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(BQ) Part 1 book “COPD - Heterogeneity and personalized treatment” has contents: Definition and epidemiology of COPD, pathology of chronic obstructive pulmonary diseases, pathogenesis of COPD, symptomatic assessment of COPD,… and other contents.
Sang-Do Lee Editor COPD Heterogeneity and Personalized Treatment 123 COPD Sang-Do Lee Editor COPD Heterogeneity and Personalized Treatment Editor Sang-Do Lee Department of Pulmonary and Critical Care Medicine Asan Medical Center University of Ulsan College of Medicine Seoul South Korea ISBN 978-3-662-47177-7 ISBN 978-3-662-47178-4 (eBook) DOI 10.1007/978-3-662-47178-4 Library of Congress Control Number: 2017947875 © Springer-Verlag Berlin Heidelberg 2017 This work is subject to copyright All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed The use of general descriptive names, registered names, trademarks, service marks, etc in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication Neither the publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained herein or for any errors or omissions that may have been made The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations Printed on acid-free paper This Springer imprint is published by Springer Nature The registered company is Springer-Verlag GmbH Germany The registered company address is: Heidelberger Platz 3, 14197 Berlin, Germany Preface Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide Over the last few decades, the study of COPD has become one of the most rapidly developing fields in medicine The recent years have provided clinicians and researchers with major advances in the understanding of underlying mechanisms in COPD In the past decades, COPD was classified solely on the basis of the degree of airflow limitation Nowadays, COPD is regarded as a heterogeneous disease, with multiple etiological factors, clinical phenotypes, and comorbidities One of the main reasons for poor understanding and poor treatment is the heterogeneity of COPD The strategy for the management of COPD is moving toward a more personalized approach compared with the historical approach Dissecting the heterogeneity would lead to a better understanding and effective personalized treatment of COPD Airway Vista, also known as Chronic Obstructive Airway Diseases Symposium, has been hosted by the Obstructive Lung Disease Research Foundation in South Korea since 2008 This academic event is designed to offer respiratory health professionals new horizons in their understanding of COPD and asthma The scientific program of the symposium includes the most significant advances in the researches of chronic airway diseases, COPD, asthma, and pulmonary functional imaging We have held Airway Vista successfully every year, featuring more than 50 world-renowned speakers respectively This year (2017) has marked the 10th anniversary of Airway Vista To celebrate the achievements of this 10-year-old symposium, we decided to publish a textbook by gathering the contents of previous symposium programs We have tried to provide readers with an overview of COPD, the current understanding of its pathobiology, and a contemporary approach to diagnosis and treatment With this goal in mind, a group of experts took the task of developing this publication, focusing on essential issues that all providers should be aware of The first chapter of this book covers overviews of COPD which include the current definition, epidemiology, risk factors, and pathogenesis of COPD The second chapter is comprised of diagnosis and assessment given to COPD patients In Chap 3, COPD heterogeneity was described in a clinical phenotype as well as radiological and genetic aspects Various pharmacological and nonpharmacological management strategies are reviewed based on evidence in the fourth chapter The final chapter outlines a future perspective on COPD This book presents state-of-the-art knowledge on issues related to heterogeneity, such as phenotypes (clinical, physiological, radiological, etc.), genotypes, tools to be used for dissecting heterogeneity (CT/MRI/Scan, Biomarkers v Preface vi etc.), and tailored treatment strategies in each subgroup of patients Especially, radiologic imaging is a new promising tool for this issue and will be presented in detail with numerous figures A further key feature is presentation about the current and future treatment strategies for tailored medicine including bronchoscopic lung volume reduction, pulmonary hypertension, and comorbidity management This textbook will become a great asset in clinical practice and research to all who are involved or interested in COPD I would like to acknowledge the work done by the members of the Korean Obstructive Lung Disease (KOLD) Cohort Study who contributed to the preparation of this book We are especially grateful to all contributing authors from abroad: Norbert Voelkel, Edwin Silverman, Meilan Han, Paul Jones, Rubin Tuder, and Nurdan Kokturk Finally we wish to thank our families for their patience and consistent support during our academic lives I hope that all readers will find these chapters as helpful and insightful as we have Seoul, South Korea Sang-Do Lee Contents Part I Overview 1 Definition and Epidemiology of COPD�������������������������������������������� 3 Young Sam Kim 2 Risk Factors: Factors That Influence Disease Development and Progression���������������������������������������������������������� 9 Ji Ye Jung 3 Pathology of Chronic Obstructive Pulmonary Diseases�������������� 17 