xwrd9zewrsxsr6efvtyxaf9o5sw0swa0d55a" timestamp="1500399666">1250</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Fletcher, C.</author><author>Peto, R.</author></authors></contributors><titles><title>The natural history of chronic airflow obstruction</title><secondary-title>Br Med J</secondary-title></titles><periodical><full-title>Br Med J</full-title></periodical><pages>1645-8</pages><volume>1</volume><number>6077</number><keywords><keyword>Adult</keyword><keyword>Age Factors</keyword><keyword>Airway Obstruction/etiology/*physiopathology</keyword><keyword>Bronchial Diseases/complications</keyword><keyword>Chronic Disease</keyword><keyword>Forced Expiratory Volume</keyword><keyword>Humans</keyword><keyword>Infection/complications</keyword><keyword>London</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Mucus/secretion</keyword><keyword>Prospective Studies</keyword><keyword>Smoking/complications</keyword></keywords><dates><year>1977</year><pub-dates><date>Jun 25</date></pub-dates></dates><isbn>0007-1447 (Print)
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ADDIN EN.CITE.DATA (2). Conversely, at least half of all smokers exhibit accelerated loss of lung function leading to abnormal spirometry. If smoking ceases sufficiently early, the rate of spirometric decline appears to return to that of normal aging, and symptoms of cough and sputum reverse ADDIN EN.CITE <EndNote><Cite><Author>Buist</Author><Year>1976</Year><RecNum>1248</RecNum><DisplayText>(6)</DisplayText><record><rec-number>1248</rec-number><foreign-keys><key app="EN" db-id="xwrd9zewrsxsr6efvtyxaf9o5sw0swa0d55a" timestamp="1500399563">1248</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Buist, A. S.</author><author>Sexton, G. J.</author><author>Nagy, J. M.</author><author>Ross, B. B.</author></authors></contributors><titles><title>The effect of smoking cessation and modification on lung function</title><secondary-title>Am Rev Respir Dis</secondary-title></titles><periodical><full-title>Am Rev Respir Dis</full-title></periodical><pages>115-22</pages><volume>114</volume><number>1</number><keywords><keyword>Adult</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Lung/*physiopathology</keyword><keyword>Lung Diseases, Obstructive/physiopathology</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Remission, Spontaneous</keyword><keyword>*Respiration</keyword><keyword>Smoking/*physiopathology/prevention & control</keyword><keyword>Total Lung Capacity</keyword><keyword>Vital Capacity</keyword></keywords><dates><year>1976</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>0003-0805 (Print)
0003-0805 (Linking)</isbn><accession-num>937828</accession-num><urls><related-urls><url>;(6). Smoking cessation at an older age may fail to prevent spirometric decline at a faster rate than that of normal ADDIN EN.CITE <EndNote><Cite><Author>Kohansal</Author><Year>2009</Year><RecNum>1249</RecNum><DisplayText>(7)</DisplayText><record><rec-number>1249</rec-number><foreign-keys><key app="EN" db-id="xwrd9zewrsxsr6efvtyxaf9o5sw0swa0d55a" timestamp="1500399620">1249</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kohansal, R.</author><author>Martinez-Camblor, P.</author><author>Agusti, A.</author><author>Buist, A. S.</author><author>Mannino, D. M.</author><author>Soriano, J. B.</author></authors></contributors><auth-address>Epidemiology and Clinical Research, Fundacion Caubet-CIMERA Illes Balears, Recinte Hospital Joan March, 07110-Bunyola, Illes Balears, Spain.</auth-address><titles><title>The natural history of chronic airflow obstruction revisited: an analysis of the Framingham offspring cohort</title><secondary-title>Am J Respir Crit Care Med</secondary-title></titles><periodical><full-title>Am J Respir Crit Care Med</full-title></periodical><pages>3-10</pages><volume>180</volume><number>1</number><keywords><keyword>Adolescent</keyword><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Aged, 80 and over</keyword><keyword>Aging/*physiology</keyword><keyword>Female</keyword><keyword>Forced Expiratory Volume</keyword><keyword>Health Surveys</keyword><keyword>Humans</keyword><keyword>Lung/growth & development/*physiology/physiopathology</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Prospective Studies</keyword><keyword>Smoking/adverse effects/*physiopathology</keyword><keyword>Smoking Cessation</keyword><keyword>Spirometry</keyword><keyword>Young Adult</keyword></keywords><dates><year>2009</year><pub-dates><date>Jul 01</date></pub-dates></dates><isbn>1535-4970 (Electronic)
1073-449X (Linking)</isbn><accession-num>19342411</accession-num><urls><related-urls><url>;(7). However, smoking is now known to lead to COPD via multiple trajectories acting at disparate life stages ADDIN EN.CITE <EndNote><Cite><Author>Rennard</Author><Year>2015</Year><RecNum>27</RecNum><DisplayText>(8)</DisplayText><record><rec-number>27</rec-number><foreign-keys><key app="EN" db-id="xwrd9zewrsxsr6efvtyxaf9o5sw0swa0d55a" timestamp="1448283019">27</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Rennard, S. I.</author><author>Drummond, M. B.</author></authors></contributors><auth-address>Department of Internal Medicine, University of Nebraska Medical Center, Nebraska Medical Center, Omaha, NE, USA. Electronic address: srennard@unmc.edu.
Johns Hopkins University School of Medicine, Baltimore, MD, USA.</auth-address><titles><title>Early chronic obstructive pulmonary disease: definition, assessment, and prevention</title><secondary-title>Lancet</secondary-title></titles><periodical><full-title>Lancet</full-title></periodical><pages>1778-88</pages><volume>385</volume><number>9979</number><keywords><keyword>Albuterol/analogs & derivatives/therapeutic use</keyword><keyword>Androstadienes/therapeutic use</keyword><keyword>Anti-Inflammatory Agents/*therapeutic use</keyword><keyword>Bronchodilator Agents/*therapeutic use</keyword><keyword>Disease Progression</keyword><keyword>Drug Combinations</keyword><keyword>Early Diagnosis</keyword><keyword>*Early Medical Intervention</keyword><keyword>Exercise Test</keyword><keyword>Forced Expiratory Volume</keyword><keyword>Humans</keyword><keyword>Pulmonary Disease, Chronic Obstructive/*diagnosis/prevention & control</keyword><keyword>Respiratory Function Tests</keyword><keyword>Severity of Illness Index</keyword><keyword>*Smoking Cessation</keyword></keywords><dates><year>2015</year><pub-dates><date>May 2</date></pub-dates></dates><isbn>1474-547X (Electronic)
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ADDIN EN.CITE.DATA (2), who are best classified as having ‘late mild’ disease ADDIN EN.CITE <EndNote><Cite><Author>Rennard</Author><Year>2015</Year><RecNum>27</RecNum><DisplayText>(8)</DisplayText><record><rec-number>27</rec-number><foreign-keys><key app="EN" db-id="xwrd9zewrsxsr6efvtyxaf9o5sw0swa0d55a" timestamp="1448283019">27</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Rennard, S. I.</author><author>Drummond, M. B.</author></authors></contributors><auth-address>Department of Internal Medicine, University of Nebraska Medical Center, Nebraska Medical Center, Omaha, NE, USA. Electronic address: srennard@unmc.edu.