Rubin M Tuder 4 Pathogenesis of COPD�������������������������������������������������������������������� 35 Ji-Hyun Lee Part II Assessment 5 Pathophysiology of COPD�������������������������������������������������������������� 57 Eun Kyung Kim 6 Diagnosis and Assessment of COPD���������������������������������������������� 65 Yong Bum Park 7 Symptomatic Assessment of COPD������������������������������������������������ 75 Paul W Jones 8 Imaging of COPD���������������������������������������������������������������������������� 87 Sang Min Lee, Sang Min Lee, Song Soo Kim, Hye Jeon Hwang, and Joon Beom Seo 9 Biomarkers of COPD�������������������������������������������������������������������� 129 Ho Il Yoon Part III Heterogeneity 10 Phenotypes of COPD �������������������������������������������������������������������� 147 Jamie Sheth and MeiLan Han 11 Genetics of COPD�������������������������������������������������������������������������� 169 Woo Jin Kim vii viii 12 Imaging Heterogeneity of COPD�������������������������������������������������� 179 Sang Min Lee and Joon Beom Seo 13 Asthma-COPD Overlap Syndrome���������������������������������������������� 189 Chin Kook Rhee 14 The Spectrum of Pulmonary Disease in COPD�������������������������� 195 Norbert F Voelkel, Shiro Mizuno, and Carlyne D Cool Part IV Management 15 Prevention of COPD���������������������������������������������������������������������� 211 HyoungKyu Yoon 16 Pharmacologic Management�������������������������������������������������������� 219 Seong Yong Lim 17 Non-pharmacologic Management: LVR, Rehabilitation, and Nutrition�������������������������������������������������������� 243 Sei Won Lee and Eun Mi Kim 18 Exacerbation of COPD������������������������������������������������������������������ 261 Jin Hwa Lee 19 Comorbidities: Assessment and Treatment�������������������������������� 267 Nurdan Kokturk, Ayse Baha, and Nese Dursunoglu 20 Personalized Treatment in COPD������������������������������������������������ 299 Jae Seung Lee and Sang-Do Lee Part V Prospectives 21 Cohort Study in COPD: Introduction to COPD Cohorts (The KOLD and COPDGene Study) and Collaborative Approaches������������������������������������������������������ 313 Deog Kyeom Kim 22 Big Data and Network Medicine in COPD���������������������������������� 321 Edwin K Silverman Index���������������������������������������������������������������������������������������������������������� 333 Contents Part I Overview Definition and Epidemiology of COPD Young Sam Kim Definition of COPD Chronic Obstructive Pulmonary Disease (COPD) is a common disease and prevalence is increasing worldwide It is characterized by persistent airway obstruction that is partially reversible but it is considered preventable and treatable disease now Airflow limitation is associated with chronic and abnormal inflammatory response in the airways and the lung to noxious stimuli [1] Airway obstruction is defined by a reduction of expiratory airflow Generally, forced expiratory volume in 1 s/forced volume capacity (FEV1/FVC) ratio of less than 70% after bronchodilator has been used to identify COPD patient The use of lower limit of normal (LLN) values has been proposed to define airflow limitation by spirometry, but current Global initiative for chronic Obstructive Lung Disease (GOLD) and American Thoracic Society/European Respiratory Society guidelines continue to recommend the fixed ratio criteria instead of an LLN for the diagnosis of COPD [1] Patients with COPD have shown a great deal of heterogeneity and can be classified according to their clinical and radiologic parameters, biomarkers, Y.S Kim Division of Pulmonology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea e-mail: ysamkim@yuhs.ac © Springer-Verlag Berlin Heidelberg 2017 S.-D Lee (ed.), COPD, DOI 10.1007/978-3-662-47178-4_1 lung function impairment and prognosis [2] Traditionally, COPD has been classified as chronic bronchitis (CB) and emphysema CB is defined as the presence of a chronic productive cough for 3 months in each of two consecutive years Emphysema is defined as the destruction of alveolar walls and permanent enlargement of the airspaces distal to the terminal bronchioles Current GOLD guidelines not include the use of these terms in the definition of COPD. Asthma and COPD represent different disease entity with different pathogeneses and risk factors Sometimes clinical manifestations of both diseases may overlap in a patient with airway obstruction and cannot be classified as COPD or asthma only Large population studies show that some of the patients with airway obstruction are classified with more than one diagnosis Therefore, overlapping diagnoses of asthma and COPD has been proposed and it is called COPD and Asthma Overlap Syndrome (ACOS) [1] Epidemiology of COPD COPD is a leading cause of morbidity and mortality worldwide The prevalence and burden of COPD is increasing now It is due to continued exposure of risk factors especially smoking and aging population Estimate of prevalence and incidence of COPD is different according to the study population and diagnostic criteria [2, 3] 154 higher than estimates based on symptoms alone Both cross-section and longitudinal studies have reported associations between the presence of reflux and poor quality of life in COPD [111] GERD has also been identified as a risk factor for COPD exacerbations [66, 112] and is specifically associated with the chronic bronchitic phenotype discussed previously The presence of GERD is associated with increased symptoms, poorer quality of life, and increased frequency of exacerbations; associations which are maintained after controlling for PPI use [113] Unfortunately, only limited data suggest that treatment of GERD may reduce the risk of exacerbations [114] bstructive Sleep Apnea (OSA) O In patients with COPD, the prevalence of obstructive sleep apnea has been estimated to be 16% [115], compared to an estimated 9% in women and 24% in men in the general population [116] However, poor sleep quality, decreased sleep efficiency, and difficulties in initiating and maintaining sleep have been reported in more than 40% of patients with COPD [117] In general, COPD patients with OSA are more severely hypercapnic, demonstrate more profound and frequent nocturnal oxygen desaturation, and have a higher risk of pulmonary hypertension [118] Untreated OSA is also a risk factor for poor quality of live, acute exacerbations, and increased all-cause mortality [119, 120] Diagnosis of OSA in COPD is important as initiation of continuous positive airway pressure therapy for patients with overlap has been associated with both decreased frisk of death and decreased incidence of severe exacerbations [119] epression and Anxiety D Coexistent depression and anxiety are seen in at least 10% of the general COPD population [121, 122]; however, with significantly higher estimated in patients with severe COPD [123] Risk factors for depression in COPD include disease severity, limited mobility, low BMI, comorbid conditions, the need for supplemental oxygen, and female gender [124, 125] COPD patients with comorbid anxiety are at risk for COPD exacerbations and higher morality [126], while J Sheth and M Han depressive symptoms are associated with increased risk of death [127, 128] While specific therapies for anxiety and depression have not been shown to improve COPD outcomes, pulmonary rehab has been shown to improve anxiety and depression in addition to overall quality of life and functional capacity [129] Two general patterns of clinical features and comorbidities have been proposed which may represent unique phenotypes: [1] emphysema, low BMI and osteoporosis and [2] chronic bronchitis, airway disease, high BMI, OSA, and diabetes [2] However, it is still unclear if these associations are related to specific mechanistic pathways that could lead to development of targeted therapies Physiologically Defined Phenotypes Spirometric indices, including FEV1, FVC, and their ratio, are used to define the presence and severity of disease While pulmonary function explains less than 10–25% of disease impact on symptoms, quality of life, and exercise performance [130–132], FEV1 remains an important outcome measure in COPD. Moreover, rapid physiologic progression as indicated by a change in FEV1 may indicate a distinct phenotype A more rapid decline in FEV1 has been associated with morbidity, mortality, and hospitalization rates in COPD [133] and also has been linked to distinct plasma biomarker signatures [134] The rate of FEV1 decline has been associated with airway reactivity, exacerbations, and possibly a chronic inflammatory state [135–139] There has been conflicting data regarding the role of inhaled corticosteroids in reducing decline in FEV1 [140, 141] Some genetic associations have also been seen, particularly with accelerated decline in FEV1 in smokers with alpha-1 antitrypsin deficiency [142] Additionally, a single nuclear polymorphism has been identified in the A disintegrin and metalloprotease 33 (ADAM33) gene, a susceptibility gene for asthma, that is associated with decline in FEV1 in COPD [143] While smoking cessation remains the best treatment for preventing FEV1 loss [133], it is unclear whether 10 Phenotypes of COPD other currently available medications are effective in slowing lung function decline although several studies suggest bronchodilators and inhaled bronchodilator/corticosteroid combinations may be effective, particularly in moderate disease [144, 145] GOLD defines an exacerbation as an event characterized by a change in the patient’s baseline dyspnea, cough, and/or sputum production that is beyond normal day-to-day variation, is acute in onset, and may warrant a change in regular medication in a patient with underlying COPD [146] In literature, exacerbations are often defined functionally (and not biologically) as “health care utilization” events requiring treatment with antibiotics, systemic corticosteroids, or both [147] The natural history of COPD is punctuated by exacerbations that appear to be associated with accelerated decline in lung function [136, 137], reduced physical activity, poorer quality of life, increased health care utilization, and increased risk of death [148–151] The Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) cohort study demonstrated that while increased exacerbations occur as lung function declines, certain individuals demonstrate a relatively stable susceptibility phenotype irrespective of lung function [66] Other factors identified as being associated with increased exacerbation frequency included a history of GERD, poorer quality of life, and elevated white blood cell count [66] Controlled trials have shown that pharmacotherapy can reduce exacerbations [144, 152], which should be applied to all patients with the frequent exacerbation phenotype across all disease severities While COPD has been characterized as a disorder with airflow obstruction that is not fully reversible [146, 153], the presence of bronchodilator reversibility