Johns Hopkins University School of Medicine, Baltimore, MD, USA.</auth-address><titles><title>Early chronic obstructive pulmonary disease: definition, assessment, and prevention</title><secondary-title>Lancet</secondary-title></titles><periodical><full-title>Lancet</full-title></periodical><pages>1778-88</pages><volume>385</volume><number>9979</number><keywords><keyword>Albuterol/analogs & derivatives/therapeutic use</keyword><keyword>Androstadienes/therapeutic use</keyword><keyword>Anti-Inflammatory Agents/*therapeutic use</keyword><keyword>Bronchodilator Agents/*therapeutic use</keyword><keyword>Disease Progression</keyword><keyword>Drug Combinations</keyword><keyword>Early Diagnosis</keyword><keyword>*Early Medical Intervention</keyword><keyword>Exercise Test</keyword><keyword>Forced Expiratory Volume</keyword><keyword>Humans</keyword><keyword>Pulmonary Disease, Chronic Obstructive/*diagnosis/prevention & control</keyword><keyword>Respiratory Function Tests</keyword><keyword>Severity of Illness Index</keyword><keyword>*Smoking Cessation</keyword></keywords><dates><year>2015</year><pub-dates><date>May 2</date></pub-dates></dates><isbn>1474-547X (Electronic)
0140-6736 (Linking)</isbn><accession-num>25943942</accession-num><urls><related-urls><url>(15)60647-X</electronic-resource-num></record></Cite></EndNote>(8). In the broadest view, COPD pathogenesis may begin before birth, as passive fetal smoke exposure in utero is associated with increased adult COPD risk, independent of later active smoking ADDIN EN.CITE <EndNote><Cite><Author>Martinez</Author><Year>2016</Year><RecNum>1278</RecNum><DisplayText>(9)</DisplayText><record><rec-number>1278</rec-number><foreign-keys><key app="EN" db-id="xwrd9zewrsxsr6efvtyxaf9o5sw0swa0d55a" timestamp="1500425944">1278</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Martinez, F. D.</author></authors></contributors><auth-address>From the Asthma and Airway Disease Research Center, University of Arizona, Tucson.</auth-address><titles><title>Early-Life Origins of Chronic Obstructive Pulmonary Disease</title><secondary-title>N Engl J Med</secondary-title></titles><periodical><full-title>N Engl J Med</full-title></periodical><pages>871-8</pages><volume>375</volume><number>9</number><keywords><keyword>Adolescent</keyword><keyword>Age of Onset</keyword><keyword>Air Pollution/adverse effects</keyword><keyword>Asthma/complications</keyword><keyword>Bronchopulmonary Dysplasia/complications</keyword><keyword>Child</keyword><keyword>Female</keyword><keyword>Forced Expiratory Volume</keyword><keyword>Humans</keyword><keyword>Infant, Premature</keyword><keyword>Lung/physiology</keyword><keyword>Pneumonia/complications</keyword><keyword>Pregnancy</keyword><keyword>Prenatal Exposure Delayed Effects</keyword><keyword>Pulmonary Disease, Chronic Obstructive/*etiology/genetics/physiopathology</keyword><keyword>Respiratory Mechanics/*genetics</keyword><keyword>Smoking/adverse effects</keyword></keywords><dates><year>2016</year><pub-dates><date>Sep 01</date></pub-dates></dates><isbn>1533-4406 (Electronic)
0028-4793 (Linking)</isbn><accession-num>27579637</accession-num><urls><related-urls><url>;(9). The same is true for both passive smoke exposure in childhood and active smoking in adolescence ADDIN EN.CITE <EndNote><Cite><Author>Martinez</Author><Year>2016</Year><RecNum>1278</RecNum><DisplayText>(9)</DisplayText><record><rec-number>1278</rec-number><foreign-keys><key app="EN" db-id="xwrd9zewrsxsr6efvtyxaf9o5sw0swa0d55a" timestamp="1500425944">1278</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Martinez, F. D.</author></authors></contributors><auth-address>From the Asthma and Airway Disease Research Center, University of Arizona, Tucson.</auth-address><titles><title>Early-Life Origins of Chronic Obstructive Pulmonary Disease</title><secondary-title>N Engl J Med</secondary-title></titles><periodical><full-title>N Engl J Med</full-title></periodical><pages>871-8</pages><volume>375</volume><number>9</number><keywords><keyword>Adolescent</keyword><keyword>Age of Onset</keyword><keyword>Air Pollution/adverse effects</keyword><keyword>Asthma/complications</keyword><keyword>Bronchopulmonary Dysplasia/complications</keyword><keyword>Child</keyword><keyword>Female</keyword><keyword>Forced Expiratory Volume</keyword><keyword>Humans</keyword><keyword>Infant, Premature</keyword><keyword>Lung/physiology</keyword><keyword>Pneumonia/complications</keyword><keyword>Pregnancy</keyword><keyword>Prenatal Exposure Delayed Effects</keyword><keyword>Pulmonary Disease, Chronic Obstructive/*etiology/genetics/physiopathology</keyword><keyword>Respiratory Mechanics/*genetics</keyword><keyword>Smoking/adverse effects</keyword></keywords><dates><year>2016</year><pub-dates><date>Sep 01</date></pub-dates></dates><isbn>1533-4406 (Electronic)
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ADDIN EN.CITE.DATA (4). Potential mechanisms include compromised lung development and growth, epigenetic changes, and altered lung microbiome composition ADDIN EN.CITE <EndNote><Cite><Author>Martinez</Author><Year>2016</Year><RecNum>1278</RecNum><DisplayText>(9)</DisplayText><record><rec-number>1278</rec-number><foreign-keys><key app="EN" db-id="xwrd9zewrsxsr6efvtyxaf9o5sw0swa0d55a" timestamp="1500425944">1278</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Martinez, F. D.</author></authors></contributors><auth-address>From the Asthma and Airway Disease Research Center, University of Arizona, Tucson.</auth-address><titles><title>Early-Life Origins of Chronic Obstructive Pulmonary Disease</title><secondary-title>N Engl J Med</secondary-title></titles><periodical><full-title>N Engl J Med</full-title></periodical><pages>871-8</pages><volume>375</volume><number>9</number><keywords><keyword>Adolescent</keyword><keyword>Age of Onset</keyword><keyword>Air Pollution/adverse effects</keyword><keyword>Asthma/complications</keyword><keyword>Bronchopulmonary Dysplasia/complications</keyword><keyword>Child</keyword><keyword>Female</keyword><keyword>Forced Expiratory Volume</keyword><keyword>Humans</keyword><keyword>Infant, Premature</keyword><keyword>Lung/physiology</keyword><keyword>Pneumonia/complications</keyword><keyword>Pregnancy</keyword><keyword>Prenatal Exposure Delayed Effects</keyword><keyword>Pulmonary Disease, Chronic Obstructive/*etiology/genetics/physiopathology</keyword><keyword>Respiratory Mechanics/*genetics</keyword><keyword>Smoking/adverse effects</keyword></keywords><dates><year>2016</year><pub-dates><date>Sep 01</date></pub-dates></dates><isbn>1533-4406 (Electronic)
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ADDIN EN.CITE.DATA (10-12). Cough and sputum production were originally thought to be key COPD risk factors (the ‘British hypothesis’), but their importance was minimized following the observation that cough and sputum were only weakly related to disease progression ADDIN EN.CITE <EndNote><Cite><Author>Fletcher</Author><Year>1977</Year><RecNum>1250</RecNum><DisplayText>(5)</DisplayText><record><rec-number>1250</rec-number><foreign-keys><key app="EN" db-id="xwrd9zewrsxsr6efvtyxaf9o5sw0swa0d55a" timestamp="1500399666">1250</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Fletcher, C.</author><author>Peto, R.</author></authors></contributors><titles><title>The natural history of chronic airflow obstruction</title><secondary-title>Br Med J</secondary-title></titles><periodical><full-title>Br Med J</full-title></periodical><pages>1645-8</pages><volume>1</volume><number>6077</number><keywords><keyword>Adult</keyword><keyword>Age Factors</keyword><keyword>Airway Obstruction/etiology/*physiopathology</keyword><keyword>Bronchial Diseases/complications</keyword><keyword>Chronic Disease</keyword><keyword>Forced Expiratory Volume</keyword><keyword>Humans</keyword><keyword>Infection/complications</keyword><keyword>London</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Mucus/secretion</keyword><keyword>Prospective Studies</keyword><keyword>Smoking/complications</keyword></keywords><dates><year>1977</year><pub-dates><date>Jun 25</date></pub-dates></dates><isbn>0007-1447 (Print)
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ADDIN EN.CITE.DATA (3, 13) as seen in the long-term follow-up of the Copenhagen City Heart Study; that study also demonstrated that most individuals who developed airflow obstruction during long-term follow-up did not report cough and sputum production PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5WZXN0Ym88L0F1dGhvcj48WWVhcj4xOTk2PC9ZZWFyPjxS
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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5WZXN0Ym88L0F1dGhvcj48WWVhcj4xOTk2PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA (13). Respiratory symptoms clearly herald the presence of a pathological process that will progress in some individuals, and are unquestionably burdensome to all. More recent studies have demonstrated that symptoms are associated with excess exacerbations and radiographic abnormalities PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Xb29kcnVmZjwvQXV0aG9yPjxZZWFyPjIwMTY8L1llYXI+
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ADDIN EN.CITE.DATA (10, 11, 14). Thus, features inadequately captured by spirometric airflow limitation are now recognized as independent clinical manifestations of COPD-related disease PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NY0Rvbm91Z2g8L0F1dGhvcj48WWVhcj4yMDExPC9ZZWFy
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ADDIN EN.CITE.DATA (15). Proposed operational definition of Early COPDIdeally, early COPD would be defined by detection of the initial events responsible for the ultimate development of pathology. While this is currently not possible, a surrogate evidence could be that of lung pathology unequivocally associated with subsequent accelerated lung function decline leading to objectively confirmed incompletely reversible airflow obstruction and other COPD-related manifestations. Fully validating that approach would require serial invasive sampling in sizeable, long-lasting prospective cohorts. Alternatively, a definition could be based solely on currently available intermediate end-points, such as symptom presence PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbGxpbnNvbjwvQXV0aG9yPjxZZWFyPjIwMTc8L1llYXI+
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ADDIN EN.CITE.DATA (4) or changes in lung structure on CT such as abnormalities in the small and large airways and early emphysema PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HYWxiYW48L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFyPjxS
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ADDIN EN.CITE.DATA (16), all of which increase progression risk in some – possibly distinct – individuals PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CaGF0dDwvQXV0aG9yPjxZZWFyPjIwMTY8L1llYXI+PFJl
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ADDIN EN.CITE.DATA (18, 19). Therefore, we propose an operational definition of early COPD as occurring in a person younger than 55; and either: (1) FEV1/FVC less than lower limit of normal; or (2) respiratory symptoms and CT abnormalities (airway abnormality and/or emphysema), (3) evidence of accelerated FEV1 decline; or (4) any combination of categories (1) through (3).? We choose 10 pack-years based on data suggesting this minimum exposure results in lung function decline in early adulthood, and because acceleration of lung function decline is detectable at this point (3).? Similarly, pathological studies have suggested a similar exposure threshold is associated with structural abnormalities in the lung (20). Whether progressive imaging abnormalities serve as a robust measurement of clinically relevant disease progression requires additional longitudinal evaluation.Burden of Early COPDOur proposed definition of early COPD depends in part on smoking history, and accepts respiratory symptoms and anatomical changes in the absence of airflow obstruction. An 8-10 pack-year smoking history has been linked to lung function decline in subjects ages 35-53 ADDIN EN.CITE <EndNote><Cite><Author>Anderson</Author><Year>1962</Year><RecNum>1224</RecNum><DisplayText>(20)</DisplayText><record><rec-number>1224</rec-number><foreign-keys><key app="EN" db-id="xwrd9zewrsxsr6efvtyxaf9o5sw0swa0d55a" timestamp="1500232713">1224</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Anderson, D. O.</author><author>Ferris, B. G., Jr.</author></authors></contributors><titles><title>Role of tobacco smoking in the causation of chronic respiratory disease</title><secondary-title>N Engl J Med</secondary-title></titles><periodical><full-title>N Engl J Med</full-title></periodical><pages>787-94</pages><volume>267</volume><keywords><keyword>*Bronchitis</keyword><keyword>*Chronic Disease</keyword><keyword>Humans</keyword><keyword>*Respiration Disorders</keyword><keyword>*Respiratory Tract Diseases</keyword><keyword>*Smoking</keyword><keyword>*Respiratory diseases</keyword></keywords><dates><year>1962</year><pub-dates><date>Oct 18</date></pub-dates></dates><isbn>0028-4793 (Print)
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ADDIN EN.CITE.DATA (3). Studying individuals aged 20-44 years, the European Community Respiratory Health Survey (ECRHS) found that chronic cough or phlegm was associated with higher COPD incidence at nine years of follow-up PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5kZSBNYXJjbzwvQXV0aG9yPjxZZWFyPjIwMDc8L1llYXI+
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b3RlPn==
ADDIN EN.CITE.DATA (22). Likewise, within the MRC National Survey of Health and Disease (NSHD), smokers reporting chronic cough or phlegm at ages 36 and 43 years were respectively 3.70 and 4.11 times more likely to have developed spirometrically defined COPD by age 63 than asymptomatic counterparts PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbGxpbnNvbjwvQXV0aG9yPjxZZWFyPjIwMTY8L1llYXI+
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ADDIN EN.CITE.DATA (3). Respiratory symptoms are common among smokers, reported by 16% during ECRHS and 40% by age 43 years in NSHD PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5kZSBNYXJjbzwvQXV0aG9yPjxZZWFyPjIwMDc8L1llYXI+
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b3RlPn==
ADDIN EN.CITE.DATA (22). At that age, chronic productive cough was present among 13% of smokers but only 2.6% of never-smokers PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbGxpbnNvbjwvQXV0aG9yPjxZZWFyPjIwMTY8L1llYXI+
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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbGxpbnNvbjwvQXV0aG9yPjxZZWFyPjIwMTY8L1llYXI+
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ADDIN EN.CITE.DATA (3). NSHD also demonstrated that the relationship between chronic respiratory symptoms and smoking evolves with age. Its finding of marked symptomatic escalation during mid-life plausibly indicates onset of COPD PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbGxpbnNvbjwvQXV0aG9yPjxZZWFyPjIwMTY8L1llYXI+
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ADDIN EN.CITE.DATA (3). Known worldwide variations in respiratory symptom burdens ADDIN EN.CITE <EndNote><Cite><Author>de Oca</Author><Year>2012</Year><RecNum>1266</RecNum><DisplayText>(23)</DisplayText><record><rec-number>1266</rec-number><foreign-keys><key app="EN" db-id="xwrd9zewrsxsr6efvtyxaf9o5sw0swa0d55a" timestamp="1500402175">1266</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>de Oca, M. M.</author><author>Halbert, R. J.</author><author>Lopez, M. V.</author><author>Perez-Padilla, R.</author><author>Talamo, C.</author><author>Moreno, D.</author><author>Muino, A.</author><author>Jardim, J. R.</author><author>Valdivia, G.</author><author>Pertuze, J.</author><author>Menezes, A. M.</author></authors></contributors><auth-address>Servicio de Neumonologia, Piso 8, Hospital Universitario de Caracas, Universidad Central de Venezuela, Los Chaguaramos, 1030, Caracas, Venezuela. mmdeoca@</auth-address><titles><title>The chronic bronchitis phenotype in subjects with and without COPD: the PLATINO study</title><secondary-title>Eur Respir J</secondary-title></titles><periodical><full-title>Eur Respir J</full-title><abbr-1>The European respiratory journal</abbr-1></periodical><pages>28-36</pages><volume>40</volume><number>1</number><keywords><keyword>Bronchitis, Chronic/complications/*epidemiology</keyword><keyword>Female</keyword><keyword>Forced Expiratory Volume</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Mexico/epidemiology</keyword><keyword>Phenotype</keyword><keyword>Prevalence</keyword><keyword>Pulmonary Disease, Chronic Obstructive/*complications</keyword><keyword>South America/epidemiology</keyword><keyword>Spirometry</keyword></keywords><dates><year>2012</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>1399-3003 (Electronic)
0903-1936 (Linking)</isbn><accession-num>22282547</accession-num><urls><related-urls><url>;(23) likely reflect differing prevalence of smoking ADDIN EN.CITE <EndNote><Cite><Author>Collaborators</Author><Year>2017</Year><RecNum>1267</RecNum><DisplayText>(24)</DisplayText><record><rec-number>1267</rec-number><foreign-keys><key app="EN" db-id="xwrd9zewrsxsr6efvtyxaf9o5sw0swa0d55a" timestamp="1500402228">1267</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>G. B. D. Tobacco Collaborators</author></authors></contributors><titles><title>Smoking prevalence and attributable disease burden in 195 countries and territories, 1990-2015: a systematic analysis from the Global Burden of Disease Study 2015</title><secondary-title>Lancet</secondary-title></titles><periodical><full-title>Lancet</full-title></periodical><pages>1885-1906</pages><volume>389</volume><number>10082</number><dates><year>2017</year><pub-dates><date>May 13</date></pub-dates></dates><isbn>1474-547X (Electronic)
0140-6736 (Linking)</isbn><accession-num>28390697</accession-num><urls><related-urls><url>(17)30819-X</electronic-resource-num></record></Cite></EndNote>(24), with which chronic cough and phlegm are closely associated, both among those with ADDIN EN.CITE <EndNote><Cite><Author>Kanner</Author><Year>1999</Year><RecNum>1268</RecNum><DisplayText>(25)</DisplayText><record><rec-number>1268</rec-number><foreign-keys><key app="EN" db-id="xwrd9zewrsxsr6efvtyxaf9o5sw0swa0d55a" timestamp="1500402269">1268</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kanner, R. E.</author><author>Connett, J. E.</author><author>Williams, D. E.</author><author>Buist, A. S.</author></authors></contributors><auth-address>Department of Internal Medicine, University of Utah Health Sciences Center, Salt Lake City 84132, USA.</auth-address><titles><title>Effects of randomized assignment to a smoking cessation intervention and changes in smoking habits on respiratory symptoms in smokers with early chronic obstructive pulmonary disease: the Lung Health Study</title><secondary-title>Am J Med</secondary-title></titles><periodical><full-title>Am J Med</full-title></periodical><pages>410-6</pages><volume>106</volume><number>4</number><keywords><keyword>Adult</keyword><keyword>Cough/etiology</keyword><keyword>Female</keyword><keyword>Forced Expiratory Volume</keyword><keyword>Humans</keyword><keyword>Lung Diseases, Obstructive/*complications/etiology/physiopathology/*therapy</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Prospective Studies</keyword><keyword>Respiratory Insufficiency/etiology</keyword><keyword>Respiratory Sounds/etiology</keyword><keyword>Smoking/*adverse effects</keyword><keyword>*Smoking Cessation</keyword><keyword>Spirometry</keyword><keyword>Treatment Outcome</keyword><keyword>Vital Capacity</keyword></keywords><dates><year>1999</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>0002-9343 (Print)
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ADDIN EN.CITE.DATA (30), but their relevance to adult COPD is not well characterized. Smoking during adolescence reduces peak lung function values ADDIN EN.CITE <EndNote><Cite><Author>Gold</Author><Year>1996</Year><RecNum>1273</RecNum><DisplayText>(31)</DisplayText><record><rec-number>1273</rec-number><foreign-keys><key app="EN" db-id="xwrd9zewrsxsr6efvtyxaf9o5sw0swa0d55a" timestamp="1500403578">1273</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Gold, D. R.</author><author>Wang, X.</author><author>Wypij, D.</author><author>Speizer, F. E.</author><author>Ware, J. H.</author><author>Dockery, D. W.</author></authors></contributors><auth-address>Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.</auth-address><titles><title>Effects of cigarette smoking on lung function in adolescent boys and girls</title><secondary-title>N Engl J Med</secondary-title></titles><periodical><full-title>N Engl J Med</full-title></periodical><pages>931-7</pages><volume>335</volume><number>13</number><keywords><keyword>Adolescent</keyword><keyword>Airway Obstruction/chemically induced</keyword><keyword>Child</keyword><keyword>Cohort Studies</keyword><keyword>Dose-Response Relationship, Drug</keyword><keyword>Female</keyword><keyword>Forced Expiratory Volume/drug effects</keyword><keyword>Humans</keyword><keyword>Lung/*drug effects/growth & development/physiology</keyword><keyword>Male</keyword><keyword>Maximal Midexpiratory Flow Rate/drug effects</keyword><keyword>Sex Factors</keyword><keyword>Smoking/adverse effects/*physiopathology</keyword><keyword>United States</keyword><keyword>Vital Capacity/drug effects</keyword></keywords><dates><year>1996</year><pub-dates><date>Sep 26</date></pub-dates></dates><isbn>0028-4793 (Print)
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ADDIN EN.CITE.DATA (32). Thus, although adverse early-life exposures are common, their precise contribution to adult COPD remains unclear, merit exploration, but also need not be considered exclusionary in an operational definition of early COPD.Detecting Early COPD and evaluating its progressionCentral to the concept of early COPD is the development of clinically evident disease over time. Validating this prediction prospectively is one of the most pressing needs to advance the field from palliative care to prevention of progression. We submit that such validation requires multiple endpoints, extending the traditional definition of COPD based solely on chronic airflow obstruction PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Wb2dlbG1laWVyPC9BdXRob3I+PFllYXI+MjAxNzwvWWVh
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0040-6376 (Linking)</isbn><accession-num>15790991</accession-num><urls><related-urls><url>;(33). Airflow obstruction remains an important metric for future studies, despite controversies regarding optimal FEV1 and FVC thresholds ADDIN EN.CITE <EndNote><Cite><Author>Rennard</Author><Year>2015</Year><RecNum>27</RecNum><DisplayText>(8)</DisplayText><record><rec-number>27</rec-number><foreign-keys><key app="EN" db-id="xwrd9zewrsxsr6efvtyxaf9o5sw0swa0d55a" timestamp="1448283019">27</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Rennard, S. I.</author><author>Drummond, M. B.</author></authors></contributors><auth-address>Department of Internal Medicine, University of Nebraska Medical Center, Nebraska Medical Center, Omaha, NE, USA. Electronic address: srennard@unmc.edu.