has been confirmed in patients clinically diagnosed with non-asthmatic COPD and may be clinically relevant [154–156] There are various spirometric criteria for bronchoreversibility The American Thoracic Society (ATS)/ European Respiratory Society (ERS) defines bronchoreversibility as an increase in FEV1 greater than or equal to 200 mL and greater than 155 or equal to 12% absolute volume [157] Alternate physiological criteria include a greater increase in FEV1 or FVC (greater than or equal to 400 mL) and a 12% increase in either variable [147] While bronchodilator reversibility defined as change in FEV1 may be less common with an emphysema-dominant phenotype [147, 158], there is a small subgroup of patients with severe emphysema that meets ATS/ERS criteria for bronchoreversibility However, the quantity of emphysema determined by HRCT is a negative predictor of meeting volume-guided bronchoreversibility criteria [147] In the severe emphysema population, bronchoreversibility as defined by a change in FEV1 is infrequent, varies over time, and is more common in males and those with less severe emphysema The proportion of patients meeting bronchoreversibility criteria varies by the physiological criteria used to define a positive response, with a propensity for an increase in FVC in patients with emphysema [147] The true impact of bronchoreversibility on clinically meaningful outcomes such as lung function decline and exacerbation frequency is controversial The ISOLDE (Inhaled Steroids in Obstructive Lung Disease in Europe) and Lung Health Study data suggest that bronchoreversibility is not associated with accelerated decline in pulmonary function [159] or the number of exacerbations [154] However, in patients with alpha antitrypsin deficiency, bronchoreversibility has been associated with a greater rate of decline in FEV1 [160] Studies in relatives of COPD patients have shown familial clustering of spirometric and bronchodilators responsiveness phenotypes [161–166] and a genome-wide linkage analysis has suggested that bronchoreversibility can be linked to a specific COPD genotype [167], which increases its utility as meaningful phenotype In addition to the above, several other physiologic parameters have been identified that predict clinically meaningful outcomes Airway hyperresponsiveness has been associated with more rapid longitudinal decline in lung function [147, 158], while hyperinflation has been related to mortality and functional impairments [168, 169] Diffusing capacity impairment is an independent predictor of the extent of radiologic emphysema J Sheth and M Han 156 [170], the presence of resting hypoxemia, exercise- induced arterial oxygen desaturation [171], and functional impairment [172] Whether these parameters are truly reflective of a unique biologic processes is unclear and represent possibilities for unique therapeutic interventions is unknown [173, 174] Radiographically Defined Phenotypes Chest radiography and computed tomography (CT) are the two imaging modalities most commonly used in COPD. Chest radiography is neither sensitive nor specific for the diagnosis of COPD, but can reveal some characteristic features including radiolucency, diaphragmatic flattening, and hyperinflation Chest CT allows for better detection and quantification of emphysema and can reveal thickened airways indicative of bronchial thickening CT has also been used as a noninvasive tool to investigate the heterogeneous manifestations of COPD as they correlate to the clinical phenotypes discussed above Lung hyperinflation in COPD impairs chest wall and respiratory muscle mechanics, increases breathlessness, impairs weaning from mechanical ventilation, decreases exercise performance, and increases mortality [175] This led to the development of techniques aimed at decreasing the markedly increased lung volumes seen in emphysema and ultimately lung volume reduction surgery (LVRS) [176–181] The National Emphysema Treatment Trial (NETT) was a multicenter prospective randomized controlled trial that compared optimal medical treatment, including pulmonary rehabilitation, with optimal medical treatment plus LVRS in patients with severe emphysema [158, 182] NETT demonstrated how physiological and radiographic phenotypes can predict patient survival as well as response to treatment In COPD patients with upper lobe predominant emphysema and a low exercise capacity post-rehabilitation, LVRS improved survival and quality of life, as compared to those with upper lobe disease and high exercise capacity or COPD patients with non-upper lobe predominant disease regardless of exercise capacity [183] CT imaging is required to assess emphysema extent and distribution for the purposes of lung volume reduction surgery [158] Several studies have demonstrated a strong relationship between emphysema and both lung function decline [184, 185] and mortality [186, 187] (Table 10.2) Bronchial thickening seen on CT also has a strong correlation with symptoms [188] Visually identified bronchiectasis may be associated with an increased risk of death compared to COPD patients without bronchiectasis [189] Table 10.2 Summary of studies examining the relationship between emphysema and mortality Zulueta et al., [186] Population Smokers n = 9046 Risk factor Presence/absence visually scored emphysema Haruna et al., [187] COPD n = 251 Johannessen et al., [190] Ever-smokers n = 974 (49% with COPD) Emphysema ≥32% Upper lobe emphysema ≥42% FEV1% 10–35% Emphysema 3–10% Emphysema >10% Hazard ratio 9.3a 1.7a 1.52b (p