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ADDIN EN.CITE.DATA (2, 34). However, both detection of early small airway disease and assessment of its progression might be accomplished non-invasively using more sensitive physiological studies, such as impedance oscillometry, nitrogen washout techniques, and measures of flow during expiratory maneuvers ADDIN EN.CITE <EndNote><Cite><Author>Hogg</Author><Year>2017</Year><RecNum>1293</RecNum><DisplayText>(35)</DisplayText><record><rec-number>1293</rec-number><foreign-keys><key app="EN" db-id="xwrd9zewrsxsr6efvtyxaf9o5sw0swa0d55a" timestamp="1501771177">1293</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Hogg, J. C.</author><author>Pare, P. D.</author><author>Hackett, T. L.</author></authors></contributors><auth-address>Centre for Heart Lung Innovation, St Paul's Hospital, University of British Columbia (UBC), British Columbia, Canada; Department of Pathology and Laboratory Medicine, UBC, British Columbia, Canada; Respiratory Division, Department of Medicine, UBC, British Columbia, Canada; and Department of Anesthesiology, Pharmacology and Therapeutics, UBC, British Columbia, Canada.</auth-address><titles><title>The Contribution of Small Airway Obstruction to the Pathogenesis of Chronic Obstructive Pulmonary Disease</title><secondary-title>Physiol Rev</secondary-title></titles><periodical><full-title>Physiol Rev</full-title></periodical><pages>529-552</pages><volume>97</volume><number>2</number><keywords><keyword>Airway Obstruction/*complications</keyword><keyword>Animals</keyword><keyword>*Early Diagnosis</keyword><keyword>Humans</keyword><keyword>Lung/*pathology</keyword><keyword>Pulmonary Disease, Chronic Obstructive/*diagnosis/*etiology</keyword><keyword>Pulmonary Emphysema/*complications</keyword><keyword>Tomography, X-Ray Computed/methods</keyword></keywords><dates><year>2017</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>1522-1210 (Electronic)
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ADDIN EN.CITE.DATA (36). Despite decades of expertise with these techniques ADDIN EN.CITE <EndNote><Cite><Author>Hogg</Author><Year>2017</Year><RecNum>1293</RecNum><DisplayText>(35)</DisplayText><record><rec-number>1293</rec-number><foreign-keys><key app="EN" db-id="xwrd9zewrsxsr6efvtyxaf9o5sw0swa0d55a" timestamp="1501771177">1293</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Hogg, J. C.</author><author>Pare, P. D.</author><author>Hackett, T. L.</author></authors></contributors><auth-address>Centre for Heart Lung Innovation, St Paul's Hospital, University of British Columbia (UBC), British Columbia, Canada; Department of Pathology and Laboratory Medicine, UBC, British Columbia, Canada; Respiratory Division, Department of Medicine, UBC, British Columbia, Canada; and Department of Anesthesiology, Pharmacology and Therapeutics, UBC, British Columbia, Canada.</auth-address><titles><title>The Contribution of Small Airway Obstruction to the Pathogenesis of Chronic Obstructive Pulmonary Disease</title><secondary-title>Physiol Rev</secondary-title></titles><periodical><full-title>Physiol Rev</full-title></periodical><pages>529-552</pages><volume>97</volume><number>2</number><keywords><keyword>Airway Obstruction/*complications</keyword><keyword>Animals</keyword><keyword>*Early Diagnosis</keyword><keyword>Humans</keyword><keyword>Lung/*pathology</keyword><keyword>Pulmonary Disease, Chronic Obstructive/*diagnosis/*etiology</keyword><keyword>Pulmonary Emphysema/*complications</keyword><keyword>Tomography, X-Ray Computed/methods</keyword></keywords><dates><year>2017</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>1522-1210 (Electronic)
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ADDIN EN.CITE.DATA (37). One such technique, parametric response mapping (PRM), uses dynamic image registration of paired scans to quantify regional changes in lung density between inspiration and expiration PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HYWxiYW48L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFyPjxS
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ADDIN EN.CITE.DATA (16). This technique’s capacity to distinguish regions of normal lung from “functional small airways disease” (PRMfSAD) and “emphysema” (PRMEmph) motivates our including imaging abnormalities in the operational definition of early COPD. Its real world relevance is shown by preliminary analyses employing ex vivo microCT data of lung explants, in which PRMfSAD has been linked to narrowing and loss of terminal and transitional bronchioles ADDIN EN.CITE <EndNote><Cite><Author>Vasilescu</Author><Year>2017</Year><RecNum>35</RecNum><DisplayText>(41)</DisplayText><record><rec-number>35</rec-number><foreign-keys><key app="EN" db-id="sd9p0p0wwes0pee9ztlx95x7er29vdzavzxe" timestamp="0">35</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Vasilescu, D</author><author>Marchetti, N.</author><author>Galban, C. J.</author><author>Meldrum, C.</author><author>Ross, B. D.</author><author>Martinez, C.</author><author>Labaki, W. W.</author><author>Kazerooni, E. A.</author><author>Criner, G.</author><author>Martinez, F. J.</author><author>Hogg, J. C.</author><author>Han, M. K.</author></authors></contributors><titles><title>The relationship between functional small airways disease and small airways pathology in COPD</title><secondary-title>Am J Respir Crit Care Med</secondary-title></titles><periodical><full-title>Am J Respir Crit Care Med</full-title></periodical><pages>A5157</pages><volume>195</volume><dates><year>2017</year></dates><urls></urls></record></Cite></EndNote>(41).High resolution computed tomographic imaging might additionally serve as an outcome biomarker for therapies designed to block progression of early structural airway changes into emphysema. Supporting this possibility, analysis of five-year COPDGene follow-up data PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CaGF0dDwvQXV0aG9yPjxZZWFyPjIwMTY8L1llYXI+PFJl
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ADDIN EN.CITE.DATA (42) suggest an association between baseline PRMfSAD and development of PRMemph one year later (Figure 2). Similarly, lower total airway count in an older cohort was associated with accelerated loss of FEV1 in a separate cohort PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LaXJieTwvQXV0aG9yPjxZZWFyPjIwMTc8L1llYXI+PFJl
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ADDIN EN.CITE.DATA (43). Collectively, results of these recent studies complement classic pathological studies defining the small airways as the earliest site of smoking-induced abnormalities PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ib2dnPC9BdXRob3I+PFllYXI+MjAwOTwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA (44-46), evident by ages 40-59 years with moderate smoking exposure ADDIN EN.CITE <EndNote><Cite><Author>Auerbach</Author><Year>1961</Year><RecNum>1229</RecNum><DisplayText>(47)</DisplayText><record><rec-number>1229</rec-number><foreign-keys><key app="EN" db-id="xwrd9zewrsxsr6efvtyxaf9o5sw0swa0d55a" timestamp="1500234312">1229</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Auerbach, O.</author><author>Stout, A. P.</author><author>Hammond, E. C.</author><author>Garfinkel, L.</author></authors></contributors><titles><title>Changes in bronchial epithelium in relation to cigarette smoking and in relation to lung cancer</title><secondary-title>N Engl J Med</secondary-title></titles><periodical><full-title>N Engl J Med</full-title></periodical><pages>253-67</pages><volume>265</volume><keywords><keyword>*Bronchi</keyword><keyword>*Carcinoma</keyword><keyword>Carcinoma, Bronchogenic/*etiology</keyword><keyword>Humans</keyword><keyword>Lung Neoplasms/*etiology</keyword><keyword>*Smoking</keyword><keyword>*Tobacco</keyword><keyword>*CARCINOMA, BRONCHOGENIC/etiology</keyword><keyword>*LUNG NEOPLASMS/etiology</keyword></keywords><dates><year>1961</year><pub-dates><date>Aug 10</date></pub-dates></dates><isbn>0028-4793 (Print)
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ADDIN EN.CITE.DATA (18, 19). All these findings are central to the unified hypothesis of early COPD development presented below. Gaining crucial mechanistic insights required to develop novel, disease-modifying therapies in early COPD could be hastened by coupling this imaging biomarker with thorough profiling of early COPD airway samples. Possible host mechanisms in Early COPD development and progressionRecent evidence implies that cigarette smoke-exposure induces sequential, stereotypical changes in distal airways culminating in susceptible individuals in development of COPD (Fig. 3). The earliest detectable step is epigenetic reprogramming of the basal epithelial cells that maintain the epithelial barrier PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IZWlqaW5rPC9BdXRob3I+PFllYXI+MjAxNDwvWWVhcj48
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ADDIN EN.CITE.DATA (62). Epithelial reprogramming also induces multiple alterations to the healthy airway surface liquid (ASL), which comprises an upper mucus layer containing secreted mucins and an underlying, aqueous, periciliary layer ADDIN EN.CITE <EndNote><Cite><Author>Boucher</Author><Year>2002</Year><RecNum>1275</RecNum><DisplayText>(63)</DisplayText><record><rec-number>1275</rec-number><foreign-keys><key app="EN" db-id="xwrd9zewrsxsr6efvtyxaf9o5sw0swa0d55a" timestamp="1500420757">1275</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Boucher, R. C.</author></authors></contributors><auth-address>Cystic Fibrosis/Pulmonary Research and Treatment Center, 7011 Thurston-Bowles Building, CB# 7248, School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. rboucher@med.unc.edu</auth-address><titles><title>An overview of the pathogenesis of cystic fibrosis lung disease</title><secondary-title>Adv Drug Deliv Rev</secondary-title></titles><periodical><full-title>Adv Drug Deliv Rev</full-title></periodical><pages>1359-71</pages><volume>54</volume><number>11</number><keywords><keyword>Bacterial Infections/complications</keyword><keyword>Cystic Fibrosis/etiology/genetics/*pathology</keyword><keyword>Cystic Fibrosis Transmembrane Conductance Regulator/genetics</keyword><keyword>Epithelium/pathology/physiopathology</keyword><keyword>Humans</keyword><keyword>Ion Transport</keyword><keyword>Lung/microbiology/*pathology/physiopathology</keyword><keyword>Mucus/secretion</keyword></keywords><dates><year>2002</year><pub-dates><date>Dec 05</date></pub-dates></dates><isbn>0169-409X (Print)
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ADDIN EN.CITE.DATA (63, 64) and on the relative concentration of the mucus and periciliary layers ADDIN EN.CITE <EndNote><Cite><Author>Boucher</Author><Year>2003</Year><RecNum>1277</RecNum><DisplayText>(65)</DisplayText><record><rec-number>1277</rec-number><foreign-keys><key app="EN" db-id="xwrd9zewrsxsr6efvtyxaf9o5sw0swa0d55a" timestamp="1500420914">1277</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Boucher, R. C.</author></authors></contributors><auth-address>Cystic Fibrosis/Pulmonary Research and Treatment Center, 7011 Thurston-Bowles Building, CB# 7248, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7248, USA. rboucher@med.unc.edu</auth-address><titles><title>Regulation of airway surface liquid volume by human airway epithelia</title><secondary-title>Pflugers Arch</secondary-title></titles><periodical><full-title>Pflugers Arch</full-title></periodical><pages>495-8</pages><volume>445</volume><number>4</number><keywords><keyword>Animals</keyword><keyword>Cystic Fibrosis/*metabolism</keyword><keyword>Cystic Fibrosis Transmembrane Conductance Regulator/*metabolism</keyword><keyword>Humans</keyword><keyword>Mucus/*metabolism</keyword><keyword>Respiratory Mucosa/*metabolism</keyword></keywords><dates><year>2003</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>0031-6768 (Print)
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ADDIN EN.CITE.DATA (3) (Fig. 3B). Focal airway injury is central to another eventful consequence of epithelial reprogramming, polymeric immunoglobulin receptor (pIgR) down-regulation. Epithelial expression of PIgR is essential to transcytose secretory IgA into the lumens of distal airways ADDIN EN.CITE <EndNote><Cite><Author>Curtis</Author><Year>2017</Year><RecNum>1246</RecNum><DisplayText>(68)</DisplayText><record><rec-number>1246</rec-number><foreign-keys><key app="EN" db-id="xwrd9zewrsxsr6efvtyxaf9o5sw0swa0d55a" timestamp="1500344038">1246</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Curtis, J. L.</author></authors></contributors><auth-address>1 Pulmonary and Critical Care Medicine Section Veterans Affairs Ann Arbor Healthcare System Ann Arbor, Michigan.
2 Division of Pulmonary and Critical Care Medicine Department of Internal Medicine and.
3 Graduate Program in Immunology University of Michigan Health System Ann Arbor, Michigan.</auth-address><titles><title>A Hairline Crack in the Levee: Focal Secretory IgA Deficiency as a First Step toward Emphysema</title><secondary-title>Am J Respir Crit Care Med</secondary-title></titles><periodical><full-title>Am J Respir Crit Care Med</full-title></periodical><pages>970-973</pages><volume>195</volume><number>8</number><dates><year>2017</year><pub-dates><date>Apr 15</date></pub-dates></dates><isbn>1535-4970 (Electronic)
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ADDIN EN.CITE.DATA (15). Airways are narrowed by both mucus plugging and remodeling ADDIN EN.CITE <EndNote><Cite><Author>Hogg</Author><Year>2009</Year><RecNum>1225</RecNum><DisplayText>(44)</DisplayText><record><rec-number>1225</rec-number><foreign-keys><key app="EN" db-id="xwrd9zewrsxsr6efvtyxaf9o5sw0swa0d55a" timestamp="1500233025">1225</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Hogg, J. C.</author><author>Timens, W.</author></authors></contributors><auth-address>Department of Pathology and Laboratory Medicine, University of British Columbia and iCapture Center, St. Paul's Hospital, Vancouver, BC, Canada. jhogg@mrl.ubc.ca</auth-address><titles><title>The pathology of chronic obstructive pulmonary disease</title><secondary-title>Annu Rev Pathol</secondary-title></titles><periodical><full-title>Annu Rev Pathol</full-title></periodical><pages>435-59</pages><volume>4</volume><keywords><keyword>Aged</keyword><keyword>Animals</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Hydroquinones/adverse effects</keyword><keyword>Hypertension, Pulmonary/pathology</keyword><keyword>Immunity, Innate</keyword><keyword>Lung/immunology/*pathology/physiopathology</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Pulmonary Disease, Chronic</keyword><keyword>Obstructive/etiology/immunology/*pathology/physiopathology</keyword><keyword>Pulmonary Emphysema/etiology/immunology/*pathology/physiopathology</keyword><keyword>Pulmonary Ventilation</keyword><keyword>Pyridines/adverse effects</keyword><keyword>Risk Factors</keyword></keywords><dates><year>2009</year></dates><isbn>1553-4014 (Electronic)
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ADDIN EN.CITE.DATA (71). Distal airway dropout might represent the extreme of airway remodeling, heightening the importance of understanding fibrotic processes in early COPD. Additionally, global gene analysis demonstrated that in COPD, tissue degradation around small airways predominates over repair PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Hb3NzZWxpbms8L0F1dGhvcj48WWVhcj4yMDEwPC9ZZWFy
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ADDIN EN.CITE.DATA (72). Hence, matrix destruction might also cause airway dropout via anoikis, leading to the epithelial apoptosis observed by multiple groups in established disease but unstudied in early COPD. Activated lung natural killer (NK) cells likely also induce epithelial apoptosis PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Cb3JjaGVyczwvQXV0aG9yPjxZZWFyPjIwMDk8L1llYXI+
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ADDIN EN.CITE.DATA (73, 74). These two cytolytic processes (not mutually exclusive and perhaps synergistic) might overwhelm compensatory epithelial cell proliferation in some individuals, leading to progression from distal small airway injury to centrilobular emphysema. Advanced CT analytical techniques PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5PZWxzbmVyPC9BdXRob3I+PFllYXI+MjAxNDwvWWVhcj48
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ADDIN EN.CITE.DATA (12, 75) demonstrate that significant emphysema can exist despite preserved FEV1 % predicted. Hence, centrilobular emphysema is relevant not only to advanced COPD but also to early COPD. Emphysema might also develop in early COPD due to loss of pulmonary endothelial cell (PEendC)-derived (“angiocrine”) factors ADDIN EN.CITE <EndNote><Cite><Author>Rafii</Author><Year>2016</Year><RecNum>109</RecNum><DisplayText>(76)</DisplayText><record><rec-number>109</rec-number><foreign-keys><key app="EN" db-id="sd9p0p0wwes0pee9ztlx95x7er29vdzavzxe" timestamp="1503858262">109</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Rafii, S.</author><author>Butler, J. M.</author><author>Ding, B. S.</author></authors></contributors><auth-address>Ansary Stem Cell Institute, Department of Medicine, Division of Regenerative Medicine, Weill Cornell Medical College, 1300 York Avenue, New York, New York 10065, USA.</auth-address><titles><title>Angiocrine functions of organ-specific endothelial cells</title><secondary-title>Nature</secondary-title><alt-title>Nature</alt-title></titles><periodical><full-title>Nature</full-title><abbr-1>Nature</abbr-1></periodical><alt-periodical><full-title>Nature</full-title><abbr-1>Nature</abbr-1></alt-periodical><pages>316-25</pages><volume>529</volume><number>7586</number><edition>2016/01/23</edition><keywords><keyword>Animals</keyword><keyword>Capillaries/cytology</keyword><keyword>Cell Differentiation</keyword><keyword>Cell Self Renewal</keyword><keyword>Endothelial Cells/*metabolism</keyword><keyword>Homeostasis</keyword><keyword>Humans</keyword><keyword>Liver Cirrhosis/metabolism/pathology</keyword><keyword>Lung/cytology/pathology</keyword><keyword>*Neovascularization, Physiologic</keyword><keyword>Organ Specificity</keyword><keyword>Osteogenesis</keyword><keyword>*Paracrine Communication</keyword><keyword>Regeneration</keyword></keywords><dates><year>2016</year><pub-dates><date>Jan 21</date></pub-dates></dates><isbn>0028-0836</isbn><accession-num>26791722</accession-num><urls></urls><custom2>PMC4878406</custom2><custom6>NIHMS783852</custom6><electronic-resource-num>10.1038/nature17040</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(76) essential to sustain epithelial proliferation, especially given the prominent role of increased EGFR signaling in smoking-reprogramed basal epithelial stem cells. The importance of PEendC production of angiocrine factors is supported by the murine model of lung hypertrophy following unilateral adult pneumonectomy. PEendC were essential for the earliest regenerative change, proliferation of cells at the bronchoalveolar duct junction. Co-culture experiments supported a role for PEendC elaboration of the membrane-anchored metalloproteinase MMP-14, which unmasks cryptic ligands for EGFR PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DYW88L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxSZWNO
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ADDIN EN.CITE.DATA (77). Loss of angiocrine signals might be the ‘final straw’ that overcomes epithelial proliferative capacity and dooms the damaged terminal airway to centrilobular emphysema. Perhaps the thorniest question regarding mechanisms of early COPD is the precise role of inflammatory cells. Pigmented macrophages prominently accumulated around and within respiratory bronchioles of male smokers dying suddenly at a mean age of 25 years ADDIN EN.CITE <EndNote><Cite><Author>Niewoehner</Author><Year>1974</Year><RecNum>111</RecNum><DisplayText>(78)</DisplayText><record><rec-number>111</rec-number><foreign-keys><key app="EN" db-id="sd9p0p0wwes0pee9ztlx95x7er29vdzavzxe" timestamp="1503864106">111</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Niewoehner, D. E.</author><author>Kleinerman, J.</author><author>Rice, D. B.</author></authors></contributors><titles><title>Pathologic changes in the peripheral airways of young cigarette smokers</title><secondary-title>N Engl J Med</secondary-title></titles><periodical><full-title>N Engl J Med</full-title></periodical><pages>755-8</pages><volume>291</volume><number>15</number><keywords><keyword>Adult</keyword><keyword>Age Factors</keyword><keyword>Bronchi/*pathology</keyword><keyword>Bronchitis/pathology</keyword><keyword>Humans</keyword><keyword>Macrophages/pathology</keyword><keyword>Pulmonary Alveoli/pathology</keyword><keyword>Pulmonary Emphysema/pathology</keyword><keyword>Smoking/*pathology</keyword></keywords><dates><year>1974</year><pub-dates><date>Oct 10</date></pub-dates></dates><accession-num>4414996</accession-num><urls></urls></record></Cite></EndNote>(78); such infiltration is often assumed to affect all young smokers, but the high mean exposure (20.1±4.1 pack-years) in this study must be considered. Relative to smokers without obstruction, COPD is associated with progressive activation of lung dendritic cell (DC) subsets in lung parenchyma ADDIN EN.CITE <EndNote><Cite><Author>Freeman</Author><Year>2017</Year><RecNum>113</RecNum><DisplayText>(79)</DisplayText><record><rec-number>113</rec-number><foreign-keys><key app="EN" db-id="sd9p0p0wwes0pee9ztlx95x7er29vdzavzxe" timestamp="1503865987">113</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Freeman, C. M.</author><author>Curtis, J. L.</author></authors></contributors><auth-address>1 Research Service, and.
2 Pulmonary and Critical Care Medicine Division, Department of Internal Medicine, University of Michigan Health System, and.
4 Pulmonary and Critical Care Medicine Section, Medicine Service, VA Ann Arbor Healthcare System, Ann Arbor, Michigan.
3 Graduate Program in Immunology, University of Michigan, Ann Arbor, Michigan.</auth-address><titles><title>Lung dendritic cells: shaping immune responses throughout chronic obstructive pulmonary disease progression</title><secondary-title>Am J Respir Cell Mol Biol</secondary-title><alt-title>American journal of respiratory cell and molecular biology</alt-title></titles><periodical><full-title>Am J Respir Cell Mol Biol</full-title><abbr-1>American journal of respiratory cell and molecular biology</abbr-1></periodical><alt-periodical><full-title>Am J Respir Cell Mol Biol</full-title><abbr-1>American journal of respiratory cell and molecular biology</abbr-1></alt-periodical><pages>152-159</pages><volume>56</volume><number>2</number><edition>2016/10/22</edition><keywords><keyword>chronic obstructive pulmonary disease</keyword><keyword>dendritic cells</keyword><keyword>lung</keyword></keywords><dates><year>2017</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>1044-1549</isbn><accession-num>27767327</accession-num><urls></urls><electronic-resource-num>10.1165/rcmb.2016-0272TR</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(79) and loss of cells with a T-regulatory phenotype there PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MZWU8L0F1dGhvcj48WWVhcj4yMDA3PC9ZZWFyPjxSZWNO
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ADDIN EN.CITE.DATA (80, 81) and in bronchoalveolar lavage (BAL) ADDIN EN.CITE <EndNote><Cite><Author>Barcelo</Author><Year>2008</Year><RecNum>115</RecNum><DisplayText>(82)</DisplayText><record><rec-number>115</rec-number><foreign-keys><key app="EN" db-id="sd9p0p0wwes0pee9ztlx95x7er29vdzavzxe" timestamp="1504364430">115</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Barcelo, B.</author><author>Pons, J.</author><author>Ferrer, J. M.</author><author>Sauleda, J.</author><author>Fuster, A.</author><author>Agusti, A. G.</author></authors></contributors><auth-address>Servei de Pneumologia, Hospital Universitari Son Dureta, Andrea Doria 55, 07014-Palma de Mallorca, Spain.</auth-address><titles><title>Phenotypic characterisation of T-lymphocytes in COPD: abnormal CD4+CD25+ regulatory T-lymphocyte response to tobacco smoking</title><secondary-title>Eur Respir J</secondary-title></titles><periodical><full-title>Eur Respir J</full-title></periodical><pages>555-62</pages><volume>31</volume><number>3</number><keywords><keyword>Bronchoalveolar Lavage Fluid/ cytology/immunology</keyword><keyword>CD8-Positive T-Lymphocytes</keyword><keyword>Cohort Studies</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Inflammation</keyword><keyword>Lymphocyte Activation</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Pulmonary Disease, Chronic Obstructive/ immunology</keyword><keyword>Smoking/ immunology</keyword><keyword>T-Lymphocytes, Regulatory</keyword></keywords><dates><year>2008</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>1399-3003 (Electronic)</isbn><accession-num>18057064</accession-num><urls></urls></record></Cite></EndNote>(82). These changes have motivated years of attempts to modify COPD progression by anti-inflammatory therapy, yet it is unproven that every inflammatory cell-type infiltrating the lungs in the transition from asymptomatic smoking to early COPD is actually harmful. A key recent advance is recognition of unique innate and innate-like lymphocyte cell-types that are largely restricted to mucosal surfaces, including the airways and which appear to play crucial roles in host defense PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BcnRpczwvQXV0aG9yPjxZZWFyPjIwMTU8L1llYXI+PFJl
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ADDIN EN.CITE.DATA (91). These considerations support the need to understand local patterns of microbial-host interaction in the lower airways. For example, this could be accomplished by obtaining protected-specimen brush sampling, for microbiome analysis, plus conventional cytological brushing, for genomic and epigenetic analysis, in identical areas of distal human airways ADDIN EN.CITE <EndNote><Cite><Author>Gronseth</Author><Year>2017</Year><RecNum>1308</RecNum><DisplayText>(92)</DisplayText><record><rec-number>1308</rec-number><foreign-keys><key app="EN" db-id="xwrd9zewrsxsr6efvtyxaf9o5sw0swa0d55a" timestamp="1506297001">1308</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Gronseth, R.</author><author>Drengenes, C.</author><author>Wiker, H. G.</author><author>Tangedal, S.</author><author>Xue, Y.</author><author>Husebo, G. R.</author><author>Svanes, O.</author><author>Lehmann, S.</author><author>Aardal, M.</author><author>Hoang, T.</author><author>Kalananthan, T.</author><author>Hjellestad Martinsen, E. M.</author><author>Orvedal Leiten, E.</author><author>Aanerud, M.</author><author>Nordeide, E.</author><author>Haaland, I.</author><author>Jonassen, I.</author><author>Bakke, P.</author><author>Eagan, T.</author></authors></contributors><auth-address>Dept of Thoracic Medicine, Haukeland University Hospital, Bergen, Norway.
Dept of Clinical Science, Faculty of Medicine and Dentistry, University of Bergen, Bergen, Norway.
Dept of Microbiology, Haukeland University Hospital, Bergen, Norway.
Computational Biology Unit, Dept of Informatics, University of Bergen, Bergen, Norway.</auth-address><titles><title>Protected sampling is preferable in bronchoscopic studies of the airway microbiome</title><secondary-title>ERJ Open Res</secondary-title></titles><periodical><full-title>ERJ Open Res</full-title></periodical><volume>3</volume><number>3</number><dates><year>2017</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>2312-0541 (Print)
2312-0541 (Linking)</isbn><accession-num>28875147</accession-num><urls><related-urls><url> openres.</custom2><electronic-resource-num>10.1183/23120541.00019-2017</electronic-resource-num></record></Cite></EndNote>(92). Simultaneous analysis of the lower airway virome and mycome is another important goal, but may need to await resolution of the technical challenges of high coverage RNA sequencing and better reference libraries.Unquestionably, PPMs could perpetuate small airway inflammation by many mechanisms PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XaWxraW5zb248L0F1dGhvcj48WWVhcj4yMDAzPC9ZZWFy
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ADDIN EN.CITE.DATA (98). In a recent pilot placebo-controlled randomized trial, macrolide administration in early emphysema was associated with changes in microbiota and decreased levels of inflammatory cytokines in lower airways ADDIN EN.CITE <EndNote><Cite><Author>Segal</Author><Year>2017</Year><RecNum>72</RecNum><DisplayText>(99)</DisplayText><record><rec-number>72</rec-number><foreign-keys><key app="EN" db-id="sd9p0p0wwes0pee9ztlx95x7er29vdzavzxe" timestamp="0">72</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Segal, L. N.</author><author>Clemente, J. C.</author><author>Wu, B. G.</author><author>Wikoff, W. R.</author><author>Gao, Z.</author><author>Li, Y.</author><author>Ko, J. P.</author><author>Rom, W. N.</author><author>Blaser, M. J.</author><author>Weiden, M. D.</author></authors></contributors><auth-address>Division of Pulmonary and Critical Care Medicine, New York University School of Medicine, New York, New York, USA.
Department of Medicine, New York University School of Medicine, New York, New York, USA.
Department of Genetics and Genomic Sciences and Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Department of Molecular and Cellular Biology & Genome Center, University of California, Davis, California, USA.
Department of Radiology, New York University School of Medicine, New York, New York, USA.</auth-address><titles><title>Randomised, double-blind, placebo-controlled trial with azithromycin selects for anti-inflammatory microbial metabolites in the emphysematous lung</title><secondary-title>Thorax</secondary-title><alt-title>Thorax</alt-title></titles><pages>13-22</pages><volume>72</volume><number>1</number><edition>2016/08/04</edition><keywords><keyword>Bronchoscopy</keyword><keyword>COPD AU Mechanisms</keyword></keywords><dates><year>2017</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>1468-3296 (Electronic)
0040-6376 (Linking)</isbn><accession-num>27486204</accession-num><urls><related-urls><url>;(99). Importantly, the net anti-inflammatory effect seemed to be mediated more by bacterial stress-induced metabolites than by direct macrolide effects on the host. Hence, rather than globally suppressing inflammatory cell function, future therapies to arrest early COPD might focus on containing the microbial invasion that drives inflammation. Future therapeutic Trials in Early COPDTo reduce COPD’s long-term societal impact, the goal of interventions must change, from a sole focus on reducing symptoms and exacerbations in advanced disease, to halting pathological progression in early disease. Current US, European, and Japanese regulatory definitions of disease progression rely on primary outcomes of mortality or rate of FEV1 decline, based on studies in moderate to severe COPD. Such studies typically require 3-4 year trials in 8,000-16,000 participants PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5WZXN0Ym88L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA (100-104). The Lung Health Study, arguably the most notable of the few studies on early COPD, required seven years of follow-up to demonstrate the benefit of smoking cessation PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbnRob25pc2VuPC9BdXRob3I+PFllYXI+MTk5NDwvWWVh
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ADDIN EN.CITE.DATA (105). Two recent large studies in milder stage (but not early) COPD successfully demonstrated that a long-acting anti-muscarinic tended PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5aaG91PC9BdXRob3I+PFllYXI+MjAxNzwvWWVhcj48UmVj
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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Zb25jaHVrPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48
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ADDIN EN.CITE.DATA (109) or Club Cell Protein 16 for FEV1 decline PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5aZW1hbnM8L0F1dGhvcj48WWVhcj4yMDE3PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA (11, 112) (less prominently than with worse airflow obstruction ADDIN EN.CITE <EndNote><Cite><Author>Decramer</Author><Year>2005</Year><RecNum>1291</RecNum><DisplayText>(33)</DisplayText><record><rec-number>1291</rec-number><foreign-keys><key app="EN" db-id="xwrd9zewrsxsr6efvtyxaf9o5sw0swa0d55a" timestamp="1501767183">1291</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Decramer, M.</author><author>Gosselink, R.</author><author>Rutten-Van Molken, M.</author><author>Buffels, J.</author><author>Van Schayck, O.</author><author>Gevenois, P. A.</author><author>Pellegrino, R.</author><author>Derom, E.</author><author>De Backer, W.</author></authors></contributors><auth-address>Respiratory Division, University Hospital, Herestraat 49, 3000 Leuven, Belgium. Marc.Decramer@uz.kuleuven.ac.be</auth-address><titles><title>Assessment of progression of COPD: report of a workshop held in Leuven, 11-12 March 2004</title><secondary-title>Thorax</secondary-title></titles><periodical><full-title>Thorax</full-title></periodical><pages>335-42</pages><volume>60</volume><number>4</number><keywords><keyword>Belgium</keyword><keyword>Cost-Benefit Analysis</keyword><keyword>Disease Progression</keyword><keyword>Exercise Tolerance</keyword><keyword>Forced Expiratory Volume/physiology</keyword><keyword>Health Care Costs</keyword><keyword>Health Status</keyword><keyword>Humans</keyword><keyword>Patient Acceptance of Health Care</keyword><keyword>Pulmonary Disease, Chronic Obstructive/diagnosis/*mortality/physiopathology</keyword><keyword>Tomography, X-Ray Computed</keyword></keywords><dates><year>2005</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>0040-6376 (Print)
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ADDIN EN.CITE.DATA (112). Similar analyses in patients with early COPD are sorely required. Whether abnormalities in muscle function or exercise capacity or response are a relevant manifestation of early COPD ADDIN EN.CITE <EndNote><Cite><Author>Elbehairy</Author><Year>2017</Year><RecNum>1296</RecNum><DisplayText>(117)</DisplayText><record><rec-number>1296</rec-number><foreign-keys><key app="EN" db-id="xwrd9zewrsxsr6efvtyxaf9o5sw0swa0d55a" timestamp="1501772859">1296</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Elbehairy, A. F.</author><author>Parraga, G.</author><author>Webb, K. A.</author><author>Neder, J. A.</author><author>O'Donnell, D. E.</author><author>Canadian Respiratory Research Network,</author></authors></contributors><auth-address>a Department of Medicine , Queen's University and Kingston General Hospital , Kingston , ON , Canada.
b Department of Chest Diseases, Faculty of Medicine , Alexandria University , Alexandria , Egypt.
c Department of Medical Biophysics, Robarts Research Institute , Western University , London , Canada.</auth-address><titles><title>Mild chronic obstructive pulmonary disease: why spirometry is not sufficient!</title><secondary-title>Expert Rev Respir Med</secondary-title></titles><periodical><full-title>Expert Rev Respir Med</full-title></periodical><pages>549-563</pages><volume>11</volume><number>7</number><keywords><keyword>Mild COPD</keyword><keyword>dyspnea</keyword><keyword>exercise</keyword><keyword>imaging</keyword><keyword>small airway remodeling</keyword><keyword>spirometry</keyword><keyword>vascular injury</keyword></keywords><dates><year>2017</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>1747-6356 (Electronic)
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ADDIN EN.CITE.DATA (118); exacerbation-tracking (EXACT? questionnaire); and use of composite measures such as the Clinically Important Deterioration ADDIN EN.CITE <EndNote><Cite><Author>Singh</Author><Year>2016</Year><RecNum>1258</RecNum><DisplayText>(119)</DisplayText><record><rec-number>1258</rec-number><foreign-keys><key app="EN" db-id="xwrd9zewrsxsr6efvtyxaf9o5sw0swa0d55a" timestamp="1500401133">1258</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Singh, D.</author><author>Maleki-Yazdi, M. R.</author><author>Tombs, L.</author><author>Iqbal, A.</author><author>Fahy, W. A.</author><author>Naya, I.</author></authors></contributors><auth-address>Medicines Evaluation Unit, University of Manchester, University Hospital of South Manchester NHS Foundation Trust, Manchester, UK.
Division of Respiratory Medicine, Women's College Hospital, University of Toronto, ON, Canada.
Precise Approach LTD, London UK.
Respiratory Medical Franchise, GSK, Research Triangle Park, NC, USA.
Respiratory Medicines Development Centre, GSK, Stockley Park, Middlesex, UK.</auth-address><titles><title>Prevention of clinically important deteriorations in COPD with umeclidinium/vilanterol</title><secondary-title>Int J Chron Obstruct Pulmon Dis</secondary-title></titles><periodical><full-title>Int J Chron Obstruct Pulmon Dis</full-title><abbr-1>International journal of chronic obstructive pulmonary disease</abbr-1></periodical><pages>1413-24</pages><volume>11</volume><keywords><keyword>Copd</keyword><keyword>Umec/vi</keyword><keyword>airway stability</keyword><keyword>deterioration</keyword></keywords><dates><year>2016</year></dates><isbn>1178-2005 (Electronic)
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ADDIN EN.CITE.DATA (120) that alter risk-benefit considerations. Imaging or procedures to stage other chronic diseases are already common practice (e.g., DEXA scans for osteoporosis or endoscopy in inflammatory bowel disease), and might become compelling in early COPD. Future clinical trials will face unique challenges. Paramount is lack of regulatory acceptance of novel endpoints, beyond use as “exploratory outcomes”. Minimal clinically important differences defined for advanced disease (e.g., changes of 4 for SGRQ; 30 m for 6MWT; 50 mL for FEV1) are likely inappropriate for an early COPD population with preserved lung function. Younger study populations pose a heightened risk of dropout, especially in longer studies due to geo-mobility and possibly of lower compliance. As novel therapies become available, placebo-controlled trials are less likely to be ethically acceptable; non-inferiority clinical trials or superiority trials with an active control arm may become standard for this at-risk population. Trial design and analysis will need to address changing risk profiles (smoking cessation, electronic cigarettes, comorbid conditions). Novel therapies introduced during a study pose the risk of irrelevance, supporting the need for shorter, more agile clinical trials.This is an exciting time for clinical research in early COPD. The increasingly obvious need for novel therapies has motivated regulators, academia and industry to work together to accelerate qualification of drug-development tools and approval of new medicines, and, through initiatives like the 21st Century Cures Act, to enhance the ability to collect real-world evidence using medical devices. Widespread acceptance of digital technology by younger subjects may extend to willingness to wear monitoring devices and to participate more interactively in clinical research. Shorter trials are facilitated when an agent’s mechanism of action suggests an immediate effect (e.g., reduced symptoms or exacerbations). Although current regulations require inclusion of multiple doses in Phase III trials lacking pharmacodynamic biomarkers for Phase II dose selection, this burden may be mitigated via event-driven studies (e.g. SUMMIT) PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5WZXN0Ym88L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA (100) or by advanced predictive analytics and machine learning methodologies to detect therapeutic response. ConclusionAlthough COPD is among the few non-communicable disorders with rising worldwide morbidity and mortality, the ability to identify patients at risk for more rapid disease progression is limited. This shortcoming jeopardizes development and validation of disease-modifying therapies for COPD, a crucial unmet clinical need. It is time for the pulmonary community to reconsider its investigational approach. Focusing on younger people to understand early COPD aligns with the goals of the recently released NHLBI COPD National Action Plan to develop strategies to prevent the onset and progression of COPD by studying disease progression. References ADDIN EN.REFLIST 1. 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An experimental demonstration of a new type of proton computed tomography using a novel silicon tracking detector. Med Phys 2016; 43: 6129.Figure legendsFigure 1. Proposed trajectories for lung function. (A) Normal lung function natural history; (B) reduced lung growth during fetal development, childhood, or adolescence, which can reduce maximally attained lung function; (C) shortened plateau; (D) accelerated lung function loss during adulthood; (E) episodic loss of lung function without full recovery; (F) late accelerated loss of lung function. FEV1=forced expiratory volume in 1 s. *Presence of early disease for each disease natural history.Figure 2. PRM images in 89 subjects evaluated over a one-year interval. Arrows indicate subjects with significant changes in PRMfSAD (yellow), PRMEmph (red) or both (orange). Black dots reflect the mean baseline and follow-up PRM values for subjects with changes in PRM smaller than predetermined thresholds from 30-day interval CT data. 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ADDIN EN.CITE.DATA (42). Figure 3. Epigenetic changes induced by smoking lead to progressive small airway damage and inflammation in early COPD. A, C: Normal small airways; B, D: Small airways in early COPD. A. Normal small airway epithelium contains basal cells, which self-renew and differentiate into ciliated, mucus-producing, and secretory (Club) cells. Mucus is separate from the epithelial surface by a robust aqueous periciliary layer. Tight junctions form an impermeable barrier to inhaled xenobiotics, microbes, and other toxic molecules. B. Smoking modifies epithelial phenotypes, inducing basal cell hyperplasia, squamous metaplasia, ciliary damage and decrease in the periciliary layer (leading to crowding of cilia); loss of Club cells and ciliated cells, mucous cell hyperplasia; and loss of the junctional barrier. C. In normal small airways, dimeric IgA (structure shown in inset) is transcytosed from the basolateral surface of epithelial cells into the mucosal lumen, by the polymeric Ig receptor (pIgR). Cleavage of pIgR at the luminal surface liberates SIgA, still bound to a portion of pIgR called the secretory component. SIgA prevents bacterial invasion of respiratory epithelium. D. Smoking reduces pIgR expression, leading to localized SIgA deficiency in small airways. In the absence of SIgA, bacteria can invade respiratory epithelial cells. The resulting nuclear factor (NF)-kB activation initiates and sustains airway inflammation.tablesTable I. Association between PRMEmph and PRMfSAD and the change in FEV1 ml/yr. as a function of Baseline GOLD stage in a subset of COPDGene subjects.*PRMfSADPRMEmphGOLD 0 (n=751; mean age 58 years)Parameter estimate per 5% (ml/yr.)Mean value CT metric (%)-2.2 (95% CI -4.2 to -0.1, p=0.04)12.4 (9.7)5.5 (95% CI -8.0 to 19.1; p=0.42)0.6 (1.4)GOLD 1-4 (n=757; mean age 64 years)Parameter estimate per 5% (ml/yr.)Mean value CT metric (%)-4.5 (95% CI -6.3 to -2.6, p<0.001)29.2 (12.3)-3.5 (95% CI -5.6 to -1.4, p=0.001)9.1 (11.4)* From PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CaGF0dDwvQXV0aG9yPjxZZWFyPjIwMTY8L1llYXI+PFJl
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ADDIN EN.CITE.DATA (17) with permission-10160749300Figure 1. Proposed trajectories for lung function. (A) Normal lung function natural history; (B) reduced lung growth during fetal development, childhood, or adolescence, which can reduce maximal attained lung function; (C) shortened plateau; (D) accelerated lung function loss during adulthood; (E) episodic loss of lung function without full recovery; (F) late accelerated loss of lung function. FEV1=forced expiratory volume in 1s. *Presence of early disease for each disease natural history. Reproduced from (8) with permission.635857250Figure 2. PRM images in 89 subjects evaluated over a one-year interval. Arrows indicate subjects with significant changes in PRMfSAD (yellow), PRMEmph (red) or both (orange). Black dots reflect the mean baseline and follow-up PRM values for subjects with changes in PRM smaller than predetermined thresholds from 30-day interval CT data. Cases with decreasing emphysema are represented by dots. With permission from PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Cb2VzPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA (42)Figure 33687191932221239930600 ................
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